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Introduction ⬇

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Associated Monographs

Natural penicillins are β-lactam antibiotics that are active against many gram-positive and -negative aerobic cocci, some gram-positive aerobic and anaerobic bacilli, and many spirochetes.10,61

Uses ⬆ ⬇

[Section Outline]

Natural penicillins are used principally for the treatment of infections caused by susceptible gram-positive aerobic cocci, gram-negative aerobic cocci, gram-positive aerobic bacilli, gram-positive anaerobic bacteria, and spirochetes.2,3,4,7,8,9,10,11,12,18,19,20,21,61,64,67,70,80 The drugs also have been used prophylactically to prevent serious infections caused by some of these organisms.2,3,18,19,20,21,61,64,71,80,292,359,375

Penicillin G potassium and penicillin G sodium are frequently referred to as aqueous, crystalline penicillin G10,61,63,64,72 and are used parenterally when rapid and high serum concentrations of penicillin G are required, as in the treatment of endocarditis, meningitis, pericarditis, septicemia, severe pneumonia, or other serious infections caused by organisms susceptible to penicillin G.8,9,10,11,12,61,64

IM penicillin G benzathine and IM penicillin G procaine are used only for the treatment of moderately severe infections caused by organisms susceptible to low concentrations of penicillin G, for prophylaxis of infections caused by these organisms, or as follow-up therapy to IM or IV penicillin G potassium or sodium.2,3,7,61,64,906 These long-acting, depot, or repository forms of penicillin G are effective for the treatment and prophylaxis of some infections when given as a single IM dose or when given once or twice weekly for several weeks.2,3,10,61,375 Penicillin G benzathine and penicillin G procaine also are commercially available in fixed-combination preparations containing both salts.4,5,64 The procaine salt provides higher initial penicillin G concentrations than the benzathine salt, and penicillin G benzathine provides lower but more prolonged penicillin G concentrations.64 Some clinicians question the rationale of these fixed combinations, however, because bacteria that are susceptible to low penicillin G concentrations are not killed more rapidly by the higher concentrations attained with the procaine salt, and bacteria that are only susceptible to the higher penicillin G concentrations attained with penicillin G procaine are not affected by the low concentrations that are maintained by penicillin G benzathine.64 The fixed combination preparations containing penicillin G benzathine and penicillin G procaine should not be used for the treatment of any form of syphilis and should not be used for the treatment of yaws, pinta, or bejel.4,5

Endocarditis !!navigator!!

IV penicillin G potassium or sodium is used for the treatment of endocarditis caused by susceptible Streptococcus pyogenes (group A β-hemolytic streptococci; GAS), S. agalactiae † (group B streptococci; GBS), other β-hemolytic streptococci (e.g., groups C, H, G, L, and M), or S. pneumoniae .8,9,11,12 The American Heart Association (AHA) states that IV penicillin G is a reasonable choice for the treatment of endocarditis caused by susceptible S. pyogenes , S. agalactiae , groups C and G streptococci, and highly penicillin-susceptible S. pneumoniae (penicillin MIC 0.1 mcg/mL or less), but concomitant use of gentamicin during the initial weeks of penicillin G treatment should be considered if endocarditis is caused by streptococci groups B, C, or G.450

For the treatment of endocarditis caused by viridans group streptococci† or nonenterococcal group D streptococci†, including S. gallolyticus † (formerly S. bovis ) that are highly susceptible to penicillin (penicillin MIC 0.12 mcg/mL or less), AHA states that IV penicillin G (with or without gentamicin) is a reasonable regimen.450,452 If endocarditis is caused by viridans group streptococci† or S. gallolyticus † relatively resistant to penicillin (penicillin MIC greater than 0.12 mcg/mL but less than 0.5 mcg/mL), AHA states that IV penicillin G should be used in conjunction with gentamicin.450,452 These recommendations include endocarditis involving native valves or prosthetic valves or other prosthetic material caused by these bacteria.450

AHA states that IV penicillin G in conjunction with gentamicin is a reasonable regimen for the treatment of native valve endocarditis caused by viridans group streptococci†, Abiotrophia defectiva †, or Granulicatella † with penicillin MIC of 0.5 mcg/mL or greater.450,452

For the treatment of endocarditis involving native valves or prosthetic valves or other prosthetic material caused by Enterococcus faecalis †, E. faecium †, or other enterococcal species susceptible to both penicillin G and gentamicin, AHA states that IV penicillin G in conjunction with gentamicin is a reasonable choice.450,452 AHA states that it is reasonable to substitute streptomycin for gentamicin in this regimen if enterococci are susceptible to penicillin and streptomycin, but resistant to gentamicin.450

IV penicillin G has been used for the treatment of endocarditis caused by nonpenicillinase-producing staphylococci.8,9,11,12,452 AHA states that IV penicillin G may be considered for the treatment of native valve endocarditis caused by penicillin-susceptible S. aureus or coagulase-negative staphylococci in pediatric patients;452 however, penicillin G is not included in AHA recommendations for the treatment of staphylococcal endocarditis in adults.450

AHA recommends that treatment of endocarditis should be managed in consultation with an infectious disease expert, especially when endocarditis is caused by S. pneumoniae , β-hemolytic streptococci, enterococci, or staphylococci.450,452

For additional information regarding the treatment of endocarditis, current guidelines from AHA should be consulted.450,452

Pharyngitis and Tonsillitis !!navigator!!

Natural penicillins (IM penicillin G benzathine, oral penicillin V potassium) are drugs of choice for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci; GAS) and prevention of initial attacks (primary prevention) of rheumatic fever.2,3,18,19,20,21,292,375,580 These natural penicillins also are used for secondary prophylaxis to prevent recurrence of rheumatic fever (see Prevention of Rheumatic Fever Recurrence under Uses).2,3,18,19,20,21,292,375

Acute pharyngitis is most frequently caused by viruses (e.g., adenovirus, coronavirus, influenza virus, parainfluenza virus, rhinovirus, respiratory syncytial virus), but may be caused by bacteria or other organisms (e.g., groups A, C, and G streptococci, Corynebacterium diphtheriae , Arcanobacterium haemolyticum , Neisseria gonorrhoeae , Mycoplasma pneumoniae , Chlamydia pneumoniae ).375,580 S. pyogenes is the most frequent bacterial cause of acute pharyngitis (15-30% of cases of acute pharyngitis in pediatric patients and 5-15% of cases in adults).580 Although pharyngitis caused by group A β-hemolytic streptococci generally is associated with certain clinical characteristics (sore throat usually with sudden onset, pain on swallowing, fever, tonsillopharyngeal erythema with or without exudates, anterior cervical lymphadenitis) and may be associated with other signs and symptoms (headache, nausea, vomiting, abdominal pain, red and swollen uvula, petechiae on the palate, excoriated nares, scarlatiniform rash), these findings are not specific for this organism.292,375,580 Because a diagnosis of group A β-hemolytic streptococci cannot be made with certainty based on clinical evaluation alone, AHA and the American Academy of Pediatrics (AAP) state that the diagnosis can be suspected on clinical and epidemiologic grounds but that a decision to treat should be made only after laboratory confirmation that the pharyngitis is caused by group A β-hemolytic streptococci.292,375,580

Anti-infective treatment usually is indicated for all patients with group A β-hemolytic streptococcal pharyngitis and tonsillitis because inadequately treated S. pyogenes infection of the upper respiratory tract may result in serious sequelae (e.g., rheumatic fever, acute glomerulonephritis) or purulent complications (e.g., otitis media, sinusitis, peritonsillar or retropharyngeal abscesses, suppurative cervical adenitis).292,375,580 There is evidence that prompt initiation of appropriate anti-infective treatment of S. pyogenes pharyngitis and tonsillitis shortens the clinical course, decreases the risk of suppurative sequelae, prevents acute rheumatic fever, and decreases the risk of transmission to close contacts.292,375,580 However, effectiveness of anti-infective treatment of S. pyogenes pharyngitis and tonsillitis for prevention of poststreptococcal glomerulonephritis has not been established.292

Selection of an anti-infective for the treatment of S. pyogenes pharyngitis or tonsillitis should be based on the drug's spectrum of activity, bacteriologic and clinical efficacy, potential adverse effects, ease of administration, patient compliance, and cost.292,375,580 No regimen has been found to date that effectively eradicates group A β-hemolytic streptococci in 100% of patients.375

Because the drugs have a narrow spectrum of activity, are inexpensive, and generally are effective with a low frequency of adverse effects, AHA,375 AAP,292 and the Infectious Diseases Society of America (IDSA)580 recommend a penicillin regimen (i.e., a single dose of IM penicillin G benzathine or 10 days of oral penicillin V potassium or oral amoxicillin) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis.292,375,580 Other anti-infectives (narrow-spectrum oral cephalosporins, oral macrolides, oral clindamycin) are recommended as alternatives in penicillin-allergic patients.292,375,580

Treatment with either a single dose of IM penicillin G benzathine or a 10-day regimen of oral penicillin V generally eradicates S. pyogenes from the pharynx and prevents acute rheumatic fever if initiated within 9 days after the onset of pharyngitis.292,375,923 In studies in children and adults 1-25 years of age with group A β-hemolytic streptococcal pharyngitis, 5-7 days of treatment with oral penicillin V potassium eradicated the organism from the pharynx in 69-82% of patients, but the recommended 10-day treatment regimen of the drug eradicated the organism in 82-94% of patients.228,923 Experts state that the single-dose IM penicillin G benzathine regimen may be preferred in patients who are unlikely to complete the 10-day regimen of oral penicillin V potassium or amoxicillin,292,375,580 in patients with a personal or family history of rheumatic fever or rheumatic heart disease, or when there are environmental factors (e.g., crowded living conditions) that place the individual at increased risk for development of rheumatic fever.375

Follow-up laboratory evaluation after treatment of group A β-hemolytic streptococcal pharyngitis or tonsillitis generally is indicated only in patients who remain symptomatic, develop recurring symptoms, or have a history of rheumatic fever and are at unusually high risk for recurrence.292,375,580

Retreatment of S. pyogenes Pharyngitis

If signs and symptoms of pharyngitis recur shortly after initial treatment (i.e., within a few weeks) and presence of S. pyogenes is documented, retreatment with the original or an alternative regimen is recommended.292,375,580 Initial treatment failures may occur more frequently with oral penicillins than with IM penicillin G benzathine because of poor adherence to the oral regimen.292,375,580 If compliance with a 10-day oral regimen is a concern, IM penicillin G benzathine should be used for retreatment.292,375,580 If initial treatment failed, some clinicians suggest retreatment with the original regimen or use of IM penicillin G benzathine if an oral regimen was used initially or retreatment with an alternative regimen (e.g., a narrow-spectrum oral cephalosporin such as cephalexin, oral fixed combination of amoxicillin and clavulanate [amoxicillin/clavulanate], oral clindamycin, oral macrolide).292,375,580 If an individual has multiple, recurrent episodes of symptomatic pharyngitis within a period of months to years, it may be difficult to determine whether these are true episodes of S. pyogenes infection or whether the patient is a long-term pharyngeal carrier of S. pyogenes who is experiencing repeated episodes of nonstreptococcal (e.g., viral) pharyngitis.292,375,580

Asymptomatic Chronic Pharyngeal Carriers of S. pyogenes

Anti-infective treatment of asymptomatic chronic pharyngeal carriers of S. pyogenes is not usually indicated and these individuals should not receive repeated courses of anti-infectives.292,375,580 However, eradication of the carrier state may be desirable in certain situations (e.g., during a local outbreak of acute rheumatic fever or acute poststreptococcal glomerulonephritis, during an outbreak of S. pyogenes pharyngitis in a closed or partially closed community, when multiple episodes of documented symptomatic S. pyogenes pharyngitis are occurring within a family for many weeks despite appropriate treatment, when there is a personal or family history of acute rheumatic fever, when tonsillectomy is being considered in an individual solely because of frequent S. pyogenes infections).292,580 In such situations, recommended regimens include oral clindamycin, a narrow-spectrum oral cephalosporin, oral amoxicillin/clavulanate, oral azithromycin, or a regimen of oral rifampin in conjunction with either IM penicillin G benzathine or oral penicillin V.292,375,580

Meningitis and Other CNS Infections !!navigator!!

IV penicillin G potassium or sodium is used alone or in conjunction with other anti-infectives for the treatment of meningitis caused by susceptible Listeria monocytogenes ,8,9,11,12,61,418,475,476 Neisseria meningitidis ,8,9,10,11,12,61,166,197,292,418,475,986 S. agalactiae † (group B streptococci; GBS),61,292,418,475,986 or S. pyogenes or other β-hemolytic streptococci (e.g., groups C, H, G, L, and M).8,9,11,12,61,986

IV penicillin G potassium or sodium is used for the treatment of meningitis or ventriculitis caused by susceptible S. pneumoniae (penicillin MIC less than 0.1 mcg/mL).8,9,10,11,12,61,292,416,418,475 Treatment failures have been reported and the possibility of S. pneumoniae with intermediate resistance or complete resistance to penicillin G should be considered.10,61

IV penicillin G potassium or sodium is recommended for the treatment of healthcare-associated ventriculitis and meningitis caused by susceptible Cutibacterium acnes † (formerly Propionibacterium acnes ).416

Pending results of CSF culture and in vitro susceptibility testing, the most appropriate anti-infective regimen for empiric treatment of suspected bacterial meningitis should be selected based on results of CSF gram stain and antigen tests, age of the patient, the most likely pathogen(s) and source of infection, and current patterns of bacterial resistance within the hospital and local community.292,418,475 When results of culture and susceptibility tests become available and the pathogen is identified, the empiric anti-infective regimen should be modified (if necessary) to ensure that the most effective regimen is being administered.292,418,475

Actinomycosis !!navigator!!

IV penicillin G potassium or sodium is used for the treatment of actinomycosis caused by Actinomyces (e.g., A. israelii ).8,9,10,11,12,27,28,29,32,61,197,292,898,901 IV penicillin G is a drug of choice for the treatment of all forms of actinomycosis, including cervicofacial, respiratory (pulmonary, bronchial, laryngeal), abdominal, and CNS infections.10,27,28,29,32,61,197,292,898,901 Prolonged treatment usually is necessary.10,27,28,29,32,61,292,898,901 Many clinicians recommend that patients with severe actinomycosis (e.g., pulmonary infections) receive 2-6 weeks of treatment with IV penicillin G potassium or sodium followed by 6-12 additional months of treatment with an oral regimen (e.g., penicillin V or amoxicillin).10,27,28,29,32,292,898,901 A shorter duration of treatment may be sufficient for less extensive disease (e.g., cervicofacial).10,27,28 Surgical procedures should be performed as indicated, but do not eliminate the need for anti-infective therapy.8,9,10,11,12,27,61,292

Cervicofacial actinomycosis has been effectively treated with oral penicillin V† given for 3-8 weeks or longer.32,898

Anthrax !!navigator!!

Natural penicillins (IV penicillin G potassium or sodium, IM penicillin G procaine, oral penicillin V) are used for the treatment of anthrax (clinically apparent inhalational, cutaneous, GI, or meningeal anthrax) caused by susceptible Bacillus anthracis .7,543,668,670,671,672,673,680,683,686 Natural penicillins (IM penicillin G procaine, oral penicillin V†) also are used as alternatives for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following suspected or confirmed exposure to aerosolized B. anthracis spores if penicillin susceptibility is confirmed.7,671,672,673,686

Postexposure Prophylaxis (Inhalational Anthrax)

Ciprofloxacin and doxycycline usually are the initial drugs of choice for postexposure prophylaxis following suspected or confirmed exposure to aerosolized B. anthracis spores, including exposures that occur in the context of biologic warfare or bioterrorism.663,668,682,683,686 If exposure is confirmed and results of in vitro testing indicate that the organism is susceptible to penicillin, then consideration can be given to changing the postexposure prophylaxis regimen to a penicillin (e.g., oral amoxicillin, oral penicillin V, IM penicillin G procaine).663,668,683,684,685,686 Although monotherapy with a penicillin is not recommended for the treatment of clinically apparent inhalational anthrax when high concentrations of the organism are likely to be present, penicillins may be considered an option for anti-infective prophylaxis in some situations, including when ciprofloxacin and doxycycline are contraindicated, since the likelihood of β-lactamase induction resulting in an increase in penicillin MICs is lower when only a small number of vegetative cells are present.685,686 If a penicillin is used for prophylaxis following exposure to aerosolized B. anthracis spores in the context of biologic warfare or bioterrorism when penicillin-susceptible strains are involved, AAP and the US Centers for Disease Control and Prevention (CDC) recommend oral amoxicillin or oral penicillin V.671,672,673

Following natural, occupational, or bioterrorism-related exposures to aerosolized B. anthracis spores, anti-infective postexposure prophylaxis should be initiated immediately or as soon as possible.663,668,683 The optimum duration of postexposure prophylaxis after an inhalation exposure to B. anthracis spores is unclear.663,683 Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, CDC and other experts recommend that the total duration of anti-infective prophylaxis should be at least 60 days.663,668,671,672,673,681,682,683,686

Treatment of Cutaneous Anthrax

Natural penicillins (e.g., IM penicillin G procaine, oral penicillin V) generally have been considered drugs of choice for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible B. anthracis that occurs as the result of naturally occurring or endemic exposures to anthrax.7,668,670,680

For the treatment of cutaneous anthrax that occurs following exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, the initial drugs of choice are ciprofloxacin or doxycycline.668,671,672,673,683,686 If penicillin susceptibility is confirmed, consideration can be given to changing to a penicillin (oral amoxicillin or oral penicillin V) in infants and children, in pregnant or lactating women, or when the drugs of choice are not tolerated or not available;668,671,672,673,683,686 oral amoxicillin may be preferred, especially in infants and children.668,671,672,673,683,686 A multiple-drug parenteral regimen is recommended for initial treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or lesions on the head and neck.668,670,686 (See Treatment of Systemic Anthrax under Uses.)

For young children (i.e., younger than 2 years of age), CDC has recommended that initial treatment of cutaneous anthrax should be IV (not oral) and a multiple-drug anti-infective regimen should be considered since it is not known whether infants and young children are at increased risk of systemic dissemination of cutaneous anthrax.703

Although 3-10 days of anti-infective treatment may be adequate for the treatment of mild, uncomplicated cutaneous anthrax that occurs as the result of natural or endemic exposures to anthrax,668,673,680,681,683,686 some experts recommend a treatment duration of 7-14 days.680 CDC and other experts recommend that anti-infectives be continued for 60 days if cutaneous anthrax occurred as the result of exposure to aerosolized B. anthracis spores (e.g., in the context of biologic warfare or bioterrorism) since the possibility of inhalational anthrax would also exist.668,671,672,673,680,683,686 Although anti-infective therapy may limit the size of the cutaneous anthrax lesion and it usually becomes sterile within the first 24 hours of treatment, the lesion will still progress through the black eschar stage despite effective treatment.668,670,671,680,681,683,680,703

Treatment of Systemic Anthrax

IV penicillin G potassium or sodium generally has been considered a drug of choice for the treatment of clinically apparent inhalational, GI, or meningeal anthrax or anthrax septicemia caused by susceptible B. anthracis that occurs as the result of natural or endemic exposures to the organism.663,668,670,680,681 Concomitant use of other anti-infectives (e.g., streptomycin or other aminoglycoside, clindamycin, clarithromycin, rifampin, vancomycin) may also be indicated.670,680

IV penicillin G potassium or sodium is considered an alternative for use in multiple-drug parenteral regimens for initial treatment of systemic anthrax (inhalational anthrax, GI anthrax, meningoencephalitis, sepsis, or cutaneous anthrax with systemic involvement, lesions on the head or neck, or extensive edema) caused by penicillin-susceptible B. anthracis that occurs in the context of biologic warfare or bioterrorism.668,671,672,673,673,683,686 Strains of B. anthracis with naturally occurring penicillin resistance have been reported rarely, and there are published reports of B. anthracis strains that have been engineered to have penicillin and tetracycline resistance as well as resistance to other anti-infectives (e.g., macrolides, chloramphenicol, rifampin).663,668,680,681 Therefore, it has been postulated that exposures to B. anthracis that occur in the context of biologic warfare or bioterrorism may involve bioengineered resistant strains and this concern should be considered when selecting initial therapy for the treatment of anthrax that occurs as the result of bioterrorism-related exposures or for postexposure prophylaxis following such exposures.668,681,686 In addition, although B. anthracis strains isolated during bioterrorism-related exposures that occurred in the US during September and October 2001 were susceptible to penicillin and amoxicillin in vitro, additional tests indicated that some of these strains had constitutive and inducible β-lactamases and there is in vitro evidence that exposure of some penicillin-susceptible B. anthracis strains to penicillins can induce β-lactamases.686 Because of concerns regarding possible penicillin resistance or induction of penicillin resistance during treatment, CDC states that use of a penicillin alone is not recommended for the treatment of inhalational anthrax that occurs as the result of biologic warfare or bioterrorism when high concentrations of the organism are likely to be present, although penicillin can be included in appropriate multiple-drug regimens.685,686

CDC recommends that treatment of inhalational anthrax that occurs as the result of exposure to B. anthracis spores in the context of biologic warfare or bioterrorism should be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 anti-infectives predicted to be effective.686 The multiple-drug parenteral regimen usually is continued for at least 2-3 weeks until the patient is clinically stable when an oral anti-infective regimen may be substituted for the parenteral regimen.668,672,673,683 Because of the possible persistence of anthrax spores in lung tissue, the total duration of anti-infective treatment of inhalational anthrax that occurs as the result of exposure to aerosolized spores in the context of biologic warfare or bioterrorism should be 60 days.668,672,673,683,686

Clostridium Infections !!navigator!!

C. botulinum

IV penicillin G potassium or sodium has been used as an adjunct in the treatment of wound botulism caused by germination of Clostridium botulinum spores in a contaminated wound and resultant in vivo toxin production.8,9,10,11,12,61,744,745,747,749,750 Anti-infectives have no known direct effects on botulinum toxin and therefore are not usually indicated in the management of the various forms of botulism, except for the treatment of concurrent infections.292,742,746,748,751,753

Botulism is a potentially fatal neuroparalytic illness caused by neurotoxins produced by C. botulinum , but may rarely be caused by other related species (e.g., C. baratii , C. butyricum ) that also can produce neurotoxins.292,742 C. botulinum form spores that are ubiquitous in the environment in soil and water sediments and can germinate into vegetative bacteria that produce toxins.292,742 The various forms of naturally occurring human botulism based on the mode of acquisition of the toxin include wound botulism (exogenous spores within a contaminated wound germinate and produce toxin), foodborne botulism (exogenous toxin is ingested in contaminated food), infant botulism (endogenous spores within the intestine of the infant germinate and produce toxin), and adult or child intestinal botulism (intestinal colonization with toxin production and there is no evidence of an exogenous source such as food or wound contamination).292,742,746,748,749,751 Botulism also could potentially occur from iatrogenic overdose or misinjection of commercially available botulinum toxins used for cosmetic or therapeutic purposes742 or from inhalation of aerosolized botulinum toxin (e.g., in the context of biologic warfare or bioterrorism).292,683,742,746,748,751 Botulism is not transmitted person to person.292,746

Botulism can vary from a mild illness to fulminate disease that progresses rapidly and can be fatal within a short time after the onset of symptoms.742,749 All forms of human botulism result in similar neurologic signs (i.e., descending flaccid paralysis, dysphagia, dysarthria, diplopia, dysphonia, ptosis, and respiratory muscle impairment leading to death).683,742,746,748,751 The initial symptoms of naturally occurring foodborne botulism may also include GI effects such as abdominal cramps, nausea, vomiting, or diarrhea.746,748

Treatment strategies for most forms of botulism include intensive supportive care (including aggressive use of respiratory care) and prompt administration of botulinum antitoxin.292,683,742,746,748,751 For the treatment of botulism caused by toxin serotypes A, B, C, D, E, F, or G, botulism antitoxin (equine) heptavalent is available in the US from CDC (see Botulism Antitoxin [Equine] 80:04).742 Timely administration of botulinum antitoxin early in the course of the illness (within 48 hours of symptom onset and ideally within 24 hours) is important since it can minimize the extent and severity of paralysis and may prevent progression to respiratory compromise or reduce the duration of mechanical ventilation and intensive care; however, the antitoxin will not reverse existing paralysis.292,683,742,746

Wound botulism occurs when anaerobic conditions in a wound allow germination of C. botulinum spores and in vivo toxin production.749 The median incubation period for wound botulism associated with trauma is 7 days (range: 4-21 days).749 Although management of wound botulism involves use of botulinum antitoxin, supportive care, and wound debridement, adjunctive use of a parenteral anti-infective active against anaerobes (e.g., penicillin G, metronidazole) may be indicated to eradicate C. botulinum at the wound site.749,751 Because C. botulinum resistant to penicillin G has been reported, in vitro susceptibility testing is recommended if adjunctive use of the drug is being considered for management of wound botulism.61

Foodborne botulism results from ingestion of exogenous botulinum toxin produced in food contaminated with C. botulinum spores, including improperly canned vegetables (especially low-acid vegetables), fruits, and meats; home-canned or fermented fish; herb-infused oils; nonpreserved foods served in restaurants or delicatessens (e.g., potatoes baked in aluminum foil and then held at room temperature, cheese sauce, bottled garlic, other condiments or foods kept warm for extended periods).742,746,754 Symptoms of foodborne botulism usually are evident within 12-72 hours after ingestion, but may be evident as soon as 2 hours or as long as 8 hours after ingestion of the toxin.746,754 The mainstay of treatment of foodborne botulism is use of botulinum antitoxin and supportive care.746,754

Infant botulism and intestinal botulism (adult or child) are treated with botulinum antitoxin and supportive care.292,742 If infant botulism is caused by toxin serotypes A or B, botulism immune globulin IV can be used for treatment (see Botulism Immune Globulin IV 80:04).292,753 Anti-infectives are not effective and should not be used in the treatment of infant botulism or intestinal botulism, unless clearly indicated for a concurrent infection.292,753

Treatment of botulism that occurs as a result of a bioterrorism incident would be the same as that for naturally occurring botulism and includes prompt administration of botulinum antitoxin and supportive care.746 Antitoxin should be given to patients with neurologic signs of botulism as soon as feasible after clinical diagnosis; administration of antitoxin should not be delayed for microbiologic testing.746 Administration of botulinum antitoxin for postexposure prophylaxis following a bioterrorism-related exposure is not recommended, but may be considered after a known high-risk exposure in certain situations.683,746

C. perfringens

IV penicillin G potassium or sodium is the drug of choice for the treatment of myonecrosis and gas gangrene caused by C. perfringens or other Clostridium species.61,292,543 IDSA recommends that IV penicillin G be used in conjunction with IV clindamycin for clostridial myonecrosis;543 if there is no definitive etiologic diagnosis, these experts recommend a broad-spectrum anti-infective regimen (e.g., vancomycin used in conjunction with the fixed combination of piperacillin and tazobactam [piperacillin/tazobactam], fixed combination of ampicillin and sulbactam [ampicillin/sulbactam], or a carbapenem).543 Anti-infectives are used as an adjunct to debridement and excision of the infected area.197,292,543

Foodborne illness caused by C perfringens usually is self-limited and anti-infectives are not indicated.292

C. tetani

IV penicillin G potassium or sodium has been used as an adjunct to tetanus immune globulin (TIG) in the treatment of tetanus.8,9,10,11,12,61,292,886 Tetanus is a neurologic disease caused by neurotoxin produced by C. tetani .292 The role of anti-infectives in the treatment of tetanus is unclear.10 Anti-infectives cannot neutralize toxin already formed and cannot eradicate C. tetani spores, which may revert to toxin-producing vegetative forms.10 In addition, the nature of wounds that become contaminated with C. tetani generally makes the organism inaccessible to anti-infectives.10,61 If an anti-infective is used for adjunctive treatment of tetanus to decrease the number of vegetative C. tetani , oral or IV metronidazole usually is the drug of choice and parenteral penicillin G is an alternative.10,292

Diphtheria !!navigator!!

