Penicillinase-Resistant Penicillins General Statement

[Section Outline]

Staphylococcal Infections
Perioperative Prophylaxis

Penicillinase-resistant penicillins are used in the treatment of infections caused by, or suspected of being caused by, susceptible penicillinase-producing staphylococci.1,2,3,4,5,8,12,18,166,168,175,202,212,224,246,247,260,263 Although penicillinase-resistant penicillins have been effective when used in the treatment of infections caused by other susceptible gram-positive aerobic cocci (e.g., Streptococcus pneumoniae , S. pyogenes , nonpenicillinase-producing staphylococci), the drugs are less active than natural penicillins against these gram-positive bacteria in vitro on a weight basis and should not be used in the treatment of infections caused by organisms susceptible to penicillin G and penicillin V.1,2,3,5,12,88,166,168,170,173,224,260 Penicillinase-resistant penicillins have been used for perioperative prophylaxis†198,254,260 but are not considered drugs of choice for such prophylaxis.257,254

Prior to initiation of therapy with a penicillinase-resistant penicillin, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility testing.1,2,3,4,5,224 A penicillinase-resistant penicillin may be used empirically for the treatment of any infection suspected of being caused by susceptible staphylococci, but the drug should be discontinued and appropriate anti-infective therapy substituted if the infection is found to be caused by an organism other than a penicillinase-producing staphylococci susceptible to penicillinase-resistant penicillins.1,2,3,5,202,224,263 If staphylococci resistant to penicillinase-resistant penicillins (oxacillin-resistant staphylococci; previously known as methicillin-resistant staphylococci) are prevalent in the hospital or community, empiric therapy of suspected staphylococcal infections should include vancomycin.8,37,188,189,202,247,263 (See Oxacillin-Resistant Staphylococcal Infections in Uses: Staphylococcal Infections.)

Penicillinase-resistant penicillins should not be used orally for the initial treatment of severe, life-threatening infections,1,2,3,4,5,166,170,224 including meningitis, but may be used as follow-up therapy after parenteral penicillinase-resistant penicillin therapy.2,3,166,170,194,202,224,263

Staphylococcal Infections

Penicillinase-resistant penicillins are the drugs of choice for the treatment of infections caused by susceptible penicillinase-producing staphylococci.8,12,166,168,170,202,246,247,260,263 The drugs have been effective when used in the treatment of upper and lower respiratory tract infections,10,18,88,260,263 skin and skin structure infections,10,18,88,269 bone and joint infections,10,18,54,83,88,168,175,190,213,215,260,263 urinary tract infections,18,88 meningitis,10,18,90,168,170,181,260 bacteremia,10,18,88,168,260,269,277 and endocarditis10,18,29,156,168,177,192,258,260,269 caused by susceptible penicillinase-producing staphylococci. Penicillinase-resistant penicillins also are used in the management of infections related to peripheral vascular and central venous catheters.247,270

Because the majority of clinical isolates of staphylococci, regardless of source, are resistant to natural penicillins,263 a penicillinase-resistant penicillin usually is indicated for initial treatment of infections suspected of being caused by staphylococci.202,247,263 If a staphylococcal infection fails to respond to therapy with a penicillinase-resistant penicillin although in vitro tests indicate that the causative organism is susceptible to the drugs, the presence of undrained abscesses or perivascular infections should be considered.169,202 Anti-infective therapy alone rarely is effective for staphylococcal infections in individuals with undrained abscesses or with infected foreign bodies; surgical intervention may be necessary.263,268 The possibility that the causative organism may be tolerant to penicillins29,30,39,106,191,202 or that the infection may be caused by oxacillin-resistant staphylococci also should be considered since routine in vitro susceptibility tests may not detect penicillin tolerance or resistance to penicillinase-resistant penicillins.29,30,33,39,106,182 (See Spectrum: In Vitro Susceptibility Testing.)

Many clinicians suggest that serum bactericidal titers (SBTs) be used to monitor the adequacy of penicillinase-resistant penicillin therapy in patients with staphylococcal endocarditis or osteomyelitis and to adjust dosage of the drugs.174,178,179,180,190,203,214,230,263 Although the value of SBTs has not been definitely established and there is a wide variation in SBTs depending on the method used, peak SBTs of 1:8 or greater in patients with staphylococcal endocarditis receiving a penicillinase-resistant penicillin generally have been associated with high cure rates.177,178,179,180,214,230 A peak SBT of 1:8 or greater also has been recommended when an oral regimen is used for the treatment of bone or joint infections;263 other clinicians suggest that SBTs in patients with osteomyelitis should be 1:16 or greater.190,193,214

Osteomyelitis

Because acute osteomyelitis, especially in children, frequently is caused by penicillinase-producing S. aureus ,174,195 a penicillinase-resistant penicillin usually is included in the empiric regimen pending results of in vitro tests.174,190,195,211,213,263,269 In neonates, the most frequent causes of osteomyelitis are S. aureus , S. agalactiae (group B streptococci), and gram-negative bacilli (e.g., Escherichia coli ),263,268 and empiric therapy with a penicillinase-resistant penicillin and a third generation cephalosporin (e.g., cefotaxime) provides coverage against these organisms.263 In older infants and children through 5 years of age, the principal pathogens usually are S. aureus , streptococci, and H. influenzae ,263,268 and many clinicians recommend empiric therapy with cefuroxime or a third generation cephalosporin (e.g., ceftriaxone, cefotaxime).263 In adults and children older than 5 years of age, osteomyelitis usually is caused by S. aureus , and a penicillinase-resistant penicillin usually is recommended for empiric therapy in these age groups;263,268 however, if arthritis is present, other pathogens may be involved and a broad-spectrum anti-infective (e.g., cefuroxime, third generation cephalosporin) may be indicated unless gram-positive cocci are demonstrated in synovial fluid samples.263

Many clinicians recommend that acute osteomyelitis in adults or children caused by susceptible penicillinase-producing staphylococci be treated with a parenteral penicillinase-resistant penicillin for 3-8 weeks.169,190,202,263,268 Alternatively, some clinicians recommend that a parenteral penicillinase-resistant penicillin be used initially followed by an oral penicillinase-resistant penicillin.175,190,195,202,263,268 In several controlled studies in children with acute osteomyelitis, penicillinase-resistant penicillin therapy was effective when the drugs were administered parenterally for 5-28 days or until the patient was afebrile for 3 consecutive days, then orally for 3-6 weeks or until the total duration of parenteral and oral therapy was at least 6 weeks.175,190,193,195,214,269

For the treatment of chronic osteomyelitis caused by penicillinase-resistant staphylococci, many clinicians recommend treatment with a parenteral penicillinase-resistant penicillin given for at least 4-6 weeks followed by an oral penicillinase-resistant penicillin given for at least an additional 1-2 months.190 Chronic osteomyelitis also has been treated successfully with high dosages of oral dicloxacillin given for prolonged periods (6 months or longer) either alone or in conjunction with probenecid.83,190,215,260

Endocarditis

IV nafcillin or IV oxacillin is used for the treatment of endocarditis caused by susceptible strains of S. aureus or S. epidermidis and are the drugs of choice for the treatment of endocarditis caused by penicillin-resistant staphylococci.192,258

Because results of in vitro studies indicate that a β-lactam antibiotic used in conjunction with an aminoglycoside results in a more rapidly bactericidal action than the β-lactam antibiotic alone, some clinicians recommend that an aminoglycoside be used in conjunction with an IV penicillinase-resistant penicillin for the initial treatment of S. aureus endocarditis.180,192,258 However, penicillinase-resistant penicillins have been effective when used parenterally alone for 4-6 weeks in the treatment of endocarditis caused by susceptible staphylococci211 and the relative efficacy of concomitant therapy compared with penicillin therapy alone has not been definitely established.106,177,180,192,202,258 Although concomitant therapy with a penicillinase-resistant penicillin and an aminoglycoside may result in accelerated bacteriologic and clinical responses compared with therapy with a penicillinase-resistant penicillin alone, such therapy does not appear to improve survival or reduce valvular damage and may be associated with an increased incidence of adverse effects.177,192 Therefore, many clinicians recommend that treatment of staphylococcal endocarditis be initiated with concomitant therapy177,192,202 but that the aminoglycoside be discontinued after clearance of bacteremia (3-7 days) and the penicillinase-resistant penicillin continued alone for 4-6 weeks.106,177,192 Gentamicin is the aminoglycoside usually recommended for concomitant use with nafcillin or oxacillin for the treatment of staphylococcal endocarditis; however, if the strain is found to be resistant to gentamicin, another aminoglycoside should be substituted based on results of in vitro susceptibility testing.192,258

Endocarditis caused by S. lugdunensis tends to cause a more virulent form of endocarditis than other coagulase-negative staphylococci.259 Most experts recommend that endocarditis caused by S. lugdunensis be treated with standard anti-infective regimens based on in vitro susceptibility test results and that patients be monitored closely for periannular extension or extracardiac spread of the infection.192

