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Introduction ⬇

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Associated Monographs

Aminopenicillins are semisynthetic penicillin antibiotics that have enhanced activity against gram-negative bacteria compared with natural and penicillinase-resistant penicillins.61,62,68,74,76,88,575,869

Uses ⬆ ⬇

[Section Outline]

Amoxicillin36,61,67,73,428,742 and ampicillin38,39,42,45,46,48,49,61,67,741,917,1098 are used orally for the treatment of upper and lower respiratory tract infections,61,67,73,428,726,732 GI tract infections,67,73 skin and skin structure infections,67,73,428,732 genitourinary tract infections,61,67,73,428,732 and otitis media61,67,428,449,728,732,742 caused by susceptible organisms. Ampicillin is used IM or IV for the treatment of meningitis, endocarditis, or severe respiratory tract, GI tract, bone and joint, or genitourinary tract infections caused by susceptible organisms.38,39,61,63,67,736,751,985 For information on the uses of amoxicillin in fixed combination with clavulanic acid (amoxicillin/clavulanate) or information on the uses of ampicillin sodium in fixed combination with sulbactam sodium (ampicillin/sulbactam), see Amoxicillin and Clavulanate Potassium or Ampicillin Sodium and Sulbactam Sodium 8:12.16.08.

Aminopenicillins are used principally for the treatment of infections caused by susceptible and gram-negative aerobic bacilli (e.g., Haemophilus influenzae , Escherichia coli , Proteus mirabilis , Salmonella ).36,38,39,42,45,46,48,49,61,67,72,864 Aminopenicillins also are used for the treatment of infections caused by susceptible gram-positive aerobic cocci (e.g., enterococci, Streptococcus pneumoniae , nonpenicillinase-producing Staphylococcus aureus and S. epidermidis ) or gram-positive bacilli (e.g., Listeria monocytogenes ).36,38,39,42,45,46,48,49,61,67,864 However, with the possible exception of enterococcal infections, natural penicillins generally are the penicillins of choice for the treatment of infections caused by susceptible gram-positive cocci and aminopenicillins should not be used when penicillin G or penicillin V would be effective.63,64,67,80,864,869,904,906

Amoxicillin and ampicillin appear to be equally effective for the treatment of most infections when used in appropriate dosages and, except for infections caused by Salmonella or Shigella , therapeutic superiority of either agent over the other has not been definitely established.67,73,76,461,741,742,744,906 Some clinicians suggest that oral amoxicillin61,74,511,744,864,906 may be preferred to oral ampicillin, especially for the treatment of respiratory tract infections, because of more complete absorption from the GI tract, higher serum and body tissue and fluid anti-infective concentrations attained following oral administration,511,906,907 less frequent dosing requirements,74,864,906 and a lower incidence of diarrhea.864,906,907

Prior to initiation of therapy with an aminopenicillin, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests.36,38,39,42,45,46,48,49 Aminopenicillin therapy may be started pending results of susceptibility tests but should be discontinued if the causative organism is found to be resistant to the drugs.36,38,39,42,45,46,48,49

Gram-positive Aerobic Bacterial Infections !!navigator!!

Streptococcal and Staphylococcal Infections

Aminopenicillins generally are effective when used for the treatment of otitis media,64 skin and skin structure infections,1089 and upper and lower respiratory tract infections64 such as tonsillitis, pharyngitis, epiglottitis, sinusitis, and acute exacerbations of chronic bronchitis caused by susceptible gram-positive aerobic cocci (e.g., S. pneumoniae , S. pyogenes [group A β-hemolytic streptococci], groups B, C, or G streptococci, nonpenicillinase-producing S. aureus and S. epidermidis ).64,1055 However, natural penicillins generally are the drugs of choice for the treatment of infections caused by susceptible strains of S. pneumoniae ,63,64,67,744,866,869,1071 groups A, B, C, or G streptococci,61,63,64,67,70,72,867,869,904,906,939,1055,1089 nonenterococcal group D streptococci,63 viridans streptococci,63,64,869 and nonpenicillinase-producing staphylococci.61,64,67,70,71,867,1089

Amoxicillin is considered by some clinicians to be a drug of choice for the empiric treatment of otitis media and many respiratory tract infections since it generally is active against both S. pneumoniae and H. influenzae , the principal etiologic agents of these infections, unless there is a high incidence of ampicillin-resistant H. influenzae in the community.61,72,866,917,971,1098,2343 (See Haemophilus Infections in Uses: Gram-negative Bacterial Infections.)

Amoxicillin is used for the treatment of pharyngitis or tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci; GAS).292,375,580 The American Academy of Pediatrics (AAP),292 Infectious Diseases Society of America (IDSA),580 and American Heart Association (AHA)375 recommend a penicillin regimen (i.e., 10 days of oral penicillin V or oral amoxicillin or a single dose of IM penicillin G benzathine) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever.292,375,580 Although anti-infective therapy is not indicated for most chronic carriers of S. pyogenes , the fixed combination of amoxicillin sodium and clavulanate potassium is one of several options when eradication of S. pyogenes carriage is desirable.292,580

Because aminopenicillins are inactivated by staphylococcal penicillinases, the drugs are ineffective for the treatment of infections caused by penicillinase-producing S. aureus or S. epidermidis .36,38,39,42,45,46,48,49,61,67

Enterococcal Infections

Ampicillin38,39,42,45,46,48,49,61,67,904,2254 and amoxicillin36,61,67,904,1070,2254 are used orally for the treatment of urinary tract infections (UTIs) caused by susceptible enterococci, including E. faecalis , E. faecium , and E. durans . Amoxicillin and ampicillin have been considered drugs of choice for the treatment of enterococcal UTIs and, because of high urinary concentrations, the drugs may be effective in these infections when used alone.61,67,904,2254 Aminopenicillins, usually used in conjunction with an aminoglycoside, also are used for the treatment of septicemia or endocarditis caused by enterococci.64,80,450,452,904,2254 In vitro studies indicate that penicillins, including aminopenicillins, are generally only bacteriostatic against enterococci when used alone;942,947 however, a synergistic bactericidal effect has been demonstrated against enterococci in vitro and in animal studies when an aminoglycoside is used in conjunction with a penicillin.80,116,942,947,1175 (See Drug Interactions: Aminoglycosides.) Therefore, a penicillin is generally used parenterally in conjunction with an aminoglycoside for the treatment of endocarditis or other severe infections caused by enterococci.64,80,450,452,904,947,1175

For the treatment of enterococcal endocarditis involving native valves or prosthetic valves or other prosthetic material caused by E. faecalis , E. faecium , or other enterococcal species susceptible to both penicillin and gentamicin, AHA states that a regimen of IV ampicillin sodium or IV penicillin G sodium given in conjunction with gentamicin is a reasonable choice.450,452 Treatment with the penicillin and aminoglycoside generally should be continued for a minimum of 4 weeks, but patients who have had symptoms of infection for more than 3 months prior to initiation of treatment and patients with prosthetic heart valves require a minimum of 6 weeks of therapy with both drugs.450 Partly because aminopenicillins are reported to be more active in vitro than natural penicillins against enterococci, some clinicians prefer IV ampicillin instead of IV penicillin G for the treatment of infections caused by E. faecalis .61,63,64,67,282,864,947 However, there are no controlled studies indicating whether IV ampicillin used in conjunction with an aminoglycoside is more effective than IV penicillin G used in conjunction with an aminoglycoside for the treatment of enterococcal endocarditis.947,1175

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

Listeria Infections

IV ampicillin61,63,67,869,904,1647,2343,2371 used alone or in conjunction with an aminoglycoside (e.g., gentamicin, kanamycin) generally is considered the treatment of choice for infections caused by Listeria monocytogenes (e.g., infections during pregnancy, granulomatosis infantiseptica, sepsis, endocarditis, meningitis, foodborne infections).61,63,67,298,869,904,905,1196,1197,1647,2254 IV penicillin G used alone or in conjunction with other anti-infectives may also be effective in these infections,64,869,1196,1197 but IV ampicillin generally is preferred.63,67,298,869,904,905,986,1196,1197,1198,2343,2371

For the treatment of foodborne Listeria infections, CDC recommends use of IV ampicillin, penicillin G, or co-trimoxazole when there is invasive disease.2524 The incubation period following ingestion of food contaminated with Listeria (e.g., soft cheeses, unpasteurized or inadequately pasteurized milk, deli meats, hot dogs) usually is 9-48 hours for GI symptoms and 2-6 weeks for invasive disease.2524

Nocardiosis

Ampicillin has been used in conjunction with sulfonamides or co-trimoxazole for the treatment of infections caused by Nocardia †.904,1412 Co-trimoxazole or a sulfonamide alone generally is considered the treatment of choice for nocardiosis,869,904,1402,2254 and tetracyclines, imipenem or meropenem, cycloserine, or linezolid are alternatives.2254

Anthrax

Amoxicillin is used as an alternative for postexposure prophylaxis of anthrax† following exposure to Bacillus anthracis spores and amoxicillin and ampicillin are used as alternatives for the treatment of anthrax†.671,672,673,2502,2505,2506 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).2499,2501,2502,2510 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.2502,2506,2510

Postexposure Prophylaxis of Anthrax

Ciprofloxacin or doxycycline generally are considered the initial drugs of choice for postexposure prophylaxis following suspected or confirmed exposure to aerosolized B. anthracis spores that occurs in the context of biologic warfare or bioterrorism.671,672,673,2499,2502,2505,2506,2508 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).671,672,673,2499,2502,2506,2507,2508,2509 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, 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.2506,2509

The possible benefits of postexposure prophylaxis against anthrax should be weighed against the possible risks to the fetus when choosing an anti-infective for postexposure prophylaxis in pregnant women.2509 CDC and other experts state that ciprofloxacin should be considered the drug of choice for initial postexposure prophylaxis in pregnant women exposed to B. anthracis spores and that, if in vitro studies indicate that the organism is susceptible to penicillin, then consideration can be given to changing the postexposure regimen to amoxicillin.672,2502,2509

Anti-infective postexposure prophylaxis should be continued until exposure to B. anthracis has been excluded.2499 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.671,672,673,2499,2502,2505,2508

Cutaneous Anthrax

Although natural penicillins (e.g., oral penicillin V, penicillin G benzathine, IM penicillin G procaine) generally have been considered drugs of choice for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible strains of B. anthracis that occurs as the result of naturally occurring or endemic exposure to anthrax,2500,2501,2502 the initial drugs of choice for the treatment of cutaneous anthrax that occurs following exposure to B. anthracis spores in the context of biologic warfare or bioterrorism are ciprofloxacin or doxycycline.671,672,673,2506 If penicillin susceptibility is confirmed, consideration can be given to changing to a penicillin (oral amoxicillin or oral penicillin V) in infants and children, pregnant or lactating women, or when the drugs of choice are not tolerated or not available;671,672,673,2506 oral amoxicillin may be preferred, especially in infants and children.671,672,673 Use of a multiple-drug parenteral regimen is recommended for the initial treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or lesions on the head and neck.671,672,673,2500,2502,2506

Although 5-10 days of anti-infective therapy may be adequate for the treatment of mild, uncomplicated cutaneous anthrax that occurs as the result of natural or endemic exposures to anthrax, CDC and other experts recommend that therapy be continued for 60 days if the cutaneous infection occurred as the result of exposure to aerosolized anthrax spores since the possibility of inhalational anthrax would also exist.671,672,673,2502,2506 Anti-infective therapy may limit the size of the cutaneous anthrax lesion and it usually becomes sterile within the first 24 hours of treatment, but the lesion will still progress through the black eschar stage despite effective treatment.2500,2501,2502

Gram-negative Aerobic Bacterial Infections !!navigator!!

Aminopenicillins are used for the treatment of a variety of infections caused by susceptible H. influenzae 36,38,39,42,45,46,48,49,61,64,726,866,869,917,1275 and for the treatment of infections caused by susceptible Enterobacteriaceae, including susceptible strains of E. coli , P. mirabilis , Salmonella , and Shigella .36,38,39,42,45,46,48,49,61,64 Aminopenicillins generally are inactive against other Enterobacteriaceae (e.g., Citrobacter , Enterobacter , Klebsiella , Proteus species other than P. mirabilis , Serratia )61,63,116,226 and Pseudomonas ,61,73,116,217,226,228,317 and should not be used alone in the empiric treatment of gram-negative bacterial infections that may be caused by these organisms.61,63,906

Strains of E. coli resistant to aminopenicillins have been reported with increasing frequency.61,64,74,139 Although amoxicillin and ampicillin have been used for the treatment of uncomplicated urinary tract infections caused by susceptible E. coli or P. mirabilis ,63,67,1007,1009,1017,1096,1127 other anti-infectives (e.g., fluoroquinolones, oral amoxicillin and clavulanate potassium, oral third generation cephalosporins) frequently are recommended for the treatment of uncomplicated urinary tract infections caused by susceptible Enterobacteriaceae in outpatients.2254 Some clinicians consider ampicillin, used alone or in conjunction with an aminoglycoside, the treatment of choice for infections caused by P. mirabilis .63,67,2254 (See Urinary Tract Infections in Uses: Gram-negative Aerobic Bacterial Infections.)

Haemophilus Infections

Aminopenicillins are used orally in infants, children, or adults for the treatment of otitis media61,511,728,731,741,742,744,869,906,917,1069,1098,1389,1656,1657,1661,1664,1672,2343,2361,2362 or upper and lower respiratory tract infections61,64,726,744,869 such as bronchopneumonia,744 sinusitis,744,866,867,869,979 and acute exacerbations of chronic bronchitis744 caused by susceptible H. influenzae or H. parainfluenzae . Ampicillin also is used IM or IV in conjunction with chloramphenicol for the initial treatment of meningitis caused by H. influenzae 39,63,67,736,751,869,985,1275 (see Uses: Meningitis) or osteomyelitis, septic arthritis, cellulitis, epiglottitis, septicemia, or other serious infections caused by the organism.39,61,63,67,736,751,985,1275 Because of the increasing incidence of ampicillin-resistant H. influenzae and because strains of the organism resistant to chloramphenicol or co-trimoxazole or to both ampicillin and one of these drugs have been reported rarely, most clinicians state that empiric treatment of serious infections that may be caused by H. influenzae should be based on the local pattern of resistance of the organism.736,869,958,1275,1299,1402,1731 Co-trimoxazole is considered by many clinicians to be the drug of choice for empiric treatment of upper respiratory tract infections or bronchitis caused by H. influenzae .2254 For empiric treatment of serious infections caused by H. influenzae , many clinicians recommend that cefuroxime, cefotaxime, or ceftriaxone be used for empiric treatment of these infections.736,869,958,1275,1299,1402,2254 However, some clinicians still consider aminopenicillins the drugs of choice for the treatment of infections caused by susceptible strains of H. influenzae .72,866,869

Although oral ampicillin has been used for chemoprophylaxis in day-care center contacts of children with H. influenzae type b meningitis†,1964 efficacy of anti-infective prophylaxis in preventing H. influenzae disease has not been determined to date and AAP states that, when prophylaxis is indicated, rifampin is the drug of choice.2343

Aminopenicillins are used orally for the prophylaxis† and treatment of acute exacerbations of chronic bronchitis caused by susceptible H. influenzae , H. parainfluenzae , or S. pneumoniae .67,431,725,726,744,793,905,975,980,1174,1192 Although some clinicians recommend the use of amoxicillin61,431,474 rather than ampicillin for the treatment of bronchitis because of higher serum, sputum, and tissue anti-infective concentrations attained with these aminopenicillins, controlled studies indicate that amoxicillin and ampicillin are equally effective for the treatment of acute exacerbations of chronic bronchitis.76,725,744,980 Studies using ampicillin, amoxicillin, tetracycline, and co-trimoxazole in the treatment of acute exacerbations of chronic bronchitis suggest that these anti-infectives are probably all equally effective.61,1143,1174 Therefore, most clinicians recommend basing the choice of anti-infective used for prophylaxis or treatment of acute exacerbations of chronic bronchitis on the current pattern of resistance of H. influenzae in the community and also recommend rotating the commonly used anti-infectives.1143,1174 Bacteriologic cures cannot be expected in all patients with chronic respiratory disease caused by H. influenzae following treatment with an aminopenicillin.73,866,1174 Although anti-infective therapy may decrease the severity and duration of acute episodes of bronchitis if initiated as soon as symptoms become apparent, there are no data from well-designed clinical studies to date that demonstrate whether prophylactic anti-infective therapy has any effect on the frequency of acute exacerbations or on the long-term prognosis of patients with chronic bronchitis.725,866,1174,1192

Gonorrhea and Associated Infections

Amoxicillin36,481,844,845,850,851,852,854,1518,1519 and ampicillin42,45,46,48,49,481,844,854,1518,1519 were used in the past for the treatment of uncomplicated gonorrhea and disseminated gonococcal infections caused by nonpenicillinase-producing strains of N. gonorrhoeae ; however, penicillins are no longer recommended for the treatment of uncomplicated or disseminated gonococcal infections and are not included in CDC guidelines for treatment of the disease.344

Urinary Tract Infections

Aminopenicillins are used orally for the treatment of urinary tract infections (UTIs) caused by susceptible organisms, including uncomplicated UTIs known to be caused by susceptible E. coli or P. mirabilis ;61,64,67,73,727,866,905,1010 however, some experts consider co-trimoxazole the drug of choice for empiric treatment of uncomplicated UTIs pending results of in vitro susceptibility tests.2254 Aminopenicillins may be ineffective for the treatment of chronic bacteriuria or complicated UTIs because these infections generally relapse or become reinfected with bacteria resistant to the drugs (e.g., Klebsiella , Enterobacter ).61 Parenteral anti-infective therapy (e.g., an aminoglycoside) is generally used for the treatment of pyelonephritis or complicated UTIs, although oral ampicillin may be used as follow-up after parenteral therapy.1096 Although safe use of aminopenicillins during pregnancy has not been definitely established, ampicillin frequently is used for the treatment of UTIs during pregnancy.61,468,1145