Treatment of Diphtheria

IV penicillin G potassium or sodium or IM penicillin G procaine† is used as an adjunct to diphtheria antitoxin in the treatment of diphtheria caused by toxigenic strains of Corynebacterium diphtheriae .8,9,10,11,12,61,166,292

Use of diphtheria antitoxin (not commercially available in the US, but may be available from CDC) is the most important aspect of treatment of respiratory diphtheria (see Diphtheria Antitoxin 80:04).10,166,292 For adjunctive anti-infective treatment of diphtheria, a 14-day regimen of IV penicillin G, IM penicillin G procaine, or oral or parenteral erythromycin usually is recommended.166,292 Anti-infective therapy may eliminate C. diphtheriae from infected sites, prevent spread of the organism and further toxin production, and prevent transmission to close contacts by eliminating the diphtheria carrier state;292 however, anti-infectives appear to be of no value in neutralizing diphtheria toxin and do not replace treatment with diphtheria antitoxin.10,61,292

Patients usually are no longer contagious 48 hours after initiation of appropriate anti-infective therapy.166,292 Eradication of C. diphtheriae should be confirmed 24 hours after completion of anti-infective treatment by 2 consecutive negative cultures taken 24 hours apart.166,292 Because diphtheria infection does not necessarily confer immunity, active immunization with an age-appropriate preparation containing diphtheria toxoid adsorbed (see 80:08) should be initiated or completed during convalescence.292

Prevention of Diphtheria in Close Contacts

IM penicillin G benzathine is used for prevention of diphtheria in asymptomatic household contacts of patients with respiratory or cutaneous diphtheria†.7,166,292 CDC, US Public Health Service Advisory Committee on Immunization Practices (ACIP), and AAP recommend that, irrespective of their immunization status, all household or other close contacts of individuals with suspected or proven diphtheria should have samples taken for C. diphtheriae cultures, receive appropriate anti-infective prophylaxis, and be kept under surveillance for evidence of the disease for 7 days.166,292 Although efficacy of anti-infective prophylaxis in preventing secondary disease is presumed and not proven, prophylaxis should be initiated promptly and should not be delayed pending culture results.292 In addition, contacts of patients with diphtheria should receive an immediate dose of an age-appropriate preparation containing diphtheria toxoid adsorbed if they are inadequately immunized against diphtheria, immunization status is unknown, or they have not received a booster dose within the last 5 years.166,292

CDC, ACIP, and AAP recommend that either a single dose of IM penicillin G benzathine or a 7- to 10-day regimen of oral erythromycin be used for chemoprophylaxis in contacts of patients with diphtheria.166,292 IM penicillin G benzathine may be preferred when there are concerns about compliance with the oral regimen.292 In addition, contacts who are inadequately immunized against diphtheria or whose immunization status is unknown should receive an immediate booster dose of an age-appropriate preparation containing diphtheria toxoid adsorbed and the primary immunization series should be completed according to the recommended schedule.166,292 Contacts who are fully immunized should receive an immediate booster dose of an age-appropriate diphtheria toxoid preparation if 5 or more years have elapsed since their last booster dose.166,292 Use of diphtheria antitoxin in unimmunized close contacts is not recommended because there is no evidence that such therapy has any additional benefit for contacts who receive recommended prophylaxis with IM penicillin G benzathine or oral erythromycin.166,292

Elimination of Diphtheria Carrier State

Natural penicillins (IM penicillin G potassium or sodium,8,9,11,12 IM penicillin G procaine,7,10 IM penicillin G benzathine†)10,292,900 have been used to eliminate the diphtheria carrier state in individuals identified as carriers of toxigenic C. diphtheriae .10,166,292,900

For elimination of the diphtheria carrier state, AAP recommends a 10- to 14-day regimen of oral erythromycin or a single dose of IM penicillin G benzathine.292 In one study, a single dose of IM penicillin G benzathine eradicated the carrier state in 84% of carriers, but 10 days of treatment with oral erythromycin or oral clindamycin eradicated the carrier state in 92-93% of carriers.900

Follow-up cultures should be obtained 24 hours after completion of the anti-infective regimen;292 individuals who continue to harbor C. diphtheriae after treatment should receive additional treatment with a 10-day course of oral erythromycin with follow-up cultures.292 Unimmunized diphtheria carriers should receive active immunization with an age-appropriate preparation containing diphtheria toxoid adsorbed; immunized carriers who have not received a booster dose within the last year should receive a booster dose of an age-appropriate diphtheria toxoid adsorbed preparation.292

Erysipelothrix Infections !!navigator!!

IV penicillin G potassium or sodium and IM penicillin G procaine are used for the treatment of infections caused by Erysipelothrix rhusiopathiae .7,8,9,10,11,12,61,64,67,197

Parenteral penicillin G is the drug of choice for the treatment of serious infections caused by E. rhusiopathie , including endocarditis, and 4-6 weeks of treatment with IV penicillin G potassium or sodium is recommended.8,9,10,11,12,64

Although uncomplicated localized cutaneous E. rhusiopathiae infections (i.e., erysipeloid) may resolve spontaneously within 3-4 weeks, anti-infective treatment may shorten the time to healing and reduce the risk of relapse.10 IM penicillin G procaine has been used for the treatment of erysipeloid;7 oral regimens (e.g., amoxicillin) often are recommended when anti-infective treatment is indicated for such infections.10

Fusobacterium Infections !!navigator!!

Natural penicillins have been used for the treatment of acute necrotizing ulcerative gingivitis (Vincent's infection, trench mouth, Fusobacterium gingivitis or pharyngitis).10,67,197,207 Oral penicillin V potassium may be effective for the treatment of mild to moderate oropharyngeal infections caused by penicillin-susceptible Fusobacterium ,10,18,19,20,21,207 but IM penicillin G procaine7 or IM or IV penicillin G potassium or sodium8,9,11,12 should be used for the treatment of moderately severe to severe cases.

In vitro susceptibility testing is recommended when selecting an anti-infective for the treatment of Fusobacterium infections.292 The increased prevalence of resistance to penicillins in organisms that cause oropharyngeal or odontogenic infections, including F. necrophorum and F. nucleatum , should be considered.10,292 Some experts recommend a combination regimen of a β-lactam anti-infective active against aerobic oral and respiratory tract pathogens (e.g., cefotaxime, ceftriaxone, cefuroxime) in conjunction with metronidazole or clindamycin for the treatment of invasive Fusobacterium infections; others recommend monotherapy with ampicillin/sulbactam, piperacillin/tazobactam, or a carbapenem.292

Neisseria Infections !!navigator!!

N. gonorrhoeae Infections

Although natural penicillins (penicillin G procaine, penicillin G potassium or sodium) were used in the past for the treatment of uncomplicated gonorrhea or disseminated gonococcal infections caused by penicillin-susceptible N. gonorrhoeae ,8,9,11,12,265,849,858 penicillins should not be used for the treatment of gonococcal infections.7,344,345 CDC has not recommended use of penicillins for the treatment of uncomplicated or disseminated gonococcal infections for over 30 years because of the widespread prevalence of penicillinase-producing N. gonorrhoeae (PPNG) resistant to penicillins.265,344 Ceftriaxone is the drug of choice for the treatment of gonococcal infections.344 (See Gonorrhea and Associated Infections under Uses, in Ceftriaxone Sodium 8:12.06.12.)

N. meningitidis Infections

IM or IV penicillin G potassium or sodium has been considered a preferred or alternative drug for the treatment of infections caused by N. meningitidis , including upper respiratory tract infections, bacteremia, and meningitis (see Meningitis and Other CNS Infections under Uses).61,63,64,67,80,292,418 However, penicillin-resistant N. meningitidis have been reported and in vitro susceptibility testing is advised.61 In addition, treatment with penicillin G does not eliminate the meningococcal carrier state and should not be used for chemoprophylaxis in asymptomatic N. meningitidis carriers.64,292 Other anti-infectives (e.g., ceftriaxone, ciprofloxacin, rifampin) are recommended to eliminate nasopharyngeal carriage of N. meningitidis .64,292

Pasteurella Infections !!navigator!!

Penicillin G potassium or sodium is used for the treatment of infections caused by Pasteurella multocida .8,9,11,12 IV penicillin G is considered a drug of choice for the treatment of local infections caused by P. multocida (e.g., wound infections including dog, cat, or other animal bites) and meningitis, bacteremia, osteomyelitis, endocarditis, or other serious P. multocida infection.10,61,67,197,292

Rat-bite Fever !!navigator!!

Natural penicillins are used for the treatment of rat-bite fever caused by Streptobacillus moniliformis (erythema arthriticum epidemicum, Haverhill fever, streptobacillary fever) or Spirillum minus (sodoku).7,8,9,10,11,12,30,31,33,61,64,197,292,887

IV penicillin G potassium or sodium usually is the drug of choice for the treatment of rat-bite fever10,30,33,61,64,197,292,887 and is effective for both the streptobacillary form and the spirillary form of the disease.61 For initial treatment of S. moniliformis endocarditis, IV penicillin G usually is used in conjunction with an aminoglycoside (streptomycin or gentamicin).10,30,33,292 Tetracyclines or streptomycin are considered alternatives (e.g., for penicillin-allergic patients).10,30,33,292

Although IM penicillin G procaine has been used for the treatment of rat-bite fever,7,10,30,292 CDC and other clinicians state that IV penicillin G potassium or sodium is more appropriate and is preferred.10,30,31,33

Oral penicillin V has been used in the treatment of rat-bite fever as follow-up therapy in patients who responded to initial treatment with IV penicillin G.10,30,31,292

Spirochetal Infections !!navigator!!

Leptospirosis

Penicillin G is used in the treatment of leptospirosis† caused by Leptospira .10,61,98,99,292,477,544,547 Penicillin G is the drug of choice for the treatment of severe leptospirosis;10,292,477 other anti-infectives (e.g., amoxicillin, ampicillin, azithromycin, cefotaxime, ceftriaxone, doxycycline, tetracycline) also have been used for the treatment of infections caused by Leptospira .10,292,477,544,545,547

Many Leptospira infections are self-limited and the effectiveness of anti-infectives in the treatment of mild disease is difficult to assess and has been questioned.10,61,544,545,546 Some studies indicate that the duration of systemic symptoms (e.g., fever) may be shortened and the incidence of renal, hepatic, meningeal, and hemorrhagic complications may be reduced if parenteral penicillin G is initiated early in the course of the disease (e.g., by the fourth day of the illness);545 however, delayed anti-infective treatment may not alter the course of the disease.545

Anti-infective therapy of leptospirosis, including treatment with penicillin G, may provoke a Jarisch-Herxheimer reaction.10,61,292,677 (See Jarisch-Herxheimer Reaction under Cautions.)

Lyme Disease

Natural penicillins (IV penicillin G sodium or potassium, oral penicillin V) are used in the treatment of Lyme disease† caused by Borrelia burgdorferi .327,328,329,331,332,333,334,335

Although oral penicillin V has been used in the treatment of early localized Lyme disease manifested as erythema migrans† and has been effective and well tolerated,327,328 some experts state that comparative efficacy data are limited and additional study is needed to identify the optimal dosage of penicillin V.329 IDSA, American Academy of Neurology (AAN), American College of Rheumatology (ACR), and others recommend that erythema migrans be treated with a 10-day regimen of oral doxycycline or a 14-day regimen of oral amoxicillin or oral cefuroxime axetil.292,329,331

IV penicillin G potassium or sodium has been used for the treatment of neurologic Lyme disease† and the treatment of Lyme arthritis†.329,332,333,334 For the treatment of meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral nervous system manifestations in patients with Lyme disease, IDSA, AAN, and ACR recommend treatment with IV ceftriaxone, IV cefotaxime, IV potassium G, or oral doxycycline.329 For the treatment of Lyme arthritis, IDSA, AAN, and ACR recommend use of oral anti-infectives (doxycycline, amoxicillin, cefuroxime axetil) based on comparative efficacy of oral and IV regimens;329 if an IV regimen is used in patients with Lyme arthritis (e.g., arthritis symptoms persist after an oral anti-infective regimen), these experts recommend IV ceftriaxone.329 IV ceftriaxone also is preferred for initial treatment of Lyme carditis in hospitalized patients.329

For additional information on the treatment of Lyme disease, current treatment guidelines from IDSA, AAN, and ACR available at the IDSA website [Web] should be consulted.329

Syphilis

Parenteral penicillin G is the treatment of choice for all stages and forms of syphilis caused by Treponema pallidum subsp pallidum , including primary syphilis infection (presents as a single painless ulcer or chancre at the infection site, but may present as multiple, atypical, or painful lesions), secondary syphilis (manifestations include rash, mucocutaneous lesions, and lymphadenopathy), latent syphilis (detected by serologic testing but lacking clinical manifestations of primary, secondary, or tertiary syphilis), tertiary syphilis (may present with cardiac involvement, gummatous lesions, tabes dorsalis, general paresis), neurosyphilis, and congenital syphilis.292,344,345,350,440 The most appropriate parenteral penicillin G preparation (penicillin G benzathine, penicillin G procaine, penicillin G potassium or sodium), dosage, and duration of treatment depend on the disease stage and clinical manifestations.292,344 Oral penicillin V and the fixed-combinations of parenteral penicillin G benzathine and penicillin G procaine should not be used in the treatment of syphilis.4,5,344

Primary and Secondary Syphilis in Adults

IM penicillin G benzathine is the drug of choice for the treatment of primary and secondary syphilis in adults.344,345,350,440 This recommendation is based on long-term experience that indicates that the drug is effective in achieving clinical resolution (i.e., healing of lesions and prevention of sexual transmission) and preventing late sequelae.344 CDC and other experts recommend a single dose of IM penicillin G benzathine (2.4 million units) for the treatment of primary and secondary syphilis in adults.344,345,350,440 There is no evidence that additional doses of IM penicillin G benzathine result in enhanced efficacy in such patients; however, some experts recommend that pregnant women with primary or secondary syphilis receive a second dose of IM penicillin G benzathine 1 week after the initial dose (see Syphilis During Pregnancy under Uses).344

Invasion of CSF by T. pallidum accompanied by CSF abnormalities is common in adults who have primary or secondary syphilis, but has unknown significance.344 In the absence of clinical neurologic findings, no evidence supports variation from the recommended treatment regimen for patients with primary or secondary syphilis.344 Development of symptomatic neurosyphilis is rare in such patients if the recommended treatment regimen is used.344 Therefore, routine CSF analysis is not usually recommended for adults with primary or secondary syphilis, unless there are clinical symptoms or signs of neurologic or ophthalmic involvement.344 Any patient with syphilis who also has signs or symptoms of neurologic disease (e.g., cranial nerve dysfunction, meningitis, stroke, altered mental state) or ocular syphilis (e.g., uveitis, neuroretinitis, optic neuritis) should be fully evaluated for neurosyphilis and syphilitic eye disease with CSF and ocular slit-lamp and other ophthalmic examinations.344

Only limited data are available to support use of alternatives to penicillin G for the treatment of primary or secondary syphilis.344 CDC states that nonpregnant adults with primary or secondary syphilis who are hypersensitive to penicillin can receive oral doxycycline (100 mg twice daily for 14 days) or oral tetracycline hydrochloride (500 mg 4 times daily for 14 days).344 Compliance may be better with doxycycline than with tetracycline.344 Limited data indicate that IM or IV ceftriaxone (1 g daily for 10 days) is effective in the treatment of primary or secondary syphilis; however, CDC cautions that the optimal dose and duration of ceftriaxone for the treatment of syphilis have not been established.344 Although there are some data suggesting that azithromycin (single 2-g oral dose) has been effective for the treatment of primary or secondary syphilis in some populations, T. pallidum resistant to azithromycin and other macrolides have been reported and azithromycin treatment failures have been documented in the US.344 Therefore, azithromycin should not be used for the treatment of syphilis.344 Careful clinical and serologic follow-up is essential if a nonpenicillin regimen is used.344 If compliance and follow-up with an alternative regimen cannot be ensured in patients with primary or secondary syphilis who are hypersensitive to penicillins, they should be desensitized, if necessary, and treated with the appropriate penicillin G benzathine regimen.344

Latent Syphilis in Adults

Latent syphilis occurs during the period after infection with T. pallidum when patients are seroreactive but have no other evidence of syphilis.344 Treatment of latent syphilis is intended to prevent the occurrence of or progression to late complications.344 Patients with latent syphilis who acquired syphilis within the preceding year are classified as having early latent syphilis (early nonprimary, nonsecondary).344 Individuals also can be classified as having early latent syphilis if, within the year preceding the evaluation, they had a documented seroconversion or fourfold or greater increase in nontreponemal test titers sustained for more than 2 weeks (in a previously treated individual), unequivocal symptoms of primary or secondary syphilis, or a sexual partner documented as having primary, secondary, or early latent syphilis.344 Other asymptomatic patients should be considered to have latent syphilis of unknown duration or late latent syphilis (duration exceeding 1 year).344

IM penicillin G benzathine is considered the drug of choice for the treatment of latent syphilis in adults.344,345,350,440 CDC and others recommend that adults with early latent syphilis receive a single dose of IM penicillin G benzathine (2.4 million units) and that adults with late latent syphilis or latent syphilis of unknown duration receive a multiple-dose regimen of IM penicillin G benzathine (2.4 million units once weekly for 3 successive weeks).344,345,350,440

Individuals who have been diagnosed with latent syphilis and have neurologic or ocular signs and symptoms (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, symptoms or signs of meningitis or stroke) should be evaluated for neurosyphilis, ocular syphilis, or otosyphilis according to their clinical presentation.344

Effectiveness of possible alternatives to penicillin G for the treatment of latent syphilis has not been well documented.344 CDC states that nonpregnant adults with clearly defined early latent syphilis who are hypersensitive to penicillins should respond to alternative regimens recommended for treatment of primary and secondary syphilis in penicillin-allergic patients (see Primary and Secondary Syphilis in Adults under Uses).344 The only acceptable alternatives for the treatment of late latent syphilis or syphilis of unknown duration are oral doxycycline (100 mg twice daily for 28 days) or oral tetracycline hydrochloride (500 mg 4 times daily for 28 days).344 Although ceftriaxone is a plausible alternative for the treatment of latent syphilis, the optimal dose and duration have not been defined and use of the drug should be considered in consultation with a specialist.344 Careful clinical and serologic follow-up is essential if a nonpenicillin regimen is used.344 If compliance and follow-up with an alternative regimen cannot be ensured in patients with latent syphilis who are hypersensitive to penicillins, they should be desensitized, if necessary, and treated with the appropriate penicillin G benzathine regimen.344

Tertiary Syphilis in Adults

IM penicillin G benzathine is considered the drug of choice for the treatment of tertiary syphilis in adults.344,345,350,440 CDC and others recommend that adults with tertiary syphilis receive a multiple-dose regimen of IM penicillin G benzathine (2.4 million units once weekly for 3 weeks).344,345,350,440 CSF examinations are recommended prior to initiation of treatment in patients with symptomatic late syphilis.344 Some experts recommend that all patients with cardiovascular syphilis receive a treatment regimen recommended for neurosyphilis (see Neurosyphilis under Uses).344 CDC recommends that patients with cardiovascular or gummatous syphilis be managed in consultation with an expert.344

Adults with tertiary syphilis who are hypersensitive to penicillins should be treated in consultation with an infectious disease specialist.344

Neurosyphilis, Ocular Syphilis, and Otosyphilis

CNS involvement can occur during any stage of syphilis.344 CSF laboratory abnormalities are common in individuals with early syphilis, even in the absence of clinical neurologic findings.344 All patients with clinical signs or symptoms suggestive of neurosyphilis (e.g., cognitive dysfunction, motor or sensory deficits, cranial nerve palsies, signs or symptoms of meningitis or stroke) should receive CSF examinations before initiation of treatment.344

Syphilitic uveitis or other ocular manifestations (e.g., neuroretinitis, optic neuritis) can occur at any stage of syphilis and can be isolated abnormalities or associated with neurosyphilis.344 Patients with ocular symptoms should receive full ophthalmic examinations, including cranial nerve evaluation; if cranial nerve dysfunction is present, CSF examinations are needed.344 If ocular syphilis is suspected, immediate referral to and management in collaboration with an ophthalmologist is crucial.344 Ocular syphilis should be treated with a regimen recommended for neurosyphilis, even if CSF examinations are normal.344

Hearing loss and other otologic symptoms can occur at any stage of syphilis and can be isolated abnormalities or associated with neurosyphilis.344 Patients with isolated auditory symptoms and normal neurologic examinations do not need CSF examinations before initiation of treatment.344 Otosyphilis should be managed in collaboration with an otolaryngologist and treated with a regimen recommended for neurosyphilis.344

CDC and others state that neurosyphilis, ocular syphilis, or otosyphilis in adults should be treated with IV penicillin G potassium or sodium (18-24 million units daily by continuous IV infusion or given as 3-4 million units every 4 hours for 10-14 days).344,440 Alternatively, if compliance can be ensured, a regimen of IM penicillin G procaine (2.4 million units once daily for 10-14 days and 500 mg of oral probenecid 4 times daily for 10-14 days) may be considered.344,440 Because these regimens recommended for neurosyphilis are shorter than those recommended for the treatment of late latent syphilis, some clinicians suggest that a regimen of IM penicillin G benzathine (2.4 million units once weekly for up to 3 weeks) be considered after completion of the IV penicillin G or IM penicillin G procaine regimen.344,440

CDC states that limited data suggest that IM or IV ceftriaxone (1-2 g daily for 10-14 days) can be used as an alternative for the treatment of neurosyphilis in patients hypersensitive to penicillin; although cross-allergenicity between penicillins and ceftriaxone can occur, the risk of cross-reactivity between penicillin and third generation cephalosporins is lower than with some other cephalosporins.344 (See Patients at Risk for Penicillin Hypersensitivity Reactions under Cautions.) Because other nonpenicillin regimens have not been adequately studied for the treatment of neurosyphilis, if safety of ceftriaxone is a concern in a patient hypersensitive to penicillin, appropriate testing should be done to confirm penicillin allergy and, if necessary, the patient should be desensitized and managed in consultation with an expert.344

Syphilis in HIV-infected Individuals

HIV-infected individuals with primary or secondary syphilis, latent syphilis, tertiary syphilis, or neurosyphilis should receive the same treatment regimens recommended for those without HIV infection.344,440 Neurosyphilis, ocular syphilis, and otosyphilis should be considered in the differential diagnosis of neurologic, ocular, and other signs and symptoms among HIV-infected individuals.344 All HIV-infected individuals with syphilis should receive careful clinical and serologic follow-up after treatment.344

Syphilis During Pregnancy

Syphilis during pregnancy can result in stillbirth, hydrops fetalis, or preterm birth; the infant may be born with congenital syphilis, including asymptomatic infection.292 The reported rate of maternal-fetal transmission of the infection is 60-100% in pregnant women with primary or secondary syphilis, 40% in those with early latent syphilis, and less than 8% in those with late latent syphilis.292 The risk of transmission to the infant increases directly with gestational age at the time of maternal infection.292

Penicillin G is the drug of choice for the treatment of syphilis during pregnancy and use of an appropriate treatment regimen in the mother can effectively prevent maternal transmission of T. pallidum and treat infection in the fetus.344 If a pregnant woman has clinical or serologic evidence of syphilis or if the diagnosis of syphilis cannot be excluded, the pregnant woman should receive the usual penicillin G regimen appropriate for the stage of syphilis.344 In addition, some experts recommend that pregnant women with primary, secondary, or early latent syphilis who are treated with IM penicillin G benzathine should receive a second dose of IM penicillin G benzathine 1 week after the first dose.344 If a pregnant patient with late latent syphilis misses a dose of the recommended multiple-dose regimen of IM penicillin G benzathine, the full course of treatment must be repeated.344

There are no proven alternatives to penicillin G for the treatment of syphilis during pregnancy, and pregnant women with any stage of syphilis who have a history of penicillin allergy should be desensitized and treated with the appropriate penicillin G regimen.292,344 Tetracyclines should be avoided during the second and third trimesters.344 Erythromycin and azithromycin should not be used for the treatment of syphilis during pregnancy since these macrolides do not reliably cure syphilis in the woman and do not treat the infection in the fetus.292,344 In addition, data are insufficient to recommend ceftriaxone or other cephalosporins for the treatment of syphilis in pregnant women.344

Congenital Syphilis

There has been a substantial increase in the incidence of congenital syphilis reported in the US during recent years that reflects the increased incidence of primary and secondary syphilis among women of reproductive potential.292,344 Data indicate that the case rate of congenital syphilis in the US increased from 9.2 cases per 100,000 live births in 2013 to 33.1 cases per 100,000 live births in 2018.292 Data for 2019 indicate 48.5 cases of congenital syphilis per 100,000 live births in the US.344 Regardless of the stage of syphilis in the pregnant woman, congenital syphilis can occur as the result of placental transmission at any time during pregnancy or via contact with maternal lesions at the time of delivery.292

Neonates born to women who have had syphilis during pregnancy should be examined carefully and tested at birth for evidence of congenital syphilis.292,344 Infected infants can have hepatosplenomegaly; snuffles (copious nasal secretions); lymphadenopathy; mucocutaneous lesions; pneumonia, osteochondritis, periostitis, and pseudoparalysis; edema; rash (maculopapular consisting of small dark red-copper spots) that is most severe on the hands and feet; hemolytic anemia; or thrombocytopenia at birth or within the first 4-8 weeks after birth.292 Untreated infants, including those asymptomatic at birth, may develop late manifestations that usually appear when the child is older than 2 years of age and may involve the CNS, bones and joints, teeth, eyes, and skin.292 Late manifestations can be prevented by treatment of congenital syphilis.292 The diagnosis of congenital syphilis is complicated by transplacental transfer of maternal nontreponemal and treponemal immunoglobulin G (IgG) antibodies to the fetus that make interpretation of reactive serologic tests for syphilis difficult in infants.344 Treatment decisions for neonates usually are made based on diagnosis of syphilis in the mother; adequacy of maternal syphilis treatment; clinical, laboratory, or radiologic evidence of syphilis in the neonate; and comparison of maternal nontreponemal serologic titers (at delivery) and titers in the neonate (using the same test and, if possible, the same laboratory).344

For neonates with confirmed proven or highly probable congenital syphilis (those with abnormal physical examination consistent with congenital syphilis, serum quantitative nontreponemal serologic titer that is 4 or more times the mother's titer [at delivery], or positive darkfield or polymerase chain reaction [PCR] test of placenta, cord, lesions, or body fluids or a positive silver stain of the placenta or cord), CDC and AAP recommend IV penicillin G potassium or sodium (50,000 units/kg every 12 hours during the first 7 days of life and 50,000 units/kg every 8 hours thereafter for a total duration of 10 days) or, alternatively, IM penicillin G procaine (50,000 units/kg once daily for 10 days).292,344 If more than 1 day of treatment is missed, the entire 10-day course of treatment should be restarted.292,344 There are insufficient data on use of other anti-infectives (e.g., ampicillin) for the treatment of congenital syphilis,292,344 and a 10-day regimen of penicillin G potassium or sodium or penicillin G procaine should be administered even if the neonate received ampicillin for another indication (e.g., empiric treatment for possible sepsis).344

For neonates with possible congenital syphilis (those with normal physical examination and serum quantitative nontreponemal serologic titer the same as or less than 4 times the mother's titer [at delivery] and the mother was not treated, inadequately treated, has no documentation of receiving treatment, was treated with a nonpenicillin regimen, or treatment was initiated less than 30 days before delivery), CDC and AAP recommend IV penicillin G potassium or sodium (50,000 units/kg every 12 hours during the first 7 days of life and 50,000 units/kg every 8 hours thereafter for a total duration of 10 days) or, alternatively, IM penicillin G procaine (50,000 units/kg once daily for 10 days).292,344 Some experts state that a single dose of IM penicillin G benzathine (50,000 units/kg) can be used as an alternative if follow-up can be ensured;292,344 however, others prefer the 10-day regimens if the mother had untreated early syphilis at the time of delivery since such neonates are at increased risk for congenital syphilis.344

For neonates less likely to have congenital syphilis (those with normal physical examination and serum nontreponemal serologic titer the same as or less than 4 times the mother's titer [at delivery] and the mother received adequate treatment during pregnancy with a regimen appropriate for the stage of syphilis and treatment was initiated at least 30 days prior to delivery and the mother has no evidence of reinfection or relapse), CDC and AAP recommend a single dose of IM penicillin G benzathine (50,000 units/kg).292,344

Although no treatment is required for neonates unlikely to have congenital syphilis (those with normal physical examination and serum nontreponemal serologic titer the same as or less than 4 times the mother's titer [at delivery] and the mother received adequate treatment before pregnancy and the mother had nontreponemal serologic titers that remained low and stable before and during pregnancy and at delivery), some experts would consider treating the neonate with a single dose of IM penicillin G benzathine (50,000 units/kg), especially if adequate follow-up of the neonate cannot be ensured and the neonate has a reactive nontreponemal test.344

There are no proven alternatives to penicillin G for the treatment of congenital syphilis, and infants who are allergic to penicillin or develop presumed penicillin allergy during treatment should be desensitized, if possible, and treated with the appropriate penicillin G regimen.292,344 Data are insufficient to date regarding use of other anti-infectives (e.g., ceftriaxone) for the treatment of congenital syphilis.292,344

Syphilis in Older Infants and Children

Infants and children 1 month of age or older diagnosed with syphilis should have CSF examinations to rule out neurosyphilis and birth and maternal medical records should be reviewed to determine whether the child has acquired or congenital syphilis.344 Such infants and children should be managed in consultation with a pediatric infectious disease specialist.344

Any infant older than 1 month of age with known or suspected congenital syphilis and children older than 2 years of age who have late and previously untreated congenital syphilis should be treated with IV penicillin G potassium or sodium (50,000 units/kg every 4-6 hours for 10 days);292,344 some experts suggest that these infants and children also receive a single dose of IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units]) after the penicillin G potassium or sodium regimen.292,344 If the infant or child has no clinical manifestations of congenital syphilis and evaluations (including CSF examinations) are normal, some experts state that treatment with IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units] once weekly for less than 3 weeks) can be considered.344

For the treatment of acquired syphilis in infants and children, CDC and AAP state that those with primary or secondary syphilis should receive a single dose of IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units]).292,344 AAP states that those with early latent syphilis should receive a single dose of IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units]), and those with late latent syphilis should receive IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units] once weekly for 3 successive weeks).292

There are no proven alternatives to penicillin G for the treatment of syphilis in infants and children, and those who have a history of penicillin allergy or develop presumed penicillin allergy during treatment should be desensitized and treated with the appropriate penicillin G regimen.292 Data are insufficient regarding use of other anti-infectives (e.g., ceftriaxone) for the treatment of syphilis in infants and children hypersensitive to penicillin.344

For additional information on the management of syphilis, current CDC sexually transmitted diseases treatment guidelines available at [Web] should be consulted.344

Yaws, Pinta, and Bejel

Penicillin G (IM penicillin G benzathine, IM penicillin G procaine) is used in the treatment of yaws ( T. pallidum subsp pertenue ), pinta ( T. carateum ), and bejel ( T. pallidum subsp endemicum ).7,10,61,676,678 A single dose of IM penicillin G benzathine has historically been the treatment of choice for these endemic treponematoses;10,61,676 however, a single dose of oral azithromycin has been recommended as the preferred regimen for the treatment of yaws in areas where the disease is endemic.675,677 The fixed combinations of penicillin G benzathine and penicillin G procaine should not be used for the treatment of yaws, pinta, or bejel.4,5

Staphylococcal Infections !!navigator!!