Native Valve Endocarditis

For the treatment of native valve endocarditis caused by staphylococci susceptible to penicillinase-resistant penicillins, the American Heart Association (AHA) recommends that adults and pediatric patients receive a 4- to 6-week regimen of IV nafcillin or IV oxacillin given with or without gentamicin.192,258 The AHA states that, although the benefits of concomitant aminoglycoside therapy have not been clearly established in these infections, gentamicin may be given concomitantly for the first 3-5 days of the penicillinase-resistant penicillin regimen.192,258 In those very rare cases when native valve endocarditis is caused by staphylococci susceptible to penicillin (penicillin MIC 0.1 mcg/mL or less), the AHA states that adults may receive a 4-6-week regimen of penicillin G sodium instead of nafcillin or oxacillin.192

The AHA states that limited data suggest that a 2-week regimen of IV nafcillin or IV oxacillin given with an aminoglycoside may be effective in IV drug abusers who have right-sided endocarditis caused by susceptible S. aureus ; however, this shorter regimen should not be used in IV drug abusers with evidence of metastatic infection or left-sided endocarditis (mitral or aortic murmur, systemic emboli or cutaneous stigmata, or echocardiographically demonstrated vegetations on mitral or aortic valves).192 In addition, it is unclear whether those with right-sided S. aureus endocarditis and echocardiographically demonstrated vegetations (tricuspid or pulmonic valve), underlying acquired immunodeficiency syndrome (AIDS), or extensive pulmonary complications of right-sided endocarditis (lung abscess) are appropriate candidates for the 2-week regimen.192

For the treatment of native valve staphylococcal endocarditis in adults and pediatric patients with a history of penicillin hypersensitivity, the AHA recommends a regimen of IV cefazolin or other first generation cephalosporin (cephalosporins should be avoided in patients who have had an immediate-type hypersensitivity reaction to penicillins) given with or without IM or IV gentamicin during the first 3-5 days of therapy or, alternatively, a regimen of IV vancomycin.192,258

Native valve endocarditis caused by oxacillin-resistant staphylococci (previously known as methicillin-resistant staphylococci) usually is treated with a regimen of IV vancomycin.192,258

Endocarditis in the Presence of Prosthetic Valves or Materials

For the treatment of endocarditis caused by staphylococci susceptible to penicillinase-resistant penicillins in adults and pediatric patients with prosthetic valves or other prosthetic material, the AHA recommends a regimen of IV nafcillin or IV oxacillin given with oral rifampin for 6 weeks or longer and with IM or IV gentamicin given for the first 2 weeks.192,258 However, coagulase-negative staphylococci causing prosthetic valve endocarditis usually are resistant to penicillinase-resistant penicillins (especially when endocarditis develops within 1 year after surgery) and, unless results of in vitro testing indicate that the isolates are susceptible to penicillinase-resistant penicillins, coagulase-negative staphylococci involved in prosthetic valve endocarditis should be assumed to be oxacillin-resistant.192

For the treatment of adults and pediatric patients with prosthetic valves or other prosthetic materials who have endocarditis caused by staphylococci resistant to penicillinase-resistant penicillins, the AHA usually recommends a combination regimen of IV vancomycin and oral rifampin given for 6 weeks or longer with IM or IV gentamicin given concomitantly during the first 2 weeks of therapy.192

Infections Related to Intravascular Catheters

Penicillinase-resistant penicillins often are used for the empiric treatment of infections related to peripheral vascular and central venous catheters since these infections usually are caused by coagulase-negative staphylococci (e.g., S. epidermidis ), S. aureus , aerobic gram-negative bacilli (e.g., Acinetobacter , Pseudomonas aeruginosa ), or Candida albicans .247,270,278 The Infectious Diseases Society of America (IDSA), American College of Critical Care Medicine, and Society for Healthcare Epidemiology of America recommend that the empiric regimen be chosen based on the severity of the patient's clinical disease, risk factors for infection, and the most likely pathogens associated with the specific intravascular device.270 Unless the hospital or area has a high incidence of oxacillin-resistant staphylococci, these experts recommend use of a penicillinase-resistant penicillin (nafcillin, oxacillin) for empiric therapy of catheter-related infections when S. aureus are suspected.270 If coagulase-negative staphylococci or oxacillin-resistant staphylococci are suspected, vancomycin should be used initially for empiric therapy but the regimen should be changed to a penicillinase-resistant penicillin if the causative organisms is found to be susceptible to the penicillins.270 In severely ill or immunocompromised patients who have suspected catheter-related bloodstream infections, a third or fourth generation cephalosporin (e.g., ceftazidime, cefepime) may be indicated to provide empiric coverage for gram-negative enteric bacilli and Pseudomonas aeruginosa .270 Although IV therapy is indicated initially, an oral anti-infective regimen (e.g., oral ciprofloxacin, co-trimoxazole, linezolid) can be substituted once the patient's condition stabilizes.270 It has been suggested that 10-14 days of anti-infective therapy may be sufficient for the treatment of uncomplicated catheter-related infections caused by S. aureus in immunocompetent patients without underlying valvular heart disease or an intravascular prosthetic device; however, 4-6 weeks of therapy may be necessary when there is persistent bacteremia after catheter removal or evidence of endocarditis or septic thrombosis and 6-8 weeks may be necessary when osteomyelitis is present.270 The recommendations of the IDSA, American College of Critical Care Medicine, and Society for Healthcare Epidemiology of America should be consulted for more specific information on management of intravascular catheter-related infections, including information on how to obtain diagnostic cultures, indications for catheter removal, and use of local anti-infective lock therapy when the catheter is not removed.270

Meningitis and Other CNS Infections

Nafcillin and oxacillin are used parenterally for the treatment of meningitis or ventriculitis caused by susceptible penicillinase-producing staphylococci.10,18,68,73,90,170,181,209,260 IV nafcillin is considered by many clinicians to be the preferred penicillinase-resistant penicillin for the treatment of CNS infections caused by susceptible penicillinase-producing staphylococci because of reportedly greater CSF penetration.68,73,90,170,181,260

Oxacillin-Resistant Staphylococcal Infections

Because oxacillin-resistant staphylococci (ORSA; previously known as methicillin-resistant staphylococci or MRSA) are being reported with increasing frequency (see Resistance: Oxacillin-Resistant Staphylococci), initial therapy for suspected staphylococcal infections should include vancomycin if oxacillin-resistant strains are prevalent in the community or hospital.8,37,171,176,189,202,210,246,247,263 Oxacillin-resistant S. aureus are an important cause of nosocomial infections, especially in patients who are seriously ill, and also have been reported with increasing frequency in community-acquired infections.183,189,247,263,265,281 Patients with lengthy hospitalizations,247,263 premature infants,247,263,280 and individuals with diabetes mellitus,189 peripheral vascular disease,189 or surgical or burn wounds183,189,263,279 are at particularly high risk of acquiring oxacillin-resistant S. aureus and these strains also have been reported frequently in patients with prosthetic valve endocarditis,185 intravascular catheters,210,247,278 infected CSF shunts,210,247 dermatologic disorders,281 renal dysfunction,281 or human immunodeficiency virus (HIV) infection,281 and in granulocytopenic children with cancer.176,219,221 Infections caused by oxacillin-resistant S. aureus or S. epidermidis generally are treated with vancomycin alone37,40,169,171,172,176,184,185,188,189,202,219,221,246,247,263 or vancomycin in conjunction with rifampin184,185,188,202,246 and/or an aminoglycoside.185,188,202,246 (See Uses: Staphylococcal Infections, in Vancomycin Hydrochloride 8:12.28.16.)

Penicillin-Tolerant Staphylococcal Infections

Optimum anti-infective therapy for infections caused by penicillin-tolerant staphylococci has not been established.29,33,106 Because in vitro studies indicate that the bactericidal activity of aminoglycosides and β-lactam antibiotics may be additive or synergistic, some clinicians recommend that an aminoglycoside be used in conjunction with a penicillinase-resistant penicillin in the treatment of severe infections, especially endocarditis, caused by penicillin-tolerant penicillinase-producing staphylococci.33,106 However, the value of concomitant therapy in the treatment of infections caused by penicillin-tolerant staphylococci has not been definitely established.29,106 Results of some studies in patients with endocarditis caused by penicillin-tolerant staphylococci indicate that concomitant therapy with an aminoglycoside and a penicillinase-resistant penicillin generally was no more effective than the penicillinase-resistant penicillin alone;29,106 however, a shorter time to defervescence occurred in patients receiving concomitant therapy.106,177

Perioperative Prophylaxis

Penicillinase-resistant penicillins have been used for perioperative prophylaxis† to reduce the incidence of infections in patients undergoing certain surgical procedures that are associated with a high incidence of staphylococcal infections,173,198,202,218,220,254,260 but are not considered drugs of choice for such prophylaxis.257,254

Although IV cefazolin usually is the drug of choice for perioperative prophylaxis in patients undergoing neurosurgical procedures (e.g., craniotomy, CSF shunting),254,257 some clinicians suggest that IV nafcillin or IV oxacillin (a single 1-g dose given at induction of anesthesia) may be used as an alternative.254 Vancomycin is preferred in hospitals where staphylococci resistant to penicillinase-resistant penicillins frequently cause wound infection and is recommended for patients allergic to penicillins and cephalosporins.254,257

Nafcillin and oxacillin have been effective when used perioperatively to reduce the incidence of infection in patients undergoing cardiovascular173,198,216,220 or orthopedic surgery,173,198,217 including open heart surgery,198,216 total hip replacement,198 implantation of prosthetic material,198 or hip fracture repair.217 However, penicillinase-resistant penicillins are not generally recommended for perioperative prophylaxis in patients undergoing these procedures.254,257 Many clinicians currently recommend IV cefazolin or IV cefuroxime for perioperative prophylaxis in patients undergoing cardiovascular surgery and IV cefazolin in patients undergoing orthopedic surgery; vancomycin is preferred in hospitals where staphylococci resistant to penicillinase-resistant penicillins frequently cause wound infection and is recommended for patients allergic to penicillins and cephalosporins.254,257

For information on current recommendations for perioperative prophylaxis, see Uses: Perioperative Prophylaxis, in the Cephalosporins General Statement 8:12.06.