Oral amoxicillin has been shown to be effective for the treatment of acute, uncomplicated UTIs in some women when given as a single dose†.866,905,1007,1009,1017,1071,1096,1127,1574 Although results of some controlled studies indicate that single-dose therapy with oral amoxicillin (3 g), oral sulfisoxazole (2 g), or oral co-trimoxazole (320 mg trimethoprim and 1600 mg sulfamethoxazole) is equally effective for the treatment of acute, uncomplicated UTIs in women,1096,1127,1145 results of other studies suggest that a single dose of amoxicillin is less effective than a single dose of co-trimoxazole in these infections.1411,1555 Some clinicians suggest that single-dose therapy with amoxicillin, co-trimoxazole, or sulfisoxazole may be as effective as conventional 5- to 14-day anti-infective therapy in women and is generally associated with fewer adverse effects, a reduced rate of emergence of resistant bacteria, and less of an effect on the normal GI, urinary, or perineal flora.1012,1017,1096,1127,1145 However, other clinicians suggest that further study is needed to establish the relative rate of relapse and recurrence of infection following use of single-dose or conventional therapy for the treatment of uncomplicated UTIs.1016,1411,1555,1574 If amoxicillin is administered as a single dose for the treatment of acute, uncomplicated UTIs in women, many clinicians recommend that follow-up cultures be done 3-7 days after administration of the dose.1017,1127 Women who have recurrence of their acute infection within 2 weeks after use of a single dose of amoxicillin may have renal infections and should receive the conventional 5-14 days of anti-infective therapy.1127 Single-dose anti-infective therapy is generally ineffective for the treatment of UTIs in patients with underlying urinary tract abnormalities or patients with acute pyelonephritis.1007,1096,1127,1411 Single-dose amoxicillin therapy should not be used for the treatment of asymptomatic bacteriuria or uncomplicated UTIs in men or in pregnant women since single-dose anti-infective regimens have not been adequately studied to date in these patients.1096,1127 Although results of one preliminary study in females 2-18 years of age with lower UTIs indicate that a single oral dose of amoxicillin (50 mg/kg) is as effective as 10 days of amoxicillin therapy (40 mg/kg daily given in 3 divided doses),1016 further study is needed to evaluate efficacy of single-dose anti-infective regimens for the treatment of these infections in children.1016,1096

Typhoid Fever and Other Salmonella Infections

Typhoid Fever

Ampicillin61,64,292,867,869,879,888,890,892,911,1053,1282,2254 and amoxicillin†292,744,866,867,879,883,885,892,911,2254 are used in adults or children for the treatment of typhoid fever (enteric fever) caused by susceptible strains of Salmonella typhi . There is some evidence that IV ampicillin is more effective than oral ampicillin for the treatment of typhoid fever. In one controlled study in children, IV amoxicillin (100 mg/kg daily given in 3 equally divided doses) was as effective as IV ampicillin (100 mg/kg given in 4 equally divided doses) for the treatment of typhoid fever;879 however, there are no controlled studies to date comparing efficacy of oral ampicillin and oral amoxicillin in the treatment of the disease. Although the time to defervescence in typhoid fever is reportedly slower with ampicillin therapy than with chloramphenicol therapy,61,869,888,892,911,1282 results of a few controlled studies indicate that the response time is faster with amoxicillin than with chloramphenicol.883,885

Various anti-infectives have been used for the treatment of typhoid fever, including chloramphenicol, ampicillin, amoxicillin, co-trimoxazole, cefotaxime, ceftriaxone, or fluoroquinolones.2304,2305,2306,2343 Multidrug-resistant strains of S. typhi (i.e., strains resistant to ampicillin, chloramphenicol, and/or co-trimoxazole) have been reported with increasing frequency, and a third generation cephalosporin (e.g., ceftriaxone, cefotaxime) or a fluoroquinolone (e.g., ciprofloxacin, ofloxacin) are considered the drugs of first choice for the treatment of typhoid fever or other severe infections known or suspected to be caused by these strains.2343,2354,2304,2305,2306

The treatment of choice for chronic typhoid carriers is usually an oral fluoroquinolone (e.g., ciprofloxacin); amoxicillin or ampicillin have also been used.866,867,869,876,884,880,892,2254 Amoxicillin, ampicillin, or ciprofloxacin is used in conjunction with cholecystectomy for the treatment of chronic typhoid carriers with gallbladder disease.866,867,869,880,2343

Salmonella Gastroenteritis

Ampicillin and amoxicillin have been used in the treatment of acute enterocolitis or uncomplicated gastroenteritis caused by Salmonella .867,878 The incubation period for Salmonella gastroenteritis usually is 1-3 days and this foodborne-illness usually is associated with ingestion of contaminated eggs, poultry, unpasteurized milk or juice, cheese, and raw fruits and vegetables (alfalfa sprouts, melons).2524 Anti-infectives generally are not indicated in the treatment of uncomplicated (noninvasive) gastroenteritis caused by Salmonella (e.g., S. enteritidis , S. typhimurium ) since such therapy may prolong the period of fecal excretion of the organism and there is no evidence that is shortens the duration of the disease.64,866,867,869,878,892,1071,1094,2343,2524,2527 Most cases of uncomplicated gastroenteritis caused by Salmonella should be treated with fluid and electrolyte replacement as needed and generally subside spontaneously without anti-infective therapy.866,867,869,1071,1094,2254,2343 However, CDC, AAP, IDSA, and others recommend anti-infective therapy (in addition to fluid and electrolyte replacement) in individuals with severe Salmonella gastroenteritis and in those who are at increased risk of invasive disease.2343,2524,2527 These individuals include infants younger than 3-6 months of a individuals older than 50 years of a individuals with hemoglobinopathies, severe atherosclerosis or valvular heart disease, prostheses, uremia, chronic GI disease, or severe colitis; and individuals who are immunocompromised because of malignancy, immunosuppressive therapy, HIV infection, or other immunosuppressive illness.64,292,866,867,869,1094,1402,2343,2524,2527

When an anti-infective agent is considered necessary in an individual with Salmonella gastroenteritis, CDC, AAP, IDSA, and others recommend use of ceftriaxone, cefotaxime, a fluoroquinolone (should be used in children only if the benefits outweigh the risks and no other alternative exists), ampicillin, amoxicillin, co-trimoxazole, or chloramphenicol, depending on the susceptibility of the causative organism.2337,2343,2524,2527 The fact that multidrug-resistant Salmonella serotype Newport have been reported with increasing frequency in the US should be considered.2528 During January-April 2002, 47 cases of gastritis caused by Salmonella Newport were reported to CDC; the vehicle of transmission appeared to be exposure to raw or undercooked ground beef.2528 These strains usually are resistant to ampicillin, amoxicillin and clavulanate potassium, cefoxitin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline and have either decreased susceptibility or resistance to ceftriaxone.2528

Shigella Infections

Ampicillin61,63,869,889,891,904,1274 has been effective when used in the treatment of GI tract infections caused by susceptible strains of Shigella . Anti-infective therapy generally is indicated in addition to fluid and electrolyte replacement for the treatment of severe cases of shigellosis61,869,889,911,1094,1274,2343 since anti-infectives appear to shorten the duration of diarrhea and the period of fecal excretion of Shigella .869,889,911,1094,2343 Although ampicillin previously was considered the anti-infective of choice for the treatment of shigellosis,61,63,889,904,911,1094 especially in children, strains of Sh. flexneri and Sh. sonnei resistant to ampicillin have been reported with increasing frequency.61,74,869,881,911 Therefore, fluoroquinolones, ceftriaxone, or co-trimoxazole are considered the anti-infectives of choice for the treatment of shigellosis when the susceptibility of the isolate is unknown,61,881,869,1094,2254,2343 especially in areas where ampicillin-resistant strains of Shigella have been reported.869,881,2343

Amoxicillin should not be used in the treatment of shigellosis61,744,906 because it is less active in vitro on a weight basis than ampicillin against susceptible strains of Shigella 229,744 and has been ineffective when used in the treatment of infections caused by this organism.64,73,461,869,877 The ineffectiveness of amoxicillin in the treatment of shigellosis may partly result from low intraluminal (GI) concentrations of amoxicillin attained following oral administration.744,877,906

Helicobacter pylori Infection

Amoxicillin is used in combination with clarithromycin and lansoprazole or omeprazole (triple therapy) for the treatment of Helicobacter pylori infection in patients with duodenal ulcer disease (active or 1-year history of duodenal ulcer).36,2283,2284,2288,2289,2290,2291 Amoxicillin also is used in combination with lansoprazole (dual therapy) for the treatment of H. pylori infection and duodenal ulcer disease in patients who are either allergic to or intolerant of clarithromycin or in whom clarithromycin resistance is known or suspected.36,2283,2284 Amoxicillin also has been used in other multiple drug regimens† for the treatment of H. pylori infection and peptic ulcer disease.1845,1848,1849,1850,1851,1852,1853,1854,1855,1856,1857,1858,1859,1860,1861,1862,1863,2114,2209,2210,2211,2212,2213,2214,2215,2216,2217,2218,2219,2221,2222,2255,2256,2257,2258,2259,2260,2261,2284,2291 Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers;1845,1848,1851,1854,1864,1865,1866,1867,1868,1869,2112,2114,2209,2214,2255,2256,2257,2258 long-term H. pylori infection also has been implicated as a risk factor for gastric cancer.1848,1867,1870,1871,1872,1873,1874,1875,1876,1877,1878,2114,2209,2258

Conventional antiulcer therapy with H2-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori , and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year).1845,1854,1869,2114,2255,2256,2258 The American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.2224,2255,2256,2257,2258 Although 3-drug regimens consisting of a bismuth salt (e.g., bismuth subsalicylate) and 2 anti-infective agents (e.g., tetracycline or amoxicillin plus metronidazole) administered for 10-14 days have been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori -associated peptic ulcer disease,1845,1848,1849,1851,1852,1853,1863,1868,1879,1880,1881,1896,2112,2114,2209,2214,2215,2218,2255,2256,2257,2258,2259,2275,2291 current evidence principally from studies in Europe suggests that 1 week of such therapy provides H. pylori eradication rates comparable to those of longer treatment periods.2256,2257,2258 Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., lansoprazole, omeprazole, H2-receptor antagonist) also have been used successfully for H. pylori eradication,36,1845,1848,1849,1857,1858,1859,1860,1861,1881,1882,2114,2209,2210,2218,2219,2221,2222,2223,2224,2225,2226,2255,2256,2257,2258,2260,2261,2283,2284,2288,2289,2290,2291 and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.2114,2224,2256,2258,2262,2275

Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti- H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance.2256,2258,2291 Therefore, the ACG and many clinicians2258,2259,2260,2291 recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.2256,2258,2260,2291

Other Gram-negative Aerobic Bacterial Infections

Ampicillin is considered the drug of choice for the treatment of infections caused by Eikenella corrodens †.2254 Although natural penicillins are considered the drugs of choice for the treatment of infections caused by Pasteurella multocida †, amoxicillin and clavulanate potassium, and ampicillin sodium and sulbactam sodium are considered alternatives.2254

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections !!navigator!!

Amoxicillin and 1430 ampicillin61,472,856,857,1430 have been used for the treatment of anaerobic and mixed aerobic-anaerobic bacterial infections including biliary tract infections61,472 or gynecologic and obstetric infection such as acute pelvic inflammatory disease (PID)856,857 and postpartum infections†.856,857 However, aminopenicillins should not be used alone for the treatment of these infections, especially when Bacteroides fragilis may be present.61,856,1430

Meningitis !!navigator!!

IV ampicillin is used in adults, children, or neonates for the treatment of meningitis caused by susceptible H. influenzae ,39,736,751,985,1181,1182 S. pneumoniae ,736,751 or N. meningitidis .39,736,751 IV ampicillin also is used alone or in conjunction with an aminoglycoside (e.g., gentamicin) for the treatment of meningitis caused by L. monocytogenes †.61,986,1196,1197,2254

Empiric Treatment of Meningitis

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.2249,2298,2300,2301,2307,2343 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.2249,2298,2301,2307

Bacterial meningitis in neonates usually is caused by S. agalactiae (group B streptococci), L. monocytogenes , or aerobic gram-negative bacilli (e.g., E. coli , K. pneumoniae ).2249,2250,2254,2298,2299,2300,2301,2343 AAP recommends that neonates 4 weeks of age or younger with suspected bacterial meningitis receive an empiric regimen of IV ampicillin and an aminoglycoside pending results of CSF culture and susceptibility testing.2343 Alternatively, neonates can receive an empiric regimen of IV ampicillin and IV cefotaxime or IV ceftazidime with or without gentamicin.2249,2250,2254,2298,2299,2300,2301,2343 Because frequent use of cephalosporins in neonatal units may result in rapid emergence of resistant strains of some gram-negative bacilli (e.g., Enterobacter cloacae , Klebsiella , Serratia ), AAP cautions that cephalosporins should be used for empiric treatment of meningitis in neonates only if gram-negative bacterial meningitis is strongly suspected.2343 While S. pneumoniae is relatively rare in neonates, consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae is suspected.2343 Because premature, low-birthweight neonates are at increased risk for nosocomial infection caused by staphylococci or gram-negative bacilli, some clinicians suggest that these neonates receive an empiric regimen of IV ceftazidime and IV vancomycin.2301

In infants beyond the neonatal stage who are younger than 3 months of age, bacterial meningitis may be caused by S. agalactiae , L. monocytogenes , H. influenzae , S. pneumoniae , N. meningitidis , or aerobic gram-negative bacilli (e.g., E. coli , K. pneumoniae ).2249,2250,2298,2299,2300,2301,2343 The empiric regimen recommended for infants in this age group is IV ampicillin and either IV ceftriaxone or IV cefotaxime.2249,2250,2298,2299,2300,2301,2343 Consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae is suspected.2307,2343

In children 3 months through 17 years of age, bacterial meningitis usually is caused by N. meningitidis , S. pneumoniae , or H. influenzae , and the most common cause of bacterial meningitis in adults 18-50 years of age is N. meningitidis or S. pneumoniae .2249,2254,2298,2300,2301,2343 Some clinicians recommend that children 3 months through 17 years of age and adults 18-50 years of age receive IV ceftriaxone or IV cefotaxime for empiric therapy of suspected bacterial meningitis;2249,2254,2298,2299,2300,2301,2343 an alternative empiric regimen in children 3 months through 17 years of age is IV ampicillin and IV chloramphenicol.2249,2298 In addition, because of the increasing prevalence of penicillin-resistant S. pneumoniae that also are resistant to or have reduced susceptibility to cephalosporins, AAP and others recommend that the initial empiric cephalosporin regimen include IV vancomycin (with or without rifampin) pending results of in vitro susceptibility tests;2250,2254,2300,2307,2308,2309,2343 vancomycin and rifampin should be discontinued if the causative organism is found to be susceptible to the cephalosporin.2254,2307,2309 While L. monocytogenes meningitis is relatively rare in this age group, the empiric regimen should include ampicillin if L. monocytogenes is suspected.2298,2299

In adults older than 50 years of age, bacterial meningitis usually is caused by S. pneumoniae , L. monocytogenes , N. meningitidis , or aerobic gram-negative bacilli, and the empiric regimen recommended for this age group is IV ampicillin given in conjunction with IV cefotaxime or IV ceftriaxone.2298,2299,2301 Because of the increasing prevalence of penicillin-resistant S. pneumoniae , some clinicians suggest that the empiric regimen also should include IV vancomycin.2301,2308

Meningitis Caused by Haemophilus influenzae

AAP suggests that children with meningitis possibly caused by H. influenzae can receive an initial treatment regimen of ceftriaxone, cefotaxime, or a regimen of ampicillin given in conjunction with chloramphenicol;2343 some clinicians prefer ceftriaxone or cefotaxime for initial treatment of meningitis caused by susceptible H. influenzae since these cephalosporins are active against both penicillinase-producing and nonpenicillinase-producing strains.2249,2301,2254,2298 Because of the prevalence of ampicillin-resistant H. influenzae ,1299,1731,2343 ampicillin should not be used alone for empiric treatment of meningitis when H. influenzae may be involved.2343 The incidence of H. influenzae meningitis in the US has decreased considerably since H. influenzae type b conjugate vaccines became available for immunization of infants.2299,2300,2343

Meningitis Caused by Neisseria meningitidis

While both IV ampicillin and IV penicillin G may be used for the treatment of meningitis caused by N. meningitidis ,2298,2300,2301 AAP and other clinicians suggest that penicillin G is the drug of choice for the treatment of these infections and ceftriaxone and cefotaxime are acceptable alternatives.2301,2343

Meningitis Caused by Streptococcus agalactiae

For the initial treatment of meningitis or other severe infection caused by S. agalactiae (group B streptococci), a regimen of IV ampicillin or IV penicillin G given in conjunction with an aminoglycoside is recommended.2298,2301,2343 Some clinicians suggest that ampicillin is the drug of choice for the treatment of group B streptococcal meningitis and that an aminoglycoside (IV gentamicin) should be used concomitantly in the first 72 hours until in vitro susceptibility testing is completed and a clinical response if observed; thereafter, ampicillin can be given alone.2301

Meningitis Caused by Listeria monocytogenes

The optimal regimen for the treatment of meningitis caused by Listeria monocytogenes has not been established.2343,2371 AAP and other clinicians generally recommend that meningitis or other severe infection caused by L. monocytogenes be treated with a regimen of IV ampicillin used in conjunction with an aminoglycoside (usually gentamicin);2254,2301,2343,2371 alternatively, co-trimoxazole or a regimen of penicillin G used in conjunction with gentamicin can be used.2254,2298,2301,2371

Otitis Media !!navigator!!