Although natural penicillins have been used in the treatment of upper and lower respiratory tract infections, skin and skin structure infections, bone and joint infections, septicemia, meningitis, endocarditis, or other infections caused by susceptible nonpenicillinase-producing S. aureus or S. epidermidis ,9,11,12,18,19,20,21,67,70,71,439,452 natural penicillins are inactivated by staphylococcal penicillinases and are ineffective for the treatment of infections caused by penicillinase-producing S. aureus and S. epidermidis .61,67,80,139,203 Because penicillin susceptibility cannot be assumed, in vitro susceptibility testing is indicated if use of a natural penicillin is being considered for the treatment of a staphylococcal infection.18,19,20,21

Streptococcal Infections !!navigator!!

S. agalactiae Infections

IV penicillin G potassium or sodium has been used for the treatment of infections caused by S. agalactiae † (group B streptococci; GBS), including bacteremia, pneumonia, endocarditis, and meningitis.61,64,292,418,450 If penicillin G potassium or sodium is used for the treatment of serious infections caused by S. agalactiae , concomitant use of an aminoglycoside usually is recommended.61,292,418,450

IV penicillin G potassium or sodium is used for intrapartum prophylaxis in pregnant women for prevention of perinatal GBS disease†.292,359 (See Prevention of Perinatal Group B Streptococcal Disease under Uses.)

S. pneumoniae Infections

Natural penicillins are used for the treatment of infections caused by susceptible S. pneumoniae , including upper and lower respiratory tract infections (e.g., pneumonia, empyema, otitis media, sinusitis), arthritis, pericarditis, endocarditis, septicemia, and meningitis.4,5,8,7,8,9,10,11,12,61,63,64,67,216,292,416,418,450,475 Although many strains of S. pneumoniae are susceptible to natural penicillins, strains that have intermediate resistance or are completely resistant to the drugs have been reported with increasing frequency and treatment failures have been reported.10,61,71,216,218,225,292 Because penicillin susceptibility cannot be assumed, in vitro susceptibility testing is indicated if use of a natural penicillin is being considered for the treatment of infections caused by S. pneumoniae .10,61,292 (See Meningitis and other CNS Infections under Uses.)

Oral penicillin V is used for prevention of S. pneumoniae infections† in children and adults at risk for invasive disease caused by the organism.55,56,57,59,61,292 (See Prevention of Invasive Pneumococcal Disease in Asplenic Individuals under Uses.)

Streptococcus pyogenes Infections

Natural penicillins are used for the treatment of infections caused by S. pyogenes (group A β-hemolytic streptococci; GAS) including upper and lower respiratory tract infections (e.g., pharyngitis, tonsillitis, otitis media, sinusitis), skin and skin structure infections (e.g., erysipelas, cellulitis, and pyoderma), and severe infections (e.g., bacteremia, septic or toxic scarlet fever, streptococcal toxic shock syndrome, streptococcal myositis, necrotizing fasciitis).2,3,8,9,11,12,18,19,20,21,292,375,450,580

Because S. pyogenes has remained uniformly susceptible to natural penicillins, they are considered drugs of choice for the treatment of a variety of S. pyogenes infections, including pharyngitis and tonsillitis (see Pharyngitis and Tonsillitis under Uses), streptococcal bacteremia, septic or toxic scarlet fever, streptococcal toxic shock syndrome, cellulitis, erysipelas, necrotizing fasciitis, and streptococcal myositis.292,375,580 However, efficacy for the treatment of some severe infections may be compromised because of various factors (e.g., inadequate dosage, delay in treatment, penicillin tolerance, overwhelming infection, irreversible effects of streptococcal pyrogenic exotoxins) and concomitant use of other anti-infectives has been recommended when a natural penicillin is used for the treatment of serious S. pyogenes infections.292 Because strains of β-hemolytic streptococci resistant to natural penicillins are extremely rare and strains of S. pyogenes resistant to penicillin G and penicillin V have not been reported, routine vitro susceptibility testing is not usually required when considering a natural penicillin for the treatment of such infections.10,61,114,292

IM penicillin G benzathine and oral penicillin V are used for secondary prophylaxis to prevent recurrence of rheumatic fever.2,3,18,19,20,21,292,375 (See Prevention of Rheumatic Fever Recurrence under Uses.)

Other Streptococcal Infections

Natural penicillins are used for the treatment of infections caused by other β-hemolytic streptococci, including groups C, F, G, H, K, L, and M streptococci.8,9,11,12,61,64,292,450 IV penicillin G potassium or sodium is labeled for use in the treatment of septicemia, empyema, pneumonia, pericarditis, endocarditis, or meningitis caused by susceptible groups C, H, G, L, and M streptococci,9,11,12

IM penicillin G benzathine is labeled for use in the treatment of mild to moderate upper respiratory tract infections caused by susceptible streptococci,2 IM fixed combinations of penicillin G benzathine and penicillin G procaine are labeled for use in the treatment of moderately severe to severe infections of the upper respiratory tract infection and skin and skin structure infections caused by susceptible streptococci,4,5 and oral penicillin V potassium is labeled for the treatment mild to moderate infections of the upper respiratory tract caused by susceptible streptococci.18,19,20,21

Whipple's Disease !!navigator!!

Penicillin G has been used in the treatment of Whipple's disease† caused by Tropheryma whipplei .10,197,716,717,719,720,724 The optimal anti-infective regimen for the treatment of Whipple's disease has not been identified, in part because of difficulties in identifying and cultivating the causative agent717,718,719,720 and because relapses may occur, even after adequate and long-term treatment.10,717,718,719,720,724 Some clinicians recommend an initial parenteral regimen (e.g., ceftriaxone, penicillin G with or without streptomycin) followed by a long-term regimen of oral co-trimoxazole.10,716,723

Prevention of Invasive Pneumococcal Disease in Asplenic Individuals !!navigator!!

Oral penicillin V is used for prevention of invasive pneumococcal infections in children with anatomic or functional asplenia† (e.g., congenital asplenia or polysplenia, splenectomy, sickle cell disease, thalassemia).55,56,57,59,61,292 Oral penicillin V also is used for prevention of invasive S. pneumoniae disease in certain asplenic adults†.55,57

Asplenic infants, children, adolescents, and adults are at increased risk of fulminant septicemia, most commonly caused by S. pneumoniae .55,59,292 In infants with sickle cell anemia, AAP recommends that penicillin V prophylaxis for prevention of invasive pneumococcal infections should be initiated as soon as the diagnosis is established (preferably by 2 months of age) and that discontinuance of prophylaxis can be considered at 5 years of age if the child is receiving regular medical attention, is fully immunized against pneumococcal disease, and has not had a severe pneumococcal infection or surgical splenectomy.292 In children with asplenia from causes other than sickle cell anemia, the appropriate duration of prophylaxis is unknown;292 some experts recommend that such children receive prophylaxis throughout childhood and into adulthood.292 In adults who have undergone splenectomy, some clinicians recommend that prophylaxis for prevention of invasive pneumococcal infections should be continued for at least 1-2 years after the procedure.55,57

Age-appropriate vaccination against pneumococcal disease is recommended in all asplenic individuals (see Pneumococcal Vaccine 80:12).55,199,200,292 Regardless of vaccination status, AAP states that anti-infective prophylaxis for prevention of invasive pneumococcal disease is recommended for young children with anatomic or functional asplenia.292

Prevention of Perinatal Group B Streptococcal Disease !!navigator!!

IV penicillin G potassium or sodium is used in pregnant women during labor (intrapartum) for prevention of early-onset neonatal group B streptococcal (GBS) disease†.292,359

GBS infection is the leading cause of neonatal infections in the US.359 Pregnant women who are colonized with GBS in the genital or rectal areas can transmit GBS infection to their infants during labor and delivery, resulting in an invasive neonatal infection that can be associated with substantial morbidity and mortality.292,359 GBS infection during pregnancy can cause asymptomatic bacteriuria, urinary tract infection, intra-amniotic infection, or endometritis in the woman and is associated with stillbirths and premature delivery.292,359 Neonatal GBS infections are characterized as early-onset GBS disease (usually occurring within the first 24 hours after birth through day 6) or late-onset GBS disease (occurring between 7-90 days of age).292,359 GBS disease in neonates usually presents as respiratory distress, apnea, shock, or pneumonia and may involve septicemia or meningitis; other manifestations such as osteomyelitis, septic arthritis, necrotizing fasciitis, adenitis, and cellulitis also can occur.292 Approximately 20% of survivors of neonatal GBS meningitis have moderate to severe neurodevelopmental impairment.292

Major risk factors for early-onset neonatal GBS disease include maternal GBS colonization in the genitourinary and GI tracts, early membrane rupture (18 hours or more before delivery), intra-amniotic infection, premature delivery (before 37 weeks' gestation), very low birth weight, intrapartum fever (38°C or higher), and previous delivery of an infant who had GBS disease.292,359 The most effective strategy for prevention of early-onset neonatal GBS disease is universal prenatal screening for GBS colonization (e.g., vaginal and rectal cultures) and use of intrapartum anti-infective prophylaxis (i.e., prophylaxis administered after onset of labor or membrane rupture but before delivery) in those with positive results.292,359 Following implementation of guidelines for targeted GBS intrapartum anti-infective prophylaxis in the US, the incidence of early-onset GBS disease was reduced by more than 80% (1.8 neonates with early-onset GBS disease per 1000 live births in the 1990s to 0.23 neonates per 1000 live births in 2015).359 Such prophylaxis has no measurable effect on the incidence of late-onset GBS disease.292,376,377

The American College of Obstetricians and Gynecologists (ACOG), AAP, and other experts recommend routine universal prenatal screening for GBS colonization (e.g., vaginal and rectal cultures) in all pregnant women at 36 through 37 weeks of gestation (i.e., performed within the time period of 36 weeks 0 days to 37 weeks 6 days of gestation), unless intrapartum anti-infective prophylaxis is already planned because the woman had known GBS bacteriuria during any trimester of the current pregnancy or has a history of a previous infant with GBS disease.292,359 Anti-infective prophylaxis for prevention of early-onset perinatal GBS is indicated in all women identified as having positive GBS cultures during the routine prenatal GBS screening during the current pregnancy, unless a cesarean delivery is performed before the onset of labor in the setting of intact membranes.292,359 Intrapartum anti-infective prophylaxis also is indicated in women with unknown GBS status at the time of onset of labor (cultures not performed or results unknown) who have risk factors for perinatal GBS infection (e.g., preterm birth at less than 37 weeks' gestation, duration of membrane rupture 18 hours or longer, intrapartum fever 38°C or higher).292,359 If a women presents in labor at term with unknown GBS status but has a history of GBS colonization during a previous pregnancy, these experts state that the risk for early-onset GBS disease in the infant is increased and it is reasonable to offer intrapartum anti-infective prophylaxis based on the history of GBS colonization.292,359

When intrapartum anti-infective prophylaxis is indicated in the mother for prevention of early-onset GBS disease in the neonate, ACOG, AAP, and other experts recommend IV penicillin G (loading dose of 5 million units followed by 2.5-3 million units every 4 hours until delivery) as the regimen of choice.292,359 IV ampicillin (loading dose of 2 g followed by 1 g every 4 hours until delivery) is the preferred alternative for such prophylaxis when penicillin G is not available.292,359 Penicillin G is considered the drug of choice since it has a narrower spectrum of activity than ampicillin and is less likely to induce resistance in other vaginal organisms.292,359

If intrapartum prophylaxis is indicated in a penicillin-allergic woman at low risk for anaphylaxis or severe non-IgE-mediated reactions if a penicillin is used (e.g., history of nonspecific symptoms unlikely to be allergic [GI distress, headaches, vaginal candidiasis]; non-urticarial maculopapular [morbilliform] rash without systemic symptoms; pruritus without rash; family history but no personal history of penicillin allergy; patient reports history of penicillin allergy but has no recollection of symptoms or treatment), ACOG, AAP, and others recommend IV cefazolin (loading dose of 2 g followed by 1 g every 8 hours until delivery).359 If intrapartum prophylaxis is indicated in a penicillin-allergic woman at high risk for anaphylaxis or severe non-IgE-mediated reactions if a penicillin is used (e.g., history suggestive of an IgE-mediated event such as pruritic rash, urticaria, immediate flushing, hypotension, angioedema, respiratory distress, or anaphylaxis; recurrent reactions to penicillin, reactions to multiple β-lactam anti-infectives, or positive penicillin allergy test; severe delayed-onset cutaneous or systemic reactions such as eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis), these experts recommend IV clindamycin (900 mg IV every 8 hours until delivery) if the GBS isolate is tested and found to be susceptible to the drug.359 If the GBS isolate is resistant to clindamycin, IV vancomycin (20 mg/kg [up to 2 g] every 8 hours until delivery) is the recommended alternative in such women.359

Routine use of anti-infective prophylaxis (e.g., penicillin G, ampicillin) in neonates born to women who received adequate GBS intrapartum prophylaxis is not recommended.292,359 Regardless of whether intrapartum GBS prophylaxis was administered to the mother, appropriate diagnostic evaluations and anti-infective treatment should be initiated in the neonate if signs or symptoms of active infection develop.292,359 Ampicillin in conjunction with an aminoglycoside is the initial regimen of choice for empiric treatment of presumptive neonatal sepsis, including presumptive GBS infection, since it is likely to be active against GBS and other possible causative agents (e.g., other streptococci, enterococci, L. monocytogenes , Escherichia coli ).292,376,377

For additional information regarding the prevention of neonatal early-onset GBS disease, the current ACOG guidelines available at [Web] should be consulted.359

Prevention of Rheumatic Fever Recurrence !!navigator!!

Natural penicillins (IM penicillin G benzathine, oral penicillin V potassium) are used for prevention of recurrent attacks of rheumatic fever (secondary prophylaxis) in individuals who have had a previous attack of rheumatic fever.2,3,18,19,20,21,292,375

Individuals who have had a previous attack of rheumatic fever are at high risk for a recurrent attack of rheumatic fever if they develop asymptomatic or symptomatic S. pyogenes pharyngitis.292,375 A recurrent attack can be associated with worsening severity of rheumatic heart disease that developed after the first attack or, less frequently, may be associated with new-onset rheumatic heart disease in those who did not develop cardiac manifestations during the first attack.375 Secondary anti-infective prophylaxis to prevent recurrent episodes of S. pyogenes pharyngitis is the most effective method to prevent development of severe rheumatic heart disease.292,375

AHA and AAP recommend secondary anti-infective prophylaxis of rheumatic fever in all patients who have a well-documented history of rheumatic fever (even if manifested solely by Sydenham's chorea) and in those with definite evidence of rheumatic heart disease (even after prosthetic valve replacement).292,375 Such prophylaxis should be initiated as soon as the diagnosis of rheumatic fever or rheumatic heart disease is made,292,375 although patients with acute rheumatic fever should first receive the usually recommended anti-infective treatment for S. pyogenes pharyngitis and tonsillitis (see Pharyngitis and Tonsillitis under Uses).375

In general, prevention of recurrent rheumatic fever requires long-term, continuous anti-infective prophylaxis.10,292,375 Some clinicians recommend that secondary prophylaxis be continued indefinitely; however, the risk of rheumatic fever recurrence depends on several factors.292,375 The risk increases with multiple previous attacks and decreases with increasing age and as the interval since the most recent attack increases.292,375 Patients who have had rheumatic carditis, with or without valvular disease, are at relatively high risk for recurrences of carditis and are likely to sustain increasingly severe cardiac involvement with each recurrence.375 Patients who have never developed rheumatic carditis are at lower risk of cardiac involvement if they have a recurrence of rheumatic fever.375 Therefore, decisions to discontinue secondary anti-infective prophylaxis for prevention of recurrent attacks of rheumatic fever must be weighed carefully, taking into account epidemiologic risk factors such as the patient's risk of exposure to streptococcal infections (e.g., those at high risk of exposure include children and adolescents, parents of young children, teachers, health-care personnel, military recruits, others living in crowded conditions, economically disadvantaged populations) and the consequences of recurrence.292,375 The clinician and patient should discuss the potential risks and benefits whenever discontinuance of such prophylaxis is being considered.375

AHA and AAP recommend that secondary anti-infective prophylaxis in patients who have had rheumatic fever without carditis should be continued for 5 years since the last episode of rheumatic fever or until 21 years of age, whichever is longer.292,375 In those who have had rheumatic fever with carditis but have no residual heart disease (no valvular disease), secondary prophylaxis should be continued for 10 years since the last episode or until 21 years of age, whichever is longer.292,375 In those who have had rheumatic fever with carditis and have residual heart disease (persistent valvular disease), AHA and AAP recommend that secondary prophylaxis should be continued for 10 years since the last episode or until 40 years of age, whichever is longer, but life-long prophylaxis may be indicated in some high-risk patients.292,375

IM penicillin G benzathine (given once every 3-4 weeks) is considered the drug of choice for secondary prophylaxis of recurrent rheumatic fever.37,38,292,325,924 A 4-week regimen is recommended by AHA and AAP for most patients in the US at risk of rheumatic fever recurrences, but a 3-week dosing interval may be warranted and is recommended when there is a particularly high risk of rheumatic fever (e.g., recurrent acute rheumatic fever despite adherence to a 4-week regimen).292,375 There is some evidence that serum penicillin concentrations may decline to subtherapeutic concentrations before the fourth week in some patients37,323,375 and there is limited evidence of an increased frequency of prophylactic failure with a 4-week interval compared with a 3-week interval in areas with a high risk of rheumatic fever.37,38,39

If patient compliance is not a problem, an oral regimen of penicillin V or sulfadiazine can be used as an alternative for secondary prophylaxis of rheumatic fever recurrence.292,375 However, because the risk of recurrence appears to be higher with oral prophylaxis than with IM penicillin G benzathine (even with optimal patient adherence), oral anti-infectives are most appropriate in patients at lower risk for rheumatic fever recurrence.375 Some clinicians use IM penicillin G benzathine initially and change to oral prophylaxis (usually with oral penicillin V) when the patient reaches late adolescence or young adulthood and has remained free of rheumatic attacks for at least 5 years.375 A regimen of oral sulfadiazine is recommended in patients with penicillin hypersensitivity; however, a macrolide (azithromycin, clarithromycin, erythromycin) should be used in patients allergic to penicillins and sulfonamides.292,375

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration !!navigator!!

Penicillin V potassium is administered orally.18,19,20,21 Although the manufacturers state that penicillin V potassium may be given with meals,18,19,20,21 maximum oral absorption is achieved when the drug is administered at least 1 hour before or 2 hours after meals.321,343 Oral penicillin V potassium should not be used for initial treatment of severe infections and should not be relied on in patients with nausea, vomiting, gastric dilatation, esophageal achalasia, or intestinal hypermotility.18,19,20,21

Penicillin G benzathine,2,3 penicillin G procaine,7 and fixed combinations containing penicillin G benzathine and penicillin G procaine4,5 are administered only by deep IM injection and should not be administered IV.2,4,5 Special precaution must be taken with these preparations to avoid inadvertent intravascular or intra-arterial administration or injection into or near major peripheral nerves or blood vessels since such injections may result in severe and/or permanent neurovascular damage.2,4,5,7 IM injections of these long-acting, depot, or repository forms of penicillin G should be made at a slow, steady rate to prevent blockage of the needle.2,4,5,7

Penicillin G potassium and penicillin G sodium are administered by IM injection, intermittent IV injection or infusion, or continuous IV infusion.8,9,11,12,61 Large IV doses of penicillin G potassium or sodium (more than 10 million penicillin G units) should be administered slowly because of the potential for serious electrolyte disturbances from the potassium and/or sodium content of these preparations.8,9,11,12

Dosage !!navigator!!

For specific information on dosage of the natural penicillins, see the individual monographs in 8::12.16.04.

Cautions ⬆ ⬇

[Section Outline]

Hypersensitivity Reactions !!navigator!!

Hypersensitivity reactions, including serious and occasionally fatal reactions, have been reported in patients receiving penicillins and may range in severity from mild rash to anaphylaxis.2,3,4,5,7,8,9,10,11,12,18,19,20,21,61,63,64,550,611,779 Although the most serious hypersensitivity reactions tend to occur following parenteral administration of penicillins, anaphylaxis has occurred following oral administration of the drugs.61,64,710,715

Manifestations of Penicillin Hypersensitivity

Hypersensitivity reactions to penicillins can be divided into 4 different types.61,63,64,550,561,570,779 Type I reactions are mediated by IgE and usually are immediate reactions (occurring within 1 hour or up to 6 hours after administration of the penicillin),61,64,550,561,570,611,615,779 but may be accelerated reactions (occurring 2-72 hours after administration of the drug);61,64,570,611,615,779 these reactions can be life-threatening and include anaphylaxis, angioedema, bronchospasm, laryngospasm, urticaria, and pruritus.61,64,70,550,555,561,570,615 Type II reactions are cytotoxic reactions that may be mediated by IgM or IgG antibodies and usually are delayed reactions occurring 5-72 hours or longer after administration of a penicillin;61,550,561,570,779 cytotoxic reactions include adverse hematologic effects such as hemolytic anemia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia.10,61,550,561,570 Type III reactions involve the formation of immune complexes consisting of the penicillin or derivatives and IgG or IgM antibodies and usually are delayed reactions occurring 24 hours or longer after administration of a penicillin;61,550,570,779 these reactions include serum sickness-like reactions, allergic vasculitis, and Arthus phenomenon.61,550,570,779 Type IV reactions are mediated by T cells and are delayed or late reactions that usually occur 48 hours or longer after administration of a penicillin;550,570,611 these reactions generally include dermatologic reactions ranging from less severe, benign skin reactions to severe cutaneous adverse reactions (SCAR).61,70,550,561,570

Dermatologic reactions are some of the most common hypersensitivity reactions to penicillins.64,341,812,828 Urticarial, erythematous, or morbilliform (maculopapular or exanthematic) rash and pruritus occur most frequently.10,61,64,70,550,611,812,828 However, severe dermatologic reactions, including erythema nodosum,611,615,812,828 erythema multiforme,64,611,615,812 fixed drug eruptions,61,615,812 Stevens-Johnson syndrome,10,61,63,550,615 exfoliative dermatitis,10,61,64,615 acute generalized exanthematous pustulosis,61,566 toxic epidermal necrolysis,61,550 or drug reactions with eosinophilia and systemic symptoms (DRESS)566 have been reported rarely. Contact dermatitis can occur as a result of occupational exposure in individuals involved in the manufacture of penicillins and in pharmacists, nurses, or other health-care personnel involved in preparing penicillins for administration.61,64,561,568 Rash has been reported more frequently with ampicillin and amoxicillin than with other currently available penicillins;61,614,812,827 however, most cases of rash reported with these aminopenicillins appear to be nonimmunologic.824

Serum sickness-like reactions has been reported to occur in about 2% of patients receiving penicillin G.61 The serum sickness-like reaction is characterized by fever, malaise, urticarial rash, arthralgia, myalgia, and lymphadenopathy;10,61,70,570,611,615,812 angioedema also occurs occasionally10,61 and erythema nodosum occurs rarely.61 The serum sickness-like reaction may occur within days to weeks (may be evident 6-10 days) after initiation of penicillin therapy.61,61 In most cases, the reaction is mild and resolves within a few days or weeks following discontinuance of the penicillin;61,64,615 however, the reaction can be severe.10,64

The most serious hypersensitivity reaction to penicillins is anaphylaxis.61,64,341 Anaphylaxis has been reported to occur in up to 0.05% of patients receiving penicillin G,61,611,615,715 and has been estimated to be fatal in up to 5-10% of reported cases.61,70,341,762 Although anaphylaxis has been reported most frequently with parenteral penicillin G,61,341,713 such reactions have been reported rarely after oral administration of penicillin G (no longer commercially available in the US) or oral penicillin V.61,703,710,713,715 Anaphylactic reactions to penicillins can occur within minutes (usually within the first 30 minutes) after administration61,611,615,713 and are manifested by nausea, vomiting, abdominal pain, pallor, tachycardia, generalized pruritus, angioneurotic edema (which may affect the larynx), severe dyspnea (caused by bronchospasms), cyanosis, diaphoresis, dizziness, rigors, loss of consciousness, and peripheral circulatory failure (caused by vasodilation and loss of plasma volume).61,64,713

Mechanisms of Penicillin Hypersensitivity

Sensitization to penicillins usually results from previous exposure to one of the drugs or its degradation products.61,64,341,611,615,779 However, immediate hypersensitivity reactions have been reported in some patients the first time they received a penicillin.61,64,70,611 In these cases, prior exposure to the drugs may have been the result of normal environmental sources of penicillium molds or penicillin,64,70,341,611 trace amounts present in milk or foods derived from penicillin-treated animals,61,70,341,611,779 prior penicillin allergy testing,779 or occupational exposures.779

Penicillin itself does not appear to be highly immunogenic since it does not readily combine with protein to produce an antigen;61,64,561,611,615,764,765,766,779 however, many penicillin metabolites or degradation products are haptens and can form antigenic complexes with proteins and polypeptides.10,61,64,96,561,611,615,764,765,766,779 These antigenic degradation products of penicillin include penicilloyl, penicilloic acid, and penicillin polymer conjugation products.10,72,95,576,577,615,764,765,766 In addition, high molecular weight protein impurities that also can act as haptens may be present in some penicillin preparations (especially less purified preparations previously available).61,62,72,95,96,577,611,763,766 Most penicillins, including penicillin G, become more allergenic after a period of time in solution.10,61,95,96,611,764,765,766 This occurs because antigenic degradation products and polymer conjugation products form during in vitro storage, especially when penicillin G solutions are exposed to high temperatures or are stored in high concentrations at room temperature.10,61,95,96,300,577,611,764,765 (See Stability under Chemistry and Stability.)

