VA Class:AM112

AHFS Class:

• Penicillinase-resistant Penicillins 8:12.16.12

Generic Name(s):

• Oxacillin Sodium

Chemical Name:

• [2 S -(2α,5α,6β)]-3,3-Dimethyl-6-[[(5-methyl-3-phenyl-4-isoxazolyl)carbonyl]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monosodium salt monohydrate

Oxacillin is a semisynthetic penicillinase-resistant penicillin antibiotic.1,4,5,9,46,70

Oxacillin shares the uses of other parenteral penicillinase-resistant penicillins (e.g., nafcillin) and generally is used only in the treatment of infections caused by, or suspected of being caused by, susceptible penicillinase-producing staphylococci.1,6,47,66,70,71 For specific information on the uses of oxacillin, see Uses in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.

Reconstitution and Administration

Oxacillin sodium is administered by IM injection or slow IV injection or infusion.1 Although oxacillin has been administered orally,3 an oral preparation of the drug is no longer commercially available in the US.

IM Injection

For IM injection, oxacillin sodium powder for injection is reconstituted by adding 5.7 or 11.4 mL of sterile water for injection to a vial containing 1 or 2 g of oxacillin, respectively, to provide solutions containing 167 mg of oxacillin per mL (250 mg/1.5 mL).1 The vials should be shaken well until a clear solution is obtained.1

IM injections of oxacillin sodium should be made deeply into a large muscle (e.g., gluteus maximus) and care should be taken to avoid sciatic nerve injury.58

Intermittent IV Injection

For direct intermittent IV injection, a solution containing approximately 100 mg/mL may be prepared by adding 10 or 20 mL of sterile water for injection or 0.45 or 0.9% sodium chloride injection to vials containing 1 or 2 g of oxacillin, respectively.1

The appropriate dose should then be injected slowly over a period of about 10 minutes.1 Particular attention to the risk of thrombophlebitis should be given when oxacillin is administered IV to geriatric patients.58

Intermittent or Continuous IV Infusion

For intermittent IV infusion, vials containing 1 or 2 g of oxacillin should be reconstituted as for direct IV injection and then further diluted with a compatible IV solution1 to a concentration of 0.5-40 mg/mL. (See Chemistry and Stability: Stability.) Alternatively, ADD-Vantage^® vials containing 1 or 2 g of the drug should be reconstituted according to the manufacturer's directions.63 Pharmacy bulk packages containing 10 g of oxacillin usually are reconstituted by adding 93 mL of sterile water for injection or 0.9% sodium chloride injection to provide a solution containing 100 mg/mL.2 Pharmacy bulk packages of the drug are not intended for direct IV infusion; doses of the drug from the reconstituted pharmacy bulk package must be further diluted in a compatible IV infusion solution prior to administration.2

Thawed solutions of the commercially available frozen oxacillin sodium in dextrose injection should be administered by continuous or intermittent IV infusion.64 These frozen oxacillin sodium injections should not be thawed by warming them in a water bath or by exposure to microwave radiation.64 A precipitate may form while the commercially available injection in dextrose is frozen; however, this usually will dissolve with little or no agitation upon reaching room temperature, and the potency of the injection is not affected.64 After thawing at room temperature or under refrigeration, the containers should be checked for minute leaks by firmly squeezing the bag.64 The injection should be discarded if the container seal is not intact or leaks are found or if the solution is cloudy, discolored, or contains a precipitate.64 Additives should not be introduced into the injection.64 The injections should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.64

For IV infusion of oxacillin, the rate of infusion should be adjusted so that the total dose of oxacillin is administered before the drug is inactivated in the IV solution.1 (See Chemistry and Stability: Stability.)

Dosage

Dosage of oxacillin sodium is expressed in terms of oxacillin.1 Dosage of the drug should be adjusted according to the type and severity of infection.1,58

Adult Dosage

For the treatment of infections caused by susceptible penicillinase-producing staphylococci, the usual adult IM or IV dosage of oxacillin is 250-500 mg every 4-6 hours for mild to moderate infections or 1 g every 4-6 hours for severe infections.1,58,64 When oxacillin is used for the treatment of acute or chronic osteomyelitis caused by susceptible penicillinase-producing staphylococci, some clinicians recommend that adults receive 1.5-2 g of the drug IV every 4 hours.49 If oxacillin is used for the treatment of staphylococcal infections related to intravascular catheters, some clinicians recommend that adults receive 2 g every 4 hours.73