Acute Otitis Media

Amoxicillin and amoxicillin and clavulanate potassium are used in the treatment of acute otitis media (AOM) and are considered the drugs of choice for uncomplicated AOM.683,1437,1656,1659,2180,2310,2311,2361,2362,2389,2398,2418,2429,2430,2432,2434,2450

AOM is the most frequently diagnosed bacterial infection in children, and 65-95% of children will have at least one episode of AOM by 3 years of age.2311,2394,2395,2362,2402,2413,2419,2432 Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis are the bacteria most frequently recovered from middle ear fluid of patients with AOM; S. pyogenes and S. aureus also are recovered rarely.683,2180,2361,2362,2398,2402,2404,2405,2426,2427,2432,2440,2441,2451,2478,2482 In addition, there is evidence that respiratory viruses (e.g., respiratory syncytial virus, rhinoviruses, influenza virus, parainfluenza virus, enteroviruses) may be present either alone or in combination with bacterial pathogens and may play a role in the etiology and pathogenesis of AOM in some patients.683,2310,2361,2362,2409,2410,2432,2458,2459,2482

Diagnosis and Management Strategies for AOM

AAP and American Academy of Family Physicians (AAFP) first issued evidence-based clinical practice guidelines for the diagnosis and management of AOM in 2004.683 In 2013, AAP revised and updated those guidelines after comprehensive reviews of more recent published evidence.683 The 2013 AAP evidence-based clinical practice guidelines provide recommendations for the diagnosis and management of uncomplicated AOM, including recurrent AOM, in children 6 months through 12 years of age and apply only to otherwise healthy children who do not have underlying conditions that may alter the natural course of AOM (e.g., tympanostomy tubes, cleft palate, genetic conditions with craniofacial abnormalities such as Down syndrome, immunodeficiencies, cochlear implants).683 These AAP guidelines should be consulted for additional information on diagnosis and management of AOM.683

Accurate diagnosis of AOM is critical for clinical decision-making since it avoids unnecessary treatment.683 AOM involves the presence of fluid in the middle ear accompanied by a wide spectrum of signs or symptoms of acute local or systemic illness (e.g., otalgia, otorrhea, hearing loss, swelling around the ear, vertigo, nystagmus, tinnitus, fever, irritability, headache, diarrhea, lethargy, anorexia, vomiting).683,2362,2404,2408,2419,2432 Older children with AOM usually have a history of rapid onset of ear pain,683 but preverbal infants and young children may have mild or nonspecific symptoms that overlap with those of an upper respiratory tract illness.683

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that clinicians should diagnose AOM in children who present with moderate to severe bulging of the tympanic membrane or new onset of otorrhea not due to acute otitis externa.683 A diagnosis of AOM also should be made in children who present with mild bulging of the tympanic membrane and recent (less than 48 hours) onset of ear pain (holding, tugging, rubbing of the ear in a nonverbal child) or intense erythema of the tympanic membrane.683 These guidelines state that a diagnosis of AOM should not be made in children who do not have middle ear effusion (MEE) based on pneumatic otoscopy and/or tympanometry.683

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that management of AOM should include an assessment of pain and, if ear pain is present, the clinician should recommend treatment to reduce the pain.683 AOM-associated pain can be substantial during the first few days of illness and often persists longer in young children.683 AAP states that pain management, especially during the first 24 hours of an AOM episode, should be addressed regardless of the use of anti-infectives.683 Treatment for otalgia should be selected based on a consideration of the benefits and risks and, whenever possible, incorporate parent and/or caregiver and patient preference.683 Acetaminophen or ibuprofen are effective for mild to moderate pain, readily available, and usually the mainstay of pain management for AOM.683

Up to 60-80% of cases of AOM resolve spontaneously within 7-14 days,2310,2311,2361,2362,2399,2404,2419,2465 and routine administration of anti-infectives is not considered necessary for the treatment of all cases of AOM.683,2399,2404,2408,2417,2425,2460,2461,2463,2464,2465,2469 Some clinicians have recommended that all cases of AOM be treated with an appropriate anti-infective regimen to facilitate resolution of the primary infection and associated symptoms and prevent suppurative complications or other sequelae, and state that judicious use of anti-infectives in the management of otitis media involves accurately diagnosing AOM and distinguishing AOM (which should be treated with anti-infectives) from otitis media with effusion (which is not usually treated with anti-infectives),2180,2184,2408,2413,2415,2416,2417,2419,2422,2424,2433,2435,2462,2482 However, for the majority of patients with uncomplicated AOM, anti-infective therapy appears to provide only minimal benefits in terms of resolution of the acute symptoms of infection (e.g., pain) and the proposed benefits of such therapy in terms of time to bacteriologic or clinical resolution of AOM or in terms of long-term consequences of otitis media (e.g., persistence of MEE, recurrence of AOM, hearing loss, need for adenoidectomy or insertion of tympanostomy tubes, mastoiditis) have never been substantiated in well-designed, placebo-controlled studies.683,2425,2460,2463,2464,2465,2466 In addition, there is evidence that overuse of anti-infectives, including overuse in the treatment of AOM, contributes to emergence of resistant bacteria (e.g., multidrug-resistant S. pneumoniae ).2460,2463,2465,2467,2476 Based on these considerations, many clinicians now recommend a management strategy for AOM that involves use of symptomatic care with analgesics and close observation via telephone contact or office visits for the majority of patients with uncomplicated AOM and use of anti-infectives only in those who do not have symptomatic improvement within 24-72 hours after diagnosis and in those who appear least likely to have spontaneous resolution and most likely to have poor outcomes (e.g., more acutely ill, those with 3 or more episodes of AOM in the past 18 months, history of serous otitis or tympanostomy tubes).683,2460,2466,2469

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age include an initial management option of observation with close follow-up without initial use of anti-infectives in certain selected children with uncomplicated AOM based on age, illness severity, and assurance of follow-up.683 The recommendation for initial observation with close follow-up in select children provides an opportunity for the patient to improve without anti-infectives and is based on results of randomized, controlled studies with limitations and consideration of the benefits and risks of such a strategy.683

Current AAP guidelines state that anti-infective treatment should be initiated in children 6 months of age or older who have AOM (bilateral or unilateral) with severe signs or symptoms (i.e., moderate or severe otalgia, otalgia for at least 48 hours, or temperature 39°C or higher) and in children 6 through 23 months of age who have nonsevere bilateral AOM without signs or symptoms (i.e., mild otalgia for less than 48 hours and temperature less than 39°C).683 However, these guidelines state that a management strategy of either initiation of anti-infective treatment or observation with close follow-up can be used in children 6 through 23 months of age who have nonsevere unilateral AOM without severe signs or symptoms (i.e., mild otalgia for less than 48 hours, temperature less than 39°C) and in children 24 months of age or older with nonsevere AOM (bilateral or unilateral) without severe signs or symptoms (i.e., mild otalgia for less than 48 hours, temperature less than 39°C).683 The strategy of observation with close follow-up should be based on joint decision-making between the clinician and the parent and/or caregiver and must include a mechanism that ensures follow-up and initiation of anti-infective therapy if AOM worsens or fails to improve within 48-72 hours after symptom onset.683

If the initial management strategy was observation with close follow-up, anti-infective therapy should be initiated if symptoms worsen or there is no improvement within 48-72 hours after onset of symptoms.683 If the initial management strategy was anti-infective treatment, consideration should be given to changing the anti-infective regimen if symptoms worsen or fail to respond within 48-72 hours after initiation of treatment.683 (See Anti-infectives for AOM after Initial Treatment Failure under Uses: Otitis Media.)

After the patient has shown clinical improvement, follow-up is based on the usual clinical course of AOM.683 Persistent MEE is common after resolution of acute symptoms of AOM and should not be viewed as requiring active therapy.683 (See Otitis Media with Effusion under Uses: Otitis Media.)

Anti-infectives for Initial Treatment of AOM

When anti-infectives are indicated for treatment of AOM, the initial anti-infective agent usually is selected empirically based on efficacy against the most probable bacterial pathogens.2178,2402,2404,2413,2419,2433,2440,2479 Other considerations in the choice of an anti-infective for initial empiric treatment of AOM include pharmacokinetic data related to distribution of the drug into middle ear fluid, compliance issues related to patient acceptance of dosage formulation and dosage schedule, adverse effects profile, and cost considerations;2181,2361,2362,2398,2399,2404,2405,2407,2443,2446,2449,2479 drug susceptibility patterns in the local community can be considered, but local surveillance data are not necessarily representative of AOM isolates found in otherwise healthy patients.2398

Amoxicillin usually is considered the drug of first choice for initial empiric treatment of AOM, unless the infection is suspected of being caused by β-lactamase-producing bacteria resistant to the drug, in which case amoxicillin and clavulanate potassium is recommended for initial treatment.683,1656,1657,1661,1664,2180,2181,2250,2310,2311,2343,2361,2362,2398,2400,2433,2446,2479,2482 The fact that multidrug-resistant S. pneumoniae are being reported with increasing frequency should be considered when selecting an anti-infective agent for empiric treatment of AOM.2181,2398,2403,2414,2428,2436,2437,2441,2455,2456,2479,2482,2485 However, AAP, AAFP, CDC, and others state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, is well tolerated, has an acceptable taste, and is inexpensive.683,2178,2343,2398,2403,2404,2413,2414,2433,2434,2476,2479,2482 Amoxicillin (when given in dosages of 80-90 mg/kg daily in 2 divided doses) usually is effective in the treatment of AOM caused by S. pneumoniae , including infections involving strains with intermediate resistance to penicillins, and also usually is effective in the treatment of AOM caused by most strains of H. influenzae .683,2398,2403,2433,2475 Because S. pneumoniae is the most frequent cause of AOM (25-50% of cases) and because AOM caused by S. pneumoniae is more likely to be severe and less likely to resolve spontaneously than AOM caused by H. influenzae or M. catarrhalis , it has been suggested that it may be more important to choose an empiric anti-infective based on its activity against S. pneumoniae rather than its activity against other possible pathogens.2362,2398,2403,2414

Various other anti-infectives, including oral cephalosporins (cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin), parenteral ceftriaxone, oral macrolides (azithromycin, clarithromycin), and oral co-trimoxazole, have been used in the treatment of AOM.683,1656,1659,1661,1664,2178,2180,2181,2250,2310,2311,2343,2361,2362,2403,2446,2452,2471,2477,2479,2482 However, these usually are considered alternatives and are used when amoxicillin or amoxicillin and clavulanate potassium cannot be used or are ineffective.683

Current AAP evidence-based guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that high-dose amoxicillin (80-90 mg/kg daily in 2 divided doses) should be used for initial treatment when a decision has been made to use anti-infective therapy and the child has not received amoxicillin within the past 30 days or does not have concurrent purulent conjunctivitis or is not allergic to penicillin.683 These guidelines state that high-dose amoxicillin and clavulanate (90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily in 2 divided doses) should be used if the child received amoxicillin within the past 30 days or has concurrent purulent conjunctivitis or has a history of recurrent AOM unresponsive to amoxicillin.683 These AAP guidelines state that the preferred alternatives for initial treatment of AOM in penicillin-allergic patients are oral cephalosporins (cefdinir, cefpodoxime proxetil, cefuroxime axetil) or parenteral ceftriaxone.683

Results of controlled clinical studies indicate that 10-day regimens of most oral anti-infectives used in the empiric treatment of AOM are equally effective, and there is no evidence that the overall response rate to anti-infectives with a broader spectrum of activity (e.g., second and third generation cephalosporins) is any better than that reported with amoxicillin or amoxicillin and clavulanate potassium.2178,2180,2184,2393,2362,2403,2429,2430,2438,2439,2445,2452,2470,2471,2479 However, there is evidence that some anti-infectives (e.g., cefaclor, cefprozil, azithromycin) may be less effective than some other available agents for the treatment of AOM when β-lactamase-producing bacteria are present1656,1657,1659,1661,1664,1673,2076,2310,2457,2479,2481,2482 and some (e.g., cefixime, ceftibuten) may be less effective than some other available agents for the treatment of when S. pneumoniae with reduced susceptibility to penicillin are present.2361,2414,2442,2454,2456,2457,2476,2482

Duration of Initial Treatment of AOM

The optimal duration of therapy for AOM is uncertain.683 Anti-infectives traditionally have been administered for 7-10 days for the treatment of AOM,2178,2343,2419,2422,2450 but shorter durations of treatment also have been used.2416,2418,2419,2422 Current AAP evidence-based guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that a 10-day regimen of an appropriate oral anti-infective is recommended for the treatment of AOM in children younger than 2 years of age and in those with severe symptoms.683 These guidelines state that a 7-day regimen of an appropriate oral anti-infective may be as effective as a 10-day regimen in children 2-5 years of age with mild to moderate AOM, and a 5- to 7-day regimen of an appropriate oral anti-infective may be adequate in children 6 years of age or older with mild to moderate AOM.683

Some clinicians suggest that short durations of treatment (i.e., 5 days or less) can be effective and may increase compliance, decrease the risk of emergence of resistant bacteria, decrease the risk of adverse effects, and decrease costs.2416,2418,2419,2422 There is some evidence from controlled clinical studies in pediatric patients with AOM that the clinical response rate to 5-day regimens of certain oral cephalosporins (e.g., cefaclor,2396 cefdinir,2496 cefpodoxime proxetil,2389 cefprozil,2395,2397 cefuroxime axetil2453,2485 ) is similar to that of 10-day regimens of oral cephalosporins, amoxicillin, or amoxicillin and clavulanate potassium.2394,2396,2453,2485 Short-term regimens of amoxicillin or amoxicillin and clavulanate potassium† also have been used in a limited number of patients for the treatment of AOM; however, efficacy of these shorter regimens compared with the usual 10-day regimens of amoxicillin or amoxicillin and clavulanate has not been fully determined to date.2311,2394,2418,2394,2495

While some clinicians suggest that 5-day regimens can be considered for adults and children 2 years of age or older with mild, uncomplicated AOM,543,2076 further study is needed to more fully evaluate efficacy of short-term regimens in infants and young children since studies to date have included only a limited number of children younger than 2 years of age.683,2076,2311,2388,2394,2396,2397,2416,2417,2418,2419 These clinicians state that short-term anti-infective regimens (i.e., 5 days or less) may not be appropriate for the treatment of AOM in children younger than 2 years of age or for patients with underlying disease, craniofacial abnormalities, recurrent or persistent AOM, or perforated tympanic membranes and spontaneous purulent drainage.2311,2388,2394,2397,2416,2417,2418,2419,2422

Anti-infectives for AOM after Initial Treatment Failure

Consideration can be given to changing the anti-infective regimen in children who do not have clinical improvement within 48-72 hours after the initial anti-infective regimen is started.683 Current AAP evidence-based clinical practice guidelines for diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that patients who fail to respond to an initial regimen of high-dose amoxicillin (80-90 mg/kg daily in 2 divided doses) should be retreated with high-dose amoxicillin and clavulanate potassium (90 mg/kg of amoxicillin and 6.4 mg of clavulanate daily in 2 divided doses).683 Those who fail to respond to an initial regimen of high-dose amoxicillin and clavulanate potassium or an initial regimen of an appropriate oral cephalosporin (cefdinir, cefpodoxime proxetil, cefuroxime axetil) should be treated with parenteral ceftriaxone (50 mg/kg daily for 3 days).683

Clindamycin (30-40 mg/kg daily in 3 divided doses) can be used (with or without a third generation cephalosporin) as an alternative for the treatment of AOM in patients who fail to respond to an initial anti-infective regimen.683 Although clindamycin may be effective for penicillin-resistant S. pneumoniae , it may not be effective against multidrug-resistant S. pneumoniae and lacks efficacy against H influenzae .683 If clindamycin is used for retreatment, concomitant use of an anti-infective active against H. influenzae and M. catarrhalis (e.g., cefdinir, cefixime, cefuroxime) should be considered.683

Because of reported resistance in S. pneumoniae , AAP states that co-trimoxazole should not be used as an alternative for the treatment of AOM in patients who fail to improve while receiving amoxicillin.683

Primary treatment failure of AOM occurs most frequently in children younger than 2 years of age.2401,2412,2420 While primary treatment failure and persistent AOM may be the result of infection with bacteria resistant to the anti-infective administered (e.g., penicillin-resistant S. pneumoniae , β-lactamase-producing H. influenzae ),2181,2401,2405,2412,2413,2420,2427,2432 many cases appear to be related to other factors since results of tympanocentesis indicate that the causative organism(s) often is susceptible in vitro to the primary treatment regimen or, in some cases, no bacteria are isolated.2412,2420,2421,2432 Patients with AOM who fail to respond to an initial anti-infective regimen often also fail to respond to a subsequent regimen, regardless of the anti-infective used.2398,2421

If AOM persists after a series of anti-infective regimens, tympanocentesis should be considered and culture of middle ear fluid performed to make a bacteriologic diagnosis and obtain in vitro susceptibility test results.683 If tympanocentesis is not available, a regimen of oral clindamycin with or without an anti-infective to provide coverage against H. influenzae and M. catarrhalis (e.g., cefdinir, cefixime, cefuroxime) may be considered.683 Consultation with a pediatric medical subspecialist (e.g., otolaryngologist) for possible tympanocentesis, drainage, and culture and consultation with an infectious disease expert before use of unconventional anti-infectives should be considered.683