The antigenic determinants of penicillin hypersensitivity have been classified as major and minor determinants, depending on how frequently they are involved in hypersensitivity reactions to the drugs rather than on how severe the reactions are.10,61,611,615,779 The major determinant (which is responsible for the greatest number of penicillin hypersensitivity reactions) is the penicilloyl derivative that is formed when the β-lactam ring is opened as the result of metabolism or degradation and allows amide linkage to body proteins.10,61,561,611,615,779 The minor determinants include the intact penicillin molecule, penicilloic acid, and other penicillin degradation products.61,64,561,615,779 The major determinant elicits IgE antibodies which mediate type I immediate and accelerated reactions such as anaphylaxis and some maculopapular and erythematous hypersensitivity reactions.10,611,615 Minor determinants also can elicit IgE antibodies.10,611,615

Patients at Risk for Penicillin Hypersensitivity Reactions

Prior to initiation of penicillin therapy, the patient should be questioned in detail regarding a previous history of hypersensitivity reactions to penicillins, cephalosporins, or other drugs.2,3,4,5,7,8,9,11,12,18,19,20,21 There is clinical and laboratory evidence of partial cross-allergenicity among β-lactam antibiotics, including penicillins, cephalosporins, and cephamycins.61,550,555,561,566,567,569,611,615,769,779

Individuals with a history of immediate hypersensitivity reaction (e.g., anaphylaxis) to a penicillin are at increased risk for developing a severe reaction if they receive one of the drugs.10,61,64,611,615 It generally has been recommended that a patient who has had a hypersensitivity reaction to one penicillin should be considered hypersensitive to all currently available penicillins, unless specific allergy testing is performed.64,576,611,615,825 However, cross-allergenicity among the penicillins (e.g., between natural penicillins and aminopenicillins) is not absolute and some patients who have had a reaction to one penicillin have subsequently tolerated a different penicillin.64,555,566,611,615

The true incidence of cross-allergenicity between penicillins and other β-lactam antibiotics has not been definitely established.566,567,615,779 In several studies when a cephalosporin was administered to patients with a history of penicillin hypersensitivity, 4.4-10% of these patients also had hypersensitivity reactions to the cephalosporin.615 Cross-allergenicity is more likely with cephalosporins that share an R1 side chain with penicillins (e.g., cephalexin, cephalothin [no longer available in the US], cefadroxil) and less likely with second and third generation cephalosporins that do not share this side chain (e.g., cefazolin, cefuroxime, ceftazidime, ceftriaxone).61,550,555,567,569 Although some cephalosporins that do not share side chains with penicillins (e.g., cefazolin, ceftriaxone) have been administered safely to individuals with a history of penicillin allergy, specific allergy testing may be indicated if use of a cephalosporin is being considered in an individual with penicillin allergy and vice versa.567 The risk of cross-allergenicity between penicillins and carbapenems (e.g., imipenem) is low and the risk of cross-allergenicity between penicillins and monobactams (e.g., aztreonam) is even lower.555,561

Appropriate assessment of patients with a history of penicillin allergy is important to guide decisions regarding continued or future use of penicillins, especially when one of the drugs is indicated for the treatment or prevention of an infection when there are no adequate alternatives or when possible alternatives are associated with an increased risk of adverse effects or have a spectrum of activity broader than that required for treatment of the causative organism and would increase the risk of inducing bacterial resistance.10,61,550,551,552,555,559,563,565,566,570,571,572,573 It has been estimated that about 10% of US patients report having had an allergic reaction to a penicillin in the past.550,558,572 However, many of these patients may actually have had a nonimmune-mediated adverse reaction.10,61,550,555,558,561,565,572,779 In addition, although penicillin allergy persists in some individuals, possibly for life, it wanes over time in a high percentage of patients.10,61,550,552,561,565,572

Comprehensive initial screening that may include a review of medical records and/or a patient interview is important to identify details about reported prior allergic reactions to penicillins (e.g., specific drug involved, manifestations, time to onset and symptom resolution, other indicators of non-IgE- versus IgE-mediated reactions, treatment received to manage the reaction, documentation of the reaction in a medical record, time elapsed since the reported reaction, history of treatment with other anti-infectives, history of skin testing and other drug allergy testing) that could be used for risk stratification and to make informed decisions regarding the need for penicillin allergy testing.550,552,555,561,565,570,571,572 A variety of screening algorithms have been suggested that could be useful in certain situations to designate patients as being at high, moderate, or low risk for experiencing a severe reaction (e.g, anaphylaxis) or a reaction that is more severe than the initially reported reaction if they receive a penicillin and/or to identify those who should receive penicillin allergy testing.550,555,558,560,561,565,571,573 Specialized references should be consulted for more specific information regarding such algorithms.550,555,558,560,561,573

Penicillin Allergy Testing and Penicillin Desensitization

Administration of penicillins to patients with a history of IgE-mediated penicillin hypersensitivity reactions can result in severe, immediate reactions.344,779 However, many individuals with a reported history of penicillin allergy are likely to have had other types of adverse drug reactions that were not hypersensitivity reactions or their penicillin sensitivity has waned over time.344,550,565 Because a reported history of penicillin hypersensitivity may not accurately differentiate between allergic and non-allergic reactions to penicillins or accurately predict the risk of a future hypersensitivity reaction, diagnostic tests may be indicated.550,551,555,559,561,562,563,779 Use of appropriate screening and penicillin allergy testing to confirm or refute a history of penicillin allergy can optimize selection of anti-infectives in patients who may have been misdiagnosed or mislabeled as penicillin allergic and supports the goals of antimicrobial stewardship.550,551,552,555,559,560,562,564,565,572,573

For patients who report a history of penicillin allergy, appropriate sensitivity testing (e.g., skin testing, patch testing, drug provocation or challenge, in vitro immunoassays) may be indicated to confirm penicillin hypersensitivity and assess the risk of a subsequent hypersensitivity reaction if the individual receives a penicillin.344,550,551,555,559,560,562,563,566,573,611,615,762,769,779 For safety reasons, certain patients with a history of penicillin hypersensitivity who are considered high risk may not be appropriate candidates for penicillin allergy testing or specific types of allergy tests.550,561,563 Some experts recommend that penicillins be avoided in individuals with a history of severe hypersensitivity reactions to the drugs (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, acute interstitial nephritis, hemolytic anemia, drug reaction with eosinophilia and systemic symptoms [DRESS]) and state that such individuals are not candidates for allergy testing.344,550,561,563,572

The proportion of patients with a history of penicillin hypersensitivity who continue to produce IgE antipenicillin antibodies decreases as the time after the patient's last exposure to penicillin increases.61,344,769,555 Therefore, penicillin allergy tests may be negative in some patients with a history of hypersensitivity to penicillins, especially if the reported reaction occurred decades ago.611,769 In several studies when skin tests with benzylpenicilloyl polylysine were administered to patients with a history of hypersensitivity reactions to penicillins, 67-93% of these patients had positive reactions to benzylpenicilloyl polylysine when the tests were given within 1 year after the reaction, 50-60% had positive reactions to the skin tests when the tests were given 1-10 years after a reaction, and only 20-25% had positive reactions when the tests were given 10 years or more after the reaction.769 However, negative test results for penicillin allergy do not completely ensure that a hypersensitivity reaction to penicillin will not occur.61,611 Although skin tests may detect the presence of IgE antipenicillin antibodies directed against the skin test antigens and are useful to predict future occurrence of most type I IgE-mediated hypersensitivity reactions,344,611,615 additional testing (e.g., drug challenge) may be recommended in some individuals with negative skin test results to further assess the risk of an IgE-mediated hypersensitivity reaction.572

Desensitization to penicillins has been used and is recommended to enable a penicillin to be administered to certain patients who are hypersensitive to the drugs and have life-threatening infections for which other effective anti-infectives are not available (e.g., endocarditis, neurosyphilis, congenital syphilis).61,64,70,344,345,350,450,550,561,563,570,611,615,762,763,779,786 In general, desensitization is performed by administering increasing doses of a penicillin preparation at relatively short intervals and is based on the premise that small, incremental doses of the penicillin will allow gradual binding of penicillin to IgE antibodies which should result in a gradual, rather than massive, release of histamine and other mediators of hypersensitivity reactions and result in short-term suppression of antigen-specific mast-cell responses.64,70,615,762,561,570,615,763 However, desensitization can be hazardous since it may cause anaphylaxis and is rarely justified when other anti-infectives are available that can be used in patients who are hypersensitive to penicillins.61,70,561,611,615 If desensitization to a penicillin is deemed necessary, the procedure usually is performed in a hospital setting; the patient should be monitored continuously during the procedure and all necessary emergency equipment should be readily available to treat a hypersensitivity reaction should it occur.64,344,550,561,570,762,783 The results of desensitization procedures that allow administration of a penicillin are only temporary.61,561,570 It has been recommended that desensitization procedures need to be repeated if additional therapeutic doses of a penicillin are indicated and the time elapsed since the last dose is longer than 4 half-lives of the drug.61,570

Specialized references should be consulted for specific information on penicillin allergy evaluation and testing, including protocols for various test types and timing and interpretation of the tests, and for specific information on desensitization procedures.344,550,555,560,561,566,570,763,615

Hematologic Effects !!navigator!!

Adverse hematologic effects reported rarely in patients receiving penicillin G or penicillin V include transient neutropenia,8,9,11,12,61 leukopenia,2,3,4,5,10,18,19,20,21,61,629,631,676 and thrombocytopenia.2,3,4,5,7,18,19,20,21,61 These adverse hematologic effects occur most frequently when high doses of penicillin G are administered IV and generally are reversible following discontinuance of the drugs.10,61,629,631,676,787 Eosinophilia and hemolytic anemia also have been reported.61,70,615 Although most adverse hematologic effects reported in patients receiving a penicillin are considered to be hypersensitivity reactions, penicillin G appeared to have a direct toxic effect on granulocyte maturation in some reported cases.61,676 Pancytopenia, presumably resulting from impaired release of mature cells from the bone marrow, has been reported rarely with high doses of IV penicillin G.61,787

Positive direct antiglobulin (Coombs') test results have been reported in patients receiving high doses of penicillin G; this reaction usually results from the presence of antipenicillin antibodies which bind to penicillin-coated erythrocytes.61,70,615 A small percentage of patients with positive direct antiglobulin test results develop hemolytic anemia during or following penicillin therapy.64,615 Hemolytic anemia has been reported most frequently with large doses of IV penicillin G; however, this adverse effect has occurred with usual doses of penicillin G and has also been reported rarely with usual doses of oral penicillin V.61 Following discontinuance of penicillin therapy, hemoglobin concentrations and reticulocyte counts return to pretreatment values, but hemolysis may persist for weeks and the direct antiglobulin test may not revert to negative for 1-3 months or longer since penicillin-coated erythrocytes and specific antibodies remain in the circulation for this period of time.61,615

Coagulation disorders have been reported rarely with high doses of IV penicillin G (e.g., 6 million units or more in uremic patients or 24 million units or more in individuals with normal renal function).10,70,655,788 In some patients, the coagulation disorder was characterized by prolonged bleeding time, abnormal platelet aggregation, an increase in antithrombin III activity, and interference with conversion of fibrinogen to fibrin.788

GI Effects !!navigator!!

Some of the most frequent adverse reactions to oral penicillin V are GI effects, including nausea, vomiting, epigastric distress, and diarrhea.18,19,20,21 Black hairy tongue also has been reported.18,19,20,21

Clostridioides difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile ).2,4,5,7,8,9,11,12,18,19,20,21,302,303,304

C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported in patients receiving nearly all anti-infectives, including penicillin G and penicillin V, and may range in severity from mild diarrhea to fatal colitis.2,4,5,8,9,11,12,18,19,20,21,302,303,304C. difficile produces toxins A and B which contribute to development of CDAD;2,4,5,8,9,11,12,18,19,20,21,302,303,304 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.2,4,5,8,9,11,12,18,19,20,21 (See Clostridioides difficile-associated Diarrhea and Colitis under Cautions.)

Renal and Metabolic Effects !!navigator!!

Renal tubular damage and interstitial nephritis have been reported in patients receiving high doses of IV penicillin G.8,9,11,12 Manifestations may include fever, rash, eosinophilia, proteinuria, eosinophiluria, hematuria, and increased BUN concentrations, and usually resolve following discontinuance of penicillin G therapy.8,9,11,12

Because of their potassium and sodium content, penicillin G potassium and penicillin G sodium preparations can cause serious and potentially fatal electrolyte disturbances.8,9,11,12,61 High doses of penicillin G sodium may result in congestive heart failure.8

Nervous System and Neurovascular Effects !!navigator!!

Neurotoxic reactions, including hyperreflexia, myoclonic twitches, seizures, and coma, have been reported following administration of massive doses of IV penicillin G potassium or penicillin G sodium, especially in patients with impaired renal function.8,9,11,12

Repeated IM injection of penicillin G preparations into the anterolateral thigh has resulted in quadriceps femoris fibrosis and atrophy.2,4,5,7

Inadvertent intravascular administration of penicillin G benzathine and/or penicillin G procaine, including inadvertent direct intra-arterial injection or injection immediately adjacent to an artery, has resulted in severe neurovascular damage, especially in neonates and children.2,4,5,7 Transverse myelitis with permanent paralysis, gangrene requiring amputation of digits and more proximal portions of extremities, and necrosis and sloughing at and surrounding the injection site have occurred following inadvertent injection of penicillin G benzathine and/or penicillin G procaine, including in the buttock, thigh, and deltoid areas.2,4,5,7 Other serious complications of suspected intravascular administration of penicillin G benzathine and/or penicillin G procaine include immediate pallor, mottling, or cyanosis of the extremity both distal and proximal to the injection site, followed by bleb formation, or severe edema requiring anterior and/or posterior compartment fasciotomy in the lower extremity.2,4,5,7

Local Effects !!navigator!!

Pain, phlebitis, and thrombophlebitis have been reported following IV administration of penicillin G.8,9,11,12

Pain, inflammation, lump, abscess, necrosis, edema, hemorrhage, cellulitis, atrophy, ecchymosis, and skin ulcer have been reported at IM injection sites of penicillin G benzathine or fixed combinations of penicillin G benzathine and penicillin G procaine.2,4,5

Jarisch-Herxheimer Reaction !!navigator!!

A Jarisch-Herxheimer reaction may occur when penicillin G is used for the treatment of syphilis.7,8,9,11,12,61,344,611 The reaction reportedly occurs in 50% of patients treated for primary syphilis, 75% of those treated for secondary syphilis, and 30% of those treated for neurosyphilis.61 Jarisch-Herxheimer reactions may also occur when penicillin G is used to treat other spirochetal infections (e.g., yaws, leptospirosis†, Lyme disease†, relapsing fever†)7,8,9,11,12,61,292,332,611,677,743 or certain bacterial infections (anthrax, brucellosis, tularemia, rat-bite fever).61,677

Jarisch-Herxheimer reactions usually begin 1-2 hours after initiation of penicillin G therapy (within the first 24 hours after initiation for treatment of syphilis)8,9,11,12,61,344,677,743 and consist of headache,8,9,11,12,61 fever,8,9,11,12,61,611,677,743 chills,8,9,11,12,61,677,743 sweating,677 sore throat,61 myalgia,8,9,11,12,61 malaise,61 tachycardia,8,9,11,12 hyperventilation,8,9,11,12 and vasodilation with flushing and mild hypotension.8,9,11,12 The reaction has been presumed to be caused by the release of pyrogen and/or endotoxins from phagocytized organisms8,9,11,12,61,677 and may be mediated by cytokines.61

Although some clinicians have suggested that concomitant administration of corticosteroids may reduce the incidence and severity of the Jarisch-Herxheimer reaction, other clinicians state that the use of corticosteroids has a minimal effect and should be considered only in patients in whom there is a serious risk of increased local damage resulting from exacerbation of existing lesions (e.g., patients with syphilitic optic atrophy).61

Antipyretics can be used to manage symptoms of the Jarisch-Herxheimer reaction, but have not been proven to prevent the reaction.344

Precautions and Contraindications !!navigator!!

Penicillin G and penicillin V are contraindicated in patients with a history of previous hypersensitivity to any penicillin.2,3,4,5,7,8,9,11,12,18,19,20,21

Penicillin G procaine and the fixed combinations of penicillin G benzathine and penicillin G procaine also are contraindicated in patients with a history of hypersensitivity to procaine.4,5,7

The commercially available frozen premixed penicillin G potassium injection in dextrose may be contraindicated in patients with known allergy to corn or corn products.11

Precautions Related to Hypersensitivity

Prior to initiation of penicillin therapy, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.2,3,4,5,7,8,9,11,12,18,19,20,21 The manufacturers state that serious hypersensitivity reactions to penicillins are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.2,3,4,5,7,8,9,11,12 The manufacturers also state that penicillins should be used with caution in patients with a history of clinically important allergies or asthma.2,3,4,5,7,8,9,8,9,11,12,11,12,18,19,20,21

If a hypersensitivity reaction occurs, penicillin G or penicillin V should be discontinued and appropriate therapy initiated as indicated (e.g., epinephrine, corticosteroids, antihistamines, bronchodilators, maintenance of an adequate airway and oxygen).2,3,8,9,10,11,12,18,19,20,21,550,555,570

To enable informed decisions regarding continued or future use of penicillins in patients who have had a hypersensitivity reaction or report a history of penicillin allergy, appropriate screening and penicillin allergy testing may be indicated.10,61,550,551,552,555,559,563,565,566,570,571,572,573 (See Hypersensitivity Reactions under Cautions.)

Procaine Sensitivity

A small percentage of the population is hypersensitive to procaine, and the manufacturers recommend that patients with a history of procaine sensitivity should receive a test dose of procaine prior to administration of penicillin G procaine.4,5,7 (See Precautions and Contraindications under Cautions, in Penicillin G Procaine 8:12.16.04.)

Administration Precautions

Special precaution should be taken to avoid IV, intravascular, or intra-arterial administration or injection of penicillin G benzathine and/or penicillin G procaine into or near major peripheral nerves or blood vessels since such injections may produce severe and/or permanent neurovascular damage.2,4,5,7 Prompt consultation with an appropriate specialist is indicated if any evidence of compromise of the blood supply occurs at, proximal to, or distal to the site of injection.2,4,5,7 (See Nervous System and Neurovascular Effects under Cautions.)

Large IV doses of penicillin G potassium or sodium should be administered slowly because of the potential for serious electrolyte disturbances.8,9,11,12 (See Renal and Metabolic Effects under Cautions.)

Laboratory Monitoring

Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with penicillin G, particularly if high dosage is used.3,4,5,7,8,9,11,12 In addition, electrolyte balance and cardiovascular status should be evaluated periodically during prolonged therapy with high dosage of IV penicillin G potassium or sodium.8,9,11,12

Superinfection/C. difficile-associated Diarrhea and Colitis

As with other anti-infectives, prolonged use of penicillin G or penicillin V may result in overgrowth of nonsusceptible organisms, including fungi.2,18,19,20,21 If superinfection occurs, appropriate therapy should be instituted.2,8,9,11,12,18,19,20,21

Because CDAD has been reported with the use of nearly all anti-infectives, including natural penicillins, it should be considered in the differential diagnosis in patients who develop diarrhea during or after penicillin G or penicillin V therapy.2,4,5,8,9,11,12,18,19,20,21,302,303,304 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.2,4,5,8,9,11,12,18,19,20,21,302,303,304

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued as soon as possible.2,4,5,8,9,11,12,18,19,20,21,302,303,304 Patients should be managed with appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.2,4,5,8,9,11,12,18,19,20,21,302,303,304

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, it is important to contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.2,4,5,8,9,11,12,18,19,20,21,302,303,304

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of natural penicillins and other antibacterials, penicillin G and penicillin V should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.2,4,5,8,9,11,12,18,19,20,21 Prescribing penicillin G or penicillin V in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.2,4,5,8,9,11,12,18,19,20,21

Patients should be advised that antibacterials (including penicillin G and penicillin V) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).2,4,5,8,9,11,12 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with natural penicillins or other antibacterials in the future.2,4,5,8,9,11,12

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.2,4,5,8,9,11,12,18,19,20,21 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.2,4,5,8,9,11,12,18,19,20,21

Because penicillin susceptibility can no longer be assumed, staphylococcal and S. pneumoniae isolates should routinely be tested for in vitro susceptibility.7,8,9,10,11,12,61,64,114

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by FDA is available at [Web].113 For most antibacterial agents, including natural penicillins, FDA recognizes the standards published by the Clinical and Laboratory Standards Institute (CLSI).113 (See In Vitro Susceptibility Testing under Spectrum.)

Mutagenicity and Carcinogenicity !!navigator!!

Long-term animal studies have not been performed to evaluate the mutagenic or carcinogenic potential of penicillin G.2,3,4,5,7,8,9,11,12

Pregnancy and Lactation !!navigator!!

Pregnancy

Although available data regarding use of penicillin G or penicillin V in pregnant women, including first-trimester exposures, have not shown evidence of adverse effects on the fetus,2,3,4,5,7,8,9,11,12,25 there are no adequate or controlled studies using natural penicillins in pregnant women.2,3,4,5,7,8,9,11,12

Reproduction studies evaluating penicillin G in mice, rats, and rabbits have not revealed evidence of impaired fertility or harm to the fetus.2,3,4,5,7,8,9,11,12,25

The manufacturers state that penicillin G should be used during pregnancy only when clearly needed.2,3,4,5,7,8,9,11,12 Some clinicians state that penicillin G and penicillin V are considered low risk25 and safe for use during pregnancy.61

Penicillin G is included in CDC recommendations for the treatment of syphilis in pregnant women344 and penicillin G and penicillin V are included in CDC recommendations for the treatment or prophylaxis of anthrax in pregnant women.672 In addition, penicillin G is included in ACOG recommendations for intrapartum anti-infective prophylaxis in pregnant women for prevention of early-onset neonatal GBS disease.359

Fertility

Data are not available regarding the effect of penicillin G on fertility.2,3,4,5,7,8,9,11,12

Lactation

Penicillin G2,3,4,5,7,8,9,11,12,61,64,355,364,374 and penicillin V40,61,355,373 are distributed into human milk.

The manufacturers state that penicillin G should be used with caution in nursing women.2,3,4,5,7,8,9,11,12

Some clinicians state that penicillin G and penicillin V usually are considered compatible with breast-feeding;25,40,61 others state that the drugs should be used with caution in nursing women.24

Drug Interactions ⬆ ⬇

[Section Outline]

Although drug interactions reported with natural penicillins have generally involved penicillin G, the possibility that some of these interactions could occur with penicillin V should be considered. In addition, the possibility that drug interactions reported with other penicillins could also occur with natural penicillins should be considered.

Drug Eliminated by Renal Secretion !!navigator!!

Concomitant use of drugs that compete with penicillin G for renal tubular secretion (e.g., aspirin, indomethacin, phenylbutazone, probenecid, sulfonamides, thiazide diuretics, furosemide, ethacrynic acid) may prolong the serum half-life of penicillin G.8,9,11,12 (See Probenecid under Drug Interactions.)

Aminoglycosides !!navigator!!

The antibacterial activity of aminoglycosides and penicillins may be additive or synergistic in vitro against some organisms.212,219,282,288,297 Although the exact mechanism of this synergistic effect has not been determined, it appears that, by inhibiting bacterial cell wall synthesis, the penicillin allows more effective ingress of the aminoglycoside to the ribosomal binding site.282,288,782

In vitro and animal studies indicate that a synergistic bactericidal effect can occur against some strains of enterococci when penicillin G is used in conjunction with amikacin, gentamicin, streptomycin, or tobramycin.282,288 The synergistic effect between penicillin G and aminoglycosides is used to therapeutic advantage in the treatment of endocarditis or other severe infections caused by enterococci.64 In vitro synergism between penicillins and aminoglycosides against enterococci does not generally occur if the strain is resistant to the aminoglycoside.282,288 Strains of enterococci resistant to streptomycin have been reported with increasing frequency,288 but strains of the organism resistant to gentamicin have been reported less frequently.288 The combination of penicillin G and streptomycin has been synergistic in vitro against 20-60% of clinical isolates of enterococci,282 but the combination of penicillin G and gentamicin is reportedly synergistic in vitro against most clinical isolates of the organism.282,289

A synergistic bactericidal effect also generally occurs in vitro against viridans streptococci when penicillin G is used in conjunction with gentamicin or streptomycin and against group G streptococci when the drug is used in conjunction with gentamicin.212

Bacteriostatic Anti-infectives !!navigator!!

Bacteriostatic anti-infectives (chloramphenicol, erythromycin, sulfonamides, tetracyclines) have been reported to antagonize the bactericidal activity of penicillins in vitro,2,3,4,5,7,8,9,11,12,305,306 and some manufacturers recommend that such antibacterials should not be used concomitantly with penicillins.2,3,4,5,7,8,9,11,12 However, in vitro additive or synergistic effects between penicillins and bacteriostatic anti-infectives against some organisms have been demonstrated and in vivo antagonism has not been convincingly documented clinically.116,305,309

Methotrexate !!navigator!!

Concomitant use of methotrexate and penicillins may reduce the renal clearance of methotrexate, resulting in increased serum concentrations of methotrexate and increased hematologic and GI toxicity.778 Patients should be carefully monitored if methotrexate and penicillins are used concomitantly.778

Colestipol !!navigator!!

Concomitant administration of colestipol and oral penicillin G (no longer commercially available in the US) resulted in decreased serum concentrations of penicillin G.780 This may occur since colestipol is an anion-exchange resin and is capable of binding certain drugs and inhibiting their GI absorption.780 The manufacturer of colestipol recommends that other drugs be administered at least 1 hour before or 4 hours after colestipol.780

Probenecid !!navigator!!

Oral probenecid administered shortly before or simultaneously with a penicillin generally produces higher and prolonged serum concentrations of the penicillin.2,3,4,5,7,8,9,11,12,320,347 This effect occurs mainly because probenecid competitively inhibits renal tubular secretion of penicillins.8,9,11,12,347 Concomitant administration of oral probenecid also reportedly increases CSF concentrations of penicillin G61,64,320,324,345,351,354 by interfering with the active transport mechanism centered in the choroid plexus that transports drugs out of CSF.351

The effect of oral probenecid on the pharmacokinetics of IM penicillin G procaine is used to therapeutic advantage when penicillin G procaine is used for the treatment of neurosyphilis.344

Proton-pump Inhibitors !!navigator!!

Concomitant use of a proton-pump inhibitor and an oral penicillin may alter absorption of the penicillin because of increased gastric pH.61

Other Information ⬆ ⬇

[Section Outline]

Laboratory Test Interferences

Although published reports of laboratory test interferences with natural penicillins generally involve penicillin G, the possibility that interferences reported with penicillin G and other penicillins could also occur with penicillin V should be considered.

Tests for CSF, Serum, or Urinary Proteins !!navigator!!

Penicillins interfere with or cause false-positive results in a variety of test methods used to determine CSF, serum, or urinary proteins.729,752,756,774,798

Studies using penicillin G,752,755,798 oxacillin,755 or nafcillin630,755,757,760 indicate that penicillins cause false-positive and falsely elevated results in qualitative and quantitative turbidimetric methods for CSF, serum, or urinary, serum proteins that use sulfosalicylic acid729,752,756,757,798 or trichloroacetic acid.729,752

Penicillin G reportedly causes false-positive results in the Folin-Ciocalteau method for CSF protein.729,774

Penicillins interfere with the binding of albumin to dyes used to determine serum albumin concentrations.803 Penicillin G, in high concentrations, competitively competes with 4'-hydroxyazobenzene-2-carboxylic acid (HABA) dye for albumin-binding sites.784,802 Although this could theoretically cause falsely decreased serum albumin concentrations when HABA dye methods are used,802 serum concentrations of penicillin G attained with usual dosages of the drug probably will not interfere with this method.784

The binding of penicillin G to albumin in patients receiving high doses of IV penicillin G reportedly may result in a double peak for serum albumin on electrophoretic scans that could be misinterpreted as bisalbuminemia;729 however, this effect should not alter the results of quantitation of albumin by electrophoresis.802

Studies using penicillin G756 or nafcillin757 indicate that penicillins also interfere with tests for urinary protein that use the biuret reagent and can cause false-positive results or an atypical color reaction which cannot be interpreted.752,756 Studies using nafcillin757 or ampicillin781 indicate that penicillins can also cause slightly increased urinary protein concentrations when the Coomassie brilliant blue method is used.781 Penicillins do not appear to interfere with tests for urinary protein that use bromphenol-blue (Albustix®).630,756,760

Tests for Glucose !!navigator!!