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration
Dosage

Administration

Dicloxacillin sodium is administered orally.1,2 Nafcillin sodium3,238 and oxacillin sodium4,5,235,239 are administered by IM injection or by slow IV injection or infusion.

In general, orally administered penicillinase-resistant penicillins should not be used for the initial treatment of severe infections1,2,3,4,5,224 and should not be relied on in patients with nausea, vomiting, gastric dilation, cardiospasm, or intestinal hypermotility.1,2,224,247

Since food interferes with GI absorption of penicillinase-resistant penicillins,10,18,45,48,49,62,72,91,224 the drugs should be administered orally at least 1 hour before or 2 hours after meals.1,2,10,224

Dosage

Dosage adjustments generally are unnecessary when dicloxacillin, nafcillin, or oxacillin is used in patients with renal impairment;84,97,168,206,207,222,223 however, some clinicians suggest that the lower range of the usual dosage of oxacillin be used in these patients.64,87,207 Dosage of nafcillin may need to be adjusted if the drug is used in patients with both impaired renal function and impaired hepatic function.238

Cautions ⬆ ⬇

[Section Outline]

Sensitivity Reactions
Hematologic Effects
GI Effects
Renal Effects
Hepatic Effects
Nervous System Effects
Local Reactions
Precautions and Contraindications
Pediatric Precautions
Mutagenicity and Carcinogenicity
Pregnancy, Fertility, and Lactation

As with other penicillins, hypersensitivity reactions are among the most frequent adverse reactions to penicillinase-resistant penicillins.18,111,224 The frequency and severity of adverse effects generally are similar among the penicillinase-resistant penicillins,109,224 although hepatotoxicity has been reported most frequently in patients receiving IV oxacillin113,114,116,117,118,224 and adverse renal effects have been reported most frequently in patients receiving IV methicillin (no longer commercially available in the US).7,18,109,134,208,224

Sensitivity Reactions

Hypersensitivity reactions reported with penicillinase-resistant penicillins are similar to those reported with other penicillins;18,109,224 however, severe hypersensitivity reactions have been reported less frequently with penicillinase-resistant penicillins than with natural penicillins.18 Hypersensitivity reactions reported with penicillinase-resistant penicillins include rash (morbilliform, maculopapular, urticarial, or erythematous),1,2,3,4,5,88,109,156,234 fever,3,4,5,18,88,109,156 eosinophilia,1,2,3,5,18,109,111,156 pruritus,1,2,3,5,234 and serum sickness-like reactions3,4,109 with fever, chills, and myalgia.109 Eosinophilia reportedly occurs in 5-38% of patients receiving a penicillinase-resistant penicillin18,109,111 and fever or rash reportedly occurs in 2-6% of patients receiving one of these drugs.18

Acute hemolytic anemia has been reported in one patient who received oral dicloxacillin in conjunction with IV nafcillin;154 however, it is not clear whether this was a hypersensitivity reaction to the drugs since the direct antiglobulin test result in this patient was negative.154

Anaphylaxis has been reported rarely with penicillinase-resistant penicillins.1,3,18,224 If a severe hypersensitivity reaction occurs during therapy with a penicillinase-resistant penicillin, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.1,2,3,4,5,224

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 high risk for hypersensitivity reactions to penicillins, see Cautions: Hypersensitivity Reactions, in the Natural Penicillins General Statement 8:12.16.04.

Hematologic Effects

In addition to eosinophilia and hemolytic anemia (see Cautions: Sensitivity Reactions), other adverse hematologic effects including transient neutropenia,2,3,4,5,79,109,111,138,139,140,141,145,146,147,148,186,224,260 leukopenia,5,136,137,141 granulocytopenia,3,4,136,139,141,143 and thrombocytopenia3,4,5,142 have occurred rarely with penicillinase-resistant penicillins. Agranulocytosis also has been reported rarely with IV nafcillin2,141,144,224 and oxacillin.2,4,260

Although adverse hematologic effects have been reported most frequently in patients receiving high dosages of the drugs parenterally,136,139,140,141,146,147 these reactions have occurred following oral administration.137,140 In most reported cases, leukopenia or neutropenia was evident only after 10 or more days of therapy with a penicillinase-resistant penicillin136,139,140,141,145,146 and resolved 2-7 days following discontinuance of the drug.140,141,145,146,186 In some cases, leukopenia and neutropenia appeared to be hypersensitivity reactions to the drugs since they had a rapid onset after initiation of therapy (within 48 hours) and recurred with subsequent penicillin therapy.61,140,141,142,148,186 In other reported cases, these adverse hematologic effects appeared to result from a dose-related toxic effect on the bone marrow and did not always recur when therapy was initiated with lower dosages of another penicillin.138,139,141,146,147

Prolonged bleeding time, which appeared to result from platelet dysfunction, has been reported rarely with IV nafcillin.135

GI Effects

Some of the most frequent adverse reactions to orally administered penicillinase-resistant penicillins are GI effects224 including nausea,1,2,3,5,10,224 vomiting,1,2,3,5,10,224,260 epigastric distress,1,2,10,88 loose stools,1,2,10 diarrhea,2,5,83,88,224,260 and flatulence.1,2,10,224 These effects rarely are severe enough to require discontinuance of the drugs.10 Black or hairy tongue2,3,5,224 and oral lesions including glossitis3 and stomatitis2,3,224 also have been reported with penicillinase-resistant penicillins.

Clostridium difficile -associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) has been reported rarely with penicillinase-resistant penicillins;18,238,260C. difficile has been isolated in feces of several children who developed diarrhea while receiving oral dicloxacillin or oral oxacillin (no longer commercially available in the US)149,260 and also has been isolated from patients receiving IV oxacillin.260 Mild cases of colitis may respond to discontinuance of the penicillinase-resistant penicillin alone, but management of moderate to severe cases should include treatment with fluid, electrolyte, protein supplementation, and appropriate anti-infective therapy (e.g., oral metronidazole, oral vancomycin) as indicated.238,248,249,250,251,252

Administration of oral dicloxacillin has rarely resulted in acute hemorrhagic colitis with severe abdominal pain and GI bleeding, but without evidence of C. difficile -associated diarrhea and colitis.152,187

Renal Effects

Acute Interstitial Nephritis

Acute interstitial nephritis, manifested by fever, rash, eosinophilia, macroscopic or microscopic hematuria, azotemia, dysuria, oliguria, proteinuria, pyuria, cylindruria, and eosinophiluria, occurs occasionally with methicillin (no longer commercially available in the US).109,110,123,127,130,131,132,134,208,224 The onset of symptoms varies from 5 days to 5 weeks after initiation of therapy with the drug;123,130,131,132,134 however, renal function can deteriorate rapidly127,131 and failure to recognize the condition may lead to progressive renal failure and death.127 Although azotemia has been reported to persist for several months in some patients130 and permanent renal impairment has been reported rarely,129 interstitial nephritis reported with methicillin therapy generally is reversible following discontinuance of the drug.7,18,61,109,110,123,65,130,131,132,208,224 Interstitial nephritis generally recurs if methicillin is readministered to a patient who developed the adverse effect while receiving the drug previously.119,123,124,128,130,134 In addition, administration of ampicillin, oxacillin, or nafcillin to patients who developed acute interstitial nephritis while receiving methicillin also has resulted in recurrence of the nephritis.119,124,208,260 Administration of corticosteroids has been reported to hasten recovery from methicillin-induced interstitial nephritis in some cases;126,127,134,208,260 however, there are no controlled studies to date that demonstrate that corticosteroids have an effect on resolution of the nephritis.127,134,208

Acute interstitial nephritis has been reported more frequently with methicillin than with currently available penicillins.4,7,18,122,134,208,224,260 Acute interstitial nephritis has been reported in up to 17% of patients receiving IV methicillin,65 most frequently in patients receiving prolonged therapy or methicillin dosages of more than 200 mg/kg daily.130,260 In one study, hematuria occurred in 4-8% of children receiving IV methicillin in dosages of 170-380 mg/kg daily.110 Acute interstitial nephritis also has been reported rarely with IV nafcillin119,128,208,224 and IV oxacillin.126 In addition, acute interstitial nephritis has been reported rarely with other penicillins, including penicillin G,132,162 amoxicillin,208 ampicillin,61,165,208 and carbenicillin,19,125,133,208