Recurrent AOM

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that anti-infective prophylaxis should not be prescribed to reduce the frequency of episodes of AOM in children with recurrent AOM.683 Recurrent AOM is defined as 3 or more episodes of AOM within a 6-month period or 4 or more episodes of AOM within a 12-month period that includes at least 1 episode in the preceding 6 months.683 About 50% of children younger than 2 years of age who are treated for AOM will have a recurrence within 6 months.683 Winter season, male gender, and passive exposure to tobacco smoke have been associated with an increased likelihood of AOM recurrence.683 Other risk factors for recurrence include AOM symptoms lasting more than 10 days, a family history of the infection, group day-care outside the home during the first 2 years of life, and use of bottles or pacifiers.683,2362,2419,2478 There is some evidence that breast-feeding for at least 4-6 months reduces episodes of AOM and recurrent AOM.683,2362,2478

Anti-infectives (e.g., amoxicillin, sulfisoxazole) have been administered as long-term prophylaxis or suppressive therapy in an attempt to prevent recurrence of AOM†2343,2419,2423,2473,2478,2482,2486,2489,2490,2491,2492,2493 or have been administered intermittently as prophylaxis† at the first sign of an upper respiratory tract infection in children with a history of recurrent AOM.2417,2419,2473,2478,2492 Although it has been suggested and there is some evidence that anti-infective prophylaxis may decrease the incidence of new symptomatic episodes of AOM in some children with a history of recurrent AOM,683,2362,2403,2408,2419,2422,2423,2432,2490,2491,2492,2493 such prophylaxis is not routinely recommended.683,2408,2419,2422,2478,2486 Results of a pooled analysis indicate that use of anti-infective prophylaxis results in an average decrease of only 0.11 episodes of AOM per patient per month (slightly more than 1 episode per year).2423 In addition, anti-infective prophylaxis does not provide any long-lasting benefit since any decrease in AOM episodes occurs only while prophylaxis is being given.683 AAP states that anti-infective prophylaxis is not appropriate for children with long-term MEE or for children with infrequent episodes of AOM.683 The small reduction in frequency of AOM must be weighed against the cost and potential adverse effects of anti-infective prophylaxis (e.g., allergic reactions, GI effects such as diarrhea)683 and concerns that prophylaxis may promote emergence of resistant bacteria, including multidrug-resistant S. pneumoniae , or alter nasopharyngeal flora and foster colonization with resistant bacteria.683,2343,2403,2408,2417,2422,2473,2478

In a retrospective study evaluating use of prophylactic anti-infectives in pediatric patients 1 month to 15 years of age with a history of recurrent AOM, patients received a 10-day regimen of oral amoxicillin or oral cefaclor for treatment of the acute episode and then a suppressive regimen of amoxicillin (20 mg/kg once daily) or cefaclor (20 mg/kg once daily) for a mean duration of 8.6 months (range: 3-20 months).2473 Results indicate that suppressive therapy failed in 47% of those receiving cefaclor and 70% of those receiving amoxicillin; most of these patients required other interventions (e.g., placement of tympanostomy tubes).2473 In addition, in a placebo-controlled study in children 3 months to 6 years of age with recurrent AOM, amoxicillin prophylaxis (20 mg/kg daily given in 1 or 2 divided doses) did not result in a lower incidence of new episodes of AOM.2486

Otitis Media with Effusion

Amoxicillin or amoxicillin and clavulanate potassium have been used in the treatment of otitis media with effusion (OME);2430,2445,2482,2488,2498 however, anti-infectives are not usually recommended for management of OME.2361,2417,2419,2422,2423,2431,2551

OME (also referred to as noninfected or nonsuppurative otitis media, secretory otitis media, serous otitis media, MEE, fluid ear, glue ear) is defined as the presence of residual or persistent MEE without signs or symptoms of acute ear infection.2419,2431,2432,2551 OME may occur as an inflammatory response following an episode of AOM or may occur spontaneously because of poor eustachian tube function.2361,2419,2422,2551 Approximately 90% of children have OME at some time before school age, usually between 6 months and 4 years of age.2551 Many episodes resolve spontaneously within 3 months, but about 30-40% of children have recurrent OME and 5-10% have episodes that last a year or longer.2551 The pathogenesis of OME is multifactorial, and the role of bacteria in OME is not completely understood.2423,2460,2482,2487 While some studies report that cultures of MEE from patients with OME rarely indicate the presence of bacteria, results of other studies using other methods (e.g., polymerase chain reaction testing) suggest the presence of bacteria, including Alloiococcus otitis (a recently recognized gram-positive cocci), in MEE fluid of patients with OME.2482,2487

In most patients with acute AOM who receive appropriate treatment with anti-infectives, MEEs usually are sterilized within 2-6 days but the effusions may persist for weeks or months before eventually resolving spontaneously without further treatment.2310,2362,2419,2422,2431,2468 Although asymptomatic OME usually resolves spontaneously, resolution rates decrease the longer the effusion is present and relapse is common.2551 About 60-70% of children have MEE present 2 weeks after successful treatment of AOM and 10-25% still have MEE at 3 months.683 In a group of children 2-6 years of age in group child-care who had OME, 80% had clearance of effusion within 2 months.2431 Chronic OME (MEE present continuously for over 3 months) may occur in some children and can be associated with conductive hearing loss, which may adversely affect language development and academic performance.2362,2472,2551 Risk factors for chronic OME include attendance in group day-care outside the home, age younger than 2 years of age, and exposure to tobacco smoke associated with parental smoking.2406,2468

AAP, AAFP, and American Academy of Otolaryngology-Head and Neck Surgery have issued evidence-based clinical practice guidelines regarding diagnosis and management of OME in children 2 months to 12 years of age (with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae).2551 These experts state that accurate diagnosis of OME is fundamental to proper management and that OME must be differentiated from AOM to avoid unnecessary anti-infective treatment.2551 The evidence-based guidelines recommend that children with OME who are not at risk for speech, language, or learning problems should be managed with watchful waiting for 3 months from the date of effusion onset (if known) or date of diagnosis (if onset is unknown).2551 This recommendation is based on systematic review of cohort studies and the preponderance of benefit over harm and take into consideration the self-limited nature of OME in most patients and the inherent risk associated with other interventions (medical or surgical).2551 These guidelines state that antihistamines and decongestants are ineffective for OME and are not recommended for treatment and that anti-infectives and corticosteroids do not have long-term efficacy and are not recommended for routine management of OME.2551 Although anti-infectives (with or without corticosteroids) have not been shown to be effective in long-term resolution of OME, some experts state that a short course of anti-infectives (10-14 days) may be considered for possible short-term benefits when the parent and/or caregiver expresses a strong aversion to impending surgery.2551 However, prolonged or repeated courses of anti-infectives or corticosteroids is strongly not recommended.2551

If OME persists for 3 months of longer or if language delay, learning problems, or a significant hearing loss is suspected, the evidence-based guidelines for management of OME recommend that the child's hearing be tested; language testing is recommended for those with hearing loss.2551 These guidelines state that if OME is asymptomatic and is likely to resolve spontaneously, intervention is unnecessary (even if OME persists for longer than 3 months) as long as there are no risk factors that would predispose the child to undesirable sequelae or predict nonresolution of the effusion.2551 Those with persistent OME without such risk factors should be reexamined at 3- to 6-month intervals until the effusion is no longer present, significant hearing loss is identified, or structural abnormalities of the eardrum or middle ear are suspected.2551 Surgical intervention may be indicated if moderate hearing loss is documented.2551 There is some evidence that surgical intervention may shorten the time to resolution of severe, chronic OME in children2468 and may provide some benefits in terms of language development.2480 The risks of continued observation of children with OME must be balanced against the risks of surgery.2551 Prolonged watchful waiting is not appropriate when regular surveillance is impossible or when the child is at risk for developmental sequelae of OME because of comorbidities.2551 For these children, the risks of anesthesia and surgery may be less than those of continued observation.2551

Although anti-infective are not usually recommended for patients with OME, amoxicillin or amoxicillin and clavulanate potassium has been suggested if an anti-infective is used.2482,2488,2498 In a study in children 7 months to 12 years of age with OME, a 14-day regimen of oral ceftibuten or oral amoxicillin resulted in resolution of MEE (based on otoscopy) in 27-30% of children, but there was recurrence of effusion at 16-week follow-up in 60-67% of children who were effusion free at completion of therapy.2445 In a placebo-controlled study evaluating 14-day regimens of amoxicillin, cefaclor, or erythromycin-sulfisoxazole in children with OME, MEE had resolved by the end of the treatment period in 22% of those who received cefaclor, 21% of those who received erythromycin-sulfisoxazole, and 31.6% of those who received amoxicillin; of those who were effusion-free at 4 weeks, there was recurrence of effusion during the next 12 weeks in 52% of those who received cefaclor, 47% of those who received erythromycin-sulfisoxazole, and 60.9% of those who received amoxicillin.2498

The evidence-based guidelines from AAP, AAFP, and American Academy of Otolaryngology-Head and Neck Surgery should be consulted for further information on the diagnosis and management of OME in children 2 months through 12 years of age (with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae), including the role of surgical intervention.2551

Spirochetal Infections !!navigator!!

Lyme Disease

Amoxicillin is considered a drug of choice for the treatment of erythema migrans and certain other manifestations of Lyme disease.329,331,2254,2320,2321,2322,2323,2325,2326,2327,2328,2337,2338,2343,2503 Lyme disease is a spirochetal disease caused by tick-borne Borrelia burgdorferi .329,331,1739,1740,1742,1744,1746,2320,2321,2326 Anti-infective therapy shortens the duration of erythema migrans and usually prevents the development of late sequelae of Lyme disease.329,331,875,1066,1146,1148,1212,1215,1216,1751,2320,2321,2322,2328,2329,2320,2321,2322,2328,2329,2501,2503,2512

IDSA, AAP, 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 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 is preferred for initial treatment of Lyme carditis in hospitalized patients;329 oral anti-infectives (doxycycline, amoxicillin, cefuroxime axetil) are used as follow-up to the initial IV regimen and can be used in patients with Lyme carditis who do not require hospitalization.329

In a randomized, controlled study, doxycycline 100 mg twice daily or amoxicillin 500 mg 3 times daily (plus probenecid 500 mg 3 times daily) for 21 days showed similar efficacy in preventing late complications (e.g., meningitis, myocarditis, arthritis) in patients with early Lyme disease (erythema migrans); mild fatigue or arthralgia occurred infrequently following antibiotic therapy but resolved in all cases within the 6-month follow-up period.1784 Amoxicillin has been recommended for use in patients with relatively mild neurologic (e.g., isolated facial nerve palsy) or cardiac (e.g., first-degree AV block with a PR interval less than 0.3 seconds) manifestations, or for arthritic manifestations of early or late Lyme disease.1739,1740,1771,2320,2326 In addition, amoxicillin may be preferred to doxycycline for the treatment of early Lyme disease† in pregnant or lactating women and in children younger than 8 years of age.1551,1580,1795,2254,2320,2321,2322,2323,2330,2337,2338,2343,2501,2503

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

Chlamydial Infections !!navigator!!

Oral amoxicillin is recommended by CDC for the treatment of uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia trachomatis † in pregnant women.344 In a controlled study in pregnant women with genital chlamydia infections, a 7-day regimen of amoxicillin (500 mg 3 times daily) was as effective as a 7-day regimen of erythromycin (500 mg 4 times daily) and was associated with a lower incidence of adverse GI effects.2251

Prophylaxis !!navigator!!

Perioperative Prophylaxis

Some experts state that the fixed combination of ampicillin sodium and sulbactam sodium is one of several options recommended for perioperative prophylaxis† in patients undergoing certain biliary tract procedures,374 colorectal procedures,360,374 gynecologic and obstetric procedures (e.g., vaginal, abdominal, or laparoscopic hysterectomy),360,374 head and neck surgery,360,374 noncardiac thoracic surgery (e.g., lobectomy, pneumonectomy, lung resection, thoracotomy),360,374 or urologic procedures (e.g., involving implanted prosthesis).374 Local susceptibility patterns of potential pathogens should be considered when selecting ampicillin sodium and sulbactam sodium for perioperative prophylaxis.360,374

Published guidelines and protocols for perioperative prophylaxis should be consulted for additional information regarding specific procedures.360,374

Prevention of Perinatal Group B Streptococcal Disease

IV ampicillin is used in pregnant women during labor (intrapartum) for prevention of early-onset neonatal group B streptococcal (GBS) disease†,292,359,1164,1307,1308,1309,1817,2130 and is considered an alternative to IV penicillin G for such prophylaxis.292,359

GBS infection is a leading cause of neonatal morbidity and mortality 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 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 , E. 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 Bacterial Endocarditis

Amoxicillin451,926,932,948,950,1070,1831,1832,1833 and ampicillin292,451,929,1195,1408,1831,1832 are used for prevention of α-hemolytic (viridans group) bacterial endocarditis† in adults and children undergoing certain dental or upper respiratory tract procedures who have cardiac conditions that put them at highest risk of adverse outcomes from endocarditis.451

The cardiac conditions identified by AHA as those associated with highest risk of adverse outcomes from endocarditis and for which anti-infective prophylaxis is reasonable are prosthetic cardiac valves or prosthetic material used for cardiac valve repair, previous infective endocarditis, cardiac valvulopathy after cardiac transplantation, or congenital heart disease (i.e., unrepaired cyanotic congenital heart disease including palliative shunts and conduits; a completely repaired congenital heart defect where prosthetic material or device was placed by surgery or catheter intervention within the last 6 months; repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device that inhibit endothelialization).451

AHA states that anti-infective prophylaxis for prevention of α-hemolytic (viridans group) streptococcal bacterial endocarditis is reasonable for patients with the above cardiac risk factors if they are undergoing any dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa (e.g., biopsies, suture removal, placement of orthodontic bands).451 AHA states that anti-infective prophylaxis is not needed for routine anesthetic injections through noninfected tissue, dental radiographs, placement of removable prosthodontic or orthodontic appliances, adjustment of orthodontic appliances, placement of orthodontic brackets, shedding of deciduous teeth, or bleeding from trauma to the lips or oral mucosa.451

AHA states that anti-infective prophylaxis for prevention of bacterial endocarditis also is reasonable for patients with the above cardiac risk factors if they are undergoing invasive procedures of the respiratory tract that involve incision or biopsy of respiratory mucosa (e.g., tonsillectomy, adenoidectomy) or surgical procedures that involve infected skin, skin structure, or musculoskeletal tissue.451 However, anti-infective prophylaxis solely to prevent infective endocarditis is no longer recommended for GI or genitourinary tract procedures.451

Oral amoxicillin is the drug of choice when prevention of bacterial endocarditis is indicated in patients undergoing certain dental or upper respiratory tract procedures who have certain cardiac conditions that put them at highest risk of adverse outcomes from endocarditis.451 If an oral regimen cannot be used in such patients, AHA recommends IM or IV ampicillin or IM or IV cefazolin or ceftriaxone.451 Alternatives for penicillin-allergic patients include oral cephalexin, oral azithromycin or clarithromycin, oral or parenteral clindamycin, or parenteral cefazolin or ceftriaxone;451 cephalosporins should not be used in individuals with a history of anaphylaxis, angioedema, or urticaria after receiving a penicillin.451

When selecting anti-infectives for prophylaxis of bacterial endocarditis, the current recommendations published by AHA should be consulted.451

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration !!navigator!!

Amoxicillin trihydrate36 and ampicillin trihydrate42,45,46,48,49 are administered orally. Ampicillin sodium is administered by IM or IV injection or by IV infusion.38,39 Amoxicillin sodium has also been administered IV95,447,448,459,1290 but parenteral preparations of the drug are not available in the US.

Since food interferes with GI absorption of ampicillin oral suspension,342,457,466 these solutions should be given orally at least 1 hour before or 2 hours after meals for maximal absorption. Amoxicillin36 tablets may be administered orally without regard to meals.

Dosage in Renal Impairment !!navigator!!

In patients with renal impairment, doses and/or frequency of administration of aminopenicillins must generally be modified in response to the degree of renal impairment.473,510,1320,1373,1374

Cautions ⬆ ⬇

[Section Outline]

The major adverse effects reported with aminopenicillins are GI effects, rash, and hypersensitivity reactions.36,38,39,42,45,46,48,49,73,74,614,732,736,804,2205 With the exception of diarrhea (which has been reported most frequently with ampicillin),725,727,731,732,741 the frequency and severity of adverse effects are generally similar between ampicillin and amoxicillin.73,725,732

Hypersensitivity Reactions !!navigator!!

Hypersensitivity reactions reported with aminopenicillins are similar to those reported with other penicillins.74,732 Hypersensitivity reactions to aminopenicillins are manifested most frequently as eosinophilia36,38,39,42,45,46,48,49,736 or rash (urticarial, erythematous, morbilliform),36,38,39,42,45,46,48,49,74,416,461,732,781,2205 less frequently as angioedema,1437 exfoliative dermatitis38,39,42,45,46,48,49 toxic epidermal necrolysis,2135 or erythema multiforme,38,39,42,45,46,48,49,2135,2206 and rarely as Stevens-Johnson syndrome.36,1437,2206 Serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever) also have been reported.1437 Eosinophilia has been reported in up to 47% of patients receiving ampicillin.736

Rash has been reported in 1.4-10% of patients receiving amoxicillin or73,461,614,708,781,804,2205 or ampicillin.61,74,614,708,732,774,804,816,820,821,826,827,829,2205 Two different types of rash have been reported with aminopenicillins.781,812,830 One type of rash resembles the hypersensitivity rash seen with other penicillins;781,812,830 this rash is usually urticarial, appears within a few days of initiation of therapy with the drugs, and may be associated with other signs of hypersensitivity.781,812,830 The second type of rash, is a generalized erythematous, maculopapular rash which, in most cases, appears to be nonimmunologic.781,812,830 For more information on the maculopapular rash reported with ampicillin and amoxicillin, see Cautions: Ampicillin Rash.