Studies using penicillin G759,798 or ampicillin759 indicate that penicillins can interfere with urinary glucose determinations using cupric sulfate (e.g., Benedict's solution, Clinitest®).759,798 In high concentrations, penicillins can cause false-positive results in these tests for urinary glucose.8,9,11,12,759,798 Glucose oxidase tests for urinary glucose (Clinistix®, Tes-Tape®) are reportedly unaffected by the presence of penicillins.8,9,11,12,759

Tests for Uric Acid !!navigator!!

Studies using penicillin G and ampicillin indicate that penicillins can cause falsely increased serum uric acid concentrations when the copper-chelate method is used;729,800 however, phosphotungstate and uricase methods for serum uric acid appear to be unaffected by the drugs.800

Tests that Use Bacteria !!navigator!!

Results of the Guthrie test for phenylketonuria (PKU) are unreliable in neonates receiving a penicillin because the drugs are active against Bacillus subtilis , the organism used in the test.796 The addition of sodium hydroxide and hydrochloric acid to blood samples prior to the Guthrie test reportedly inactivates penicillins and permits interpretation of the test.796

Penicillins also are active against Lactobacillus casei , the organism used in microbiologic assays of folic acid; therefore, this method should not be used to determine serum folic acid concentrations in patients receiving a penicillin.729

Tests for Urinary Steroids !!navigator!!

Penicillin G acts as a ketogenic chromogen and has caused falsely increased concentrations of urinary 17-ketogenic steroids and 17-ketosteroids by interfering with the Norymberski method and the Zimmerman color reaction, respectively.801 The Glenn-Nelson technique for determining 17-hydroxycorticosteroids is reportedly unaffected by the presence of penicillin G.801

Immunohematology Tests !!navigator!!

Positive direct antiglobulin (Coombs') test results have bee reported in patients receiving large doses of penicillin G.615 This reaction usually results from the presence of antipenicillin antibodies which bind to penicillin-coated erythrocytes61,70,615 and may interfere with hematologic studies or transfusion cross-matching procedures.341

Other Laboratory Tests !!navigator!!

Penicillins may decrease urinary excretion of aminohippurate sodium (PAH)773 and phenolsulfonphthalein (PSP)795,774 by competing for renal tubular secretion with these diagnostic agents. Therefore, the PAH and PSP excretion tests should not be performed in patients receiving a penicillin.795

Penicillin G interferes with the Mauzerall and Granick method for determining urinary concentrations of δ-aminolevulinic acid (ALA) resulting in falsely increased concentrations of the compound.797 Because an increased urinary concentration of ALA generally indicates lead intoxication, the Mauzerall and Granick procedure should not be used to evaluate lead intoxication in patients who are receiving a penicillin unless a separation procedure is first used to remove ALA from the urine specimen.797

Mechanism of Action

Penicillins usually are bactericidal in action.61,63,64,109,217,382 Like most other β-lactam antibiotics, the antibacterial activity of the drugs results from inhibition of mucopeptide synthesis in the bacterial cell wall.61,63,64,89,106,217

Although the exact mechanism(s) of action of penicillins has not been fully elucidated, β-lactam antibiotics reversibly bind to several enzymes in the bacterial cytoplasmic membrane (e.g., carboxypeptidases, endopeptidases, transpeptidases) that are involved in cell-wall synthesis and cell division.61,63,107,108,109,112,115,148 It has been hypothesized that β-lactam antibiotics act as structural analogs of acyl-d-alanyl-d-alanine, the usual substrate for these enzymes.88,106 This interferes with cell-wall synthesis and results in the formation of defective cell walls and osmotically unstable variants of the organisms.61,64,88 Cell death following exposure to β-lactam antibiotics usually results from lysis, which is mediated by endogenous bacterial autolysins such as peptidoglycan hydrolases.61,64,88,106 Penicillins are most active against susceptible bacteria while they are in the logarithmic phase of growth;64 bacteria must generally be actively dividing to be affected by the drugs.62,64,88,146

The target enzymes of β-lactam antibiotics have been classified as penicillin-binding proteins (PBPs) and appear to vary substantially among bacterial species.88,106,107,108,111,112,115,147,148 Differences in the affinity of various β-lactam antibiotics for PBPs contribute to differences in morphology that occur in susceptible organisms following exposure to these antibiotics88,106,107,108,109,111,112,148 and may also explain some differences in spectra of activity of β-lactam antibiotics that do not result from the presence or absence of β-lactamase production in the organisms.106,108

Although the clinical importance is unclear, β-lactam antibiotics (including penicillins) vary in their rate of bactericidal action and in the completeness of this effect.61,88,109 This appears to result partly from differences in drug-induced morphologic effects on susceptible bacteria and subsequent formation of bacterial variants with varying degrees of osmotic stability.61,88,109 Most penicillins, including natural penicillins, cause the formation of spheroplasts which are unstable and usually lyse rapidly.88 Although amoxicillin and ampicillin have similar chemical structures and similar spectra of activity, amoxicillin appears to cause rapid formation of spheroplasts and lysis in susceptible bacteria whereas ampicillin produces abnormally elongated or filamentous forms which are more stable and lyse at a slower rate.61,88,109 It has been suggested that the differences in morphologic response to different penicillins may have clinical importance.109 Since the organisms would have less opportunity for renewed growth, penicillin derivatives that cause rapid spheroplast formation and lysis theoretically could be more effective compared with derivatives that cause delayed lysis; however, this has not been proven clinically.109

The antibacterial activity of penicillins depends partly on their ability to gain access and bind to the target enzymes.61,115,148 The cell walls of gram-positive bacteria are relatively permeable to most penicillins, especially natural penicillins; however, gram-negative bacteria have an outer membrane around the cell wall that decreases accessibility to the PBPs.61,62,117,148 Penicillins vary in their ability to penetrate the outer membrane of gram-negative bacteria.61,148 Natural penicillins are unable to penetrate the outer membranes of many gram-negative bacteria.61,148 The bulky side chains of penicillinase-resistant penicillins, which help to protect them from hydrolysis by staphylococcal penicillinases, also prevent these derivatives from penetrating the outer membrane of most gram-negative bacteria.61,88 Aminopenicillins and extended-spectrum penicillins can more readily penetrate the outer membranes of gram-negative bacteria,61,148 and it has been suggested that the greater ability of these derivatives to gain access to the PBPs may be related to the fact that they have polar groups on the side chain at R on the penicillin nucleus.61,148

Spectrum

Natural penicillins are active in vitro against many gram-positive and gram-negative aerobic cocci (except penicillinase-producing strains),61,71,88,205 some gram-positive aerobic and anaerobic bacilli,61,88,194 and many spirochetes.61,88,178 The drugs generally are inactive against gram-negative aerobic and anaerobic bacilli61,210 and also are inactive against mycobacteria, Mycoplasma , Rickettsia , fungi, and viruses.61

Penicillin G and penicillin V have similar spectra of activity; however, penicillin V is slightly less active than penicillin G in vitro on a weight basis against many susceptible organisms.61,71

In Vitro Susceptibility Testing !!navigator!!

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI), clinical isolates identified as susceptible are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection, resulting in likely clinical efficacy.114 Clinical isolates identified as intermediate have MICs or zone diameters that approach usually attainable blood and tissue concentrations and/or for which response rates may be lower than response rates for isolates identified as susceptible.114 The intermediate category also includes a buffer zone for inherent variability in test methods that should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.114 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant , the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs or zone diameters fall in the range where specific microbial resistance mechanisms are likely and clinical efficacy of the drug against the isolate has not been reliably demonstrated in clinical studies.114

Strains of staphylococci resistant to penicillinase-resistant penicillins also should be considered resistant to natural penicillins, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drugs.114

Strains of enterococci identified as susceptible to penicillin G by in vitro susceptibility tests may be susceptible only if high dosage is used for the treatment of serious enterococcal infections; concomitant use of an aminoglycoside usually is indicated for the treatment of serious infections (e.g., endocarditis) caused by penicillin-susceptible enterococci.114 Synergy between penicillin G and an aminoglycoside is best predicted for enterococci using a high-level aminoglycoside screening test.114

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test in vitro susceptibility to natural penicillins, a disk containing 10 penicillin G units should be used for most organisms (except S. pneumoniae ) and results can be applied to both penicillin G and penicillin V and, in some cases, results also can be applied to certain other penicillin classes.114

When the penicillin G disk is used to test susceptibility of staphylococci and the test is performed according to CSLI standardized procedures, results can be applied to natural penicillins, aminopenicillins, and extended-spectrum penicillins.114 Staphylococci with growth inhibition zones of 29 mm or greater are considered susceptible to natural penicillins, aminopenicillins, and extended-spectrum penicillins and those with zones of 28 mm or less are considered resistant to these penicillins.114

When the penicillin G disk is used to test susceptibility of enterococci to natural penicillins, enterococci with growth inhibition zones of 15 mm or greater are considered susceptible to natural penicillins and those with zones of 14 mm or less are considered resistant to the drugs.114

When the penicillin G disk is used to test susceptibility of β-hemolytic streptococci (streptococcal groups A [ S. pyogenes ], B [ S. agalactiae ], C, G), strains with growth inhibition zones of 24 mm or more are considered susceptible to natural penicillins and aminopenicillins.114

Because penicillin G-resistant strains of S. pneumoniae may not be detected in the disk-diffusion procedure if the penicillin G disk is used, a disk containing 1 mcg of oxacillin should be used to test susceptibility of S. pneumoniae to natural penicillins.114 When the oxacillin disk is used and the test is performed according to CLSI standardized procedures, S. pneumoniae (nonmeningeal isolates) with growth inhibition zones of 20 mm or greater are considered susceptible to natural penicillins and aminopenicillins.114 The disk-diffusion test does not distinguish between strains that have intermediate resistance (relatively resistant) and those that are highly resistant, and a dilution susceptibility test should be used to determine susceptibility of S. pneumoniae (nonmeningeal isolates) that have growth inhibition zones of 19 mm or less in the disk-diffusion test using the oxacillin disk.114 A dilution susceptibility test also should be used to test susceptibility of all S. pneumoniae isolates from patients with meningitis.114

When the penicillin G disk is used to test susceptibility of N. gonorrhoeae to natural penicillins, N. gonorrhoeae with growth inhibition zones of 47 mm or greater are considered susceptible to natural penicillins, those with zones of 27-46 mm are considered to have intermediate susceptibility, and those with zones of 26 mm or less are considered resistant to the drugs.114 N. gonorrhoeae with growth inhibition zones of 19 mm or less are likely to be penicillinase-producing strains (PPNG); the β-lactamase test should be used for rapid, accurate recognition of this form of resistance.114

Dilution Susceptibility Tests

When dilution susceptibility testing is performed according to CLSI standardized procedures to determine in vitro susceptibility of staphylococci to natural penicillins, those with a penicillin G MIC of 0.12 mcg/mL or less are considered susceptible and those with a penicillin G MIC of 0.25 mcg/mL or greater are considered resistant.114

When dilution susceptibility testing of S. pneumoniae (nonmeningeal isolates) is performed according to CLSI standardized procedures, those with an MIC of 2 mcg/mL or less are considered susceptible to natural penicillins, those with an MIC of 4 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 8 mcg/mL are considered resistant.114 When S. pneumoniae from patients with meningitis are tested, those with an MIC of 0.06 mcg/mL or less are considered susceptible to penicillin G and those with an MIC of 0.12 mcg/mL or greater are considered resistant.114

When dilution susceptibility testing of β-hemolytic streptococci (streptococcal groups A [ S. pyogenes ], B [ S. agalactiae ], C, G) is performed, those with a penicillin G MIC of 0.12 mcg/mL or less are considered susceptible to natural penicillins and aminopenicillins.114

Viridans group streptococci ( S. mutans , S. salivarius , S. bovis , S. anginosus , and S. mitis groups) with a penicillin G MIC of 0.12 mcg/mL or less are considered susceptible to natural penicillins, those with an MIC of 0.25-2 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 4 mcg/mL or greater are considered resistant.114 Those with intermediate susceptibility may require concomitant use of an aminoglycoside for effective bactericidal activity.114

When dilution susceptibility testing of enterococci is performed according to CLSI standardized procedures, those with a penicillin G MIC of 8 mcg/mL or less are considered susceptible to natural penicillins and those with a penicillin G MIC of 16 mcg/mL or greater are considered resistant.114

When testing susceptibility of N. gonorrhoeae using dilution susceptibility testing according to CLSI standardized procedures, those with a penicillin G MIC of 0.06 mcg/mL or less are considered susceptible to natural penicillins, those with an MIC of 0.12-1 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 2 mcg/mL or greater are considered resistant.114

N. meningitidis with a penicillin G MIC of 0.06 mcg/mL or less in dilution susceptibility testing are considered susceptible to penicillin G, those with an MIC of 0.12-0.25 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 0.5 mcg/mL are considered resistant.114

Gram-positive Aerobic Bacteria !!navigator!!

Natural penicillins are active in vitro against many gram-positive aerobic cocci including non-penicillinase-producing Staphylococcus aureus and S. epidermidis ;8,9,11,12,18,19,20,21,61,116,205 Streptococcus pneumoniae ;8,9,11,12,18,19,20,21,61,177,206,581 S. pyogenes (group A β-hemolytic streptococci; GAS);2,3,4,5,7,8,9,11,12,18,19,20,21,61 S. agalactiae (group B streptococci; GBS);61,174 other β-hemolytic streptococci (e.g., groups C, G, H, L, M, R);2,3,4,5,7,8,9,11,12,18,19,20,21,61,261 viridans streptococci;18,19,20,21,61,173 and nonenterococcal group D streptococci.61 Although some strains of enterococci are susceptible to penicillin G in vitro, many strains are resistant and penicillin tolerance has been reported.61,116,288 Penicillinase-producing strains of S. aureus and S. epidermidis are resistant to penicillin G and penicillin V.2,3,4,5,7,8,9,11,12,18,61

Natural penicillins also are active in vitro against some gram-positive aerobic bacilli, including Bacillus anthracis ,8,9,11,12,18,19,20,21,61 Corynebacterium diphtheriae ,8,9,11,12,18,19,20,21,61 Erysipelothrix rhusiopathiae ,61 and Listeria monocytogenes .8,9,11,12,18,19,20,21,61

Gram-negative Aerobic Bacteria !!navigator!!

Haemophilus

Natural penicillins are active in vitro against some strains of Haemophilus influenzae 61,71,205 and H. parainfluenzae .211 Although most strains of H. ducreyi are β-lactamase producers and are resistant to natural penicillins, some strains of the organism are inhibited in vitro by penicillin G concentrations of 4 mcg/mL.201

Neisseria

Natural penicillins usually are active in vitro against N. meningitidis .8,9,11,12,61 Strains of N. meningitidis resistant to natural penicillins appear to be rare in the US, and the organism generally is inhibited in vitro by penicillin G concentrations of 0.03 mcg/mL.61

Although natural penicillins may be active in vitro against strains of non-penicillinase-producing N. gonorrhoeae ,8,9,11,12,61,169,171 penicillinase-producing strains of N. gonorrhoeae (PPNG) are resistant.61,123,171,172,176,213

Other Gram-Negative Aerobic Bacteria

Natural penicillins are active against Bordetella pertussis 61,182 and Eikenella corrodens .61

Penicillin G has some activity in vitro against Legionella , although the drug may not be effective clinically.61,184,185,202 In vitro, some strains of L. pneumophila , L. gormanii , and L. dumoffii may be inhibited by penicillin G concentrations of 1-16 mcg/mL.184,185,202 Penicillin G concentrations of 0.04-1 mcg/mL inhibit some strains of L. micdadei (the Pittsburgh pneumonia agent) and L. bozemanii in vitro.184

Pasteurella multocida , an organism that can be aerobic or facultatively anaerobic, is usually inhibited in vitro by penicillin G61,183 concentrations of 0.2-0.8 mcg/mL or penicillin V concentrations of 0.4-16 mcg/mL.183 Natural penicillins also are active in vitro against Streptobacillus moniliformis 8,9,11,12,18,19,20,21,61,208 and Spirillum minus .8,9,11,12,61

Although some strains of Moraxella catarrhalis are inhibited in vitro by penicillin V, many strains of the organism are β-lactamase producers and are therefore resistant to penicillin G and penicillin V.214

Natural penicillins are inactive against Enterobacteriaceae61,71,88 and Pseudomonas .61,210,217

Anaerobic Bacteria !!navigator!!

Natural penicillins are active in vitro against many gram-positive anaerobic bacteria, including Actinomyces ,8,9,11,12,18,19,20,21,61 Arachnia ,61 Bifidobacterium ,61 Clostridium (including C. botulinum , C. perfringens , and C. tetani ),8,9,11,12,18,19,20,21,61,194 Cutibacterium acnes (formerly Propionibacterium acnes ),61,179 Eubacterium ,61 Lactobacillus ,61 Peptococcus ,61,194 and Peptostreptococcus .61

Gram-negative anaerobic bacteria vary in their susceptibility to natural penicillins.61,194 Penicillin G may be active in vitro against some strains of Fusobacterium 61,194,209 and Veillonella .61,194 Although penicillin G may be active in vitro against some strains of Bacteroides melaninogenica 61,194,215 or B. oralis ,61,194 the B. fragilis group (e.g., B. fragilis , B. distasonis , B. ovatus , B. thetaiotaomicron , B. vulgatus ) require high penicillin G concentrations for in vitro inhibition and usually are resistant.61,215

Spirochetes !!navigator!!

Penicillin G and penicillin V are active against spirochetes61,178 including Treponema pallidum subsp pallidum ,2,3,4,5,7,8,9,11,12,61 T. pallidum subsp pertenue ,61 T. carateum ,2 Borrelia burgdorferi ,61,220,221,224,711,712,783 B. hermsii ,61 B. recurrentis ,178 and Leptospira .8,9,11,12,18,19,20,21,61

Resistance

Mechanisms of Penicillin Resistance !!navigator!!

The major mechanisms of resistance to β-lactam antibiotics, including penicillins, are the production of β-lactamases and/or intrinsic resistance.61,63,64,89,142,145,148,161,204β-Lactamases can inactivate the drugs by hydrolyzing the β-lactam ring.61,63,64,89,142,145,148 Intrinsic resistance can result from the presence of a permeability barrier in the outer membrane of the organism or alterations in the properties of the target enzymes (PBPs).61,63,64,89,142,145,148,161,204

The production of β-lactamases is considered the principal cause of bacterial resistance to β-lactam antibiotics.89,141,142,144,148,161 However, the presence or absence of β-lactamases, especially in gram-negative bacteria, does not entirely dictate susceptibility or resistance to penicillins.144,145β-Lactamases produced by different bacterial species differ in physical, chemical, and functional properties.132,141,148,204 Staphylococcal β-lactamases are usually inducible, plasmid-mediated extracellular penicillinases.132,141,145,148,204 A variety of β-lactamases are produced by gram-negative bacteria and these are usually secreted in the periplasmic space between the inner and outer membranes of the organisms.132,145,148,204

Tolerance !!navigator!!

Tolerance to the bactericidal effects of penicillins has been reported in many strains of gram-positive cocci including S. aureus ,61,119,120,124,126,134,135,137,138,148,161,381 groups A,126 B,121,133,136 and G261 streptococci, S. pneumoniae ,120,146,147,148 E. faecalis (formerly S. faecalis ),148 S. milleri ,152 S. mutans ,152 and S. sanguis .152 Most susceptible bacteria have penicillin MBCs that are 1-4 times greater than the MICs of the drugs.120,124,133,134 However, bacteria that are tolerant to penicillins generally have an MBC of the drugs 16 or more times greater than the MIC,120,124,133,134 and these organisms may be inhibited but are either not killed or are killed at a slower rate than bacteria that are not tolerant.61,88,120,121,124,134,161 Tolerance appears to result from decreased autolytic activity in the tolerant organism which may be caused by defective enzymes or the presence of an unidentified inhibitor of autolysis.61,88,120,121,133,134,146

Infections caused by organisms tolerant to penicillins may persist during penicillin therapy although in vitro susceptibility tests indicate that the organisms are susceptible.61,119,120,121,133,134,135,138,580 The presence of penicillin-tolerant organisms in some serious infections where a rapid and complete bactericidal activity is important (e.g., endocarditis, bacteremia) or in infections in immunocompromised patients may result in a less favorable response to penicillin therapy in terms of mortality and length of positive cultures.135,136,138,152,161

Resistance in Gram-positive Bacteria !!navigator!!

Penicillinase-producing S. aureus and S. epidermidis are resistant to natural penicillins because these penicillins are readily inactivated by staphylococcal penicillinases.61,139 The appearance of penicillin G-resistant staphylococci in patients treated for infections caused by organisms that were initially susceptible to the drug usually results from selection of penicillinase-producing staphylococci that were present prior to therapy or, particularly in hospitalized patients, superinfection by penicillinase-producing strains.61

Strains of S. pneumoniae that are relatively resistant and strains that are completely resistant to penicillins have been reported with increasing frequency.61,147,158,177,581,204,206,218,223,225,226,229 Penicillin resistance in S. pneumoniae is intrinsic and appears to be caused by altered PBPs.126,146,147,148,204,227 Strains of S. pneumoniae completely resistant to penicillin G also are generally resistant to penicillin V, penicillinase-resistant penicillins, aminopenicillins, and cephalosporins.61,177,223,225,227,229 Some strains of S. pneumoniae resistant to penicillins may also be resistant to cephalosporins, tetracyclines, chloramphenicol, erythromycin, clindamycin, and co-trimoxazole,10,61,177,206,223,226,227 but may be susceptible to rifampin or vancomycin.10,206,226 There is considerable geographic variability in the susceptibility of S. pneumoniae , and the reported incidence of penicillin G-resistant S. pneumoniae may be high in some areas.223

Strains of α-hemolytic streptococci resistant to penicillin G have been isolated from the oral flora of patients who have received prolonged treatment with the drug.126 Resistance to penicillin G has been reported rarely in various streptococci in the viridans group.140,152,450,928

Although resistance to penicillin G has been induced in vitro in S. pyogenes (group A β-hemolytic streptococci; GAS), clinical isolates resistant to penicillin have not been documented to date.61,114,126,375

Resistance in Gram-negative Bacteria !!navigator!!

Strains of H. influenzae or other Haemophilus that produce β-lactamases are generally resistant to natural penicillins, aminopenicillins, and extended-spectrum penicillins.61,116,155,156,205

Penicillinase-producing strains of N. gonorrhoeae (PPNG) are completely resistant to natural penicillins123,171,172,176,222 and also usually resistant to aminopenicillins,61,172 but may be inhibited by spectinomycin.61,171

Many gram-negative aerobic bacilli are intrinsically resistant to natural penicillins because the drugs are unable to penetrate the outer membrane of these organisms.61,89,117,118,130,139,148 However, β-lactamase production is also involved in resistance of some gram-negative bacilli (e.g., E. coli , Ps. aeruginosa )61,117,118,130 and is the principal mechanism for penicillin resistance in many anaerobic bacteria (e.g., Bacteroides ).116,129,215 Although B. melaninogenicus was generally susceptible to penicillin G in the past, β-lactamase-producing strains of the organism that are resistant to the drug have been reported with increasing frequency.10,116

Pharmacokinetics

For more specific information on the pharmacokinetics of penicillin G and penicillin V, see Pharmacokinetics in the individual monographs in 8:12.16.04.

Absorption !!navigator!!

Oral Administration

Following oral administration, absorption of penicillins occurs mainly in the duodenum64,70,72,370 and upper jejunum,370 although a small amount of the drugs may be absorbed in the stomach64,370 and large intestine.370 The extent of absorption of oral penicillins is variable and depends on several factors, including the particular penicillin derivative,61,62,63,64,70,88,320 dosage form administered,62,88 gastric and intestinal pH,62,64,70,320 and presence of food in the GI tract.61,62,64,70,320,321,343

Because natural penicillins are hydrolyzed in the presence of acid, acidic gastric secretions may inactivate the drugs following oral administration.62,64,70,81,320 Penicillin G potassium is very susceptible to acid-catalyzed hydrolysis61,63,67,70,72,575 (only about 15-30% of an orally administered dose of the drug is absorbed in healthy, fasting adults)63,64,70,88,320 and an oral formulation of penicillin G is no longer commercially available in US. Penicillin V is more resistant to acid-catalyzed inactivation than penicillin G and, therefore, is better absorbed following oral administration.67,70,71,81 Approximately 60-73% of an oral dose of penicillin V (no longer commercially available in the US) or penicillin V potassium is absorbed from the GI tract in healthy, fasting adults.63,88,320

Following oral administration of a single dose of penicillin V61,67,70,71,420 or penicillin V potassium67,75,76,356,357,370,420 in fasting children or adults, peak serum concentrations of penicillin V generally are attained within 30-60 minutes and serum concentrations are low or undetectable 6 hours after the dose.67,75,76,356,357,370,420

Because natural penicillins are acid-labile, patients with achlorhydria or other individuals with decreased gastric acid production (e.g., neonates, adults 60 years of age or older) absorb orally administered penicillin V to a greater extent than do children older than 1 month of age or adults younger than 60 years of age.64 GI absorption of penicillins generally is reduced in patients with malabsorption syndromes.61

Variable results have been obtained in studies evaluating the effect of food on GI absorption of penicillin V and penicillin V potassium.61,70,320,321,343 In most studies, presence of food in the GI tract resulted in lower and delayed peak serum concentrations of penicillin V.18,19,20,21,61,70,343 If penicillin V is administered 1 hour before a meal, peak serum concentrations may be threefold higher and the total amount absorbed may be twofold higher compared with administration with food.61

Parenteral Administration

The rate of absorption of penicillin G after IM injection depends on many factors including dose, concentration, and solubility of the particular preparation administered.64

Penicillin G potassium and penicillin G sodium are rapidly absorbed following IM administration,9,61,64,70,72 and serum concentrations of penicillin G generally are the same following IM administration of equivalent doses of either salt.64 Following IM administration in adults of a single dose of penicillin G potassium or sodium, peak serum concentrations of penicillin G generally are attained within 15-30 minutes;61,64,70,72 serum concentrations of the drug decline rapidly and generally are low or undetectable 3-6 hours later.61,70

Because penicillin G benzathine and penicillin G procaine are relatively insoluble, IM administration of preparations containing these salts provides a tissue depot from which the drugs are slowly absorbed and hydrolyzed to penicillin G.2,3,4,5,7,10,61,63,64,70,81 IM administration of penicillin G benzathine results in serum concentrations of penicillin G that are more prolonged, but lower, than those attained with an equivalent IM dose of penicillin G procaine or penicillin G potassium or sodium.2,3,10,61,64,70,81 IM administration of penicillin G procaine results in serum concentrations of penicillin G that generally are more prolonged, but lower, than those attained with an equivalent IM dose of penicillin G potassium or sodium.61,64

Following IM administration of a single dose of penicillin G benzathine in adults,67,70,81 children,234 or neonates,353,365,371 peak serum concentrations of penicillin G are attained in 13-24 hours81,234,353,365,371 and usually are detectable for 1-4 weeks depending on the dose.70,81,234,353,365,371

Following IM administration of a single dose of penicillin G procaine in adults61,64,67 or neonates,352,368 peak serum concentrations of penicillin G generally are attained in 1-4 hours61,64,67,352 and the drug usually is detectable in serum for 1-2 days; however, penicillin G may be detectable in serum for up to 5 days (depending on the dose).61,64,67,70,352,368 In general, increasing the dose of penicillin G procaine to more than 600,000 units tends to prolong the duration of penicillin G serum concentrations rather than increase peak serum concentrations.63,70

Following IV infusion of penicillin G potassium or sodium, peak serum concentrations are attained immediately after completion of the infusion.8,9,11,12 In a study in 10 patients who received 5 million units of penicillin G given IV over 3-5 minutes, mean serum concentrations were 400, 273, and 3 mcg/mL at 5-6 minutes, 10 minutes, and 4 hours after administration, respectively.8,9,11,12 In a study in 5 healthy adults who received 1 million units of penicillin G given IV over 4 or 60 minutes, mean serum concentrations at 8 minutes after administration were 45 or 14.4 mcg/mL, respectively.8,9,11,12

Penicillin G potassium or sodium is absorbed from the peritoneal cavity following local instillation.61,64 Penicillin G also is absorbed from pleural surfaces, pericardium, and joint cavities.64

Distribution !!navigator!!