Acute interstitial nephritis appears to be a hypersensitivity reaction to penicillins;123,127,129,130,131,134,208,260 however, several possible immunologic mechanisms have been identified.123,126,127,129,131,134,208 The reaction may be mediated by IgG and IgM antibodies specific for the penicilloyl hapten group of the drugs;126 the penicilloyl hapten of methicillin appears to bind to renal structural proteins in the tubular basement membrane which may stimulate an immune response to the antigen-protein complex.126,131,208,260 In addition, circulating antibodies to tubular basement membrane have been detected in a few patients who developed interstitial nephritis during methicillin therapy.123,130,131 Renal biopsy generally indicates severe interstitial disease with edema and a mononuclear cell infiltrate in the tubules;123,132,134,208 the glomeruli are usually normal.132,134,208

Other Adverse Renal Effects

Hypokalemia with excessive urinary loss of potassium has been reported rarely in patients receiving nafcillin in dosages of 200-300 mg/kg daily;120,121,260 in several cases, the hypokalemia resolved when dosage of the drug was reduced to 100-150 mg/kg.120 Although it has been suggested that hypokalemia during penicillin therapy may result from redistribution of potassium within the body,163 hypokalemia appears to be related to the fact that penicillins act as nonabsorbable anions in the distal renal tubules and therefore promote urinary loss of potassium.121

Hepatic Effects

Hepatic dysfunction resembling hepatitis or intrahepatic cholestasis occurs occasionally during therapy with IV oxacillin, especially when high dosage (e.g., 12 g or more daily) is used.113,114,116,117,118,224,234,236,237,260 Hepatotoxicity is manifested by elevations in serum concentrations of alkaline phosphatase,113,117,234,236 AST (SGOT),2,113,114,115,117,118,224,234,236,237 ALT (SGPT),114,115,117,118,234,236,237 and LDH114,115,234 and may be associated with concomitant fever,2,113,114,116,118,224,234 anorexia,113,116,234 nausea,2,113,114,116,118,224,234 vomiting,2,113,114,118,224,234 hepatomegaly,114 eosinophilia,113,114,116 and rash.114,115 If hepatotoxicity occurs during oxacillin therapy, elevations in serum liver enzyme concentrations are generally detectable 2-24 days after initiation of therapy117,271 and effects are generally reversible following discontinuance of the drug.113,114,115,117,234,236,260 In several reported cases, hepatotoxicity resolved and did not recur when therapy was changed to nafcillin.112,115 However, elevations in serum aminotransferase concentrations persisted in at least one patient following discontinuance of oxacillin and initiation of nafcillin therapy.234 It has been suggested that in most reported cases, hepatic dysfunction during oxacillin therapy was the result of a hypersensitivity reaction to the drug.113,114,115,118,234 However, some clinicians suggest that hepatotoxicity may result from a direct, dose-related toxic effect of the drug, since it appears to occur more commonly in patients receiving relatively high dosages of oxacillin.234,236,237,260 Limited evidence suggests that patients with human immunodeficiency virus (HIV) infection may be at greater risk of developing hepatoxicity than other patients.245,260

Although the clinical importance is unclear, asymptomatic and transient increases in serum concentrations of alkaline phosphatase,109,112,234 AST,1,2,109,111 and ALT109,111,112,234 have been reported occasionally with oral dicloxacillin1,2 and parenteral therapy nafcillin.109,111,234

Nervous System Effects

Adverse nervous system effects similar to those reported with penicillin G have been reported rarely with penicillinase-resistant penicillins (e.g., oxacillin),4,153,260 especially when large dosages were administered IV to patients with impaired renal function.153,224 Seizures and clonus occurred in one patient with impaired renal function following IV administration of 12 g of oxacillin daily.153 Neurotoxicity in this patient appeared to be associated with high CSF concentrations of oxacillin since CSF concentrations of the drug were 70 mcg/mL at the time of seizures and 6 mcg/mL 48 hours later when seizures had subsided.153

Local Reactions

IV administration of nafcillin3,79,150 or oxacillin occasionally results in phlebitis79 or thrombophlebitis,3,4,5,224 especially when the drugs are administered to geriatric patients.3,4,5,224 Extravasation of nafcillin can cause potentially severe chemical irritation of perivascular tissues, possibly resulting in ulceration, tissue necrosis, sloughing (including full-thickness skin loss), and gangrene;150,233,260 occasionally, surgical debridement and skin grafting have been necessary,150,233,260 including in several infants and children.150,233 To reduce the risk of thrombophlebitis and other local reactions, the manufacturers suggest that IV nafcillin therapy be used only for short periods of time (24-48 hours) whenever possible,3 and at recommended concentrations. If the patient complains of pain during IV infusion of nafcillin, the infusion should be stopped immediately and the patient evaluated for possible thrombophlebitis or perivascular extravasation. If extravasation is present, some clinicians suggest that local injury can be minimized by prompt infiltration of hyaluronidase at the extravasated site.233,260

Sterile abscesses at the injection site have occurred rarely following IM administration of penicillinase-resistant penicillins.

Precautions and Contraindications

Dicloxacillin,1,2 nafcillin,3,224 and oxacillin4,5,224 are contraindicated in patients who are hypersensitive to any penicillin.

Prior to initiation of therapy with a penicillinase-resistant penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.1,2,3,4,5,224 There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.1,2,3,4,5,108,155,161 Although it has not been proven that allergic reactions to antibiotics are more frequent in atopic individuals,164 the manufacturers state that penicillinase-resistant penicillins should be used with caution in patients with a history of allergy, particularly to drugs.1,2,3,4,5,224 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.

Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with a penicillinase-resistant penicillin.1,2,3,4,5,111,166,224 Because adverse hematologic effects have occurred during therapy with penicillinase-resistant penicillins (see Cautions: Hematologic Effects), total and differential white blood cell (WBC) counts should be performed prior to initiation of therapy with the drugs and 1-3 times weekly during therapy.2,4,5,139,140,141,144,146,166,224 Urinalysis should be performed and serum creatinine and BUN concentrations should be determined prior to and periodically during penicillinase-resistant penicillin therapy.2,4,5,166,224 AST (SGOT) and ALT (SGPT) should also be determined periodically during therapy to monitor for hepatotoxicity.2,4,5,224

Prolonged use of penicillinase-resistant penicillins may result in overgrowth of nonsusceptible organisms,1,2,3,4,5,8,88,224 including fungi8 or gram-negative bacteria88 such as Pseudomonas .8,88 Careful observation of the patient during therapy with a penicillinase-resistant penicillin is essential.1,2,3,4,5 If suprainfection or superinfection occurs, the drug should be discontinued and appropriate therapy instituted.1,2,3,4,5,224

Pediatric Precautions

Penicillinase-resistant penicillins should be used with caution in neonates since elimination of penicillins is delayed in this age group.2,3,4,5,224 When penicillinase-resistant penicillins are administered to neonates, serum concentrations of the drugs should be monitored and appropriate reductions in dosage and frequency of administration made when indicated;2,3,4,5,224 organ systems should also be evaluated frequently.2,4,5,224

Mutagenicity and Carcinogenicity

It is not known if penicillinase-resistant penicillins are mutagenic or carcinogenic in humans.2,4,224

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of dicloxacillin,1,2,224 nafcillin,3,224 or oxacillin4,5,224 during pregnancy has not been definitely established. Reproduction studies in mice, rats, and rabbits using penicillinase-resistant penicillins have not revealed evidence of harm to the fetus.2,3,4,224 Clinical experience with use of penicillins during pregnancy in humans has not revealed evidence of adverse effects on the fetus.4,224 However, there are no adequate and controlled studies in pregnant women, and penicillinase-resistant penicillins should be used during pregnancy only when clearly needed.2,4,224

Fertility

Reproduction studies in mice, rats, and rabbits using penicillinase-resistant penicillins have not revealed evidence of impaired fertility.2,3,4,224

Lactation

Because dicloxacillin232 and oxacillin4,5,10,100 are distributed into milk, penicillinase-resistant penicillins should be used with caution in nursing women.2,4,224

Drug Interactions ⬆ ⬇

[Section Outline]

Aminoglycosides
Cyclosporine
Probenecid
Rifampin
Tetracyclines
Warfarin

For further information on these and other drug interactions reported with penicillins, see Drug Interactions in the Natural Penicillins General Statement 8:12.16.04. Although not all drug interactions reported with other penicillins have been reported with penicillinase-resistant penicillins, the fact that some of these interactions could occur with the drugs should be considered.