Positive direct antiglobulin (Coombs') test results and hemolytic anemia have been reported rarely with ampicillin.809 Acute hemolytic anemia, with a negative direct antiglobulin test result, has also been reported in one patient who received ampicillin;709 however, it is not clear whether this was a hypersensitivity reaction.709

Anaphylaxis has been reported rarely with oral811 or parenteral ampicillin.61,713 Anaphylaxis has also been reported in at least one patient who apparently inhaled ampicillin after opening a bottle of the drug for reconstitution.1276 If a severe hypersensitivity reaction occurs during therapy with an aminopenicillin, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.36,38,39,42,45,46,48,49

For a more complete discussion on manifestations of penicillin hypersensitivity and information on the mechanisms of these reactions, the management of patients with hypersensitivity reactions, and how to identify patients at risk for hypersensitivity reactions to penicillins, see Cautions: Hypersensitivity Reactions, in the Natural Penicillins General Statement 8:12.16.04.

Ampicillin Rash !!navigator!!

In addition to the usual urticarial hypersensitivity rash reported with other penicillins (see Cautions: Hypersensitivity Reactions), ampicillin781,804,812,830,831 and amoxicillin61,73,428,701,708,804,815 frequently cause a generalized erythematous, maculopapular rash. The maculopapular rash, when it occurs, generally appears 3-14 days after initiation of therapy with the drugs,61,781,812,816,817,818,819,820,821,824 begins on the trunk, and spreads peripherally to involve most of the body.812,816,819,824 The rash may be most intense at pressure areas and elbows and knees;812,819,824 mucous membranes may or may not be involved.816 In most patients, the rash is mild and subsides after 6-14 days despite continued therapy with the drugs;61,448,781,812,816,817,824 however, the rash may be severe with coalescence of lesions and purpura.812,816,820 If the drug is discontinued, the rash generally resolves in 1-7 days.824

Rash has been reported more frequently with ampicillin and amoxicillin than with other currently available penicillins.61,73,614,781,812,827 More than 65% of rashes reported with ampicillin appear to be of the maculopapular type.781,824 A maculopapular rash reportedly occurs in 5-10% of children receiving ampicillin.817,830 The frequency of rash reported with ampicillin does not appear to be related to dosage of the drug,702 but the rash has been reported more frequently in women than in men.816 In one study, maculopapular rash occurred in 3.7% of males and 13.4% of females receiving ampicillin.816

A high incidence of rash occurs when aminopenicillins are used in patients with viral disease,61,73,428,701,781,812,815,816,819,823,1277 including viral respiratory tract infections,816 infectious mononucleosis,61,73,428,701,722,781,812,815,816,819,822,1277 and cytomegalovirus infections.816,823 Rash has been reported in 65-100% of patients with infectious mononucleosis who received ampicillin61,819,822 and has also been reported frequently when amoxicillin was used in patients with the disease.73,428,701,815 The maculopapular rash has been reported in up to 90% of patients with lymphatic leukemia and a high percentage of patients with reticulosarcoma and other lymphomas who received ampicillin.61 An increased incidence of rash has also been reported in patients with hyperuricemia receiving allopurinol and concomitant ampicillin or amoxicillin compared with those receiving ampicillin, amoxicillin, or allopurinol alone.712,774,812,829 (See Drug Interactions: Allopurinol.)

The mechanism of the maculopapular rash reported with ampicillin and amoxicillin is unknown;812,824,831,871 however, in most cases, it appears to be nonimmunologic.824,828,831,871 Skin tests for penicillin hypersensitivity have been negative in the majority of patients with these rashes who were tested.61,817,821,824,830,871 In addition, many patients have received subsequent treatment with ampicillin or another penicillin without recurrence of the rash or evidence of a hypersensitivity reaction.816,821,824,871 Therefore, some clinicians consider the rash nonimmunologic61,816,821,824,828 and suggest that the occurrence of a maculopapular rash during aminopenicillin therapy, without other signs of hypersensitivity, does not necessarily imply hypersensitivity to penicillins or contraindicate future use of aminopenicillins or other penicillins.61,816,831,906 However, the possibility that the rash is the result of a hypersensitivity reaction to protein impurities contained in commercially available preparations cannot be ruled out61,812,871 since, in several studies, a lower incidence of the rash has been reported in patients receiving more purified forms of ampicillin than in those receiving less purified forms of the drug.813,814

The frequency of aminopenicillin-induced adverse dermatologic effects, including rash (morbilliform, macular), urticaria, pruritus, and, rarely, erythema multiforme is substantially higher (about 10-fold) in patients with human immunodeficiency virus (HIV) infections (including those with acquired immunodeficiency syndrome [AIDS]) than in other patients.2131,2132,2133 The exact mechanism(s) of this increased risk of aminopenicillin-induced adverse effects has not been determined,2132,2133 but may be immunologically based. Limited data indicate that aminopenicillin-associated rash may be associated with absolute helper/inducer (CD4+, T4+) T-cell counts of 200/mm3 or less.2132,2133 It also has been suggested that aminopenicillin-associated rash in such patients may be associated with lymphocyte proliferation and production of lymphokines.2132 In patients in whom HIV infection progresses to AIDS, an even further increase in adverse dermatologic reactions has been observed;2131 however, a causal relationship to drug therapy has not been established, since progressive HIV infection has been associated with increased infectious and noninfectious dermatoses.2131,2133,2207,2208 Some clinicians state that further therapy or rechallenge with aminopenicillins should not be contraindicated when such reactions occur in patients with HIV infection.2132,2134

Hematologic Effects !!navigator!!

In addition to eosinophilia and hemolytic anemia (see Cautions: Hypersensitivity Reactions), other adverse hematologic effects including anemia, leukopenia,36,38,39,42,45,46,48,49,61,62,63,615 neutropenia,448,615,674,1028,1030 agranulocytosis,36,38,39,42,45,46,48,49,61 thrombocytopenia,36,38,39,42,45,46,48,49,61,615,1028 and thrombocytopenic purpura36,38,39,42,45,46,48,49 have been reported in patients receiving aminopenicillins. These adverse hematologic effects are usually reversible following discontinuance of the drugs.36,38,39,42,45,46,48,49,448,674,1028,1030 Although these hematologic effects are generally considered hypersensitivity reactions to the drugs,36,38,39,42,45,46,48,49,615,1030 an immunologic mechanism has not been definitely established.615

Abnormal platelet aggregation, prolongation of bleeding time, and prolongation of activated partial thromboplastin time (APTT) have been reported in children and healthy adults receiving ampicillin or amoxicillin.655,673

GI Effects !!navigator!!

Some of the most frequent adverse reactions to orally administered aminopenicillins are GI effects804 including nausea,36,38,39,42,45,46,48,49,61,614,725,726 vomiting,36,38,39,42,45,46,48,49,461,614,725,728 anorexia,725 epigastric distress,61,725,726,728,731 diarrhea,36,38,39,42,45,46,48,49,61,461,614,725,726,728,731,732,781,804 and gastritis.614 Black hairy tongue,38,48,49 glossitis,38,39,42,45,46,48,49,725 and stomatitis38,39,42,45,46,48,49 have also been reported. Adverse GI effects appear to be dose related64,614,690,804 and may occasionally be severe enough to require discontinuance of the drugs.61,64,461,732

Diarrhea occurs less frequently during therapy with oral amoxicillin61,64,73,804 than during therapy with oral ampicillin, presumably because these derivatives are more completely absorbed from the GI tract than ampicillin61,64,73,614,732,804 and therefore have less of an effect on normal flora in the GI tract.727,804 Diarrhea reportedly occurs in 9-17% of adults receiving usual doses of oral ampicillin61,341,614,732,781,804 and 0.5-5% of adults receiving usual doses of oral amoxicillin.61,73,614,804 Aminopenicillins cause diarrhea most frequently in children61,690 and in geriatric patients.61 Diarrhea has been reported to occur in up to 20% of children receiving oral ampicillin and may be severe enough to require discontinuance of therapy in 8% of children receiving the drug.61 In one study of children receiving usual doses of amoxicillin as an oral suspension, loose stools occurred in 42% of children younger than 8 months of age, 20% of children 8-16 months of age, and 8.5% of children 24-36 months of age.390

The reported incidence of upper GI effects (nausea, vomiting, epigastric pain) following oral administration of the various aminopenicillins appears to be similar.73,804 Nausea and vomiting have been reported in 2% of patients receiving amoxicillin614,804 and 2-2.9% of patients receiving ampicillin.614,804

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile ).302 C. difficile -associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis; CDAD) has been reported during or following discontinuance of ampicillin61,63,341,806,807,1287,1289 or amoxicillin.61,744,806,1289 C. difficile produces toxins A and B which contribute to development of CDAD.302 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.36,302

Acute, transient enterocolitis with severe abdominal pain and bloody diarrhea, but without evidence of C. difficile -associated diarrhea and colitis, also has been reported in several patients receiving oral ampicillin or oral amoxicillin.42,45,46,48,49,685,1032

Nausea and diarrhea have occurred in up to 3% of patients receiving IV ampicillin.61 Acute pancreatitis has been reported in at least one patient receiving IV ampicillin therapy.1713

Renal Effects !!navigator!!

Acute interstitial nephritis has been reported rarely with ampicillin61,341,781,808,1291 and amoxicillin.1290 In most reported cases, the nephritis resembled that reported with methicillin (no longer commercially available in the US) and appeared to be a hypersensitivity reaction to the drugs.61,808,1290 For more information on penicillin-induced acute interstitial nephritis, see Cautions: Renal Effects, in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.

At least one case of glomerulonephritis, which occurred as part of Henoch-Schönlein purpura, has been reported with oral ampicillin.793 The syndrome appeared to be a hypersensitivity reaction to the drug and was characterized by urticaria, bloody diarrhea, arthralgia, proteinuria, and hyaline and erythrocyte casts in the urine;793 focal glomerulonephritis was present histologically.793

Crystals of ampicillin have been found rarely in the urine of patients receiving large IV doses of ampicillin.781,792,810 Ampicillin, in high concentrations, apparently can crystallize in vitro in urine with a pH of 5 or less.792 It is not known if the ampicillin crystals found in the urine of these patients were formed in vitro or in vivo;781,792 however, there was no clinical or pathologic evidence of renal damage.792,810

Hepatic Effects !!navigator!!

A moderate increase in serum concentrations of AST (SGOT) and/or ALT (SGPT) have been reported rarely during therapy with aminopenicillins,36,38,39,42,45,46,48,49,61,73,1437 especially when the drugs were administered to infants.38,39,42,45,46,48,49,64 Hepatic dysfunction (cholestatic, hepatocellular, or mixed cholestatic-hepatocellular) has been reported rarely in patients receiving aminopenicillins; signs and symptoms may appear during or after therapy and resolve completely with time.1437

Nervous System Effects !!navigator!!

Headache and dizziness have been reported rarely with ampicillin.

Myoclonic seizures have occurred rarely following IV administration of high doses of ampicillin,61,63 especially in patients with impaired renal function.61,63 Although a causal relationship has not been definitely established, generalized seizures have also been reported in at least 2 patients receiving oral ampicillin.694

Local Reactions !!navigator!!

Phlebitis has been reported rarely with IV administration of ampicillin. Pain at the injection site occurs frequently following IM administration of ampicillin.67

Precautions and Contraindications !!navigator!!

Prior to initiation of therapy with an aminopenicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.36,38,39,42,45,46,48,49 There is clinical and laboratory evidence of partial cross-allergenicity among bicyclic β-lactam antibiotics including penicillins, cephalosporins, cephamycins, and carbapenems.611,615,720,769,781,1193,1629,1630 There appears to be little cross-allergenicity between bicyclic β-lactam antibiotics and monobactams (e.g., aztreonam).1629,1630,1631,1632,1633 However, the true incidence of cross-allergenicity between penicillins and other β-lactam antibiotics has not been definitely established.615,720,1289,1629 Amoxicillin and36 ampicillin38,39,42,45,46,48,49 are contraindicated in patients who are hypersensitive to any penicillin. In addition, although it has not been proven that allergic reactions to antibiotics are more frequent in atopic individuals,805 the manufacturers state that aminopenicillins should be used with caution in patients with a history of allergy, particularly to drugs.36,38,39,42,45,46,48,49 For more information on hypersensitivity reactions to penicillins and precautions associated with these reactions, see Cautions: Hypersensitivity Reactions, in the Natural Penicillins General Statement 8:12.16.04.

Because a high percentage of patients with infectious mononucleosis have developed rash during therapy with aminopenicillins (see Cautions: Ampicillin Rash), aminopenicillins probably should not be used in patients with the disease.73,428

Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with aminopenicillins,36,38,39,42,45,46,48,49 especially when the drugs are administered to patients with liver or renal impairment.

Use of aminopenicillins may result in overgrowth of nonsusceptible organisms36,38,39,42,45,46,48,49,63,64,341 including Candida .36,49,341,683 The majority of bacterial superinfections during therapy with aminopenicillins are caused by Enterobacter ,36,461 Klebsiella ,461 E. coli ,461 Aerobacter ,49 or Pseudomonas .36,49,64 Oral726 or vaginal341,683 candidiasis occurs occasionally with oral aminopenicillins. Superinfections are more likely to occur when large doses of aminopenicillins are used or when therapy is prolonged. Careful observation of the patient is essential during therapy with an aminopenicillin.36,38 If suprainfection or superinfection occurs, the drug should be discontinued36,38,48,49 and appropriate therapy instituted.36,38,39,42,45,46,48,49

Mutagenicity and Carcinogenicity !!navigator!!

Studies to evaluate the mutagenic or carcinogenic potential of aminopenicillins generally have not been performed to date.

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Safe use of amoxicillin or36 ampicillin38,39,42,45,46,48,49 during pregnancy has not been definitely established. However, amoxicillin and ampicillin have been administered to pregnant women without evidence of adverse effects to the fetus.61,468,723,1145

Amoxicillin is included in the US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of chlamydial infections† during pregnancy344 and included in CDC recommendations for the treatment of cutaneous anthrax† or for postexposure prophylaxis of anthrax† following exposure to Bacillus anthracis spores.672,2499,2506,2509 In addition, ampicillin is recommended by the American College of Obstetricians and Gynecologists (ACOG), AAP, and others for intrapartum anti-infective prophylaxis for prevention of early-onset neonatal group B streptococcal (GBS) disease†.359

Reproduction studies in mice and rats using amoxicillin doses up to 10 times the usual human dose36 have not revealed evidence of harm to the fetus.36 There are no adequate or controlled studies to date using aminopenicillins in pregnant women, and the drugs should be used during pregnancy only when clearly needed.36

Aminopenicillins generally are poorly absorbed when given orally during labor.36 Although the mechanism is unclear and the clinical importance has not been determined to date, studies using oral ampicillin indicate that, when administered during pregnancy, the drug interferes with metabolism and enterohepatic circulation of steroids resulting in decreased urinary concentrations of estrogen metabolites.36,1023,1024,1045 IV administration of ampicillin to guinea pigs slightly decreased uterine tone and frequency of uterine contractions but moderately increased the height and duration of contractions; however, it is not known whether use of the drug in humans during labor or delivery could have any immediate or delayed adverse effects on the fetus, prolong the duration of labor, or increase the likelihood of forceps delivery, other obstetrical intervention, or resuscitation of the neonate.36

Fertility

Reproduction studies in mice and rats using amoxicillin doses up to 10 times the usual human dose36 have not revealed evidence of impaired fertility.36

Lactation

Because aminopenicillins are distributed into milk and may lead to sensitization of infants, the drugs should be used with caution in nursing women.36,61,73,355,496

Drug Interactions ⬆ ⬇

[Section Outline]

Although not all drug interactions reported with other penicillins have been reported with aminopenicillins, the fact that some of these interactions could occur with aminopenicillins should be considered.

Anti-infective Agents !!navigator!!