Penicillins are widely distributed following absorption from the GI tract or IM or IV administration sites.2,3,4,5,7,8,9,11,12,18,19,20,21,61,64,70,71,81,320 The volume of distribution of penicillin G is reportedly 0.53-0.67 L/kg in adults with normal renal function.340

Penicillin G and penicillin V are readily distributed into ascitic,9,61,339 synovial,8,9,11,12,61,64,320,323,326 pleural,8,9,11,12,61 pericardial,9,61 peritoneal,8,9,11,12 and interstitial fluids.9 Following oral, IM, or IV administration, concentrations of the drugs in ascitic fluid339 and synovial fluid323,326 may be equal to or greater than concurrent serum concentrations. Penicillin V is distributed into bile in low concentrations.61 Penicillin G concentrations in bile generally are greater than those attained in serum,63,64,72,320 unless biliary obstruction is present.320

Natural penicillins are distributed into body tissues in widely varying amounts.2,3,4,5,7,8,9,11,12,61,64,70,81,320 Highest concentrations generally are attained in the kidneys,2,3,4,5,7,18,19,20,21 with lower amounts in the liver,2,3,4,5,18,19,20,21,64 lungs,320 skin,2,3,4,5,18,19,20,21 intestines,2,3,4,5,18,19,20,21,64 and muscle.320 The drugs also are distributed into erythrocytes, and concentrations of penicillin G within erythrocytes may exceed concurrent serum concentrations of the drug.61 Low concentrations of penicillin G64,321,330 and penicillin V64,321,599 generally are distributed into tonsils,330 maxillary sinus secretions,61,599 and saliva.64,321 Only negligible amounts of natural penicillins may be attained in avascular areas,61,70 abscesses,61,70 aqueous humor,63 sweat,64 tears,64,321 or bone.61,72

Minimal concentrations of natural penicillins generally are attained in CSF following oral, IM, or IV administration of the drugs in patients with uninflamed meninges.7,8,9,11,12,18,19,20,21,61,70,320,324,349,353,354,360 In addition to being passively transported back into the venous system via the arachnoid villi, penicillins appear to be cleared from CSF by an active transport mechanism61,64,70,320 centered in the choroid plexus which transports the drugs and other organic acids out of CSF.61,320 Slightly higher penicillin concentrations are attained in CSF in patients with inflamed meninges because of increased vascular permeability and partial inhibition of the organic acid transport mechanism.61,320,325,349 Concurrent administration of oral probenecid with IM or IV administration of penicillin G salts also results in increased CSF concentrations of penicillin G.61,64,70,81,320,324,325,345,351,354 (See Probenecid under Drug Interactions.) Following IM administration of penicillin G procaine or IV administration of penicillin G sodium, concentrations of penicillin G in CSF reportedly range from 0-10% of concurrent serum concentrations of the drug in patients with normal meninges.325,349,352,354,360,688 The minimum treponemicidal concentration of penicillin G is generally defined as 0.03 penicillin G units/mL or 0.02 mcg/mL.325,354 In 2 adults with syphilis who received a daily IV dosage of 5 or 10 million units of penicillin G (as the potassium salt) for at least 10 days, penicillin G concentrations in CSF immediately following completion of therapy were 0.3 or 2.4 mcg/mL, respectively.360 In one study in children 2 weeks to 11 years of age with meningitis who received penicillin G potassium in a dosage of 250,000 units/kg daily given in 6 divided doses by IV infusion over 15 minutes, penicillin G concentrations in CSF specimens obtained between doses averaged 0.8, 0.7, and 0.3 mcg/mL on the first, fifth, and tenth days of therapy, respectively.349 IM administration of penicillin G procaine generally results in higher penicillin G concentrations in CSF than IM administration of penicillin G benzathine.324,360 In one study in adults who received IM penicillin G benzathine given in a dosage of 3.6 million units once weekly for up to 4 weeks, penicillin G was undetectable in CSF of 12/13 patients in CSF specimens obtained following administration of the last dose.360 In a study in neonates who received a single IM dose of penicillin G benzathine of 100,000 units/kg, peak CSF penicillin G concentrations occurred 12-24 hours after the dose and ranged from 0.012-0.2 mcg/mL; however, CSF penicillin G concentrations were less than 0.01 mcg/mL 48 hours after the dose.353

The degree of protein binding varies considerably among penicillins81 and is enhanced by hydrophilic side chains at R on the penicillin nucleus and decreased by hydrophilic substitutions on the penicillin nucleus.62 Penicillin V is more highly protein bound than penicillin G.63,64,67,320 Penicillin G is approximately 45-68%2,3,4,5,7,61,63,64,67,70,81,320,336,337,340,361 and penicillin V is approximately 75-89%18,19,20,21,61,63,68,116,320,336,337,420 bound to serum protein. Protein binding of the drugs is lower in neonates than in adults; penicillin G is reportedly 49% bound to serum proteins in neonates.81 Penicillins also are less protein bound in patients with hyperbilirubinemia or azotemia since the drugs are displaced from protein binding sites by bilirubin and other endogenous compounds.81

Penicillin G8,9,11,12,40,61,70,320,359 and penicillin V40,61,70 cross the placenta.

Penicillin G2,3,4,5,7,8,9,11,12,61,64,355,364,374 and penicillin V40,61,355,373 are distributed into milk.

Elimination !!navigator!!

In adults with normal renal function, the serum half-life of penicillin G is reportedly 0.4-0.9 hours8,9,11,12,61,64,67,81,320,338,340,348,361,367 and the serum half-life of penicillin V is reportedly 0.5 hours.81 Serum concentrations of natural penicillins may be higher and half-lives prolonged in patients with impaired renal function.8,9,11,12,64,70,81,320,348,367,369

Both penicillin G and penicillin V are metabolized to some extent by hydrolysis of the β-lactam ring to penicilloic acids which are microbiologically inactive.88,320,366,370,420 Although it has been suggested that, following oral administration, this hydrolysis occurs partly in the GI tract prior to absorption,370 the drugs appear to undergo metabolism mainly in the liver.366 Approximately 16-30% of an IM dose of penicillin G sodium366 and 35-70% of an oral dose of penicillin V or penicillin V potassium88,320,366,370,420 is metabolized to penicilloic acid. Small amounts of 6-aminopenicillanic acid (6-APA), formed by removal of the side chain at R on the penicillin nucleus, have also been identified in urine of patients receiving penicillin G64,70,366 or penicillin V.366 In addition, the drugs appear to be hydroxylated to a small extent to one or more microbiologically active metabolites which also are eliminated in urine.61,370,420

Natural penicillins and their metabolites are rapidly excreted in urine mainly by tubular secretion.2,3,4,5,7,8,9,11,12,61,64,70,71,81,88,320,348,369,370 Small amounts of the drugs also are excreted in feces370 and bile.8,9,11,12,61,64,70,81 In adults with normal renal function, 58-85% of a single IM or IV dose of penicillin G potassium or sodium is excreted in urine as unchanged drug and active metabolites within 6 hours;8,9,11,12,61,64,70,71,88 approximately 10% of this amount is excreted by glomerular filtration and the remaining 90% is excreted by active tubular secretion.61,64 Following oral administration of a single dose of penicillin V or penicillin V potassium in adults with normal renal function, 20-65% of the dose is excreted in urine as unchanged drug and metabolites within 6-8 hours;70,81,88,370,420 approximately 32% of the dose is excreted in feces.370 Approximately 20% of an oral dose of penicillin G potassium is excreted in urine in patients with normal renal function.

Following IM administration of penicillin G benzathine or penicillin G procaine, the drugs are slowly absorbed and hydrolyzed to penicillin G and elimination of penicillin G in urine continues over a prolonged period of time.64,234 Penicillin G has been detected in urine for up to 12 weeks after a single IM dose of penicillin G benzathine of 1.2 million units.64

Renal clearance of penicillins is delayed in neonates and premature or young infants because of an immature mechanism for tubular secretion.2,3,4,5,7,8,9,10,11,12,18,19,20,21,61,64,368 The serum half-life of penicillin G in neonates varies inversely with age8,9,11,12,61 and appears to be independent of birthweight.368 As tubular function matures, penicillins are cleared more rapidly and children older than 3 months of age generally excrete the drugs similarly to adults.64,70,321,330

Renal clearance of penicillins may be delayed in geriatric patients because of diminished tubular secretion ability.61

Renal clearance of penicillin G and penicillin V may be increased in pregnant women40,61 during the second and third trimesters.40

Concurrent administration of oral probenecid competitively inhibits renal tubular secretion of natural penicillins resulting in higher and more prolonged serum concentrations of the drugs.2,3,4,5,7,61,64,70,71,81,320,347,348,354 (See Probenecid under Drug Interactions.)

Penicillin G is removed by hemodialysis8,9,10,11,12,61,63,320,369 and may be removed to a lesser extent by peritoneal dialysis.10

Chemistry and Stability

Chemistry !!navigator!!

Natural penicillins are produced by fermentation of mutant strains of Penicillium chrysogenum .61,64,68,70,89 Natural penicillins with different side chains at R on the penicillin nucleus are produced by altering the culture media of Penicillium .61,64,68,70,89 (For information on the penicillin nucleus, see the Preface to the Penicillins 8:12.16.) Although various natural penicillins have been produced (e.g., penicillins F, G, N, O, V, X), only penicillin G and penicillin V are used clinically.64,68,70,89,575 Penicillin G and penicillin V are produced by adding phenylacetic acid or phenoxyacetic acid, respectively, to the culture media.61,64,68,70,89 The phenoxymethyl group on penicillin V imparts more acid stability and slightly less potent antibacterial activity compared with the phenyl group on penicillin G.89

Penicillin G is commercially available as benzathine,2,3,4,5 procaine,4,5,7 potassium,9,11,12 and sodium8 salts; penicillin V is commercially available as the potassium salt.18,19,20,21 Penicillin G potassium or sodium and penicillin V potassium frequently are referred to as aqueous, crystalline forms of the drugs and penicillin G benzathine and penicillin G procaine frequently are referred to as long-acting, depot, or repository forms of penicillin G.61 The potassium and sodium salts of the drugs generally are very soluble in water; however, the benzathine and procaine salts of penicillin G are only slightly or very slightly soluble in water.1

Potency of penicillin G and its salts usually is expressed in terms of penicillin G units,1,2,3,4,5,7,8,9,10,11,12,292,344,375,580 but also has been expressed as mg of penicillin G.61,680 Although potency of penicillin V potassium usually is expressed in terms of mg of penicillin V, it may be expressed in terms of penicillin V units.1,18,19,20,21

Stability !!navigator!!

Penicillins generally are inactivated in the presence of heat, alkaline or acid pH, oxidizing agents, alcohols, glycols, and metal ions such as copper, mercury, or zinc.1,62,575 In currently available penicillins, cleavage at any point in the penicillin nucleus, including the β-lactam ring, results in complete loss of antibacterial activity.62 The major cause of inactivation of penicillins is hydrolysis of the β-lactam ring.62,575 The course of hydrolysis and nature of the degradation products can vary and are generally influenced by pH.62,575

Penicillin G potassium and penicillin G sodium are moderately hygroscopic and dry powders of the drugs should be protected from moisture to prevent hydrolysis.1,575 In the dry state, natural penicillins and their salts are generally stable for several years at room temperature;62,575 however, the drugs deteriorate more rapidly at higher temperatures.62

In solution, penicillins are stable for short periods of time and their stability is temperature and pH dependent.62,94,300 At 25°C, penicillin G potassium and penicillin G sodium are stable in the pH range of 6.5-7.5 (maximum stability at pH 6.8).300 Commercially available penicillin G potassium or sodium powders for injection contain a sodium citrate and citric acid buffer.300 At 37°C, penicillin G potassium and penicillin G sodium are unstable in acid and reportedly have a half-life of about 5 minutes in vitro in solutions with a pH of approximately 2.104 These penicillin G salts may be rapidly inactivated in vivo by acidic gastric secretions following oral administration.61,575 Penicillin G benzathine is more stable than other penicillin G salts at the pH of gastric acid secretions.575 The phenoxymethyl group on penicillin V stabilizes it against acid-catalyzed hydrolysis,575 and penicillin V reportedly has a half-life of 5 hours in vitro in solutions with a pH of 1.81 Penicillin V is more resistant than penicillin G to inactivation by acidic gastric secretions following oral administration.67,70

Another major cause of in vivo inactivation of penicillins is hydrolysis by bacterial enzymes including β-lactamases and acylases.62,89,132β-Lactamases hydrolyze the amide bond of the β-lactam ring of penicillins to produce penicilloic acid which is inactive;62,89,132 penicilloic acid is also formed in vitro in penicillin solutions.62,95,96,575 Natural penicillins are susceptible to the action of many β-lactamases and this is a major mechanism of bacterial resistance to the drugs.89,132 (See Mechanisms of Penicillin Resistance under Resistance.) Acylases, produced by many gram-negative bacteria, can also inactivate penicillins by hydrolyzing the acylamino side chains of the drugs.62,132 Although acylases appear to be of minor importance in terms of bacterial resistance,89 these enzymes are used commercially to produce semisynthetic penicillin derivatives.89,132

Commercially available penicillin G or penicillin V preparations may contain small amounts of high molecular weight protein impurities that originate from the fermentation process used to produce the drugs.62 In addition, small amounts of polymer conjugation products can form in aqueous penicillin solutions during in vitro storage, especially when high penicillin concentrations are stored at room temperature.95,96,300,577 When stored at room temperature, in vitro studies indicate that penicillin degradation products may form within a few hours in penicillin G solutions with a concentration of 10 million units/L in sterile water, 0.9% sodium chloride, or glucose.96 The high molecular weight impurities and degradation products of penicillins (e.g., penicillenic acid, penicilloic acid, penicilloyl) are potential antigens when combined with protein and appear to play a role in allergic sensitization to penicillins.62,95,96,575,577 Therefore, although potency of the drugs may not be adversely affected, penicillin solutions for parenteral use generally should be refrigerated or used shortly following preparation.95,96 .

Penicillins are potentially physically and/or chemically incompatible with some drug, but the compatibility depends on the specific drug and several other factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature).300 Specialized references should be consulted for specific compatibility information.300

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions August 16, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

1. The United States pharmacopeia, 41st rev, and The national formulary, 35th ed. From USP website. Accessed 2018 March 27. [Web]

2. Pfizer. Bicillin® L-A (penicillin G benzathine) injectable suspension prescribing information. New York, NJ; 2016 Jun.

3. Pfizer. Permapen® isoject® (penicillin G benzathine) injectable suspension 1,200,000 units for intramuscular use only prescribing information. New York, NY; undated.

4. Pfizer. Bicillin® C-R 900/300 (penicillin G benzathine and penicillin G procaine) injectable suspension for deep IM injection only prescribing information. New York, NY; 2016 Jun.

5. Pfizer. Bicillin® C-R (penicillin G benzathine and penicillin G procaine) injectable suspension disposable syringe for deep IM injection only prescribing information. New York, NY; 2016 Jun.

7. Pfizer. Penicillin G procaine injectable suspension for deep IM injection only prescribing information. New York, NY; 2016 Oct.

8. Sandoz. Penicillin G sodium for injection, USP 5 million units prescribing information. Princeton, NJ; 2014 May.

9. Pfizer. Pfizerpen (penicillin G potassium) for injection prescribing information. Princeton, NJ; 2016 Dec.

10. Bennett JE, Dolin R, Blaser MK, eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 8th ed. Elsevier Saunders; Philadelphia, PA; 2015.

11. Baxter Healthcare Corporation. Penicillin G potassium injection, USP for intravenous use only prescribing information. Deerfield, IL; 2017 Nov.

12. WG Critical Care. Penicillin G potassium for injection, USP prescribing information. Paramus, NJ; 2013 Feb.

17. Charles L. Pamplin. Dear healthcare professional letter regarding administration and use of penicillin G benzathine and penicillin G procaine. Bristol, TN: King Pharmaceuticals, Inc; 2004.

18. Teva Pharmaceuticals USA, Inc. Penicillin V potassium tablets, USP and penicillin V potassium for oral solution, USP prescribing information. North Wales, PA; 2014 Nov.

19. Par Pharmaceutical. Penicillin V potassium tablets, USP and penicillin V potassium for oral solution, USP prescribing information. Fort Lee, NJ; 2014 Mar.

20. Sandoz Inc. Penicillin-VK® (penicillin V potassium) tablets, USP prescribing information. Princeton, NJ; 2014 Apr.

21. Aurobindo Pharma Limited. Penicillin V potassium tablets, USP prescribing information. Dayton, NJ; 2017 Aug.

24. Tschudy MM, Arcara KM, eds. The Harriet Lane handbook: a manual for pediatric house officers. 19th ed. Philadelphia, PA: Elsevier Mosby; 2012:902-5.

25. Penicillin G and penicillin V. In: Briggs GG, Freeman RK, Towers CV et al. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 11th ed. Philadelphia, PA: Wolters Kluwer Health; 2017:1130-32.

27. Valour F, Sénéchal A, Dupieux C et al. Actinomycosis: etiology, clinical features, diagnosis, treatment, and management. Infect Drug Resist . 2014; 7:183-97. [PubMed 25045274]

28. Sudhakar SS, Ross JJ. Short-term treatment of actinomycosis: two cases and a review. Clin Infect Dis . 2004; 38:444-7. [PubMed 14727221]

29. Reichenbach J, Lopatin U, Mahlaoui N et al. Actinomyces in chronic granulomatous disease: an emerging and unanticipated pathogen. Clin Infect Dis . 2009; 49:1703-10. [PubMed 19874205]

30. Elliott SP. Rat bite fever and Streptobacillus moniliformis. Clin Microbiol Rev . 2007; 20:13-22. [PubMed 17223620]

31. Centers for Disease Control and Prevention (CDC). Fatal rat-bite fever--Florida and Washington, 2003. MMWR Morb Mortal Wkly Rep . 2005; 53:1198-202. [PubMed 15635289]

32. Smego RA, Foglia G. Actinomycosis. Clin Infect Dis . 1998; 26:1255-63. [PubMed 9636842]

33. Madhubashini M, George S, Chandrasekaran S. Streptobacillus moniliformis endocarditis: case report and review of literature. Indian Heart J . 2013 Jul-Aug; 65:442-6. [PubMed 23993005]

37. Ayoub EM. Prophylaxis in patients with rheumatic fever: every three or every four weeks? J Pediatr . 1989; 115:89-91. Editorial.

38. Lue HC, Wu MH, Hsieh KH et al. Rheumatic fever recurrences: controlled study of 3-week versus 4-week benzathine penicillin prevention programs. J Pediatr . 1986; 108:299-304. [PubMed 3511209]

39. Padmavati S, Gupta V, Prakash K et al. Penicillin for rheumatic fever prophylaxis 3-weekly or 4-weekly schedule?. J Assoc Physicians India . 1987; 35:753-5. [PubMed 3449509]

40. Nahum GG, Uhl K, Kennedy DL. Antibiotic use in pregnancy and lactation: what is and is not known about teratogenic and toxic risks. Obstet Gynecol . 2006; 107:1120-38. [PubMed 16648419]

55. Bonanni P, Grazzini M, Niccolai G et al. Recommended vaccinations for asplenic and hyposplenic adult patients. Hum Vaccin Immunother . 2017; 13:359-368. [PubMed 27929751]

56. Rankine-Mullings AE, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev . 2017; 10:CD003427. [PubMed 28994899]

57. Rubin LG, Schaffner W. Clinical practice. Care of the asplenic patient. N Engl J Med . 2014; 371:349-56. [PubMed 25054718]

58. Waldman JD, Rosenthal A, Smith AL et al. Sepsis and congenital asplenia. J Pediatr . 1977; 90:555-9. [PubMed 320299]

59. Gaston MH, Verter JI, Woods G et al. Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trial. N Engl J Med . 1986; 314:1593-9. [PubMed 3086721]

61. Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018:.

62. Hou JP, Poole JW. β-Lactam antibiotics: their physiochemical properties and biological activities in relation to structure. J Pharm Sci . 1971; 60:503-27. [PubMed 4336386]

63. Neu HC. Penicillins: microbiology, pharmacology, and clinical use. In: Kagan BM, ed. Antimicrobial therapy. 3rd ed. Philadelphia: WB Saunders Company; 1980:20-34.

64. Mandell GL, Sande MA. Antimicrobial agents: penicillins and cephalosporins. In: Gilman AG, Goodman L, Gilman A, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 6th ed. New York: Macmillan Publishing Company; 1980:1126-61.

67. Wilkowske CJ. The penicillins. Mayo Clin Proc . 1977; 52:616-24. [PubMed 242733]

68. Rolinson GN, Sutherland R. Semisynthetic penicillins. Adv Pharmacol Chemother . 1973; 11:152-220.

70. Fishman LS, Hewitt WL. The natural penicillins. Med Clin North Am . 1970; 54:1081-99. [PubMed 4248661]

71. Sabath LD. Phenoxymethylpenicillin (penicillin V) and phenethicillin. Med Clin North Am . 1970; 54:1101-11. [PubMed 4990453]

72. Ball AP, Gray JA, Murdoch JM. Antibacterial drugs today: Part I. Drugs . 1975; 10:1-55. [PubMed 1100345]

75. Lederle Laboratories. Ledercillin® VK (penicillin V potassium) bioavailability studies. Pearl River, NY.

76. Eli Lilly and Company. V-Cillin K® (penicillin V potassium) bioavailability study. Indianapolis, IN.

80. Barza M. Antimicrobial spectrum, pharmacology and therapeutic use of antibiotics. Part 2: penicillins. Am J Hosp Pharm . 1977; 34:57-67. [PubMed 318800]

81. Bergan T. Penicillins. In: Schonfeld H, ed. Antibiotics and chemotherapy. Vol 25. Basel: S. Karger; 1978:1-122.

88. Selwyn S. The mechanisms and range of activity of penicillins and cephalosporins. In: Selwyn S, ed. The beta-lactam antibiotics: penicillins and cephalosporins in perspective. London: Hodder and Stoughton; 1980:56-90.

89. Wolff ME, ed. Burger's medicinal chemistry. 4th ed. New York: John Wiley & Sons; 1980:84-157.

94. Jaffe JM, Certo NM, Pirakitikuir P et al. Stability of several brands of ampicillin and penicillin V potassium oral liquids following reconstitution. Am J Hosp Pharm . 1976; 33:1005-10. [PubMed 9829]

95. Nicholas E, Hess G, Colten HR. Degradation of penicillin, ticarcillin, and carbenicillin resulting from storage of unit doses. N Engl J Med . 1982; 306:547-8. [PubMed 7057866]

96. Neftel KA, Walti M, Spengler H et al. Effect of storage of penicillin-G solutions on sensitization to penicillin-G after intravenous administration. Lancet . 1982; 1:986-7. [PubMed 6122846]

98. Watt G, Padre LP, Tuazon ML et al. Placebo-controlled trial of intravenous penicillin for severe and late leptospirosis. Lancet . 1988; 1:433-5. [PubMed 2893865]

99. Suputtamongkol Y, Niwattayakul K, Suttinont C et al. An open, randomized, controlled trial of penicillin, doxycycline, and cefotaxime for patients with severe leptospirosis. Clin Infect Dis . 2004; 39:1417-24. [PubMed 15546074]

104. Newton DW, Kluza RB. pKa Values of medicinal compounds in pharmacy practice. Drug Intell Clin Pharm . 1978; 12:546-54.

106. Tipper DJ. Mode of action of β-lactam antibiotics. Rev Infect Dis . 1979; 1:39-53. [PubMed 400939]

107. Tomasz A. Penicillin-binding proteins in bacteria. Ann Intern Med . 1982; 96:502-4. [PubMed 7039448]

108. Reynolds P, Chase H. β-Lactam-binding proteins: identification as lethal targets and probes of β-lactam accessibility. In: Salton M, Shockman GD, eds. β-Lactam antibiotics: mode of action, new developments, and future prospects. New York: Academic Press; 1981:153-68.

109. Rolinson GN, Macdonald AC, Wilson DA. Bactericidal action of β-lactam antibiotics on Escherichia coli with particular reference to ampicillin and amoxycillin. J Antimicrob Chemother . 1977; 3:541-53. [PubMed 340439]

111. Williamson R, Hakenbeck R, Tomasz A. In vivo interaction of β-lactam antibiotics with the penicillin-binding proteins of Streptococcus pneumoniae . Antimicrob Agents Chemother . 1980; 18:629-37. [PubMedCentral][PubMed 7447421]

112. Curtis NA, Orr D, Ross GW et al. Affinities of penicillins and cephalosporins for the penicillin-binding proteins of Escherichia coli K-12 and their antibacterial activity. Antimicrob Agents Chemother . 1979; 16:533-9. [PubMedCentral][PubMed 393164]

113. US Food and Drug Administration. FDA-recognized antimicrobial susceptibility test interpretive criteria. From FDA website. Accessed 2021 Jul 8. [Web]

114. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing . 31st edition. CLSI supplement M100. Wayne, PA; Mar 2021. [Web]

115. Curtis NA, Brown C, Boxall M et al. Inhibition of Escherichia coli K-12 by β-lactam antibiotics with poor antibacterial activity: interaction of permeability and intrinsic activity against penicillin-binding proteins. Antimicrob Agents Chemother . 1979; 15:332-6. [PubMedCentral][PubMed 380457]

116. Lorian V, ed. Antibiotics in laboratory medicine. Baltimore: Williams & Wilkins; 1980:298-341, 418-73, 607-722.

117. Ohmori H, Azuma A, Suzuki Y et al. Factors involved in beta-lactam antibiotic resistance in Pseudomonas aeruginosa . Antimicrob Agents Chemother . 1977; 12:537-9. [PubMedCentral][PubMed 411418]

118. Sawada Y, Yaginuma S, Tai M et al. Plasmid-mediated penicillin beta-lactamases in Pseudomonas aeruginosa . Antimicrob Agents Chemother . 1976; 9:55-60. [PubMedCentral][PubMed 4010]

119. Peterson LR, Denny AE, Gerding DN et al. Determination of tolerance to antibiotic bactericidal activity on Kirby-Bauer susceptibility plates. Am J Clin Pathol . 1980; 74:645-50. [PubMed 6969542]

120. Sabath LD. Mechanisms of resistance to beta-lactam antibiotics in strains of Staphylococcus aureus . Ann Intern Med . 1982; 97:339-44. [PubMed 6981367]

121. Horne D, Tomasz A. pH-Dependent penicillin tolerance of group B streptococci. Antimicrob Agents Chemother . 1981; 20:128-35. [PubMedCentral][PubMed 7025749]

123. Scudamore RA, Reveridge TJ, Goldner M. Penetrability of the outer membrane of Neisseria gonorrhoeae in relation to acquired resistance to penicillin and other antibiotics. Antimicrob Agents Chemother . 1979; 15:820-7. [PubMedCentral][PubMed 112915]

124. Bradley JJ, Mayhall CG, Dalton HP. Incidence and characteristics of antibiotic-tolerant strains of Staphylococcus aureus . Antimicrob Agents Chemother . 1978; 13:1052-7. [PubMedCentral][PubMed 249263]

126. Gutman L, Tomasz A. Penicillin-resistant and penicillin-tolerant mutants of group A streptococci. Antimicrob Agents Chemother . 1982; 22:128-36. [PubMedCentral][PubMed 6181734]

129. Weinrich EA, Del Bene VE. Beta-lactamase activity in anaerobic bacteria. Antimicrob Agents Chemother . 1976; 10:106-11. [PubMedCentral][PubMed 984742]

130. Medeiros AA, Kent RL, O'Brien TF. Characterization and prevalence of the different mechanisms of resistance to beta-lactam antibiotics in clinical isolates of Escherichia coli . Antimicrob Agents Chemother . 1974; 6:791-801. [PubMedCentral][PubMed 4615632]

132. Sykes RB. The classification and terminology of enzymes that hydrolyze β-lactam antibiotics. J Infect Dis . 1982; 145:762-5. [PubMed 6978915]

133. Kim KS, Anthony BF. Penicillin tolerance in group B streptococci isolated from infected neonates. J Infect Dis . 1981; 144:411-9. [PubMed 7031141]

134. Rajashekaraiah KR, Rice T, Tao VS et al. Clinical significance of tolerant strains of Staphylococcus aureus in patients with endocarditis. Ann Intern Med . 1980; 93:796-801. [PubMed 6905714]

135. Denny AE, Peterson LR, Gerding DN et al. Serious staphylococcal infections with strains tolerant to bactericidal antibiotics. Arch Intern Med . 1979; 139:1026-31. [PubMed 475520]

136. Steinbrecher UP. Serious infection in an adult due to penicillin-tolerant group B streptococcus. Arch Intern Med . 1981; 141:1714-5. [PubMed 7030251]

137. Rozenberg-Arska M, Fabius GT, Beens-Dekkers AA et al. Antibiotic sensitivity and synergism of penicillin-tolerant Staphylococcus aureus . Chemotherapy . 1979; 25:352-5. [PubMed 260698]

138. Hilty MD, Venglarcik JS, Best GK. Oxacillin-tolerant staphylococcal bacteremia in children. J Pediatr . 1980; 96:1035-7. [PubMed 6900061]

139. Richmond MH. β-Lactam antibiotics and β-lactamases: two sides of a continuing story. Rev Infect Dis . 1979; 1:30-6. [PubMed 400938]

140. Parrillo JE, Borst GC, Iannini P et al. Endocarditis due to resistant viridans streptococci during oral penicillin chemoprophylaxis. N Engl J Med . 1979; 300:296-300. [PubMed 252640]

141. Lacey RW. The role of beta-lactamases in bacterial resistance. In: Selwyn S, ed. The beta-lactam antibiotics: penicillins and cephalosporins in perspective. London: Hodder and Stoughton; 1980:172-9.

