Penicillinase-Resistant Penicillins General Statement (Monograph)

Drug class: Penicillinase-resistant Penicillins
VA class: AM112

Introduction

Penicillinase-resistant penicillins are semisynthetic penicillin antibiotics that are resistant to staphylococcal penicillinases.^{6 7 9 10 11 15 16 18 168 224 260}

Uses for Penicillinase-Resistant Penicillins General Statement

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^{† [off-label]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 endocarditis^{10 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 penicillins^{29 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 therapy^{177 192 202} 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 wounds^{183 189 263 279} 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 alone^{37 40 169 171 172 176 184 185 188 189 202 219 221 246 247 263} or vancomycin in conjunction with rifampin^{184 185 188 202 246} and/or an aminoglycoside.^{185 188 202 246}

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^{† [off-label]} 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 cardiovascular^{173 198 216 220} 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}

Penicillinase-Resistant Penicillins General Statement Dosage and Administration

Administration

Dicloxacillin sodium is administered orally.^{1 2} Nafcillin sodium^{3 238} and oxacillin sodium^{4 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 infections^{1 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 for Penicillinase-Resistant Penicillins General Statement

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 oxacillin^{113 114 116 117 118 224} 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 reactions^{3 4 109} with fever, chills, and myalgia.¹⁰⁹ Eosinophilia reportedly occurs in 5–38% of patients receiving a penicillinase-resistant penicillin^{18 109 111} 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}

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 thrombocytopenia^{3 4 5 142} have occurred rarely with penicillinase-resistant penicillins. Agranulocytosis also has been reported rarely with IV nafcillin^{2 141 144 224} 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 penicillin^{136 139 140 141 145 146} 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 tongue^{2 3 5 224} and oral lesions including glossitis³ and stomatitis^{2 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;^{18 238 260} C. 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 rapidly^{127 131} 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 nafcillin^{119 128 208 224} 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 LDH^{114 115 234} 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 therapy^{117 271} 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 ALT^{109 111 112 234} have been reported occasionally with oral dicloxacillin^{1 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 nafcillin^{3 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 oxacillin^{4 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}

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 oxacillin^{4 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 oxacillin^{4 5 10 100} are distributed into milk, penicillinase-resistant penicillins should be used with caution in nursing women.^{2 4 224}

Drug Interactions

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 nafcillin^{201 238 240 241 242} 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 anticoagulant^{201 238 240 241} 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}

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 nafcillin^{120 158 159 160} 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}

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 mecA 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 mecA or the protein expressed by mecA (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 mecA 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 mecA 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 mecA or PBP 2a may be appropriate for strains having MICs of 0.5–2 mcg/mL.²⁵⁵ Staphylococcal isolates that are shown to carry mecA 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. saprophyticus¹⁹⁶ 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 oxacillin^{10 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 oxacillin^{21 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 oxacillin^{10 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

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 staphylococci^{7 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 mecA 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 vancomycin^{12 37 40 171 172 184 210} or co-trimoxazole^{37 172} 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 inS. 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}

Penicillinase-Resistant Penicillins General Statement 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 duodenum^{7 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 dicloxacillin^{13 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 dicloxacillin^{2 9 18 45 46 72 76 80} or oxacillin^{9 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}

Oxacillin^{49 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/mL^{13 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 nafcillin^{69 89} or oxacillin^{69 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 nafcillin^{13 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 nafcillin^{52 273} or oxacillin^{274 275 276} 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 oxacillin^{5 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 dicloxacillin^{2 13 18 52 61 64 98 102} and oxacillin^{5 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 bile^{18 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 dose^{66 76} or 17–70% of the oxacillin dose^{5 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 oxacillin^{69 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 nafcillin^{18 52 69 84 97} and the isoxazolyl penicillins^{13 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 nafcillin^{3 74 94 95 96} and isoxazolyl penicillins^{18 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 oxacillin^{18 52 57 64 87} are only minimally removed by hemodialysis^{18 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}

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.

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