Aminoglycosides

Synergism with Aminoglycosides

In vitro and animal studies indicate that a synergistic bactericidal effect can occur against some strains of enterococci when ampicillin is used in conjunction with amikacin, gentamicin, streptomycin, or tobramycin.80,116,282,300,942,947 The synergistic effect between ampicillin and aminoglycosides is used to therapeutic advantage in the treatment of endocarditis or other severe infections caused by enterococci.64,80,282,288,904,947

A synergistic bactericidal effect has also been reported in vitro against group B streptococci when ampicillin was used in conjunction with amikacin, gentamicin, kanamycin, or tobramycin116,295 and against L. monocytogenes when ampicillin was used in conjunction with gentamicin.298,1198

Although the clinical importance has not been determined, in vitro studies indicate that gentamicin and ampicillin may be synergistic against some strains of Enterobacteriaceae (e.g., Enterobacter , P. mirabilis , E. coli ).116

Incompatibility with Aminoglycosides

Aminopenicillins are physically and/or chemically incompatible with aminoglycosides and can inactivate the drugs in vitro.82,116,341,1035,1115 In vitro inactivation of aminoglycosides by aminopenicillins can occur if the drugs are administered in the same syringe or IV infusion container.82,116,341,1035 When concomitant therapy is indicated, in vitro mixing of aminopenicillins and aminoglycosides should be avoided and the drugs administered separately.82,341 Ampicillin can also inactivate aminoglycosides in vitro in serum samples obtained from patients receiving concomitant therapy with the drugs.1035,1115 This could adversely affect results of serum aminoglycoside assays performed on the serum samples.1035,1115

-Lactamase Inhibitors

In vitro and in vivo studies indicate that the combination of amoxicillin311,312,314,316,318,1298,1311,1437,1446,1450,1453,1454,1473,1486,1494,1501 or ampicillin310,312,317 with clavulanic acid or the combination of amoxicillin or ampicillin with sulbactam1902,1903,1954,1955,1959,1962,1969,1991,1998,2004,2039 results in a synergistic bactericidal effect against many strains of β-lactamase-producing bacteria. This synergism occurs because clavulanic acid and sulbactam are β-lactamase inhibitors that have a high affinity for and irreversibly bind to certain β-lactamases that can inactivate aminopenicillins.143,318,1315,1901,1903,1925,1955,1961,1962,1964,1991,2004,2039,2050 Concomitant use of clavulanic acid with amoxicillin or ampicillin does not result in a synergistic effect against resistant organisms if intrinsic resistance to aminopenicillins rather than β-lactamase production is involved.316,318

The fact that concomitant use of clavulanic acid or sulbactam sodium broadens the spectrum of activity of aminopenicillins is used to therapeutic advantage in the treatment of infections that may be caused by β-lactamase-producing organisms which are generally resistant to aminopenicillins.315,318,1312,1313,1437,1457,1475,1486,1488,1901,1902,1903,1954,1955 Amoxicillin is commercially available in fixed combination with clavulanate potassium (amoxicillin/clavulanate) for oral use.1437 Ampicillin sodium is commercially available in a fixed combination with sulbactam sodium (ampicillin/sulbactam) for parenteral use.1901 For information on these fixed combinations, see Amoxicillin and Clavulanate Potassium or see Ampicillin Sodium and Sulbactam Sodium 8:12.16.08.

Chloramphenicol

In some in vitro studies, chloramphenicol reportedly antagonized the bactericidal activity of ampicillin against H. influenzae ,306,1167 N. meningitidis ,305 and S. pneumoniae .305 However, indifferent, additive, or synergistic effects have also occurred in vitro when chloramphenicol was used in conjunction with ampicillin against these organisms.305,309,1167 In one in vitro study using H. influenzae , chloramphenicol antagonized the bactericidal activity of ampicillin, but ampicillin did not interfere with the antibacterial activity of chloramphenicol.1167 Although some clinicians recommend that concomitant use of chloramphenicol and penicillins be avoided,306,1153 in vivo antagonism between these drugs has not been demonstrated to date and ampicillin is generally used in conjunction with chloramphenicol for the empiric treatment of bacterial meningitis with no apparent decrease in activity.157,305,309,866,905,986,1059,1181,1182,1275

Rifampin

In one in vitro study using group B streptococci, rifampin used in conjunction with ampicillin resulted in a lower rate of killing than ampicillin alone;388 however, in another in vitro study using H. influenzae , concomitant use of rifampin and ampicillin resulted in an additive or indifferent effect and no synergism or antagonism.1295 Although in vitro antagonism has also been reported when rifampin was used in conjunction with penicillinase-resistant penicillins, antagonism appears to occur only when high concentrations of the penicillin are present and indifference or synergism appears to occur when low concentrations of the penicillin are present.1392,1393 (See Drug Interactions: Rifampin, in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.)

Sulfasalazine

In one study, administration of oral ampicillin (250 mg 4 times daily for 5 days) prior to administration of sulfasalazine resulted in a decrease in the area under the serum concentration-time curve (AUC) of sulfapyridine (a metabolite of sulfasalazine) compared with administration of sulfasalazine alone.773 Although the mechanism by which ampicillin decreased the AUC of sulfapyridine has not been determined, ampicillin may have altered the GI flora and consequently sulfasalazine metabolism.773

Acetohydroxamic Acid !!navigator!!

Results of one in vitro study indicate that the antibacterial activity of acetohydroxamic acid, a urease inhibitor, and ampicillin may be synergistic against some organisms, including Escherichia coli , Klebsiella , Morganella morganii , Providencia rettgeri , and Pseudomonas aeruginosa ; however, indifferent or antagonistic effects also occurred.1180

Methotrexate !!navigator!!

Concomitant use of penicillins (e.g., amoxicillin) may decrease renal clearance of methotrexate,1408 presumably by inhibiting renal tubular secretion of the drug.2285,2287 Increased serum concentrations of methotrexate, resulting in GI or hematologic toxicity, have been reported in patients receiving concomitant administration of low- or high-dose methotrexate therapy with penicillins.1408,2285,2287 Patients receiving methotrexate and penicillins concomitantly should be monitored carefully.1408,2285,2287

Oral Contraceptives !!navigator!!

Concomitant use of ampicillin and estrogen-containing oral contraceptives reportedly may decrease efficacy of the contraceptive and increase the incidence of breakthrough bleeding.771,772,781,1043,1153 These effects have also been reported when penicillin V was used in patients receiving oral contraceptives.1043 Studies in animals indicate that anti-infective agents such as ampicillin may decrease or eliminate enterohepatic circulation of oral contraceptives by disrupting the GI bacterial flora.772,1043 GI bacteria produce enzymes which hydrolyze conjugates of estrogens (e.g., ethinyl estradiol) that have been excreted into the GI tract via bile; hydrolysis of these conjugates allows enterohepatic circulation of the pharmacologically active drug.1043

The clinical importance of this potential interaction between penicillins and oral contraceptives has not been determined.772,1153 Pregnancies have occurred in a few patients receiving an oral contraceptive and ampicillin concomitantly.1153 However, in several studies, administration of ampicillin to women receiving oral contraceptives did not affect plasma concentrations of ethinyl estradiol, levonorgestrel, norethisterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), or progesterone,771,772,1044 although decreased concentrations of ethinyl estradiol were noted in a few women.772,1044,1292 Therefore, although some clinicians suggest that a supplemental method of contraception be used in patients receiving oral contraceptives and ampicillin concomitantly, other clinicians state that most women taking oral contraceptives probably do not need to use alternative contraceptive precautions while receiving ampicillin.771,772,1043,1044

Probenecid !!navigator!!

Oral probenecid administered shortly before or simultaneously with aminopenicillins slows the rate of renal tubular secretion of the penicillins and produces higher and prolonged serum concentrations of the drugs.36,76,347,447 Studies using amoxicillin indicate that the peak serum concentration and half-life of the drug are generally increased by 30-60% and the area under the serum concentration-time curve (AUC) may be increased by 60%.73,229,346,492 In addition, concurrent administration of oral probenecid decreases the volumes of distribution of IM or IV ampicillin or amoxicillin by about 20% which may contribute to higher serum concentrations of the drugs.347,447 Concomitant administration of oral probenecid also reportedly increases CSF concentrations of ampicillin and amoxicillin.76,447

Allopurinol !!navigator!!

An increased incidence of rash reportedly occurs in patients with hyperuricemia who are receiving allopurinol and concomitant ampicillin or amoxicillin compared with those receiving ampicillin, amoxicillin, or allopurinol alone.712,774,812,829,1153 Some clinicians suggest that either allopurinol or hyperuricemia may potentiate aminopenicillin allergenicity.712,829 However, other clinicians state that the rash reported in patients receiving allopurinol and aminopenicillins concomitantly is generally the delayed ampicillin rash which appears to be nonimmunologic.774 (See Cautions: Ampicillin Rash.) The clinical importance of this effect has not been determined;1153 however, some clinicians suggest that concomitant use of the drugs should be avoided if possible.712

Other Information ⬆ ⬇

[Section Outline]

Laboratory Test Interferences

For more complete information on these and other laboratory test interferences reported with penicillins, see Laboratory Test Interferences in the Natural Penicillins General Statement 8:12.16.04. Although there is limited information on laboratory test interferences with aminopenicillins and although not all laboratory test interferences reported with other penicillins have been reported with ampicillin, the possibility that these interferences could occur with any of the aminopenicillins should be considered.

Tests for Urinary and Serum Proteins !!navigator!!

Ampicillin has caused slightly increased urinary protein concentrations when the Coomassie brilliant blue method is used1118 and has also reportedly caused falsely increased serum albumin concentrations when the bromcresol green (BCG) procedure was used.803

Tests for Glucose !!navigator!!

Like other penicillins, ampicillin reportedly interferes with urinary glucose determinations using cupric sulfate (e.g., Benedict's solution, Clinitest®)759 but does not affect glucose oxidase methods (e.g., Clinistix®, Tes-Tape®).759

In one study ampicillin apparently interfered with the Sigma modification of Hall and Tucker's automated glucose oxidase/peroxidase/ferrocyanide method for serum glucose.1158 However, in another study ampicillin did not appreciably interfere with serum glucose methods that used hexokinase, glucose oxidase, or o -toluidine.799

Tests for Uric Acid !!navigator!!

Ampicillin can cause falsely increased serum uric acid concentrations when the copper-chelate method is used;800 however, phosphotungstate and uricase methods for serum uric acid determinations appear to be unaffected by the drug.800

Immunohematology Tests !!navigator!!

Positive direct antiglobulin (Coombs') test results have been reported in patients receiving ampicillin.809 (See Cautions: Hypersensitivity Reactions.) This reaction may interfere with hematologic studies or transfusion cross-matching procedures and should be considered in patients receiving penicillins.341

Serum Aminoglycoside Assays !!navigator!!

Because ampicillin inactivates aminoglycosides in vitro (see Drug Interactions: Aminoglycosides), presence of the drug in serum samples to be assayed for aminoglycoside concentrations may result in falsely decreased results.1035,1115

Other Laboratory Tests !!navigator!!

Ampicillin in urine reportedly can cause false-positive results for leucine/isoleucine, phenylalanine, and β-aminoisobutyric acid in paper chromatography studies of urinary amino acids and false-positive results for phenylalanine in paper electrophoretograms.792

In one study, ampicillin in urine caused a false-positive result in the iodine-azide spot test used to screen for sulfite oxidase deficiency.1039 A transient decrease in plasma concentration of total conjugated estriol, estriol glucuronide, conjugated estrone, and estradiol reportedly has occurred in pregnant women taking ampicillin; this effect may also occur with amoxicillin.36 (See Cautions: Pregnancy, Fertility, and Lactation.)

Mechanism of Action

Aminopenicillins have a mechanism of action similar to that of other penicillins.61,107 For information on the mechanism of action of penicillins, see Mechanism of Action in the Natural Penicillins General Statement 8:12.16.04.

Partly because of the presence of a free amino group at R on the penicillin nucleus, aminopenicillins can penetrate the outer membrane of gram-negative bacteria more readily than natural or penicillinase-resistant penicillins and are therefore active against some gram-negative bacteria that are resistant to natural or penicillinase-resistant penicillins.61,99,148,575

Amoxicillin and ampicillin reportedly vary in their rate of bactericidal action and in the completeness of this effect.61,76,88,109 Although the clinical importance is unclear, in vitro studies using Escherichia coli and ampicillin and amoxicillin in concentrations twice those of the MIC of the drugs for this organism indicate that amoxicillin causes rapid formation of spheroplasts and lysis of susceptible E . coli , whereas ampicillin produces abnormally elongated or filamentous forms of the organism.61,88,109 The elongated or filamentous forms of E . coli are more osmotically stable than spheroplasts and lyse at a slower rate;61,88,109 these forms are also capable of rapidly resuming growth if ampicillin is removed before the cells lyse.109 In one study, ampicillin caused rapid lysis of E . coli only at concentrations 10-20 times the MIC of the drug for the organism.109

Spectrum

Aminopenicillins are active in vitro against most gram-positive and gram-negative aerobic cocci (except penicillinase-producing strains),61,63,64,73,76,116,226,228 some gram-positive aerobic and anaerobic bacilli,61,116,228 and some spirochetes.61,75 The drugs are also active in vitro against some gram-negative aerobic and anaerobic bacilli.61,73,116,228 Aminopenicillins are inactive against Mycoplasma , Rickettsia , fungi, and viruses.61

Although amoxicillin and ampicillin generally have the same spectrum of activity61,64,68,73,75,226,228,229,575 and the same level of activity against susceptible organisms,73,75,228,229,575 amoxicillin is more active in vitro on a weight basis than ampicillin against enterococci and Salmonella but less active than ampicillin against Shigella and Enterobacter .73,149,150,151,228,229,1314

Fixed-ratio combinations of amoxicillin and clavulanate potassium312,318,1311,1438,1446,1450,1454,1457,1486 or fixed-ratio combinations of ampicillin sodium and sulbactam sodium1901,1902,1903,1925,1955,1964,1994,2014,2039 are active in vitro against organisms susceptible to amoxicillin or ampicillin alone. In addition, because clavulanic acid and sulbactam can inhibit certain β-lactamases that generally inactivate aminopenicillins, combinations of amoxicillin and clavulanate potassium311,312,314,316,318,1298,1437,1446,1450,1453,1454,1473,1486,1489,1494,1501 or ampicillin sodium and sulbactam sodium1901,1902,1903,1925,1955,1961,1962,1964,1986,1991,1994,2004,2014,2039 are active in vitro against many β-lactamase-producing organisms that are resistant to the aminopenicillin alone. For information on the spectrum of activity of these fixed combinations, see Spectrum in Amoxicillin and Clavulanate Potassium 8:12.16.08 and in Ampicillin Sodium and Sulbactam Sodium 8:12.16.08.

In Vitro Susceptibility Testing !!navigator!!

Results of in vitro susceptibility tests with aminopenicillins may be affected by test media,76 inoculum size,68,76,229,1263 and pH.76,229 Susceptibility testing for gram-negative bacilli is particularly affected by inoculum size.73

The Clinical and Laboratory Standards Institute (CLSI) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to aminopenicillins, then an infection caused by this strain may be appropriately treated with the dosage of the drugs recommended for that type of infection and infecting species, unless otherwise contraindicated.2365 If results indicate that a clinical isolate has intermediate susceptibility to aminopenicillins, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue levels and response rates may be lower than for strains identified as susceptible.2365 Therefore, the intermediate category implies clinical applicability in body sites where the drugs are physiologically concentrated (e.g., urine) or when a high dosage of the drugs can be used.2365 This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.2365 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to aminopenicillins, the strain is not inhibited by systemic concentrations of the drugs achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical studies.2365

Standard in vitro susceptibility tests cannot detect tolerance to penicillins since these tests do not directly measure bactericidal activity.119,120,124,125,133,138,152 This fact should be considered when evaluating results of in vitro susceptibility tests for gram-positive cocci.119,120,133,152

Strains of staphylococci resistant to penicillinase-resistant penicillins also should be considered resistant to aminopenicillins, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drugs.2365

CLSI states that strains of enterococci identified as susceptible to aminopenicillins by in vitro susceptibility tests may be susceptible only if high dosages of the drugs are used for the treatment of serious enterococcal infections; treatment of enterococcal endocarditis caused by susceptible enterococci requires concomitant treatment with an aminoglycoside.2365 In addition, the fact that ampicillin-resistant strains of enterococci that produce β-lactamase may not be reliably detected using the inoculum concentration recommended for routine disk or dilution susceptibility tests should be considered.2365 CLSI recommends that, for enterococcal isolates from blood or CSF, resistance may be detected by a β-lactamase test performed using an inoculum of 107 CFU/mL or greater (or direct colony growth) and a nitrocefin-based substrate.2365 Synergy between ampicillin and an aminoglycoside is best predicted for enterococci by screening for susceptibility to 500 mcg of gentamicin or 1000-2000 mcg of streptomycin per mL.2365

Disk Susceptibility Tests

When disk-diffusion procedures are used to test susceptibility to aminopenicillins, a disk containing 10 mcg of ampicillin is used and results generally can be applied to ampicillin and amoxicillin.2365

CLSI states that, for non-β-lactamase-producing enterococci, results of disk-diffusion in vitro susceptibility tests using the ampicillin disk can be used to predict susceptibility to amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium.2365 However, for staphylococci, Enterobacteriaceae, and Haemophilus , disks containing fixed combinations of amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium should be used.2365

When disk-diffusion procedures are performed according to CLSI standardized procedures to test susceptibility of Enterobacteriaceae using the ampicillin disk, CLSI recommends that organisms with growth inhibition zones of 17 mm or greater be considered susceptible to aminopenicillins and those with zones of 13 mm or less be considered resistant to the drugs.2365 CLSI recommends that Enterobacteriaceae with zones of 14-16 mm be considered to have intermediate susceptibility to aminopenicillins.2365

Enterococci with growth inhibition zones of 17 mm or greater are considered susceptible to aminopenicillins and those with zones of 16 mm or less are considered resistant to the drugs.2365

Susceptibility of staphylococci to aminopenicillins should preferably be tested using a disk containing 10 penicillin G units, with interpretation of results being the same as for natural penicillins.2365 However, if the ampicillin disk is used to test susceptibility of staphylococci, CLSI recommends that staphylococci with growth inhibition zones of 29 mm or greater be considered susceptible to aminopenicillins and those with zones of 28 mm or less be considered resistant to the drugs.2365

When the disk diffusion procedure is performed according to CLSI standardized procedures using the ampicillin disk and Haemophilus Test Media (HTM), CLSI recommends that Haemophilus with growth inhibition zones of 22 mm or greater be considered susceptible to aminopenicillins, those with zones of 19-21 be considered to have intermediate susceptibility, and those with zones of 18 mm or less be considered resistant to the drugs.2365