Aminoglycosides

Synergism with Aminoglycosides

In vitro studies indicate that a synergistic bactericidal effect can occur against penicillinase-producing and nonpenicillinase-producing S. aureus susceptible to penicillinase-resistant penicillins when nafcillin or oxacillin is used in conjunction with an aminoglycoside (e.g., gentamicin, tobramycin).21,50,260

Although the clinical importance is unclear, in vitro synergism has also been reported against some strains of oxacillin-resistant S. aureus (previously known as methicillin-resistant S. aureus ) when high concentrations of nafcillin or oxacillin were used in conjunction with amikacin, gentamicin, or kanamycin.21,51

Incompatibility with Aminoglycosides

Penicillinase-resistant penicillins, like other penicillins, are physically and/or chemically incompatible with aminoglycosides and can inactivate the drugs in vitro.14,21,61 If concomitant therapy is indicated, in vitro mixing of penicillinase-resistant penicillins and aminoglycosides should be avoided and the drugs should be administered separately.14,61 Penicillinase-resistant penicillins can also inactivate aminoglycosides in vitro in serum samples obtained from patients receiving concomitant therapy with the drugs.197 This could adversely affect results of serum aminoglycoside assays performed on the serum samples.197 (See Laboratory Test Interferences: Serum Aminoglycoside Assays.)

Cyclosporine

Concomitant administration of nafcillin and cyclosporine can result in decreased cyclosporine concentrations.238,243,244 .261 In one patient receiving cyclosporine concomitantly with nafcillin, serum concentrations of cyclosporine decreased to subtherapeutic levels during 2 separate courses of therapy.238,243,244 It has been suggested that nafcillin may increase hepatic metabolism of cyclosporine probably by induction of hepatic microsomal enzymes resulting in decreased serum concentrations of cyclosporine.238,243,244 The manufacturer of nafcillin suggests that cyclosporine concentrations should be monitored if nafcillin is used concomitantly.238 Some clinicians suggest that an alternative anti-infective be used in patients receiving cyclosporine.261

Probenecid

Oral probenecid administered shortly before or simultaneously with penicillinase-resistant penicillins slows the rate of renal tubular secretion of the penicillins and produces higher and prolonged serum concentrations of the drugs.1,2,217,63,224,235,260 In one study, probenecid decreased the volume of distribution of nafcillin by about 20%.63

Rifampin

In vitro studies indicate that antagonism can occur when nafcillin or oxacillin is used in conjunction with rifampin against S. aureus .78,228 However, antagonism between the drugs appears to be dose-dependent and occurs only when high concentrations of the penicillin are present.228,229 In vitro studies indicate that when low concentrations of oxacillin are present, indifference or synergism generally occurs.228,229 Although some clinicians suggest that rifampin not be used concomitantly with penicillins,67 concomitant use of oxacillin and rifampin appears to delay or prevent the emergence of rifampin-resistant strains of S. aureus and the drugs have been used concomitantly with no apparent decrease in activity.228,229

Tetracyclines

Tetracyclines may antagonize the bactericidal effects of penicillins, including penicillinase-resistant penicillins, and concomitant administration of the drugs should be avoided.1,2,235,238

Warfarin

Concomitant administration of nafcillin201,238,240,241,242 or dicloxacillin262 and warfarin has been reported to decrease the hypoprothrombinemic effect of the anticoagulant. In several patients (some of whom were stabilized on warfarin), IV nafcillin (usually given in high dosages of 9-12 g daily) decreased the hypoprothrombinemic effect of the anticoagulant. 201,238,240,241,242 It has been suggested that nafcillin may decrease the serum half-life of warfarin by increasing metabolism of the anticoagulant, probably by induction of hepatic microsomal enzymes.201,240,241,242 Prothrombin time should be monitored carefully during concomitant administration of a penicillinase-resistant penicillin and a coumarin anticoagulant201,238,240,241 and for several weeks after discontinuance of the penicillin,241,242 since in some patients prothrombin time did not return to pretreatment levels until about 30 days after discontinuance of nafcillin.238,241,242 Dosage of the anticoagulant should be adjusted as required when a penicillinase-resistant penicillin is administered to a patient receiving a coumarin anticoagulant.201,238,240,241,242

Other Information ⬆ ⬇

[Section Outline]

Tests for Urinary and Serum Proteins
Serum Aminoglycoside Assays
In Vitro Susceptibility Testing
Gram-Positive Aerobic Bacteria
Gram-Negative Aerobic Bacteria
Anaerobic Bacteria
Spirochetes
Oxacillin-Resistant Staphylococci
Tolerance
Resistance in Gram-Negative Bacteria
Absorption
Distribution
Elimination
Chemistry
Stability

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 not all laboratory test interferences reported with other penicillins have been reported with penicillinase-resistant penicillins, the possibility that these interferences could occur with the drugs should be considered.

Tests for Urinary and Serum Proteins

Like other penicillins, penicillinase-resistant penicillins interfere with or cause false-positive results in a variety of test methods used to determine urinary or serum proteins.120,157,158,159,160,260,238 Studies using oxacillin158 and nafcillin120,158,159,160 indicate that the drugs cause false-positive or falsely elevated results in turbidimetric methods for urinary and serum proteins that use sulfosalicylic acid or trichloroacetic acid. Nafcillin also interferes with tests for urinary protein that use the biuret reagent159 and can cause slightly increased urinary protein concentrations when the Coomassie brilliant blue method is used.159 Nafcillin does not appear to interfere with tests for urinary protein that use bromphenol-blue (Albustix^®, Albutest^®).120

Serum Aminoglycoside Assays

Because penicillinase-resistant penicillins inactivate aminoglycosides in vitro (see Drug Interactions: Aminoglycosides), presence of the drugs in serum samples to be assayed for aminoglycoside concentrations may result in falsely decreased results.197 .

Mechanism of Action

Penicillinase-resistant penicillins have a mechanism of action similar to that of other penicillins.18,20,260 For information on the mechanism of action of penicillins, see Mechanism of Action in the Natural Penicillins General Statement 8:12.16.04.

Spectrum

The commercially available penicillinase-resistant penicillins (dicloxacillin, nafcillin, oxacillin) have similar spectra of activity.45,46,47,260 Penicillinase-resistant penicillins are active in vitro against many gram-positive aerobic cocci.9,10,11,15,18,48,260 Because penicillinase-resistant penicillins are not inactivated by most staphylococcal penicillinases, the drugs are active against many penicillinase-producing strains of Staphylococcus aureus and S. epidermidis that are resistant to other commercially available penicillins.15,18,42,45,46,47,48,260 Penicillinase-resistant penicillins also are active in vitro against a few gram-positive aerobic and anaerobic bacilli and some gram-negative cocci; however, the drugs generally are inactive against gram-negative aerobic and anaerobic bacilli.15,18,21,45,48 Penicillinase-resistant penicillins are inactive against mycobacteria, Mycoplasma , Rickettsia , fungi, and viruses.260

In Vitro Susceptibility Testing

Results of in vitro susceptibility tests with penicillinase-resistant penicillins may be affected by inoculum size, period of incubation, pH of the media, or the presence of human serum.45,48,49,199,200,260

Detection of oxacillin-resistant staphylococci (ORSA; previously known as methicillin-resistant staphylococci or MRSA) generally requires use of specialized testing procedures and culture media.2,189,210,255,256,260,267 In vitro, the expression of resistance to penicillinase-resistant penicillins is influenced by temperature, pH, and sodium chloride concentration of the media.210,260 To optimize detection of oxacillin-resistant staphylococci in dilution susceptibility testing, the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]) recommends addition of 2% sodium chloride to the broth or agar dilution media, use of the direct method of colony suspension (equivalent to a 0.5 McFarland standard), and incubation for 24 hours at 35°C.255 CLSI states that oxacillin is the preferred derivative for in vitro testing since the drug is more resistant to degradation during storage than other penicillinase-resistant penicillins and more likely to detect heteroresistant staphylococci.255,256

Standard in vitro susceptibility tests cannot detect tolerance to penicillinase-resistant penicillins because the minimum inhibitory concentrations (MICs) of tolerant and nontolerant strains are generally similar and these tests do not directly measure bactericidal activity.22,23,25,26,28,33,36,182 This fact should be considered when evaluating results of in vitro susceptibility tests.22,23,28,36 For information on tolerance, see Resistance: Tolerance.

Disk Diffusion Tests

When the disk-diffusion procedure is used to test in vitro susceptibility to penicillinase-resistant penicillins, a disk containing 1 mcg of oxacillin may be used and results can be applied to all currently available penicillinase-resistant penicillins (dicloxacillin, nafcillin, oxacillin).256 CLSI states that an oxacillin disk is preferred since it is more resistant to degradation in storage and because it is more likely to detect heteroresistant staphylococci.256 Although a disk containing 1 mcg of nafcillin may be used to determine susceptibility of S. aureus , interpretive criteria have not been established for testing other staphylococci using a nafcillin disk.256

When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures using the 1-mcg oxacillin disk or the 1-mcg nafcillin disk, S. aureus with growth inhibition zones of 13 mm or greater are susceptible to penicillinase-resistant penicillins, those with zones of 11-12 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drugs.256 S. aureus with intermediate susceptibility to penicillinase-resistant penicillins should be tested further using the oxacillin-salt agar screening test.256

When the disk-diffusion procedure is performed according to CLSI standardized procedures using the 1-mcg oxacillin disk, coagulase-negative staphylococci with growth inhibition zones of 18 mm or greater are susceptible to penicillinase-resistant penicillins and those with zones of 17 mm or less are resistant to the drugs.256 Interpretive criteria for coagulase-negative staphylococci correlate with the presence or absence of the mec A gene that encodes resistance to penicillinase-resistant penicillins in S. epidermidis .256 These criteria may overcall resistance for other coagulase-negative staphylococci (e.g., S. lugdunensis , S. saprophyticus ).256 For serious infections with coagulase-negative staphylococci other than S. epidermidis , testing for mec A or the protein expressed by mec A (penicillin-binding protein 2a [PBP 2a]) may be appropriate for strains having zone diameters in the intermediate or resistant range.256 Isolates that are shown to carry mec A or produce PBP 2a should be reported as oxacillin resistant.256