Staphylococcal Endocarditis

For the treatment of native valve endocarditis caused by staphylococci susceptible to penicillinase-resistant penicillins, the American Heart Association (AHA) recommends that adults receive oxacillin in a dosage of 2 g IV every 4 hours for 4-6 weeks.50 Although the benefits of concomitant aminoglycoside therapy have not been clearly established in these infections, the AHA states that gentamicin (1 mg/kg IM or IV every 8 hours) may be given concomitantly during the first 3-5 days of oxacillin therapy.50

For the treatment of staphylococcal endocarditis in the presence of prosthetic valves or other prosthetic material in patients with infections caused by isolates susceptible to penicillinase-resistant penicillins, the AHA states that adults should receive oxacillin in a dosage of 2 g IV every 4 hours for 6 weeks or longer in conjunction with rifampin (300 mg orally every 8 hours for 6 weeks or longer) and gentamicin (1 mg/kg IM or IV every 8 hours during the first 2 weeks of oxacillin therapy).50 However, because coagulase-negative staphylococci causing prosthetic valve endocarditis usually are resistant to penicillinase-resistant penicillins (especially when endocarditis develops within 1 year after surgery), coagulase-negative staphylococci involved in prosthetic valve endocarditis should be assumed to be resistant to penicillinase-resistant penicillins unless results of in vitro testing indicate that the isolates are susceptible to the drugs.50 (See Uses: Endocarditis in the Penicillinase-resistant Penicillins General Statement 8:12.16.12.)

Pediatric Dosage

Children weighing 40 kg or more may receive the usual adult dosage of oxacillin.1,58,64

The usual IM or IV dosage of oxacillin for the treatment of mild to moderate infections caused by susceptible penicillinase-producing staphylococci in children weighing less than 40 kg is 50 mg/kg daily given in equally divided doses every 6 hours.1,58,64 For severe infections, the usual IM or IV dosage in children weighing less than 40 kg is 100-200 mg/kg daily given in equally divided doses every 4-6 hours.1,47,49,58,64,67,71 The American Academy of Pediatrics (AAP) recommends that children 1 month of age or older receive IM or IV oxacillin in a dosage of 100-150 mg/kg daily in 4 divided doses for the treatment of mild to moderate infections or 150-200 mg/kg daily in 4 divided doses for the treatment of severe infections.67

The manufacturer recommends that neonates receive IM or IV oxacillin in a dosage of 25 mg/kg daily.1 The AAP and other clinicians recommend that neonates younger than 1 week of age receive IM or IV oxacillin in a dosage of 25-50 mg/kg every 12 hours if they weigh 2 kg or less (25 mg/kg every 12 hours for those less than 1.2 kg) or 25-50 mg/kg every 8 hours if they weigh more than 2 kg.67,71,72 Neonates 1-4 weeks should receive 25-50 mg/kg every 8 hours if they weigh 2 kg or less (25 mg/kg every 12 hours for those less than 1.2 kg) or 25-50 mg/kg every 6 hours if they weigh more than 2 kg.67,71,72 The higher dosages are recommended for meningitis.67

Staphylococcal Endocarditis

For the treatment of native valve endocarditis caused by staphylococci susceptible to penicillinase-resistant penicillins, the AHA recommends that pediatric patients receive oxacillin in a dosage of 200 mg/kg daily given IV in divided doses every 4-6 hours for 6 weeks (maximum daily dosage 12 g).69 In addition, during the first 3-5 days of oxacillin therapy, gentamicin (3 mg/kg daily given IM or IV in divided doses every 8 hours; dosage adjusted to achieve peak serum gentamicin concentrations approximately 3 mcg/mL and trough concentrations less than 1 mcg/mL) may be given concomitantly if the causative organism is susceptible to the drug.69

For the treatment of staphylococcal endocarditis in the presence of prosthetic valves or other prosthetic material in patients with infections caused by isolates susceptible to penicillinase-resistant penicillins, the AHA recommends that pediatric patients receive oxacillin in a dosage of 200 mg/kg daily given IV in divided doses every 4-6 hours for 6 weeks or longer (maximum daily dosage 12 g) in conjunction with rifampin (20 mg/kg daily given orally in divided doses every 8 hours for 6 weeks or longer) and gentamicin (3 mg/kg daily given IM or IV in divided doses every 8 hours during the first 2 weeks of oxacillin therapy; dosage adjusted to achieve peak serum gentamicin concentrations approximately 3 mcg/mL and trough concentrations less than 1 mcg/mL).69