CLSI recommends that when susceptibility of β-hemolytic streptococci to aminopenicillins is evaluated using the ampicillin disk and Mueller-Hinton agar (with 5% sheep blood), strains with growth inhibition zones of 24 mm or greater be considered susceptible to aminopenicillins.2365 Because strains of β-hemolytic streptococci with growth inhibition zones less than 24 mm have not been reported to date, any such strains should be submitted to a reference laboratory.2365 CLSI states that disk-diffusion susceptibility tests are not reliable for testing susceptibility of S. pneumoniae to aminopenicillins; dilution susceptibility tests should be used for this organism.2265 Because strains of β-hemolytic streptococci with growth inhibition zones less than 24 mm have not been reported to date, any such strains should be submitted to a reference laboratory.2365 CLSI states that disk-diffusion susceptibility tests are not reliable for testing susceptibility of S. pneumoniae to aminopenicillins; dilution susceptibility tests should be used for this organism.2365

When disk-diffusion procedures are performed according to CLSI standardized procedures using the ampicillin disk, Vibrio cholerae with growth inhibition zones of 17 mm or greater are considered susceptible to aminopenicillins, those with zones of 14-16 mm are considered to have intermediate susceptibility, and those with zones of 13 mm or less are considered resistant to aminopenicillins.2365

Dilution Susceptibility Tests

When dilution susceptibility testing (e.g., agar or broth dilution) is used, results of tests using ampicillin generally can be applied to ampicillin and amoxicillin.2365 CLSI states that, for streptococci (including S. pneumoniae ) and non-β-lactamase-producing enterococci, results of dilution tests using ampicillin can be used to predict susceptibility to amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium.2365 However, for staphylococci, Enterobacteriaceae, and Haemophilus , dilution susceptibility testing should be performed using combinations of amoxicillin and clavulanate potassium or ampicillin sodium and sulbactam sodium.2365

When dilution susceptibility testing is performed according to CLSI standardized procedures using ampicillin, CLSI recommends that Enterobacteriaceae with MICs of 8 mcg/mL or less be considered susceptible to aminopenicillins, those with MICs of 16 mcg/mL be considered to have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater be considered resistant to the drugs.2365

Enterococci with ampicillin MICs of 8 mcg/mL or less are considered susceptible and those with MICs of 16 mcg/mL or greater are considered resistant to aminopenicillins.2365 Susceptible strains of enterococci require high aminopenicillin dosage for the treatment of serious infections and concomitant use of an aminoglycoside in patients with enterococcal endocarditis.2365

When dilution susceptibility testing is performed according to CLSI standardized procedures, staphylococci with ampicillin MICs of 0.25 mcg/mL or less are considered susceptible to aminopenicillins and those with ampicillin MICs of 0.5 mcg/mL or greater are considered resistant to the drugs.2365

When susceptibility of Haemophilus is tested in a broth dilution procedure according to CLSI standardized procedures using ampicillin and HTM, Haemophilus with MICs of 1 mcg/mL or less are considered susceptible to aminopenicillins, those with MICs of 2 mcg/mL are considered to have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are considered resistant to the drugs.2365

When testing susceptibility of viridans streptococci using CLSI standardized procedures, CLSI recommends that those with ampicillin MICs of 0.25 mcg/mL or less be considered susceptible to aminopenicillins, those with MICs of 0.5-4 mcg/mL be considered to have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater be considered resistant to the drugs.2365 When testing β-hemolytic streptococci, those with ampicillin MICs of 0.25 mcg/mL or less are considered susceptible to aminopenicillins.2365 Because strains of β-hemolytic streptococci with ampicillin MICs greater than 0.25 mcg/mL have not been reported to date, any such strains should be submitted to a reference laboratory.2365

Vibrio cholerae with ampicillin MICs of 8 mcg/mL or less are considered susceptible to aminopenicillins, those with MICs of 16 mcg/mL are considered to have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are considered resistant to aminopenicillins.2365

Gram-positive Aerobic Bacteria !!navigator!!

Aminopenicillins are active in vitro against many gram-positive aerobic cocci including nonpenicillinase-producing strains of Staphylococcus aureus 36,38,39,42,45,46,48,49,61,73,76,116,205,226,228 and S . epidermidis ;36,38,39,42,45,46,48,49,61,76,116,205 groups A, B, C, and G streptococci;61,76,116,205,226,228 Streptococcus pneumoniae ;36,38,39,42,45,46,48,49,61,73,76,116,177,205,226,228 viridans streptococci;61,116,176,205,228 and some strains of enterococci.36,38,39,42,45,46,48,49,61,73,116,176,196,205,226,228,229,1303 Penicillinase-producing strains of S. aureus and S. epidermidis are resistant to the drugs.36,38,39,42,45,46,48,49,61,64,68,75,76,116,226,228,229 In vitro, aminopenicillins are slightly less active on a weight basis than natural penicillins against most susceptible gram-positive cocci;64,68 however, the drugs are generally more active in vitro than natural penicillins against enterococci.61,64,67

The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of amoxicillin73,226,228 or ampicillin73,116,205,226,228 reported for most strains of nonpenicillinase-producing S. aureus is 0.12-0.25 mcg/mL. The MIC90 of the drugs reported for nonpenicillinase-producing S. epidermidis is 0.12-0.4 mcg/mL.116,205 In one in vitro study, several strains of S. simulans , S. hominis , and S. warneri were inhibited by ampicillin concentrations of 0.125-0.25 mcg/mL and several strains of S. haemolyticus were inhibited by ampicillin concentrations of 1 mcg/mL.1108

Amoxicillin61,73,116,177,226,228 or ampicillin61,116,175,176,181,205,226,228,1055 concentrations of 0.01-0.25 mcg/mL generally inhibit groups A,61,116,176,205,226,228 B,61,116,175,176,181,205 C,176,205 and G176,205,1055 streptococci, S. pneumoniae ,61,73,116,176,177,205,226,228 and viridans streptococci61,116,176,205,228 in vitro.

Amoxicillin reportedly is slightly more active on a weight basis than ampicillin against Enterococcus faecalis ,73,228,229 and susceptible strains of the organism are generally inhibited in vitro by amoxicillin concentrations of 0.38-3 mcg/mL61,73,116,226,228,229 or ampicillin concentrations of 0.5-5 mcg/mL.61,73,176,196,205,226,1303 Although some strains of E. faecium are inhibited in vitro by 0.5-8 mcg/mL of ampicillin,2091,2093,2099 many strains of the organism require concentrations of 16 mcg/mL or greater for in vitro inhibition and are considered resistant to aminopenicillins.2091,2093,2096,2099

Aminopenicillins are also active in vitro against several gram-positive aerobic bacilli.116,228 Corynebacterium diphtheriae is reportedly inhibited in vitro by amoxicillin or ampicillin concentrations of 0.02-0.4 mcg/mL.116,228 Susceptible strains of Listeria monocytogenes are inhibited in vitro by 0.1-0.8 mcg/mL of either drug.61,116,228,1197,1198

In vitro, amoxicillin concentrations of 0.25 mcg/mL116,228 or ampicillin concentrations of 0.03 mcg/mL116 inhibit some strains of Bacillus anthracis . Erysipelothrix rhusiopathiae is generally inhibited in vitro by amoxicillin or ampicillin concentrations of 0.02-0.05 mcg/mL.116,228

Although most strains of Nocardia are resistant to aminopenicillins, a few strains are reportedly inhibited in vitro by amoxicillin or ampicillin concentrations of 1.6-16 mcg/mL.116,163,1104,1302,1412

Gram-negative Aerobic Bacteria !!navigator!!

Neisseria

Aminopenicillins are active in vitro against most strains of Neisseria meningitidis 36,38,39,42,45,46,48,49,61,116,228 and nonpenicillinase-producing N . gonorrhoeae .36,38,39,42,45,46,48,49,61,116,170,171,196,228,1102,1103

N . meningitidis is generally inhibited in vitro by amoxicillin116,228 or ampicillin61,116 concentrations of 0.02-0.06 mcg/mL.

Nonpenicillinase-producing strains of N. gonorrhoeae are generally inhibited by amoxicillin or ampicillin concentrations of 0.01-0.35 mcg/mL.170,171,196,1102,1103,1263 Some strains of N. gonorrhoeae that are relatively resistant to penicillin G may be susceptible to amoxicillin73 or ampicillin;68,1103 however, penicillinase-producing strains of N. gonorrhoeae are usually also resistant to aminopenicillins.61,1102,1263

Haemophilus

Aminopenicillins are active in vitro against many strains of Haemophilus influenzae 36,38,39,42,45,46,48,49,61,68,73,116,170,196,205,218,226 and some strains of H. parainfluenzae 1166,1250,1337 and H. ducreyi .116,314,1165

Susceptible strains of H. influenzae or H. parainfluenzae are inhibited in vitro by amoxicillin concentrations of 0.05-0.8 mcg/mL61,73,116,226,228,449 or ampicillin concentrations of 0.025-1 mcg/mL;61,68,116,170,196,205,218,226,306,309,1167,1250,1295β-lactamase-producing strains are resistant to aminopenicillins.61,170,205,309,449,1166,1167,1250,1275 Although most strains of H. ducreyi are β-lactamase producers and are resistant to aminopenicillins, some strains of the organism are inhibited in vitro by amoxicillin or ampicillin concentrations of 0.25-2 mcg/mL.116,314,1165

Enterobacteriaceae

Aminopenicillins also have some activity against Enterobacteriaceae and are active in vitro against some strains of Escherichia coli ,36,38,39,42,45,46,48,49,61,73,76,116,217,226,228 Proteus mirabilis ,36,38,39,42,45,46,48,49,61,76,116,226,228 Salmonella ,38,39,42,45,46,48,49,61,76,116,226,228,229,1273 and Shigella .38,39,42,45,46,48,49,61,76,116,226,228 Although rare strains of P. vulgaris ,61 Enterobacter aerogenes ,116,149 and Citrobacter freundii 116 are reportedly inhibited in vitro by high concentrations of ampicillin, aminopenicillins are inactive against most strains of these organisms.61,63,116,226

Although strains of E. coli resistant to aminopenicillins have been reported with increasing frequency, some strains of the organism are inhibited in vitro by amoxicillin61,73,116,226,228 or ampicillin61,116,217,226,228 concentrations of 1.25-12.5 mcg/mL. Susceptible strains of P. mirabilis are reportedly inhibited in vitro by amoxicillin61,116,226 or ampicillin61,116,226 concentrations of 0.8-5 mcg/mL.

Amoxicillin is reportedly slightly more active on a weight basis than ampicillin against susceptible Salmonella ;72,229 however, ampicillin is reportedly slightly more active on a weight basis than other aminopenicillins against susceptible Shigella .229 Susceptible strains of Salmonella are generally inhibited in vitro by amoxicillin concentrations of 0.8-3 mcg/mL116,226,228,229,454 and ampicillin.61,116,226,454,1294 In one study, the MIC90 of ampicillin for S. typhi was 0.5 mcg/mL and the MIC90 for S. enteritidis was 2.5 mcg/mL.1293 In vitro, susceptible strains of Shigella are generally inhibited by amoxicillin concentrations of 1.5-12.5116,226,228 or ampicillin concentrations of 1-5 mcg/mL.116,226

Other Gram-negative Aerobic Bacteria

Aminopenicillins are active in vitro against Bordetella pertussis 61,116,182,228 and Eikenella corrodens ,116 and most strains of these organisms are reportedly inhibited in vitro by ampicillin concentrations of 0.1-8 mcg/mL.61,116,182

Ampicillin has some activity in vitro against Legionella , although the drug may not be effective clinically.116,184,185,1170,1402 In vitro, some strains of L. pneumophila are inhibited by ampicillin concentrations of 0.25-4 mcg/mL.116,184,185,1170 Ampicillin concentrations of 0.06-1 mcg/mL inhibit some strains of L. micdadei (the Pittsburgh pneumonia agent), L. bozemanii , and L. gormanii and ampicillin concentrations of 4-16 mcg/mL inhibit some strains of L. dumoffii in vitro.184

Pasteurella multocida , an organism that can be aerobic or facultatively anaerobic, is usually inhibited in vitro by ampicillin concentrations of 0.1-1.6 mcg/mL.68,183 In vitro, amoxicillin116,228 or ampicillin61,68,116 concentrations of 0.1-2.5 mcg/mL reportedly inhibit some strains of Brucella .

Ampicillin concentrations of 0.13 mcg/mL generally inhibit Gardnerella vaginalis .191

In vitro, ampicillin concentrations of 0.12 mcg/mL generally inhibit strains of Moraxella catarrhalis that do not produce β-lactamase; however, many strains of the organism are β-lactamase producers and are therefore resistant to the drug.1395

Amoxicillin and ampicillin reportedly have some in vitro activity against Campylobacter fetus , and the MIC90 of the drugs reported for some strains of C. fetus subsp. jejuni is 6.3-12.5 mcg/mL.116,187 The MIC90 of ampicillin for Helicobacter pylori reportedly is less than 0.03 mcg/mL.1634,1844 Limited data indicate that H. pylori generally is inhibited by amoxicillin concentrations of 0.06 mcg/mL or less;1845 amoxicillin also has demonstrated bactericidal activity against slowly growing H. pylori .1846 The combination of amoxicillin plus metronidazole or its hydroxy metabolite has demonstrated synergism in vitro against H. pylori .1847

Some strains of Vibrio cholerae are reportedly inhibited in vitro by amoxicillin concentrations of 5 mcg/mL.116,228

Aminopenicillins are inactive against Pseudomonas , including Ps. aeruginosa .61,73,116,217,226,228,317

Anaerobic Bacteria !!navigator!!

Aminopenicillins are active in vitro against many gram-positive anaerobic bacteria including some strains of Actinomyces ,61,68,116 Arachnia ,61 Bifidobacterium ,61,116 Clostridium tetani ,116,228 C . perfringens ,116 Eubacterium ,61,116 Lactobacillus ,61,116 Peptococcus ,116 Peptostreptococcus ,116 and Propionibacterium .61 The MIC90 of ampicillin reported for Peptococcus and Peptostreptococcus is 0.25 mcg/mL.116 Ampicillin concentrations of 0.25-6.2 mcg/mL reportedly inhibit susceptible strains of Clostridium , including C . perfringens .116 Some strains of C . tetani are reportedly inhibited in vitro by amoxicillin concentrations of 0.05 mcg/mL.228

Fusobacterium , a gram-negative anaerobe, is generally inhibited in vitro by ampicillin concentrations of 6.2 mcg/mL.116 Many strains of Bacteroides melaninogenicus ( Prevotella melaninogenica ) are inhibited in vitro by amoxicillin concentrations of 0.5-1 mcg/mL61 or ampicillin concentrations of 0.5-4 mcg/mL.61 The B. fragilis group (e.g., B. fragilis , B. distasonis , B. ovatus , B. thetaiotaomicron , B. vulgatus ) is usually resistant to aminopenicillins.61,63,1298

Spirochetes !!navigator!!

Aminopenicillins are active against some spirochetes including Treponema pallidum .61,75 T. pallidum is generally inhibited in vitro by amoxicillin concentrations of 0.5 mcg/mL.75 Borrelia burgdorferi , the causative organism of Lyme disease, reportedly may be inhibited in vitro by ampicillin concentrations of 0.25-1 mcg/mL or less1628,1756 and by amoxicillin concentrations of 0.5 mcg/mL;1754 minimum bactericidal concentrations of amoxicillin for B. burgdorferi generally have ranged from 0.4-3.2 mcg/mL.1133,1743,1770

Resistance

For a discussion of the possible mechanisms of bacterial resistance to penicillins, see Resistance: Mechanisms of Penicillin Resistance, in the Natural Penicillins General Statement 8:12.16.04.

Complete cross-resistance generally occurs between amoxicillin and ampicillin.73,75,226,228

Resistance in Gram-positive Bacteria !!navigator!!

Because aminopenicillins are readily inactivated by staphylococcal penicillinases, penicillinase-producing S. aureus and S. epidermidis are resistant to the drugs.36,38,39,42,45,46,48,49,61,64,68,75,76,116,226,228,229

Some strains of S. pneumoniae that are relatively resistant to penicillin G may be susceptible to ampicillin;61,1178 however, strains of S. pneumoniae that are completely resistant to penicillin G are also resistant to ampicillin.61,177

Enterococcus faecium generally is resistant to aminopenicillins.2091,2092,2093,2096,2097,2099 Resistance to aminopenicillins in some enterococci (e.g., E. faecalis , E. faecium ) can result from β-lactamase production2090,2091,2092,2094,2095,2096,2097,2098 or from decreased binding to and/or increased production of penicillin-binding proteins with a low affinity for the drugs (e.g., PBP 5 or 6).2090,2091,2092,2093,2098,2099 Enterococci that exhibit ampicillin resistance secondary to β-lactamase production may be susceptible in vitro when the aminopenicillin is combined with a β-lactamase inhibitor (e.g., clavulanic acid, sulbactam);2092,2095,2097 however, addition of the β-lactamase inhibitor does not necessarily result in susceptibility to the aminopenicillin in such strains.2096,2097 Some strains of enterococci with relatively high aminopenicillin resistance secondary to β-lactamase production may remain resistant or be only moderately more susceptible to the aminopenicillin combined with a β-lactamase inhibitor.2096,2097 Strains that exhibit ampicillin resistance secondary to alterations in PBPs remain resistant when the drug is combined with a β-lactamase inhibitor such as sulbactam or clavulanic acid,2091,2092 and some evidence suggests that such strains occasionally may emerge secondary to high-dose drug exposure.2091 In addition, enterococci resistant to multiple drugs (e.g., vancomycin, teicoplanin, aminoglycosides, ampicillin, penicillin G, imipenem, tetracyclines, synergistic combinations of β-lactam anti-infectives) have been reported with increasing frequency.2090,2091,2092,2093,2094,2095,2096,2098

Resistance in Gram-negative Bacteria !!navigator!!