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to CLSI standardized procedures using oxacillin or nafcillin, S. aureus with MICs of 2 mcg/mL or less are susceptible to penicillinase-resistant penicillins and those with MICs of 4 mcg/mL or greater are resistant to the drugs.255

When dilution susceptibility testing is performed according to CLSI standardized procedures using oxacillin, coagulase-negative staphylococci with MICs of 0.25 mcg/mL or less are susceptible to penicillinase-resistant penicillins and those with MICS of 0.5 mcg/mL or greater are resistant to the drugs.255 Interpretive criteria for coagulase-negative staphylococci correlate with the presence or absence of the mec A gene that encodes resistance to penicillinase-resistant penicillins in S. epidermidis .255 These criteria may overcall resistance for other coagulase-negative staphylococci (e.g., S. lugdunensis , S. saprophyticus ).255 For serious infections with coagulase-negative staphylococci other than S. epidermidis , testing for mec A or PBP 2a may be appropriate for strains having MICs of 0.5-2 mcg/mL.255 Staphylococcal isolates that are shown to carry mec A or that produce PBP 2a should be reported as oxacillin resistant.255

Gram-Positive Aerobic Bacteria

Gram-Positive Aerobic Cocci

Penicillinase-resistant penicillins are active in vitro against many gram-positive aerobic cocci including penicillinase-producing and nonpenicillinase-producing strains of S. aureus 18,21,42,46,47,48,260 and S. epidermidis .18,21,42,47,260,267 In addition to S. epidermidis , the drugs are active in vitro against some other coagulase-negative staphylococci including some strains of S. haemolyticus, 196,267 S. hominis ,196,267 S. lugdunensis, 264 S. saprophyticus 196 S. schleiferi ,267 S. simulans, 196,267 and S. warneri .196,267 However, many strains of coagulase-negative staphylococci are resistant to penicillinase-resistant penicillins. 267

Penicillinase-resistant penicillins are active in vitro against Streptococcus pyogenes (group A β-hemolytic streptococci), S. agalactiae (group B streptococci), groups C and G streptococci,21,42,46,47,48,49,260 S. pneumoniae ,18,21,42,45,46,47,48,49,260 and some viridans streptococci.18,21,42,48 Enterococci, including E. faecalis (formerly S. faecalis ), usually are resistant to the drugs.9,18,21,47,48,260

Nonpenicillinase-producing strains of S. aureus usually are inhibited in vitro by dicloxacillin,10,18,46 nafcillin,10,18,21,48 or oxacillin10,18,21 concentrations of 0.1-0.8 mcg/mL and penicillinase-producing strains of S. aureus usually are inhibited by concentrations of 0.3-1.6 mcg/mL.10,18,21,45,46,47,48 Susceptible strains of S. epidermidis usually are inhibited by oxacillin concentrations of 0.125 mcg/mL or less.267

With the exception of penicillinase-producing staphylococci, penicillinase-resistant penicillins generally are less active in vitro on a weight basis than natural penicillins against susceptible gram-positive cocci.6,15,18,45,260 The MIC₉₀ (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of dicloxacillin,18,47 nafcillin,18,47 or oxacillin21,42 reported for most susceptible S. pneumoniae and groups A, B, C, and G streptococci is 0.1-0.4 mcg/mL. Viridans streptococci generally are inhibited in vitro by penicillinase-resistant penicillin concentrations of 0.1-1.6 mcg/mL.10,18,42,48

Gram-Positive Aerobic Bacilli

Penicillinase-resistant penicillins are active in vitro against a few gram-positive aerobic bacilli.21 Corynebacterium diphtheriae reportedly is inhibited in vitro by oxacillin concentrations of 1.6-3.1 mcg/mL.21 In vitro, oxacillin concentrations of 0.01-0.03 mcg/mL inhibit some strains of Erysipelothrix rhusiopathiae .21

Gram-Negative Aerobic Bacteria

Neisseria

Although penicillinase-resistant penicillins generally are less active in vitro on a weight basis than natural penicillins against gram-negative aerobic cocci, the drugs are active in vitro against some strains of Neisseria meningitidis 10,11,15,18,21,45,48,204 and N. gonorrhoeae .10,11,18,21,41,45,48,204

N. meningitidis generally requires dicloxacillin,18 nafcillin,10,18,21,48 or oxacillin10,18,21 concentrations of 0.5-8 mcg/mL for in vitro inhibition.10,18,21,45,48 Penicillinase-producing and nonpenicillinase-producing strains of N. gonorrhoeae generally are inhibited in vitro by penicillinase-resistant penicillin concentrations of 1.6-12.5 mcg/mL.10,18,21,41,45,48,204

Haemophilus

Some strains of Haemophilus influenzae reportedly are inhibited in vitro by nafcillin48 concentrations of 1-12.5 mcg/mL; however, most strains of the organism are resistant to penicillinase-resistant penicillins.10,18,45

Other Gram-Negative Aerobes

Pasteurella multocida , an organism that can be aerobic or facultatively anaerobic, reportedly is inhibited in vitro by dicloxacillin, nafcillin, or oxacillin concentrations of 3.1-12.5 mcg/mL.43

Penicillinase-resistant penicillins generally are inactive against other gram-negative aerobic bacilli including Enterobacteriaceae and Pseudomonas .9,10,15,18,21,45,48

Anaerobic Bacteria

Some gram-positive anaerobic bacteria, including some strains of Actinomyces ,21 Clostridium,18 Peptococcus ,18 and Peptostreptococcus ,18 are inhibited in vitro by penicillinase-resistant penicillins; however, penicillinase-resistant penicillins are less active against these organisms than other penicillins.21 Gram-negative anaerobic bacteria, including Bacteroides , generally are resistant to penicillinase-resistant penicillins.18,21

Spirochetes

Penicillinase-resistant penicillins have some activity against spirochetes, although less than that of the natural penicillins.15

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 among penicillinase-resistant penicillins.49,168,260 Minor differences in the degree of resistance to the various penicillinase-resistant penicillins have been reported in results of in vitro susceptibility tests; however, resistance to any penicillinase-resistant penicillin should be interpreted as resistance to all currently available penicillinase-resistant penicillins.1,2,3,4,5,224

Oxacillin-Resistant Staphylococci

Although in the past both penicillinase-producing and nonpenicillinase-producing staphylococci generally were susceptible to penicillinase-resistant penicillins, staphylococci resistant to penicillinase-resistant penicillins have been reported with increasing frequency.11,18,37,40,183,210,247,265,281 Historically, staphylococci resistant to penicillinase-resistant penicillins have been referred to as methicillin-resistant staphylococci and methicillin-resistant Staphylococcus aureus have been referred to as MRSA; however, methicillin is no longer commercially available in the US and oxacillin has become the preferred drug for testing in vitro susceptibility to penicillinase-resistant penicillins.255,256 Therefore, although the prior terminology may still be used, staphylococci resistant to penicillinase-resistant penicillins are now being referred to as oxacillin-resistant staphylococci and oxacillin-resistant S. aureus are being referred to as ORSA.255,256

In the US, up to 50% of clinical isolates of S. aureus 11,18,37,40,183,189,265,281 and up to 80% of clinical isolates of coagulase-negative staphylococci7,10,11,12,27,176,186,210,265 are oxacillin-resistant. Approximately 63-79% of S. epidermidis isolates from patients with prosthetic valve endocarditis or infected CNS shunts reportedly are oxacillin-resistant.185,210 Data obtained from some US hospitals between 1998-1999 indicated that about 35% of clinical isolates of S. aureus from hospitalized patients and about 23% from outpatients were oxacillin-resistant strains and 64-74% of coagulase-negative staphylococci from hospitalized patients and about 44% from outpatients were oxacillin-resistant strains.265 Surveillance data from 33 US hospitals during 2000 indicate that 45.7% of S. aureus isolates obtained from hospitalized patients and 28.9% of isolates obtained from outpatients were resistant to penicillinase-resistant penicillins.281

Resistance to penicillinase-resistant penicillins is intrinsic and usually is mediated by the presence of the mec A gene that encodes a specific penicillin-binding protein (PBP 2a) that has a low affinity for and is not inhibited by β-lactam antibiotics.10,18,34,167,189,266,269 Resistant to penicillinase-resistant penicillins may also occur as the result of penicillinase production or modification of existing PBPs.10,18,34,167,189,266,269

Isolates of oxacillin-resistant staphylococci, especially coagulase-negative staphylococci, generally are heterogeneous and only a small portion of the cells may demonstrate resistance in vitro.11,210,260,266,267,269 Therefore detection of oxacillin resistance is complex and resistant isolates may not always be detected by routine in vitro susceptibility testing.210,267 (See Spectrum: In Vitro Susceptibility Testing.)