142. Levy SB. Microbial resistance to antibiotics: an evolving and persistent problem. Lancet . 1982; 2:83-8. [PubMed 6123819]

144. Hamilton-Miller JM. β-Lactamases and their clinical significance. J Antimicrob Chemother . 1982; 9(Suppl B):11-9. [PubMed 7037734]

145. Richmond M. Beta-lactamases and bacterial resistance to beta-lactam antibiotics. In: Salton M, Shockman GD, eds. β-Lactam antibiotics: mode of action, new developments, and future prospects. New York: Academic Press; 1981:261-72.

146. Tomasz A. Penicillin tolerance and the control of murein hydrolases. In: Salton M, Shockman GD, eds. β-Lactam antibiotics: mode of action, new developments, and future prospects. New York: Academic Press; 1981:227-41.

147. Williamson R, Zighelboim S, Tomasz A. Penicillin-binding proteins of penicillin-resistant and penicillin-tolerant Streptococcus pneumoniae . In: Salton M, Shockman GD, eds. β-Lactam antibiotics: mode of action, new developments, and future prospects. New York: Academic Press; 1981:215-26.

148. Sykes RB, Georgopapadakou NH. Bacterial resistance to β-lactam antibiotics: an overview. In: Salton M, Shockman GD, eds. β-Lactam antibiotics: mode of action, new developments, and future prospects. New York: Academic Press; 1981:199-214.

152. Holloway Y, Dankert J, Hess J. Penicillin tolerance and bacterial endocarditis. Lancet . 1980; 1:589. [PubMed 6102299]

155. Markowitz SM. Isolation of an ampicillin-resistant, non-β-lactamases-producing strain of Haemophilus influenzae . Antimicrob Agents Chemother . 1980; 17:80-3. [PubMedCentral][PubMed 6965443]

156. Bell SM, Plowman D. Mechanisms of ampicillin resistance in Haemophilus influenzae from respiratory tract. Lancet . 1980; 2:279-82. [PubMed 6105438]

158. Cates KL, Gerrard JM, Giebink GS. A penicillin-resistant pneumococcus. J Pediatr . 1978; 93:624-5. [PubMed 29951]

161. Sabath LD, Wheeler N, Laverdiere M et al. A new type of penicillin resistance of Staphylococcus aureus . Lancet . 1977; 1:443-7. [PubMed 65561]

166. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 13th ed. Washington DC: Public Health Foundation; 2015. Available at CDC website. [Web]

169. Simpson ML, Khan MY, Siddiqui Y et al. Comparison of piperacillin and penicillin in the treatment of uncomplicated gonorrhea. Antimicrob Agents Chemother . 1982; 21:727-9. [PubMedCentral][PubMed 6213195]

171. Hall WH, Schierl EA, Maccani JE. Comparative susceptibility of penicillinase-positive and -negative Neisseria gonorrhoeae to 30 antibiotics. Antimicrob Agents Chemother . 1979; 15:562-7. [PubMedCentral][PubMed 111617]

172. Cohen MS, Cooney MH, Blackman E et al. In vitro antimicrobial susceptibility of penicillinase-producing and intrinsically resistant Neisseria gonorrhoeae strains. Antimicrob Agents Chemother . 1983; 24:597-9. [PubMedCentral][PubMed 6418065]

173. Bourgault AM, Wilson WR, Washington JA. Antimicrobial susceptibilities of species of viridans streptococci. J Infect Dis . 1979; 140:316-21. [PubMed 501146]

174. Bayer AS, Morrison JO, Kim KS. Comparative in vitro bactericidal activity of cefonicid, ceftizoxime, and penicillin against group B streptococci. Antimicrob Agents Chemother . 1982; 21:344-6. [PubMedCentral][PubMed 6280602]

176. Rodriguez J, Fuxench-Chiesa Z, Ramirez-Ronda CH et al. In vitro susceptibility of 50 non-β-lactamase-producing Neisseria gonorrhoeae strains to 12 antimicrobial agents. Antimicrob Agents Chemother . 1983; 23:242-4. [PubMedCentral][PubMed 6404217]

177. Tarpay MM, Welch DF, Salari H et al. In vitro activity of antibiotics commonly used in the treatment of otitis media against Streptococcus pneumoniae isolates with different susceptibilities to penicillin. Antimicrob Agents Chemother . 1982; 22:145-7. [PubMedCentral][PubMed 6922691]

178. Barbour AG, Todd WJ, Stoenner HG. Action of penicillin on Borrelia hermsii . Antimicrob Agents Chemother . 1982; 21:823-9. [PubMedCentral][PubMed 7103461]

179. Denys GA, Jerris RC, Swenson JM et al. Susceptibility of Propionibacterium acnes clinical isolates to 22 antimicrobial agents. Antimicrob Agents Chemother . 1983; 23:335-7. [PubMedCentral][PubMed 6838191]

182. Field LH, Parker CD. Antibiotic susceptibility testing of Bordetella pertussis . Am J Clin Pathol . 1980; 74:312-6. [PubMed 6251713]

183. Stevens DL, Higbee JW, Oberhofer TR et al. Antibiotic susceptibilities of human isolates of Pasteurella multocida . Antimicrob Agents Chemother . 1979; 16:322-4. [PubMedCentral][PubMed 507787]

184. Pasculle AW, Dowling JN, Weyant RS et al. Susceptibility of Pittsburgh pneumonia agents ( Legionella micdadei ) and other newly recognized members of the genus Legionella to nineteen antimicrobial agents. Antimicrob Agents Chemother . 1981; 20:793-9. [PubMedCentral][PubMed 7325645]

185. Thornsberry C, Baker CN, Kirven LA. In vitro activity of antimicrobial agents on Legionnaires disease bacterium. Antimicrob Agents Chemother . 1978; 13:78-80. [PubMedCentral][PubMed 626494]

194. Marrie TJ, Haldane EV, Swantee CA et al. Susceptibility of anaerobic bacteria to nine antimicrobial agents and demonstration of decreased susceptibility of Clostridium perfringens to penicillin. Antimicrob Agents Chemother . 1981; 19:51-5. [PubMedCentral][PubMed 6264842]

197. . Drugs for bacterial infections. Treat Guidel Med Lett . 2010; 8:43-52. [PubMed 20489679]

199. US Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) recommended child and adolescents immunization schedule for 18 years or younger, United States, 2021. Updates may be available at CDC website. [Web]

200. US Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) recommended adult immunization schedule for ages 19 years or older, United States, 2021. Updates may be available at CDC website. [Web]

201. Bilgeri YR, Ballard RC, Duncan MO et al. Antimicrobial susceptibility of 103 strains of Haemophilus ducreyi isolated in Johannesburg. Antimicrob Agents Chemother . 1982; 22:686-8. [PubMedCentral][PubMed 6983858]

202. Edelstein PH, Meyer RD. Susceptibility of Legionella pneumophila to twenty antimicrobial agents. Antimicrob Agents Chemother . 1980; 18:403-8. [PubMedCentral][PubMed 7425611]

203. Sheagren JN. Staphylococcus aureus—the persistent pathogen (second of two parts). N Engl J Med . 1984; 310:1437-42. [PubMed 6371536]

204. Neu HC. Changing mechanisms of bacterial resistance. Am J Med . 1984; 77(Suppl B):11-23. [PubMed 6087659]

205. Sanders CC. Comparative activity of mezlocillin, penicillin, ampicillin, carbenicillin, and ticarcillin against gram-positive bacteria and Haemophilus influenzae . Antimicrob Agents Chemother . 1981; 2:843-6.

206. Jacobs MR, Path FF, Path MR et al. Emergence of multiply resistant pneumococci. N Engl J Med . 1978; 299:735-40. [PubMed 29219]

207. Ryan ME, Hopkins K, Wilbur RB. Acute necrotizing ulcerative gingivitis in children with cancer. Am J Dis Child . 1983; 137:592-4. [PubMed 6846294]

208. Shanson DC, Gazzard BG, Midgley J et al. Streptobacillus moniliformis isolated from blood in four cases of Haverhill fever: first outbreak in Britain. Lancet . 1983; 2:92-4. [PubMed 6134972]

209. Seidenfeld SM, Sutker WL, Luby JP. Fusobacterium necrophorum septicemia following oropharyngeal infection. JAMA . 1982; 248:1348-50. [PubMed 6955528]

210. Fass RJ, Barnishan J. In vitro susceptibilities of nonfermentative gram-negative bacilli other than Pseudomonas aeruginosa to 32 antimicrobial agents. Rev Infect Dis . 1980; 2:841-52. [PubMed 7012987]

211. Mayo JB, McCarthy LR. Antimicrobial susceptibility of Haemophilus parainfluenzae . Antimicrob Agents Chemother . 1977; 11:844-7. [PubMedCentral][PubMed 587028]

212. Lam K, Bayer AS. In vitro bactericidal synergy of gentamicin combined with penicillin G, vancomycin, or cefotaxime against group G streptococci. Antimicrob Agents Chemother . 1984; 26:260-2. [PubMedCentral][PubMed 6091537]

213. Hall WH, Opfer BJ. Influence of inoculum size on comparative susceptibilities of penicillinase-positive and -negative Neisseria gonorrhoeae to 31 antimicrobial agents. Antimicrob Agents Chemother . 1984; 26:192-5. [PubMedCentral][PubMed 6435514]

214. Brorson JE, Martinell J, Wilske H. Branhamella catarrhalis : antibiotic susceptibility and β-lactamase production. J Antimicrob Chemother . 1981; 7:208-9. [PubMed 6971288]

215. Aldridge KE, Sanders CV, Janney A et al. Comparison of the activities of penicillin G and new β-lactam antibiotics against clinical isolates of Bacteroides species. Antimicrob Agents Chemother . 1984; 26:410-3. [PubMedCentral][PubMed 6334491]

216. Feldman C, Kallenback JM, Miller SD et al. Community-acquired pneumonia due to penicillin-resistant pneumococci. N Engl J Med . 1985; 313:615-7. [PubMed 4022048]

217. Moore BA, Jevons S, Brammer KW. Peptidoglycan transpeptidase inhibition in Pseudomonas aeruginosa and Escherichia coli by penicillins and cephalosporins. Antimicrob Agents Chemother . 1979; 15:513-7. [PubMedCentral][PubMed 111613]

218. Friedland IR. Comparison of the response to antimicrobial therapy of penicillin-resistant and penicillin-susceptible pneumococcal disease. Pediatr Infect Dis J . 1995; 14:885-90. [PubMed 8584317]

219. Kapusnik JE, Barriere SL. Antibacterial synergy with new beta-lactam antimicrobials. Drug Interact Newsl . 1982; 2:35-40.

220. Mursic VP, Wilske B, Schierz G. In vitro and in vivo susceptibility of Borrelia burgdorferi . Eur J Clin Microbiol . 1987; 6:424-6. [PubMed 3665899]

221. Johnson RC, Kodner C, Russell M. In vitro and in vivo susceptibility of the Lyme disease spirochete, Borrelia burgdorferi, to four antimicrobial agents. Antimicrob Agents Chemother . 1987; 31:164-7. [PubMedCentral][PubMed 3566246]

222. Centers for Disease Control and Prevention. Sentinel surveillance for antimicrobial resistance in Neisseria gonorrhoeae —United States, 1988-1991. MMWR Morb Mortal Wkly Rep . 1993; 42(SS-3):29-39.

223. Chesney PJ. The escalating problem of antimicrobial resistance in Streptococcus pneumoniae . Am J Dis Child . 1992; 146:912-6. [PubMed 1636656]

224. Johnson RC. Isolation techniques for spirochetes and their sensitivity to antibiotics in vitro and in vivo. Rev Infect Dis . 1989; 11(Suppl 6):S1505-10. [PubMed 2682963]

225. Leggiadro RJ. Penicillin- and cephalosporin-resistant Streptococcus pneumoniae : an emerging microbial threat. Pediatrics . 1994; 93:500-3. [PubMed 8115213]

226. Appelbaum PC. Antimicrobial resistance in Streptococcus pneumoniae : an overview. Clin Infect Dis . 1992; 15:77-83. [PubMed 1617076]

227. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev . 1990; 3:1171-96.

228. Gerber MA, Randolph MF, Chanatry J et al. Five vs ten days of penicillin V therapy for streptococcal pharyngitis. Am J Dis Child . 1987; 141:224-7. [PubMed 3101484]

229. Spika JS, Facklam RR, Plikaytis BD et al. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. J Infect Dis . 1991; 163:1273-8. [PubMed 2037792]

234. Ginsburg CM, McCracken GH, Zweighaft TC. Serum penicillin concentrations after intramuscular administration of benzathine penicillin G in children. Pediatrics . 1982; 69:452-4. [PubMed 7041073]

253. Pickering LK, Rutherford I. Effect of concentration and time upon inactivation of tobramycin, gentamicin, netilmicin and amikacin by azlocillin, carbenicillin, mecillinam, mezlocillin and piperacillin. J Pharmacol Exp Ther . 1981; 214:345-9.

255. McLaughlin JE, Reeves DS. Clinical and laboratory evidence for inactivation of gentamicin by carbenicillin. Lancet . 1971; 1:261-4. [PubMed 4100015]

259. Pickering LK, Gearhart P. Effect of time and concentration upon interaction between gentamicin, tobramycin, netilmicin, or amikacin and carbenicillin or ticarcillin. Antimicrob Agents Chemother . 1979; 15:592-6. [PubMedCentral][PubMed 464591]

260. Hale DC, Jenkins R, Matsen JM. In-vitro inactivation of aminoglycoside antibiotics by piperacillin and carbenicillin. Am J Clin Pathol . 1980; 74:316-9. [PubMed 6447998]

261. Lam K, Bayer AS. Serious infections due to group G streptococci: report of 15 cases with in vitro-in vivo correlations. Am J Med . 1983; 75:561-70. [PubMed 6556004]

262. Ervin FR, Bullock WE, Nuttall CE. Inactivation of gentamicin by penicillins in patients with renal failure. Antimicrob Agents Chemother . 1976; 9:1004-11. [PubMedCentral][PubMed 938018]

263. Davies M, Morgan JR, Anand C. Interactions of carbenicillin and ticarcillin with gentamicin. Antimicrob Agents Chemother . 1975; 7:431-4. [PubMedCentral][PubMed 1147579]

264. Kradjan WA, Burger R. In vivo inactivation of gentamicin by carbenicillin and ticarcillin. Arch Intern Med . 1980; 140:1668-70. [PubMed 7458498]

265. Centers for Disease Control. Sexually transmitted diseases treatment guidelines 1989. MMWR Morb Mortal Wkly Rep . 1989; 38(Suppl 8S):1-43S. [PubMed 2491906]

267. Thompson MI, Russo ME, Saxon BJ et al. Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease. Antimicrob Agents Chemother . 1982; 21:268-73. [PubMedCentral][PubMed 6462107]

269. Chow MS, Quintiliani R, Nightingale CH. In vivo inactivation of tobramycin by ticarcillin. JAMA . 1982; 247:658-9. [PubMed 6798229]

270. Weibert RT, Keane WF. Carbenicillin-gentamicin interaction in acute renal failure. Am J Hosp Pharm . 1977; 34:1137-9. [PubMed 920745]

282. Serra P, Brandimarte C, Martino P et al. Synergistic treatment of enterococcal endocarditis: in vitro and in vivo studies. Arch Intern Med . 1977; 137:1562-7. [PubMed 921443]

288. Kaye D. Enterococci: biologic and epidemiologic characteristics and in vitro susceptibility. Arch Intern Med . 1982; 142:2006-9. [PubMed 6812524]

289. Glew RH, Moellering RC. Effect of protein binding on the activity of penicillins in combination with gentamicin against enterococci. Antimicrob Agents Chemother . 1979; 15:87-92. [PubMedCentral][PubMed 426508]

292. American Academy of Pediatrics. Red Book: 2018-2021 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics.

293. Henderson JL, Polk RE, Kline BJ. In vitro inactivation of gentamicin, tobramycin, and netilmicin by carbenicillin, azlocillin, or mezlocillin. Am J Hosp Pharm . 1981; 38:1167-70. [PubMed 6455916]

294. O'Bey KA, Jim LK, Gee JP et al. Temperature dependence of the stability of tobramycin mixed with penicillins in human serum. Am J Hosp Pharm . 1982; 39:1005-8. [PubMed 7102681]

297. Duperval R, Bill NJ, Geraci JE et al. Bactericidal activity of combinations of penicillin or clindamycin with gentamicin or streptomycin against species of viridans streptococci. Antimicrob Agents Chemother . 1975; 8:673-6. [PubMedCentral][PubMed 1211918]

299. Calderwood SA, Wennersten C, Moellering RC. Resistance to six aminoglycosidic aminocyclitol antibiotics among enterococci: prevalence, evolution, and relationship to synergism with penicillin. Antimicrob Agents Chemother . 1977: 12:401-5.

300. ASHP Injectable Drug Information. Penicillin G potassium and Penicillin G sodium (updated May 1, 2020). Bethesda, MD: American Society of Health-System Pharmacist.

302. McDonald LC, Gerding DN, Johnson S et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis . 2018; 66:987-994. Updates may be available at IDSA website at www.idsociety.org. [PubMed 29562266]

303. Surawicz CM, Brandt LJ, Binion DG et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol . 2013; 108:478-98; quiz 499. [PubMed 23439232]

304. Debast SB, Bauer MP, Kuijper EJ et al. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect . 2014; 20 Suppl 2:1-26. [PubMed 24118601]

305. Feldman WE, Zweighaft T. Effect of ampicillin and chloramphenicol against Streptococcus pneumoniae and Neisseria meningitidis . Antimicrob Agents Chemother . 1979; 15:240-2. [PubMedCentral][PubMed 34360]

306. Rocco V, Overturf G. Chloramphenicol inhibition of the bactericidal effect of ampicillin against Haemophilus influenzae . Antimicrob Agents Chemother . 1982; 21:349-51. [PubMedCentral][PubMed 6978674]

309. Cole FS, Daum RS, Teller L et al. Effect of ampicillin and chloramphenicol alone and in combination on ampicillin-susceptible and -resistant Haemophilus influenzae type B. Antimicrob Agents Chemother . 1979; 15:415-9. [PubMedCentral][PubMed 313752]

320. Barza M, Weinstein L. Pharmacokinetics of the penicillins in man. Clin Pharmacokinet . 1976; 1:297-308. [PubMed 797501]

321. McCracken GH, Ginsburg CM, Clahsen JC et al. Pharmacologic evaluation of orally administered antibiotics in infants and children: effect of feeding on bioavailability. Pediatrics . 1978; 62:738-43. [PubMed 581516]

323. Kaplan EL, Berrios X, Speth J et al. Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after injection of 1,200,000 units. J Pediatr . 1989; 115:146-50. [PubMed 2738782]

324. Ducal J, Robson HG. Cerebrospinal fluid penicillin levels during therapy for latent syphilis. JAMA . 1981; 246:2583-4. [PubMed 7299984]

325. Dunlop EM, Al-Egaily SS, Houang ET. Production of treponemicidal concentration of penicillin in cerebrospinal fluid. BMJ . 1981; 283:646. [PubMedCentral][PubMed 6790114]

326. Nelson JD. Antibiotic concentrations in septic joint effusions. N Engl J Med . 1971; 284:349-53. [PubMed 5539915]

327. Torbahn G, Hofmann H, Rücker G et al. Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis: A Network Meta-analysis. JAMA Dermatol . 2018; 154:1292-1303. [PubMedCentral][PubMed 30285069]

328. Eliassen KE, Reiso H, Berild D et al. Comparison of phenoxymethylpenicillin, amoxicillin, and doxycycline for erythema migrans in general practice. A randomized controlled trial with a 1-year follow-up. Clin Microbiol Infect . 2018; 24:1290-1296. [PubMed 29505880]

329. Lantos PM, Rumbaugh J, Bockenstedt LK et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis . 2021; 72:e1-e48. [PubMed 33417672]

330. Kaplan JM, McCracken GH, Culbertson MC. Penicillin and erythromycin concentrations in tonsils: relevance to treatment failures in streptococcal pharyngitis. Am J Dis Child . 1974; 127:206-11.

331. . Antibacterial drugs for Lyme disease. Med Lett Drugs Ther . 2021; 63:73-75. [PubMed 33976091]

332. Steere AC, Pachner AR, Malawista SE. Neurologic abnormalities in Lyme disease: successful treatment with high-dose intravenous penicillin. Ann Intern Med . 1983; 99:767-72. [PubMed 6316826]

333. Halperin JJ, Shapiro ED, Logigian E et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology . 2007; 69:91-102. [PubMed 17522387]

334. Steere AC, Green J, Schoen RT et al. Successful parenteral penicillin therapy of established lyme arthritis. N Engl J Med . 1985; 312:869-74. [PubMed 3883177]

335. Dattwyler RJ, Halperin JJ, Volkman DJ et al. Treatment of late Lyme borreliosis—randomized comparison of ceftriaxone and penicillin. Lancet . 1988; 1:1191-4. [PubMed 2897008]

336. Kunin CM. Clinical pharmacology of the new penicillins: the importance of serum protein binding in determining antimicrobial activity and concentrations in serum. Clin Pharmacol Ther . 1966; 7:166-79. [PubMed 4956690]

337. Kunin CM. Clinical significance of protein binding of the penicillins. Ann NY Acad Sci . 1967; 145:282-90. [PubMed 4998178]

338. Bergan T, Oydvin B. Cross-over study of penicillin pharmacokinetics after intravenous infusions. Chemotherapy . 1974; 20:263-79. [PubMed 4412673]

339. Gerding DN, Hall WH, Schierl EA. Antibiotic concentrations in ascitic fluid of patients with ascites and bacterial peritonitis. Ann Intern Med . 1977; 86:708-13. [PubMed 869351]

340. Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants: age-related differences and therapeutic implications. Clin Pharmacokinet . 1980; 5:485-527. [PubMed 7002417]

341. Selwyn S. Applied pharmacology, adverse effects and drug interactions. In: Selwyn S, ed. The beta-lactam antibiotics: penicillins and cephalosporins in perspective. London: Hodder and Stoughton; 1980:91-126.

343. Yinkel Y, Bolme P, Eriksson M. The effect of food on the oral absorption of penicillin V preparations in children. Acta Pharmacol Toxicol (Copenh) . 1981; 49:301-4. [PubMed 6805255]

344. Workowski KA, Bachmann LH, Chan PA et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep . 2021; 70:1-187. [PubMed 34292926]

345. . Drugs for sexually transmitted infections. Med Lett Drugs Ther . 2017; 59:105-112. [PubMed 28686575]

347. Gibaldi M, Schwartz MA. Apparent effect of probenecid on the distribution of penicillins in man. Clin Pharmacol Ther . 1968; 9:345-9. [PubMed 5649987]

348. Giusti DL. A review of the clinical use of antimicrobial agents in patients with renal and hepatic insufficiency: the penicillins. Drug Intell Clin Pharm . 1973; 7:62-74.

349. Hieber JP, Nelson JD. A pharmacologic evaluation of penicillin in children with purulent meningitis. N Engl J Med . 1977; 297:410-3. [PubMed 882110]

350. World Health Organization. WHO guidelines for treatment of Treponema pallidum (syphilis). Geneva, Switzerland; WHO; 2016. Available at WHO website. [Web]

351. Spector R, Lorenzo AV. The effects of salicylate and probenecid on the cerebrospinal fluid transport of penicillin, aminosalicylic acid and iodide. J Pharmacol Exp Ther . 1974; 188:55-65. [PubMed 4809276]

352. Speer ME, Mason EO, Scharnberg JT. Cerebrospinal fluid concentrations of aqueous procaine penicillin G in the neonate. Pediatrics . 1981; 67:387-8. [PubMed 7243477]

353. Speer ME, Taber LH, Clark DB et al. Cerebrospinal fluid levels of benzathine penicillin G in the neonate. J Pediatr . 1977; 91:996-7.

354. Dunlop EM, Al-Egaily S, Houang ET. Penicillin levels in blood and CSF achieved by treatment of syphilis. JAMA . 1979; 241:2538-40.

355. Anderson PO. Drugs and breast feeding—a review. Drug Intell Clin Pharm . 1977; 11:208-23.

356. Crouthamel WG, Chun AH, Ritschel WA et al. Bioavailability monograph: penicillin V potassium. J Am Pharm Assoc . 1977; NS17:243-6.

357. Dimmling T, Bredehorst HG, Elst EV. Bioavailability of various preparations and doses of penicillin V. Eur J Clin Pharmacol . 1976; 10:55-8.

359. . Prevention of Group B Streptococcal Early-Onset Disease in Newborns: ACOG Committee Opinion, Number 797. Obstet Gynecol . 2020; 135:e51-e72. [Web][PubMed 31977795]

360. Mohr JA, Griffiths W, Jackson R et al. Neurosyphilis and penicillin levels in cerebrospinal fluid. JAMA . 1976; 236:2208-9. [PubMed 989815]

361. Dittert LW, Griffen WO, LaPiana JC et al. Pharmacokinetic interpretation of penicillin levels in serum and urine after intravenous administration. Antimicrob Agents Chemother . 1969:42-8.

364. Greene HF, Burkhart B, Hobby GL. Excretion of penicillin in human milk following parturition. J Obstet Gynecol . 1946; 51:732-3.

365. Kaplan JM, McCracken GH. Clinical pharmacology of benzathine penicillin G in neonates with regard to its recommended use in congenital syphilis. J Pediatr . 1973; 82:1069-72.

366. Cole M, Kening MD, Hewitt VA. Metabolism of penicillins to penicilloic acids and 6-aminopenicillanic acid in man and its significance in assessing penicillin absorption. Antimicrob Agents Chemother . 1973; 3:463-8. [PubMedCentral][PubMed 4364176]

367. Plaut ME, O'Connell CJ, Pabico RC et al. Penicillin handling in normal and azotemic patients. J Lab Clin Med . 1969; 74:13-8.