Penicillinase-producing strains of N. gonorrhoeae that are completely resistant to natural penicillins are usually also resistant to aminopenicillins;61,215,241,1263 however, some strains of N. gonorrhoeae that are relatively resistant to natural penicillins may be inhibited in vitro by aminopenicillins.61

Strains of E. coli that are resistant to aminopenicillins have been reported with increasing frequency.61,64,74,139 Approximately 30-50% of clinical isolates of E. coli have been reported to be resistant to the drugs.61,64,116,139 Resistance to aminopenicillins in these organisms generally results from the production of β-lactamases61,139,229 which can be either plasmid-mediated or chromosomally mediated.61,132,139,1177 Strains of P. mirabilis that produce β-lactamases are also generally resistant to aminopenicillins.61 Resistance to aminopenicillins in Citrobacter 139 and Enterobacter 139,150 also generally results from the production of β-lactamases that inactivate the drugs.

Resistance to aminopenicillins has been reported only rarely in Salmonella typhi ;61,63,1294,1398 however, resistant strains of nontyphoidal Salmonella (e.g., S. typhimurium ) have been reported with increasing frequency.1272,1273,1305 Approximately 40% of clinical isolates of S. typhimurium are reportedly resistant to aminopenicillins.61,74 Strains of Salmonella resistant to aminopenicillins may also be resistant to aminoglycosides, tetracyclines, and sulfonamides.1272,1305,1398 Resistance in Salmonella generally results from a plasmid-mediated resistance factor that is acquired by conjugation.61,1398

A large percentage of clinical isolates of Shigella are reportedly resistant to aminopenicillins; however, susceptibility shows considerable geographic variability.61,74,1402 Ampicillin resistance occurs more frequently in strains of Sh. sonnei than in strains of Sh. flexneri or Sh. dysenteriae .61,74 Resistance to ampicillin in Shigella usually results from a plasmid-mediated resistance factor which can be acquired by conjugation.61,116,131 Strains of Shigella resistant to ampicillin are also generally resistant to chloramphenicol, sulfonamides, streptomycin, and tetracyclines,61,116 but may be susceptible to co-trimoxazole.116

Ampicillin-Resistant Haemophilus

Ampicillin-resistant strains of H. influenzae and H. parainfluenzae have been reported with increasing frequency;61,64,76,155,156,1166,1167,1246,1275,1299,1731 however, susceptibility shows considerable geographic variability.116,1166,1169,1275,1389,1731 Approximately 2-35% of clinical isolates of H. parainfluenzae 61,64,116,156,218,917,972,1169,1275,1389,1391,1731 and 15-86% of clinical isolates of H. parainfluenzae type b, H. influenzae nontype b, and in nonencapsulated (nontypable) strains of the organism.61,156,1169,1391,1731

Ampicillin resistance in H. influenzae or H. parainfluenzae generally results from β-lactamases that are plasmid-mediated and can be acquired by conjugation;61,156,306,309,1166,1167,1246,1250,1265,1275,1391,1731 however, resistance has also been reported rarely in strains of H. influenzae that did not produce β-lactamases.155,156,1246,1265,1731 Ampicillin-resistant strains of H. influenzae or H. parainfluenzae are also resistant to natural penicillins61,155,156,205,218,1166,1167 and extended-spectrum penicillins,100,170,205,241 but may be susceptible to chloramphenicol, gentamicin, co-trimoxazole,61,155,218,1167,1246,1299,1731 or second or third generation cephalosporins (e.g., cefaclor, cefotaxime, cefoxitin, cefuroxime).61,218,249,1246,1299 Strains of H. influenzae that are resistant to both ampicillin and chloramphenicol or ampicillin and co-trimoxazole have been reported rarely.1275,1299,1731

Pharmacokinetics

For additional information on the pharmacokinetics of amoxicillin and ampicillin, see Pharmacokinetics in the individual monographs in 8:12.16.08.

Absorption !!navigator!!

Like other penicillins, absorption of orally administered aminopenicillins occurs mainly in the duodenum and upper jejunum81 and the rate and extent of absorption depends on the particular aminopenicillin derivative,64,320,328,351,366,443,466,479,487 dosage form administered,76 gastric and intestinal pH,341,428 and presence of food in the GI tract.61,68,342,428,449,457,478,490

Aminopenicillins are more resistant to acid-catalyzed hydrolysis than natural penicillins64,65,68,90,575 and most penicillinase-resistant penicillins.68,575 Amoxicillin,36,73,341,428 amoxicillin trihydrate,64,81 ampicillin,64,68,81,341 and ampicillin trihydrate42,45,46,48,49,68 are generally stable in the presence of acidic gastric secretions and are fairly well absorbed following oral administration; however, there are variations in the extent and rate of absorption of the drugs from the GI tract.328,351,366,428,433,449,493

Following oral administration of single doses of the drugs in healthy, fasting adults, peak serum concentrations of ampicillin68,81,443,512 or amoxicillin36,81,328,346,455,494 are generally attained within 1-2 hours and serum concentrations are usually low or undetectable 6-8 hours later.479 Although the drugs are generally absorbed at the same rate, amoxicillin is more completely absorbed from the GI tract than is ampicillin73,328,351,366,428,493 and peak serum concentrations of amoxicillin are generally 2-2.5 times higher than those attained with an equivalent oral dose of ampicillin.73,81,328,428,479,493 Approximately 74-92% of a single oral dose of amoxicillin61,73,320,366,487 is absorbed from the GI tract in fasting adults, but only 30-55% of a single oral dose of ampicillin is absorbed.63,67,81,320,341,366,494,487 In one crossover study in healthy, fasting adults who received single 500-mg oral doses of amoxicillin and ampicillin, the area under the serum concentration-time curve (AUC) was approximately 50% larger with amoxicillin than with ampicillin.479

As oral dosage of amoxicillin433 is increased, the fraction of the dose absorbed from the GI tract decreases only slightly and peak serum concentrations and AUCs of the drugs generally increase linearly with increasing dosage. However, as oral dosage of ampicillin is increased from 500 mg to 2 g, the fraction of the dose absorbed decreases and there is a nonlinear relationship between dosage and peak serum concentrations or AUCs of ampicillin.433

Preliminary data indicate that the volume of water administered with amoxicillin capsules may influence the extent of absorption of the drug.455,457,466 In one study, the mean peak serum concentration and AUC of amoxicillin were lower when two 250-mg capsules of the drug were administered with 25 mL of water than when the same dose was administered with 250 mL of water.466 This effect did not occur when two 250-mg capsules of ampicillin were administered with 25 mL or 250 mL of water, presumably because ampicillin is more water soluble than amoxicillin.466

Oral absorption of aminopenicillins is delayed in neonates compared with absorption of the drugs in children and adults.73,340,358 Following oral administration of a single dose of amoxicillin in neonates, peak serum concentrations of the drug are generally attained within 3-4.5 hours340,358 compared with 1-2 hours in children340,449,462,489 and adults.81,328,346,358,455,494 In one study in a limited number of patients with celiac disease, absorption of amoxicillin, but not ampicillin, was reduced following oral administration.1108

Presence of food in the GI tract generally decreases the rate and extent of absorption of ampicillin.342,457,466 Although presence of food in the GI tract reportedly results in lower and delayed peak serum concentrations of amoxicillin,226,228,466 the total amount of drug absorbed does not appear to be affected.73,228,342,428,457,466

Ampicillin sodium is well absorbed following IM administration and peak serum concentrations of the drug are generally higher than those resulting from equivalent doses of the drug given orally.67,338,404,453 Following IM administration of a single dose of ampicillin sodium in healthy adults, peak serum concentrations of ampicillin are generally attained within 1 hour67,72,404,453 and serum concentrations are low or undetectable 6-8 hours later.404,453 Rapid IV administration of ampicillin sodium results in peak serum concentrations of the drug immediately after completion of the infusion and serum concentrations are still detectable 6 hours later.556

Ampicillin is absorbed from the peritoneal cavity following local instillation of the drug.328

Distribution !!navigator!!

Aminopenicillins are widely distributed following absorption from the GI tract or injection sites.61,73,333 The apparent volumes of distribution of amoxicillin455,487 and ampicillin453,482 are reportedly 0.267-0.315 L/kg in adults with normal renal function. Studies using IM or IV ampicillin or amoxicillin indicate that concurrent administration of oral probenecid decreases the volumes of distribution of the drugs.347,447 (See Drug Interactions: Probenecid.)

Aminopenicillins are generally distributed into ascitic,339 synovial,68,323,326,335 and pleural68,435 fluids. The drugs are also distributed into the liver,495,511 lungs,495 gallbladder,483,495 prostate,332 and muscle.492 Amoxicillin and73,333,428,431,511 ampicillin333,431,511,1171 are generally distributed into middle ear effusions,511 bronchial secretions,333,432,1171 sputum,73,428,431 maxillary sinus secretions,73,599 and tonsils.73 Low concentrations of the drug are also attained in saliva,73,321,500 sweat,500 and tears.500 Aminopenicillins are distributed into bile in varying amounts.320,428,495 If biliary obstruction is not present, concentrations of amoxicillin63,428,495 or ampicillin61,72,320 in bile are generally 1-30 times greater than concurrent serum concentrations of the drugs. Like other penicillins, only negligible amounts of amoxicillin73 or ampicillin320,780 have been detected in aqueous humor following oral, IM, or IV administration of the drugs.

Only minimal concentrations of aminopenicillins are attained in CSF following oral, IM, or IV administration in patients with uninflamed meninges;61,456 higher concentrations may be attained when meninges are inflamed.456 In one study in patients with inflamed meninges who received a single 1-g oral dose of amoxicillin, CSF concentrations of the drug ranged from 0.1-1.5 mcg/mL 2 hours after the dose.446 Concurrent administration of oral probenecid with amoxicillin or ampicillin generally results in increased CSF concentrations of the drug.76,447 (See Drug Interactions: Probenecid.)

Because aminopenicillins contain a free amino group at R on the penicillin nucleus, these drugs are considerably less protein bound than other currently available penicillins.575 Amoxicillin and ampicillin are 17-2036,64,81,226,428,491 and 15-25%38,39,42,45,46,48,49,68,72,81,336,491 bound to serum proteins, respectively. The drugs bind mainly to serum albumin.320 Protein binding of the drugs is lower in neonates than in children or adults;81,340 ampicillin is reportedly 8-12% bound to serum proteins in neonates.81,340

Amoxicillin73,439 and ampicillin61,68,320,467 readily cross the placenta. Amoxicillin concentrations in cord blood are reportedly 25-33% of concurrent maternal serum concentrations of the drug.73 Amoxicillin61,73,496 and ampicillin355,1568 are distributed into milk in low concentrations.

Elimination !!navigator!!

Serum concentrations of amoxicillin503,601 and ampicillin decline in a biphasic manner. The distribution half-life (t½α) of amoxicillin is reportedly 0.19-0.39 hours in adults with normal renal function.487,601 The elimination half-lives (t½βs) of amoxicillin320,341,428,455,479,493,500,601 and ampicillin341,453 are similar and are reportedly 0.7-1.4 hours in adults with normal renal function.

Aminopenicillins are metabolized to varying extents.81,366,455,477 The drugs are partially metabolized by hydrolysis of the β-lactam ring to penicilloic acids which are microbiologically inactive.73,81,366,455,477 Approximately 19-33% of a single oral dose of amoxicillin,73,81,320,341,366,477 7-11% of a single oral dose of ampicillin,81,366,455,477 or 10-12% of a single IM dose of ampicillin sodium320,366 is excreted in urine as penicilloic acids. Trace amounts of 6-aminopenicillanic acid (6-APA), formed by removal of the side chain at R on the penicillin nucleus, have also been found in urine following oral administration of ampicillin.366

Aminopenicillins and metabolites of the drugs are rapidly excreted in urine.61,76 Like other penicillins, the drugs are excreted by renal tubular secretion and to a lesser extent by glomerular filtration.61 Small amounts of the drugs are also excreted in feces and bile.61,76,509 In adults with normal renal function, approximately 20-64% of a single oral dose of ampicillin73,81,336,351,443,479,493 and 43-80% of a single oral dose of amoxicillin36,73,81,226,228,428,479,493 are excreted unchanged in urine within 6-8 hours. Approximately 60-70% of a single IM dose of ampicillin sodium336,337 or 73-90% of a single IV dose of the drug490 is excreted unchanged in urine.

Serum clearance of amoxicillin is reportedly 283 mL/minute601 and serum clearance of ampicillin is reportedly 259 mL/minute in adults with normal renal function.

Serum concentrations of aminopenicillins are higher and the serum half-lives of the drugs are prolonged in patients with renal impairment.61,76,81,320,328,348,438,473,510,601 The serum half-lives of amoxicillin438,601 and ampicillin61,320,348 reportedly range from 7.4-21 hours in patients with creatinine clearances less than 10 mL/minute.

Serum concentrations of amoxicillin and ampicillin are generally higher and the serum half-lives of the drugs are longer in neonates than in older children or adults.340,358,444,470,484 Serum half-lives of the drugs are generally inversely proportional to birthweight, gestational age, and chronologic age.340 This appears to result from immature mechanisms for renal tubular secretion of the drugs.340,470 The serum half-life of ampicillin is reportedly 4 hours in neonates 2-7 days of age, 2.8 hours in neonates 8-14 days of age, and 1.7 hours in neonates 15-30 days of age.61 The serum half-life of amoxicillin is reportedly 3.7 hours in full-term neonates and 0.9-1.9 hours in infants and children.340

Renal clearance of aminopenicillins is also decreased in geriatric patients because of diminished tubular secretory ability; therefore, serum concentrations of the drugs are generally higher and the serum half-lives prolonged in these patients.482 In one study in 5 geriatric patients 67-76 years of age, the t½β of ampicillin ranged from 1.4-6.2 hours.482

Oral probenecid administered shortly before or with aminopenicillins competitively inhibits renal tubular secretion of the penicillins and produces higher and prolonged serum concentrations of the drugs.61,73,76,81,226,229,328,346,347 (See Drug Interactions: Probenecid.)

Amoxicillin63,73,81,428,438,451,473,601,1373,1554 and ampicillin63,64,320,348,510,1373 are removed by hemodialysis. The amount of the drugs removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow-rate); however, a 4- to 6-hour period of hemodialysis generally removes 30-40% of a single oral or IV dose of the drugs into the dialysate when the dose is given immediately prior to dialysis.438,510,601 Only minimal amounts of amoxicillin509,1373 or ampicillin64,328,340,348,1373 appear to be removed by peritoneal dialysis.

Chemistry and Stability

Chemistry !!navigator!!

Aminopenicillins are semisynthetic penicillin derivatives produced by acylation of 6-aminopenicillanic acid (6-APA).61,76 Aminopenicillins have a free amino group at the α-position at R on the penicillin nucleus62,68,74,76,88,297,575 which results in enhanced activity against gram-negative bacteria compared with natural penicillins and penicillinase-resistant penicillins.62,68,74,88,297,575 (For information on the penicillin nucleus, see the Preface to the Penicillins General Statements 8:12.16.) The aminopenicillins group includes amoxicillin and ampicillin.76

Ampicillin is the prototype drug of the aminopenicillins.64,76,77 Ampicillin differs structurally from penicillin G only in the presence of an amino group at the α-position on the benzene ring at R on the penicillin nucleus.88 Amoxicillin is the p -hydroxyl analog of ampicillin.68,89,575

Amoxicillin is commercially available as the trihydrate36 and ampicillin is commercially available as the trihydrate or sodium salt.38,39 Amoxicillin also is commercially available in fixed-ratio combinations with clavulanate potassium,1437 and ampicillin sodium also is commercially available in a fixed-ratio combination with sulbactam sodium.1901 Potency of amoxicillin36 and ampicillin42,45,46,48,49 is calculated on the anhydrous basis.

Stability !!navigator!!

Aminopenicillins are generally stable in the dry state;64 however, the drugs are stable only for short periods of time in solution.38,39,64,82,94 Like other penicillins, the stability of aminopenicillins is pH and temperature dependent.82,90,94 Aminopenicillins are more resistant to acid-catalyzed hydrolysis than natural penicillins64,65,68,90,575 and are generally stable in the presence of acidic gastric secretions following oral administration.90,228 Amoxicillin and ampicillin reportedly have half-lives of 15-20 hours in solutions with a pH of 2 at 35°C.90

Commercially available ampicillin preparations may contain small amounts of polymeric impurities.575 In addition, small amounts of ampicillin polymers can form in ampicillin solutions during in vitro storage.575 These polymers are potential antigens when combined with protein and appear to play a role in allergic sensitization to penicillins.575 For a discussion of allergic sensitization to penicillins, see Cautions: Hypersensitivity Reactions, in the Natural Penicillins General Statement 8:12.16.04.

The stability of ampicillin sodium in solution is concentration dependent and decreases as the concentration of the drug increases.82 Ampicillin sodium appears to be especially susceptible to inactivation in solutions containing dextrose, which appears to have a catalytic effect on hydrolysis of the drug.82,93 Although solutions of most other penicillins are reportedly stable when frozen,82 ampicillin at certain concentrations and in certain solutions rapidly decomposes when frozen.82,93 For a more complete discussion of the stability of amoxicillin and ampicillin, and solutions of the drugs, see Chemistry and Stability: Stability, in the individual monographs in 8:12.16.08.

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions February 2, 2022. 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.

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