In addition to being cross-resistant to all currently available penicillins, oxacillin-resistant staphylococci generally are resistant to other β-lactam antibiotics including first, second, or third generation cephalosporins.10,27,37,49,167,172,183,184,205,210 These strains also generally are resistant to tetracyclines, chloramphenicol, macrolides, and clindamycin and may be resistant to aminoglycosides and fluoroquinolones.21,37,172,184,189,210,269 However, most strains of oxacillin-resistant staphylococci are susceptible to vancomycin12,37,40,171,172,184,210 or co-trimoxazole37,172 and may be susceptible to rifampin.37,171,172,176,184

Tolerance

Tolerance to the bactericidal effects of penicillinase-resistant penicillins has been reported in 30-63%29,32,33,39,106,260 of clinical isolates of S. aureus .25,26,27,29,30,33,38,39,77,182,191,260 Tolerance to the bactericidal effects of oxacillin has also been reported rarely in S. epidermidis .38 Most staphylococci susceptible to penicillinase-resistant penicillins have an MBC (minimum bactericidal concentration) of the drugs that is 1-4 times greater than the MIC of the drugs;18,23,25,28,29,269 however, bacteria with an MBC that is 16 or more times greater than the MIC of the drugs are generally considered tolerant to penicillinase-resistant penicillins.18,23,25,26,28,29,106,269 Results of some studies indicate that all isolates of S. aureus contain a small percentage of tolerant strains and that high MBCs are only detectable when a substantial percentage of tolerant organisms is present.106

The clinical importance of tolerance has not been fully elucidated.20,22,23,24,28,29,30,33,106,260,269 In vitro, bacteria tolerant to penicillinase-resistant penicillins may be inhibited by the drugs but are either not killed or are killed at a slower rate than bacteria that are not tolerant.15,18,20,23,24,25,26,29,39,106,260 Infections caused by tolerant bacteria may persist during therapy although in vitro susceptibility tests indicate that the organisms are susceptible to the drugs.20,22,23,24,28,29,30,33,106,260 The presence of tolerant staphylococci in serious infections where rapid and complete bactericidal activity is important (e.g., endocarditis, bacteremia) could result in a less favorable response to penicillinase-resistant penicillin therapy.30,31,33,36,39,260 Therefore, although the value of concomitant therapy has not been definitely established, some clinicians suggest that a rapidly bactericidal anti-infective (e.g., an aminoglycoside) be used in conjunction with a penicillinase-resistant penicillin for the treatment of severe infections caused by tolerant staphylococci.33,106,260 (See Penicillin-Tolerant Staphylococcal Infections in Uses: Staphylococcal Infections.)

Tolerance appears to occur in strains that have a deficiency in an autolytic enzyme on their cell surface that is necessary for the bactericidal effect of penicillins or may be the result of the presence of an autolysin inhibitor.15,18,20,23,24,26,28,29,35,106,260 Staphylococci that are tolerant to penicillinase-resistant penicillins may also be cross-tolerant to some cephalosporins and/or vancomycin.23,39

Resistance in Gram-Negative Bacteria

Gram-negative bacteria generally are intrinsically resistant to penicillinase-resistant penicillins because the bulky side chains of the drugs, which help to protect these derivatives from hydrolysis by penicillinases, also prevent the drugs from penetrating the outer membrane of most gram-negative bacteria.11,15,16,18,105

Pharmacokinetics

For more specific information on the pharmacokinetics of dicloxacillin, nafcillin, and oxacillin, see Pharmacokinetics in the individual monographs in 8:12.16.12.

In all studies described in the pharmacokinetics section, penicillinase-resistant penicillins were administered as sodium salts. Dosages and concentrations of dicloxacillin sodium, nafcillin sodium, and oxacillin sodium are expressed in terms of their bases.

Absorption

Like other penicillins, absorption of orally administered penicillinase-resistant penicillins occurs mainly in the duodenum7,9,18,86 and upper jejunum86 and the rate and extent of absorption depend on the particular penicillin derivative,7,9,18,66 dosage form administered,72,76 gastric and intestinal pH,6,7,9,61,81 and presence of food in the GI tract.9,11,18,45,48,49,61,62,72,91,224

Isoxazolyl penicillins (cloxacillin [no longer commercially available in the US], dicloxacillin, oxacillin) are acid stable and are rapidly but incompletely absorbed from the GI tract.2,13,70,86,88,98,103 In healthy, fasting adults, approximately 35-76% of an orally administered dose of dicloxacillin13,18,52,72,98 or 30-35% of an orally administered dose of oxacillin (oral dosage forms no longer commercially available in the US)9,13,18,52,66 is absorbed from the GI tract.

Following oral administration of a single oral dose of dicloxacillin2,9,18,45,46,72,76,80 or oxacillin9,10,18,44,49,80,88,100,103 in healthy, fasting adults, peak serum concentrations of the drugs usually are attained within 30 minutes to 2 hours;2,9,18,45,46,48,49,70,72,76,80,86,88,91,100,101 serum concentrations of the drugs then decline rapidly and generally are low or undetectable 4-6 hours after the dose.18,45,46,47,49,70,72,80,88,91,100,101 In one study in healthy, fasting adults, oral administration of a single 500-mg dose of dicloxacillin or oxacillin as capsules resulted in peak serum concentrations of the drugs ranging from 5-7 mcg/mL, 7.5-14.4 mcg/mL, or 10-17 mcg/mL, respectively.6

Presence of food in the GI tract generally decreases the rate and extent of absorption of penicillinase-resistant penicillins.2,9,10,11,18,45,48,49,61,62,72,91,224

Oxacillin49,88,100 is rapidly absorbed from IM injection sites. Following IM administration of single 1-g doses of oxacillin in adults, peak serum concentrations of the drug range from 6-18 mcg/mL13,81,88,100,101 and generally are attained within 30-60 minutes;9,13,18,48,49,64,81,88,97,100,101 serum concentrations then decline rapidly and are low or undetectable 4-6 hours after the dose.18,48,49,81,100,101 Rapid IV injection of a single 500-mg or 1-g dose of nafcillin69,89 or oxacillin69,88 generally results in peak serum concentrations of the drugs that range from 26-63 mcg/mL immediately following injection; however, serum concentrations of the drugs are low or undetectable 2-3 hours later.13,18,69,81,88,89

Distribution

Penicillinase-resistant penicillins are widely distributed following absorption from the GI tract or injection sites.18,93 The volume of distribution of oxacillin reportedly is 0.39-0.43 L/kg in healthy adults.65,231 The volume of distribution of nafcillin reportedly ranges from 0.57-1.55 L/kg in adults,60,97 0.85-0.91 L/kg in children 1 month to 14 years of age,79 and 0.24-0.53 L/kg in neonates.74 Nafcillin has a greater volume of distribution than other currently available penicillins, presumably because it is sequestered in the liver.69,79 Concomitant administration of oral probenecid may decrease the volume of distribution of nafcillin.63 (See Drug Interactions: Probenecid.)

Penicillinase-resistant penicillins are readily distributed into ascitic,18,224 synovial,10,18,54,55,75 pleural,2,3,5,10,18,224 and pericardial fluids.3,18,224 The drugs also are distributed into kidneys, liver,93 gallbladder,93 bone,18,53,56,75,93,211,260 bile,2,4,5,10,52,64,86,93,100,224 skin,93 intestines,93 prostate,81,93 tonsils,93 and muscle.93 Unlike natural penicillins, therapeutic concentrations of penicillinase-resistant penicillins may be attained in bone following parenteral administration of the drugs.18,53,56,75,93,211 Following IM or IV administration of oxacillin, bone concentrations of the drug reportedly may be 5-23% of concurrent serum concentrations.53,75,211 Penicillinase-resistant penicillins are distributed into bile in varying degrees.2,52,64,93,100,224,260 Small amounts of isoxazolyl penicillins are distributed into bile;100 however, concentrations of nafcillin13,52,69,93 in bile generally are equal to or greater than concurrent serum concentrations of the drugs. Biliary concentrations of the drugs are proportional to hepatobiliary function and may be negligible if biliary obstruction is present.13,52 Only negligible concentrations of nafcillin52,273 or oxacillin274,275,276 are attained in aqueous humor following oral, IM, or IV administration.52,273,274,224,275,276

Like natural penicillins, only minimal concentrations of penicillinase-resistant penicillins are attained in CSF following oral, IM, or IV administration in patients with uninflamed meninges.2,4,5,18,52,68,73,90,92,100,151,224 Slightly higher concentrations of the drugs are attained in CSF in patients with inflamed meninges.4,5,52,68,73,90,151 In one study in patients receiving nafcillin doses of 95-200 mg/kg every 4-6 hours, CSF concentrations of nafcillin were 1.9-30% of concurrent serum concentrations in specimens obtained 1-2 hours after administration of the drug.68 In one study in rabbits with meningitis, CSF concentrations of nafcillin or oxacillin averaged 1.4-2% or 1-2.8%, respectively, of concurrent serum concentrations of the drugs.227