368. McCracken GH, Ginsberg C, Chrane DF et al. Clinical pharmacology of penicillin in newborn infants. Pediatr Pharmacol Ther . 1973; 82:692-8.

369. Bryan CS, Stone WJ. Comparably massive penicillin G therapy in renal failure. Ann Intern Med . 1975; 82:189-95. [PubMed 1115440]

370. Hellstrom K, Rosen A, Swahn A. Absorption and decomposition of potassium-35S-phenoxymethyl penicillin. Clin Pharmacol Ther . 1974; 16:826-33. [PubMed 4214641]

371. Klein JO, Schaberg MJ, Buntin M et al. Levels of penicillin in serum of newborn infants after single intramuscular doses of benzathine penicillin G. Pediatr Pharmacol Ther . 1973; 82:1065-8.

373. Matheson I, Samseth M, Løberg R et al. Milk transfer of phenoxymethylpenicillin during puerperal mastitis. Br J Clin Pharmacol . 1988; 25:33-40. [PubMed 3130891]

374. Matsuda S. Transfer of antibiotics into maternal milk. Biol Res Pregnancy . 1984; 5:57-60.

375. Gerber MA, Baltimore RS, Eaton CB et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation . 2009; 119:1541-51. [PubMed 19246689]

376. Puopolo KM, Benitz WE, Zaoutis TE et al. Management of Neonates Born at ≤34 6/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics . 2018; 142 [PubMed 30455344]

377. Puopolo KM, Benitz WE, Zaoutis TE et al. Management of Neonates Born at ≥35 0/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics . 2018; 142 [PubMed 30455342]

381. Goessens WH, Fontijne P, Michel MF. Factors influencing detection of tolerance in Staphylococcus aureus . Antimicrob Agents Chemother . 1982; 22:364-8. [PubMedCentral][PubMed 6923712]

382. Thonus IP, Fontijne P, Michel MF. Ampicillin susceptibility and ampicillin-induced killing rate of Escherichia coli . Antimicrob Agents Chemother . 1982; 22:386-90. [PubMedCentral][PubMed 6753736]

416. Tunkel AR, Hasbun R, Bhimraj A et al. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis . 2017; 64:e34-e65. Updates may be available at IDSA website at www.idsociety.org. [PubMed 28203777]

418. Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis . 2004; 39:1267-84. [PubMed 15494903]

420. Bond JM, Lightbown JW, Barber M et al. A comparison of four phenoxypenicillins. Br Med J . 1963; 2:955-61.

439. Witkowski JA, Parish LC. Bacterial skin infections: management of common streptococcal and staphylococcal lesions. Postgrad Med . 1982; 72:167-85. [PubMed 7088741]

440. Panel on Opportunistic Infection in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed 2021 Jul 18. Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

450. Baddour LM, Wilson WR, Bayer AS et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation . 2015; 132:1435-86. [PubMed 26373316]

452. Baltimore RS, Gewitz M, Baddour LM et al. Infective Endocarditis in Childhood: 2015 Update: A Scientific Statement From the American Heart Association. Circulation . 2015; 132:1487-515. [PubMed 26373317]

475. Quagliarello V, Scheld WM. Treatment of bacterial meningitis. N Engl J Med . 1997; 336:708-16. [PubMed 9041103]

476. Lavetter A, Leedom JM, Mathies AW et al. Meningitis due to Listeria monocytogenes : review of 25 cases. N Engl J Med . 1971; 285:598-603. [PubMed 4998254]

477. US Centers for Disease Control and Prevention. Leptospirosis fact sheet for clinicians. Dated 2018 Jan 30. From CDC website. Accessed 2021 Jul 9. [Web]

543. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis . 2014; 59:147-59. Updates may be available at IDSA website at www.idsociety.org. [PubMed 24947530]

544. Brett-Major DM, Coldren R. Antibiotics for leptospirosis. Cochrane Database Syst Rev . 2012; :CD008264. [PubMed 22336839]

545. Cucinell SA. Early diagnosis and treatment of leptospirosis. Mil Med . 1980; 145:495-7. [PubMed 6772994]

546. Sanford JP. Leptospirosis—time for a booster. N Engl J Med . 1984; 310:524-5. [PubMed 6694697]

547. Shaunak S, Brettle RP, Inglis JM et al. More on leptospirosis. N Engl J Med . 1984; 311:261-2. [PubMed 6738629]

550. Shenoy ES, Macy E, Rowe T et al. Evaluation and Management of Penicillin Allergy: A Review. JAMA . 2019; 321:188-199. [PubMed 30644987]

551. Ramsey A, Staicu ML. Use of a Penicillin Allergy Screening Algorithm and Penicillin Skin Testing for Transitioning Hospitalized Patients to First-Line Antibiotic Therapy. J Allergy Clin Immunol Pract . 2018; 6:1349-1355. [PubMed 29242142]

552. Kufel WD, Justo JA, Bookstaver PB et al. Penicillin Allergy Assessment and Skin Testing in the Outpatient Setting. Pharmacy (Basel) . 2019; 7 [PubMedCentral][PubMed 31546887]

555. Romano A, Atanaskovic-Markovic M, Barbaud A et al. Towards a more precise diagnosis of hypersensitivity to beta-lactams - an EAACI position paper. Allergy . 2020; 75:1300-1315. [PubMed 31749148]

558. Soria A, Autegarden E, Amsler E et al. A clinical decision-making algorithm for penicillin allergy. Ann Med . 2017; 49:710-717. [PubMed 28844171]

559. Chen JR, Tarver SA, Alvarez KS et al. A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients. J Allergy Clin Immunol Pract . 2017; 5:686-693. [PubMed 27888034]

560. Ham Y, Sukerman ES, Lewis JS 2nd et al. Safety and efficacy of direct two-step penicillin challenges with an inpatient pharmacist-driven allergy evaluation. Allergy Asthma Proc . 2021; 42:153-159. [PubMedCentral][PubMed 33685561]

561. Mirakian R, Leech SC, Krishna MT et al. Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy . 2015; 45:300-27. [PubMed 25623506]

562. Turner NA, Wrenn R, Sarubbi C et al. Evaluation of a Pharmacist-Led Penicillin Allergy Assessment Program and Allergy Delabeling in a Tertiary Care Hospital. JAMA Netw Open . 2021; 4:e219820. [PubMedCentral][PubMed 33983399]

563. Macy E, Ngor E. Recommendations for the management of beta-lactam intolerance. Clin Rev Allergy Immunol . 2014; 47:46-55. [PubMed 23549754]

564. Bland CM, Bookstaver PB, Griffith NC et al. A practical guide for pharmacists to successfully implement penicillin allergy skin testing. Am J Health Syst Pharm . 2019; 76:136-147. [PubMed 30689753]

565. Cheon E, Horowitz HW. New Avenues for Antimicrobial Stewardship: The Case for Penicillin Skin Testing by Pharmacists. Clin Infect Dis . 2019; 68:2123-2124. [PubMed 30281071]

566. Thompson G, McLean-Tooke A, Lucas M. Cross With Caution: Antibiotic Cross-Reactivity and Co-Reactivity Patterns in Severe Cutaneous Adverse Reactions. Front Immunol . 2021; 12:601954. [PubMedCentral][PubMed 33717082]

567. Chaudhry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and β-Lactam Cross-Reactivity. Pharmacy (Basel) . 2019; 7 [PubMedCentral][PubMed 31362351]

568. Pinheiro V, Pestana C, Pinho A et al. Occupational allergic contact dermatitis caused by antibiotics in healthcare workers - relationship with non-immediate drug eruptions. Contact Dermatitis . 2018; 78:281-286. [PubMed 29399806]

569. Romano A, Valluzzi RL, Caruso C et al. Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins. J Allergy Clin Immunol Pract . 2018; 6:1662-1672. [PubMed 29408440]

570. Legendre DP, Muzny CA, Marshall GD et al. Antibiotic hypersensitivity reactions and approaches to desensitization. Clin Infect Dis . 2014; 58:1140-8. [PubMed 24368623]

571. Kwiatkowski S, Mulugeta S, Davis S et al. Optimizing preoperative antibiotics in patients with β-lactam allergies: A role for pharmacy. Am J Health Syst Pharm . 2021; [PubMedCentral][PubMed 34037708]

572. US Centers for Disease Control and Prevention. Evaluation and diagnosis of penicillin allergy for healthcare professionals. From CDC website. Accessed 20201 Jul 15. [Web]

573. Chua KYL, Vogrin S, Bury S et al. The Penicillin Allergy Delabeling Program: A Multicenter Whole-of-Hospital Health Services Intervention and Comparative Effectiveness Study. Clin Infect Dis . 2020; [PubMed 32756983]

575. Martin AR. Antibiotics. In: Doerge RF, ed. Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry. 8th ed. Philadelphia: JB Lippincott Company; 1982:228-47.

576. Parker CW. Drug allergy. In: Wolff ME, ed. Burger's medicinal chemistry. 4th edition. New York: Wiley-Interscience Publications; 1980:419-47.

577. Schneider CH. Immunochemistry of penicillin. In: McGovern JP, Stewart GT, eds. Penicillin allergy: clinical and immunologic aspects. Springfield, IL: Charles C Thomas; 1970:23-54.

580. Shulman ST, Bisno AL, Clegg HW et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis . 2012; 55:1279-82. Updates may be available at IDSA website at www.idsociety.org. [PubMed 23091044]

581. Anderson KC, Maurer MJ, Dajani AS. Pneumococci relatively resistant to penicillin: a prevalence survey in children. J Pediatr . 1980; 97:939-41. [PubMed 6904489]

599. Ekedahl C, Holm SE, Bergholm AM. Penetration of antibiotics into the normal and diseased maxillary sinus mucosa. Scand J Infect Dis . 1978; 14(Suppl):279-84.

611. Idsoe O, Guthe T, Willcox RR et al. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull World Health Organ . 1968; 38:159-88. [PubMedCentral][PubMed 5302296]

614. Demers B, Simor AE, Vellend H et al. Severe invasive group A streptococcal infections in Ontario, Canada: 1987-1991. Clin Infect Dis . 1993; 16:792-800. [PubMed 8329511]

615. Erffmeyer JE. Adverse reactions to penicillin. Ann Allergy . 1981; 47:288-300. [PubMed 6171185]

629. Neftel KA, Muller MR, Hauser SP. More on penicillin-induced leukopenia. N Engl J Med . 1983; 308:901. [PubMed 6835289]

630. Andreoli SP, Kleiman MB, Glick MR et al. Nafcillin, pseudoproteinuria, and hypokalemic alkalosis. J Pediatr . 1980; 97:841-2. [PubMed 7431181]

631. Anagnou I. Penicillin-induced leukopenia. Lancet . 1984; 1:452. [PubMed 6142177]

655. Brown CH, Bradshaw MW, Natelson EA et al. Defective platelet function following the administration of penicillin compounds. Blood . 1976; 47:949-56. [PubMed 1276476]

663. Wright JG, Quinn CP, Shadomy S et al. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep . 2010; 59(RR-6):1-30. [PubMed 20651644]

668. Inglesby TV, O'Toole T, Henderson DA et al for the Working Group on Civilian Biodefense. Anthrax as a biological weapon 2002: updated recommendations for management. JAMA . 2002; 287:2236-52. [PubMed 11980524]

670. Dixon TC, Meselson M, Guillemin J et al. Anthrax. N Engl J Med . 1999; 341:815-26. [PubMed 10477781]

671. Bradley JS, Peacock G, Krug SE et al. Pediatric anthrax clinical management. Pediatrics . 2014; 133:e1411-36. [PubMed 24777226]

672. Meaney-Delman D, Zotti ME, Creanga AA et al. Special considerations for prophylaxis for and treatment of anthrax in pregnant and postpartum women. Emerg Infect Dis . 2014; 20 [PubMed 24457117]

673. Hendricks KA, Wright ME, Shadomy SV et al. Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis . 2014; 20 [PubMed 24447897]

675. World Health Organizatin. Yaw. May 17, 2021. From WHO website. [Web]

676. Marks M. Advances in the Treatment of Yaws. Trop Med Infect Dis . 2018; 3 [PubMedCentral][PubMed 30274488]

677. Bryceson AD. Clinical pathology of the Jarisch-Herxheimer reaction. J Infect Dis . 1976; 133:696-704. [PubMed 932495]

678. Giacani L, Lukehart SA. The endemic treponematoses. Clin Microbiol Rev . 2014; 27:89-115. [PubMed 24396138]

679. Mitjà O, Hays R, Ipai A et al. Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial. Lancet . 2012; 379:342-7. [PubMed 22240407]

680. World Health Organization. Anthrax in human and animals. 4th ed. Geneva, Switzerland: World Health Organization. 2008. From WHO website. [Web]

681. Swartz MN. Recognition and management of anthrax—an update. N Engl J Med . 2001; 345:1621-6. [PubMed 11704686]

682. Centers for Disease Control and Prevention. Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines, October 2001. MMWR Morb Mortal Wkly Rep . 2001; 50:889-93. [PubMed 11686472]

683. US Army Medical Research Institute of Infectious Diseases. USAMRIID's medical management of biologic casualties handbook. 8th ed. Fort Detrick, MD: USAMRIID; 2014 Sep.

684. Food and Drug Administration. Notice regarding doxycycline and penicillin G procaine administration for inhalational anthrax (post-exposure). 2001 Oct 30. From FDA website. [Web]

685. Centers for Disease Control and Prevention. Updated recommendations for antimicrobial prophylaxis among asymptomatic pregnant women after exposure to Bacillus anthracis . 2001; 50:960.

686. Centers for Disease Control and Prevention. Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep . 2001; 50:909-19. [PubMed 11699843]

688. Richards ML, Prince RA, Kenaley KA et al. Antimicrobial penetration into cerebrospinal fluid. Drug Intell Clin Pharm . 1981; 15:341-68. [PubMed 7023900]

703. Centers for Disease Control and Prevention. Notice to readers: update: interim recommendations for antimicrobial prophylaxis for children and breastfeeding mothers and treatment of children with anthrax. MMWR Morb Mortal Wkly Rep . 2001; 50:1014-6. [PubMed 11724160]

710. Simmonds J, Hodges S, Nicol F et al. Anaphylaxis after oral penicillin. Br J Med . 1978; 2:1404.

711. Mursic VP, Wilske B, Schierz G. In vitro and in vivo susceptibility of Borrelia burgdorferi . Eur J Clin Microbiol . 1987; 6:424-6. [PubMed 3665899]

712. Johnson RC, Kodner C, Russell M. In vitro and in vivo susceptibility of the Lyme disease spirochete, Borrelia burgdorferi, to four antimicrobial agents. Antimicrob Agents Chemother . 1987; 31:164-7. [PubMedCentral][PubMed 3566246]

713. MacFarlane MD, McCarron MM. Anaphylactic shock and anaphylactoid reaction: analysis of 62 cases. Drug Intell Clin Pharm . 1973; 7:394-405.

714. Kelly JF, Patterson R. Anaphylaxis: course, mechanisms and treatment. JAMA . 1974; 227:1431-6.

715. Spark RP. Fatal anaphylaxis due to oral penicillin. Am J Clin Pathol . 1971; 56:407-11. [PubMed 5094502]

716. Fenollar F, Puéchal X, Raoult D. Whipple's disease. N Engl J Med . 2007; 356:55-66. [PubMed 17,202456]

717. Ryser RJ, Locksley RM, Eng SC et al. Reversal of dementia associated with Whipple's disease by trimethoprim-sulfamethoxazole, drugs that penetrate the blood-brain barrier. Gastroenterology . 1984; 86:745-52. [PubMed 6199255]

718. Schmitt BP, Richardson H, Smith E et al. Encephalopathy complicating Whipple's disease: failure to respond to antibiotics. Ann Intern Med . 1981; 94:51-2. [PubMed 6160797]

719. Feldman M, Hendler RS, Morrison EB. Acute meningoencephalitis after withdrawal of antibiotics in Whipple's disease. Ann Intern Med . 1980; 93:709-11. [PubMed 6163384]

720. Singer R. Diagnosis and treatment of Whipple's disease. Drugs . 1998; 55:699-704. [PubMed 9585865]

723. Adler CH, Galetta SL. Oculo-facial-skeletal myorhythmia in Whipple disease: treatment with ceftriaxone. Ann Intern Med . 1990; 112:467-9. [PubMed 1689977]

724. Bures J, Kopácová M, Douda T et al. Whipple's Disease: Our Own Experience and Review of the Literature. Gastroenterol Res Pract . 2013; 2013:478349. [PubMed 23843784]

729. Sher PP. Drug interferences with clinical laboratory tests. Drugs . 1982; 24:24-63. [PubMed 6179732]

742. Rao AK, Sobel J, Chatham-Stephens K et al. Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021. MMWR Recomm Rep . 2021; 70:1-30. [PubMedCentral][PubMed 33956777]

743. Butler T, Jones PK, Wallace CK. Borrelia recurrentis infection: single-dose antibiotic regimens and management of the Jarisch-Herxheimer reaction. J Infect Dis . 1978; 137:573-7. [PubMed 659915]

744. Merson MH, Dowell VR Jr. Epidemiological, clinical and laboratory aspects of wound botulism. N Engl J Med . 1973; 289:1005-10. [PubMed 4582478]

745. Morris JG Jr, Hatheway CL. Botulism in the United States, 1979. J Infect Dis . 1980; 142:302-5.

746. Arnon SS, Schechter R, Inglesby TV et al for the Working Group on Civilian Biodefense. Botulinum toxin as a biological weapon: medical and public health management. JAMA . 2001; 285:1059-70. [PubMed 11209178]

747. Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med . 1998; 129:221-8. [PubMed 9696731]

748. Patt HA, Feigin RD. Diagnosis and management of suspected cases of bioterrorism: a pediatric perspective. Pediatrics . 2002; 109:685-92. [PubMed 11927716]

749. Baymiller S. Botulism in critical care: a case study in wound botulism. Am J Crit Care . 2001; 10:172-80. [PubMed 11340740]

750. Schulte M, Hamsen U, Schildhauer TA et al. Effective and rapid treatment of wound botulism, a case report. BMC Surg . 2017; 17:103. [PubMed 29073888]

751. Bossi P, Tegnell A, Baka A et al. Bichat guidelines for the clinical management of botulism and bioterrorism-related botulism. Euro Surveill . 2004; 9:E13-4. [PubMed 15677843]

752. Muir A, Hensley WJ. Pseudoproteinuria due to penicillins, in the turbidometric measurement of proteins with trichloroacetic acid. Clin Chem . 1979; 25:1662-3. [PubMed 466794]

753. Infant Botulism Treatment and Prevention Program. Division of Communicable Disease Control, California Department of Health Services. From IBTPP website. Accessed 2019 Mar 13 [Web]

754. Centers for Disease Control and Prevention. Diagnosis and management of foodborne illnesses: a primer for physicians. MMWR Morb Mortal Wkly Rep . 2001; 50(No. RR-2):1-69. [Fulltext MMWR][PubMed 11215787]

755. Line DE, Adler S, Fraley DS et al. Massive pseudoproteinuria caused by nafcillin. JAMA . 1976; 235:1259. [PubMed 946235]

756. Andrassy K, Ritz E, Koderisch J et al. Pseudoproteinuria in patients taking penicillin. Lancet . 1978; 2:154. [PubMed 78351]

757. Glick MR, Kleiman MB, Moorehead WR et al. Nafcillin may cause a subtle pseudoproteinuria. Clin Chem . 1981; 27:506-7. [PubMed 7471409]

759. MacCara ME, Parker WA. In vitro effect of penicillins and aminoglycosides on commonly used tests for glycosuria. Am J Hosp Pharm . 1981; 38:1340-5. [PubMed 6269424]

760. Felice-Johnson J, Nappi JM. Nafcillin interference with quantitative protein urinalysis. Am J Hosp Pharm . 1981; 38:1360-1. [PubMed 7282724]

762. Sullivan TJ, Yecies LD, Shatz GS et al. Desensitization of patients allergic to penicillin using orally administered β-lactam antibiotics. J Allergy Clin Immunol . 1982; 69:275-82. [PubMed 7061769]

763. Wendel GD, Stark BJ, Jamison RB et al. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med . 1985; 312:1229-32. [PubMed 3921835]

764. Dudley KH, Butler TC, Johnson D. Chemical studies of potential relevance to penicillin hypersensitivity: kinetic studies of methicillin, phenoxymethylpenicillin and their penicillenic acids. J Pharmacol Exp Ther . 1974; 188:491-503. [PubMed 4361250]

765. Stewart GT. Macromolecular residues contributing to the allergenicity of penicillins and cephalosporins. Antimicrob Agents Chemother . 1967:543-9.

766. Weston RD. Penicilloylated protein contaminating 6-aminopenicillanic acid and benzylpenicillin. Antimicrob Agents Chemother . 1967:553-8.

769. Sullivan TJ, Wedner HJ, Shatz GS et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol . 1981; 68:171-80. [PubMed 6267115]

773. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 28th ed. London: The Pharmaceutical Press; 1982:515,1076-1231.

774. Caraway WT, Kammeyer CW. Chemical interference by drugs and other substances with clinical laboratory test procedures. Clin Chim Acta . 1972; 41:395-434. [PubMed 4581804]

776. Riff LJ, Thomason JL. Comparative aminoglycoside inactivation by β-lactam antibiotics: effect of a cephalosporin and six penicillins on five aminoglycosides. J Antibiot . 1982; 35:850-7. [PubMed 7174538]

777. Edwards DJ, Schentag JJ. In vitro interactions between β-lactam antibiotics and tobramycin. Clin Chem . 1981; 27:341. [PubMed 6970094]

778. Mylan. Methotrexate injection prescribing information. Rockford, IL; 2016 Jul.

779. Kishiyama JL, Adelman DC. The cross-reactivity and immunology of β-lactam antibiotics. Drug Saf . 1994; 10:318-27. [PubMed 8018304]

780. Pharmacia and Upjohn Company. Colestid® (colestipol hydrochloride) tablets prescribing information. New York, NY; 2017 May.

781. Lott JA, Stephan VA, Pritchard KA. Evaluation of the Coomassie brilliant blue G-250 method for urinary protein. Clin Chem . 1983; 29:1946-50. [PubMed 6354513]

782. Davis BD. Bactericidal synergism between β-lactams and aminoglycosides: mechanism and possible therapeutic implications. Rev Infect Dis . 1982; 4:237-46. [PubMed 7051225]

783. Johnson RC, Kodner CB, Jurkovich PJ et al. Comparative in vitro and in vivo susceptibilities of the Lyme disease spirochete Borrelia burgdorferi to cefuroxime and other antimicrobial agents. Antimicrob Agents Chemother . 1990; 34:2133-6. [PubMedCentral][PubMed 2073103]

784. Yosselson-Superstine S, Granit D, Superstine E. Drug interferences with tests performed by a 12-channel autoanalyzer. Am J Hosp Pharm . 1980; 37:1333-8. [PubMed 7424929]

786. Wendel GD, Stark BJ, Jamison RB et al. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med . 1985; 312:1229-32. [PubMed 3921835]

787. Joorabchi B, Kohout E. Apparent penicillin-induced arrest of mature bone marrow elements. Br Med J . 1973; 2:26-7. [PubMedCentral][PubMed 4695694]

788. Andrassy K, Ritz E, Hasper B et al. Penicillin-induced coagulation disorder. Lancet . 1976; 2:1039-41. [PubMed 62897]

790. Tattersall MH, Battersby G, Spiers AS. Antibiotics and hypokalaemia. Lancet . 1972; 1:630-1. [PubMed 4110324]

795. Healy JK, Edwards KD, Whyte HM. Simple tests of renal function using creatinine, phenolsulphonphthalein, and pitressin. J Clin Pathol . 1964; 17:557-63. [PubMedCentral][PubMed 14207792]

796. Bracco G, Pagliardini S. Guthrie test recalls due to antibiotic inhibition. Lancet . 1983; 1:1331-2. [PubMed 6134115]

797. Kornfeld JM, Ullmann WW. Penicillin interference with the determination of δ-aminolevulinic acid. Clin Chim Acta . 1973; 46:187-90. [PubMed 4745363]

798. Whipple RL, Bloom WL. The occurrence of false positive tests for albumin and glucose in the urine during the course of massive penicillin therapy. J Lab Clin Med . 1950; 36:635-9. [PubMed 14779080]

800. Lum G, Gambino SR. Comparison of four methods for measuring uric acid: copper-chelate, phosphotungstate, manual uricase, and automated kinetic uricase. Clin Chem . 1973; 19:1184-6. [PubMed 4741958]

801. Bower BF, McComb R, Ruderman M. Effect of penicillin on urinary 17-ketogenic and 17-ketosteroid excretion. N Engl J Med . 1967; 277:530-2. [PubMed 6034894]

802. Arvan DA, Ritz A. Measurement of serum albumin by the HABA-dye technique: a study of the effect of free and conjugated bilirubin, of bile acids and of certain drugs. Clin Chim Acta . 1969; 26:505-16. [PubMed 5390906]

803. Beng CG, Lim KL. An improved automated method for determination of serum albumin using bromcresol green. Am J Clin Pathol . 1973; 59:14-21. [PubMed 4688562]

812. Almeyda J, Levantine A. Drug reactions XIX: adverse cutaneous reactions to the penicillins—ampicillin rashes. Br J Dermatol . 1972; 87:293-6. [PubMed 4342950]

824. Bierman CW, Pierson WE, Zeitz SJ et al. Reactions associated with ampicillin therapy. JAMA . 1972; 220:1098-100. [PubMed 5067510]

825. Stewart RH, Webster SB. Cross reactivity between ampicillin and penicillin G. JAMA . 1970; 213:131. [PubMed 4246490]

827. Shapiro S, Slone D, Siskind V et al. Drug rash with ampicillin and other penicillins. Lancet . 1969; 2:969-72. [PubMed 4186974]

828. Levine BB. Skin rashes with penicillin therapy: current management. N Engl J Med . 1972; 286:42-3. [PubMed 5006924]

849. Holmes KK, Karney WW, Harnisch JP et al. Single-dose aqueous procaine penicillin G therapy for gonorrhea: use of probenecid and cause of treatment failure. J Infect Dis . 1973; 127:455-60. [PubMed 4632882]

858. Landis SJ, Ramphal R, Mansheim BJ et al. Comparative efficacy of piperacillin and penicillin G in treatment of gonococcal urethritis. Antimicrob Agents Chemother . 1981; 20:693-5. [PubMedCentral][PubMed 6459764]

886. Rothstein RJ, Baker FJ. Tetanus: prevention and treatment. JAMA . 1978; 240:675-6. [PubMed 671693]

887. Raffin BJ, Freemark M. Streptobacillary rat-bite fever: a pediatric problem. Pediatrics . 1979; 64:214-7. [PubMed 112571]

898. Robbins TS, Scott SA. Actinomycosis: the disease and its treatment. Drug Intell Clin Pharm . 1981; 15:99-102. [PubMed 7274029]

900. McCloskey RV, Green MJ, Eller J et al. Treatment of diphtheria carriers: benzathine penicillin, erythromycin, and clindamycin. Ann Intern Med . 1974; 81:788-91. [PubMed 4215352]

901. de la Monte SM, Gupta PK, White CL. Systemic Actinomyces infection: a potential complication of intrauterine contraceptive devices. JAMA . 1982; 248:1876-7. [PubMed 7120609]

906. Eichenwald HF, McCracken GH. Antimicrobial therapy in infants and children. Part I. Review of antimicrobial agents. J Pediatr . 1978; 93:336-56.

923. Schwartz RH, Wientzen RL, Pedreiro F et al. Penicillin V for group A streptococcal pharyngotonsillitis: a randomized trial of seven vs ten days' therapy. JAMA . 1981; 246:1790-5. [PubMed 6792379]

924. Massel BF. Prophylaxis of streptococcal infections and rheumatic fever: a comparison of orally administered clindamycin and penicillin. JAMA . 1979; 241:1589-94. [PubMed 372593]

928. Wilson WR, Geraci JE, Wilkowske CJ et al. Short-term intramuscular therapy with procaine penicillin plus streptomycin for infective endocarditis due to viridans streptococci. Circulation . 1978; 57:1158-60. [PubMed 639238]

986. Bell WE. Treatment of bacterial infections of the central nervous system. Ann Neurol . 1981; 9:313-27. [PubMed 7013653]