Duration of Therapy

The duration of oxacillin therapy depends on the type and severity of infection and should be determined by the clinical and bacteriologic response of the patient.1,58,64 In serious staphylococcal infections, therapy should be continued for at least 1-2 weeks; more prolonged therapy is necessary for the treatment of osteomyelitis or endocarditis.1,58,64,71

When oxacillin is used parenterally in the treatment of acute or chronic osteomyelitis caused by susceptible penicillinase-producing staphylococci, the drug generally is given for 3-8 weeks;48,49,52,57,71 follow-up therapy with an oral penicillinase-resistant penicillin (e.g., dicloxacillin) generally is recommended for the treatment of osteomyelitis.49,51,71 In the treatment of acute osteomyelitis, a shorter course of parenteral penicillinase-resistant therapy (5-28 days) followed by 3-6 weeks of oral penicillinase-resistant penicillin therapy also has been effective.49,51,52,57

Dosage in Renal Impairment

Modification of dosage generally is unnecessary when oxacillin is used in patients with renal impairment;18,53,56 however, some clinicians suggest that the lower range of the usual dosage (1 g IM or IV every 4-6 hours) be used in adults with creatinine clearances less than 10 mL/minute.22,28,54,68

Adverse Effects

Adverse effects reported with oxacillin are similar to those reported with other penicillinase-resistant penicillins.1,58,64 However, adverse hepatic effects have been reported more frequently with IV oxacillin than with other commercially available penicillinase-resistant penicillins.35,36,37,38,39,58 For information on adverse effects reported with penicillinase-resistant penicillins, see Cautions in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.

Precautions and Contraindications

Oxacillin is contraindicated in patients who are hypersensitive to any penicillin.1,58,64

Oxacillin shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed.1,58,64 Prior to initiation of therapy with oxacillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.1,58,64 There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.1,33,34,42,43

Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with oxacillin.1,58 Because adverse hematologic effects have occurred during therapy with penicillinase-resistant penicillins, CBCs and differential should be performed prior to initiation of therapy and 1-3 times weekly during therapy.40,41,58,64 In addition, urinalysis should be performed and BUN and serum creatinine, AST (SGOT), and ALT (SGPT) concentrations should be determined prior to and periodically during therapy.1,58,64

For a more complete discussion of these and other precautions associated with the use of oxacillin, see Cautions: Precautions and Contraindications, in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.

Pediatric Precautions

Elimination of penicillins is delayed in neonates because of immature mechanisms for renal excretion, and abnormally high serum concentrations of the drugs may occur in this age group.58,63 If oxacillin is used in neonates, they should be monitored closely for clinical and laboratory evidence of toxic or adverse effects including renal impairment;1,58,63 organ systems1 and serum concentrations of the drug58 should be monitored frequently and appropriate reductions in dosage and frequency of administration made when indicated.58

Pregnancy and Lactation

Pregnancy

Safe use of penicillinase-resistant penicillins during pregnancy has not been definitely established.1,58,63 Clinical experience with use of penicillins during pregnancy in humans has not revealed evidence of adverse effects on the fetus.58 However, there are no adequate and controlled studies using penicillinase-resistant penicillins in pregnant women, and oxacillin should be used during pregnancy only when clearly needed.58,63

Lactation

Because oxacillin is distributed into milk, the drug should be used with caution in nursing women.58,63

Spectrum

Based on its spectrum of activity, oxacillin is classified as a penicillinase-resistant penicillin.4,5,9,46,58,70 For information on the classification of penicillins based on spectra of activity, see the Preface to the General Statements on Penicillins 8:12.16.

Like other penicillinase-resistant penicillins, oxacillin is resistant to inactivation by most staphylococcal penicillinases and is active against many penicillinase-producing strains of Staphylococcus aureus and S. epidermidis that are resistant to other commercially available penicillins.9,11,58,70 For specific information on the spectrum of activity of oxacillin and resistance to the drug, see the sections on Spectrum and on Resistance in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, oxacillin was administered as the sodium salt; dosages and concentrations of the drug are expressed in terms of oxacillin.