The degree of protein binding varies among penicillinase-resistant penicillins;6,7,8,9,11,52,58,59,224 protein binding of the isoxazolyl penicillins increases with the number of chlorine atoms present on the heterocyclic side chains of the drugs.15,46,105 Dicloxacillin is 95-99%,2,6,7,8,9,13,46,52,58,59,224 nafcillin is 70-90%,7,8,9,52,58,59,224 and oxacillin is 89-94%6,7,8,9,52,58,59,224 bound to serum proteins. The drugs bind mainly to serum albumin.2,10,11,52,224

All currently available penicillinase-resistant penicillins readily cross the placenta.2,4,5,10,18,95,99,100 The drugs distribute into amniotic fluid.2,224 Fetal serum concentrations of oxacillin100 or dicloxacillin99 reportedly range from 0-26% of concurrent maternal serum concentrations. Dicloxacillin232 and oxacillin5,10,100 are distributed into milk. Although specific information on the distribution of nafcillin into milk is not available, this penicillinase-resistant penicillin is probably also distributed into milk.18,224

Elimination

In adults with normal renal function, serum half-lives of dicloxacillin2,13,18,52,61,64,98,102 and oxacillin5,13,18,52,61,64,69 are similar and range from 0.3-0.9 hours.2,13,18,52,61,64,69,72,81,82,92,98,224 Nafcillin has a slightly longer serum half-life than other penicillinase-resistant penicillins and the serum half-life of the drug in adults with normal renal and hepatic function ranges from 0.5-1.5 hours.52,60,61,97,224

The penicillinase-resistant penicillins are metabolized to varying degrees;9,10,13,18,52,66,85,86,89,260 nafcillin is the most extensively metabolized.18,52,89 Penicillinase-resistant penicillins are partially metabolized by hydrolysis of the β-lactam ring to penicilloic acids which are microbiologically inactive.13,18,66,86,104 Although it has been suggested that following oral administration this hydrolysis occurs partly in the GI tract prior to absorption, the drugs appear to undergo metabolism mainly in the liver following oral or parenteral administration.66,86 The extent of inactivation of isoxazolyl penicillins decreases with halogen substitution, and oxacillin is metabolized to a greater extent than is dicloxacillin.15,66,105,260 In one study following oral administration of single 500-mg oral doses of the drugs, 49% of oxacillin absorbed from the GI tract (oral dosage forms no longer commercially available in the US) was hydrolyzed to penicilloic acids whereas only 10% of dicloxacillin absorbed were hydrolyzed to penicilloic acids.66 In this study, there was no evidence of 6-APA in urine following oral administration of oxacillin.66 Isoxazolyl penicillins also appear to be hydroxylated to a small extent to microbiologically active metabolites which are excreted in urine.9,85,86 The hydroxyl metabolite of dicloxacillin and oxacillin are slightly less active than the parent drugs.85

Isoxazolyl penicillins and their metabolites are rapidly excreted in urine mainly by tubular secretion and glomerular filtration.2,5,6,10,13,18,81,85,86,97,224,260 These drugs also are partly excreted in feces via biliary elimination.18,52,86,224,260 Although small amounts of nafcillin are excreted in urine, the drug is eliminated mainly via bile18,52,84,89,97 and undergoes enterohepatic circulation.84 Following oral administration of a single 500-mg dose of the drugs in adults with normal renal function, 33-49% of the dicloxacillin dose66,76 or 17-70% of the oxacillin dose5,47,66,100 is excreted in urine as unchanged drug and active metabolites within 6 hours. Only about 27-31% of a single IM or IV dose of nafcillin is excreted in urine as unchanged drug and active metabolites within 12 hours.48,97 Approximately 40-70% of a single IM dose of oxacillin is excreted in urine within 6 hours as unchanged drug and active metabolites.5,100

Serum clearance of oxacillin in adults with normal renal function has been reported to be 380 mL/minute per 1.73 m².69 Nafcillin has a serum clearance of 410-583 mL/minute per 1.73 m² in adults with normal renal and hepatic function.69,89

Unlike most other penicillins, the serum half-lives of nafcillin,18,84,97 dicloxacillin,18,52,98,102 and oxacillin69,87 are only slightly prolonged in patients with renal impairment.13,18,52,57,64,69,71,82,87,98,102 This presumably results from the fact that nafcillin is excreted mainly by nonrenal mechanisms and isoxazolyl penicillins undergo extensive biotransformation to inactive metabolites.52 The serum half-lives of nafcillin18,52,69,84,97 and the isoxazolyl penicillins13,18,52,57,64,69,71,82,98,102 in patients with renal impairment reportedly range from 0.5-2.8 hours. In one study in patients with cirrhosis, the t_½α of nafcillin averaged 0.26 hours, the t_½β of the drug averaged 1.2 hours, and serum clearance of the drug averaged 291.5 mL/minute.89

Serum concentrations of nafcillin3,74,94,95,96 and isoxazolyl penicillins18,96,225,226 generally are higher and the serum half-lives more prolonged in neonates than in older children. The serum half-lives of the drugs generally are inversely proportional to birthweight, gestational age, and chronologic age.74,94,225,226 This appears to result partly from immature mechanisms for conjugation of the drugs in the liver94 and immature mechanisms for renal tubular secretion.94 The serum half-life of oxacillin is 1.6 hours in neonates 8-15 days of age and 1.2 hours in neonates 20-21 days of age.260 In one study, the serum half-life of nafcillin ranged from 2.2-5.5 hours in neonates 3 weeks of age or younger and 1.2-2.3 hours in neonates 4-9 weeks of age.74

Oral probenecid administered shortly before or with penicillinase-resistant penicillins competitively inhibits renal tubular secretion of the penicillins and produces higher and prolonged serum concentrations of the drugs.2,18,45,48,81,100,101 (See Drug Interactions: Probenecid.)

Studies using dicloxacillin indicate that patients with cystic fibrosis eliminate the drug up to 3 times faster than healthy individuals because of increased tubular secretion.107,260 This effect may be clinically important since use of usual dosages of penicillinase-resistant penicillins in cystic fibrosis patients may result in lower serum concentrations of the drugs than expected.107

Dicloxacillin,7,13,18,52,64,71 nafcillin,7,52,64,84,97 and oxacillin18,52,57,64,87 are only minimally removed by hemodialysis18,52,64,82,84,87,168 or peritoneal dialysis.7,18,57,64,71

Chemistry and Stability

Chemistry

Penicillinase-resistant penicillins are semisynthetic penicillin derivatives produced by acylation of 6-aminopenicillanic acid (6-APA).6,7,9,10,11,15,16,18 Penicillinase-resistant penicillins have bulky side chains at R on the penicillin nucleus that result in steric hindrance around the α-carbon of the acylamino group and help to prevent attachment of staphylococcal penicillinases to the β-lactam ring.6,9,10,11,15,16,105 (For information on the penicillin nucleus, see the Preface to the General Statements on Penicillins 8:12.16.)

Penicillinase-resistant penicillins commercially available in the US include dicloxacillin,1,2 nafcillin,3,238 and oxacillin.4,5,235,239 Nafcillin is a naphthyl analog of methicillin (no longer commercially available in the US) and has slightly increased acid stability and antibacterial activity compared with methicillin.16 Dicloxacillin, oxacillin, and cloxacillin (no longer commercially available in the US) are isoxazolyl penicillins;1,2,9,10,16,45,46,47,105,260 these penicillinase-resistant penicillins have heterocyclic side chains that result in slightly greater acid stability compared with nafcillin.16,105,260 Oxacillin, cloxacillin, and dicloxacillin differ structurally only in the presence of 0, 1, and 2 chlorine atoms, respectively.15,45,46,47,102,260 The addition of chlorine generally increases in vitro antibacterial activity on a weight basis and increases absorption from the GI tract, serum half-life, and protein binding.13,15,46,102,105

Penicillinase-resistant penicillins are commercially available as sodium salts.1,2,3,4,5 Potency of the drugs generally is expressed in terms of the bases.1,2,3,4,5,253 In general, penicillinase-resistant penicillins occur as white to off-white crystalline powders and are freely soluble in water and soluble in alcohol.253

Stability

Penicillinase-resistant penicillins generally are stable in the dry state at room temperature for several years;14 however, the drugs are stable only for short periods of time in solution14 unless frozen.14 Stability of the drugs is pH and temperature dependent.6,14,17 Nafcillin and oxacillin generally are stable at pH 5-8.6,14 Other penicillinase-resistant penicillins are more resistant than nafcillin and oxacillin to acid-catalyzed hydrolysis and generally are stable in the presence of acidic gastric secretions following oral administration.2,11,105

Nafcillin and oxacillin are potentially physically and/or chemically incompatible with some drugs, including aminoglycosides, but the compatibility depends on the specific drug and several other factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature).14,17 Oxacillin14 is especially susceptible to inactivation in solutions containing dextrose, which appears to have a catalytic effect on hydrolysis of the drug.14 For a more complete discussion of the stability of dicloxacillin, nafcillin, and oxacillin and solutions of the drugs, see Chemistry and Stability: Stability in the individual monographs in 8:12.16.12.

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions January 1, 2009. 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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section name header

Introduction ⬇

AHFS Class:

Associated Monographs

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Copyright ⬆ ⬇

References ⬆