Absorption

Oxacillin is resistant to inactivation in the presence of acidic gastric secretions and is rapidly but incompletely absorbed from the GI tract.32,70 In healthy, fasting adults, 30-35% of an orally administered dose of oxacillin is absorbed from the GI tract4,7,15,23 and peak serum concentrations of the drug are generally attained within 0.5-2 hours.5,12,25,29,30,31,32 Presence of food in the GI tract generally decreases the rate and extent of absorption of oxacillin.5,14,30,58,70

Following oral administration of a single 250- or 500-mg dose of oxacillin as capsules (no longer commercially available in the US) in healthy, fasting adults, peak serum concentrations of the drug average 1.65 or 2.6-3.9 mcg/mL, respectively.13,25 Following oral administration of oxacillin as an oral solution (no longer commercially available in the US), peak serum concentrations occur about 30 minutes after the dose and average 1.9 mcg/mL after a single 250-mg dose and 4.8 mcg/mL after a single 500-mg dose.3

Oxacillin is rapidly absorbed from IM injection sites.1,14,29,30,31 Following IM injection of a single 250- or 500-mg dose of oxacillin in healthy adults with normal renal function, peak serum concentrations of the drug are generally attained within 30 minutes1,14,31 and average 5.3 and 10.9 mcg/mL, respectively.1 Following IM administration of a single 500-mg dose of oxacillin in healthy adults, serum concentrations of the drug averaged 7.4, 7.4, 4.3, and 0.8 mcg/mL at 30 minutes, 1 hour, 2 hours, and 4 hours, respectively, after the dose.30

Following rapid IV injection of a single 500-mg dose of oxacillin in healthy adults, peak serum concentrations of the drug average 52-63 mcg/mL.29

In one study in children 1 week to 2 years of age with staphylococcal infections who received an IM oxacillin dosage of 100 mg/kg daily in divided doses every 6 hours, peak serum concentrations of the drug occurred 30 minutes after a dose and ranged from 45-86 mcg/mL; trough serum concentrations ranged from 2.5-7.5 mcg/mL.26 Following IM injection of a single 20-mg/kg dose of oxacillin in neonates, peak serum concentrations of the drug reportedly average 51.5 mcg/mL in those 8-15 days of age and 47 mcg/mL in those 20-21 days of age.70

Distribution

Oxacillin is distributed into synovial,5,24 pleural,1,5 pericardial,10 and ascitic fluids.10 The drug is also distributed into bone,10,16,17,24,55 lungs,62 sputum,5 and bile.1,5,31 The volume of distribution of oxacillin is reportedly 0.39-0.43 L/kg in healthy adults.74

Following IM or IV administration, oxacillin concentrations in bone may be 5-20% of concurrent serum concentrations.16,55 In one study in adults who received a single 2-g IV dose of oxacillin, concentrations of the drug in bone ranged from 1.1-18.5 mcg/g.17

Like other penicillins, only low concentrations of oxacillin are attained in CSF.1,10,31 Following IM administration, oxacillin does not appear to distribute into aqueous humor in measurable concentrations;44,59 in animals, the drug is not distributed into aqueous humor even in the presence of inflammation.44 In rabbits, subconjunctival injection of a 100-mg dose of oxacillin produced aqueous humor concentrations of 145 mcg/mL 1 hour after the injection and 70 mcg/mL 2 hours after the injection.60

Oxacillin is 89-94% bound to serum proteins.4,15,19,20,70

Oxacillin is distributed into cord serum and amniotic fluid31 and crosses the placenta5,31 Oral administration of a single 500-mg dose of oxacillin to pregnant women in labor has resulted in fetal serum concentrations of the drug of 1.4 mcg/mL and amniotic fluid concentrations of 3.2 mcg/mL.31 Oxacillin is distributed into milk.1,5,31 Following IM administration of a single 500-mg dose of oxacillin in lactating women, milk concentrations of the drug were 0.2-0.7 mcg/mL 1 and 2 hours after the dose and 0.2-0.4 mcg/mL 4 hours after the dose.61

Elimination

The serum half-life of oxacillin in adults with normal renal function is 0.3-0.8 hours.1,7,10,15,21,22,45

Oxacillin is partially metabolized to active and inactive metabolites.10,23,27 In one study following a single 500-mg oral dose of oxacillin (no longer commercially available in the US), 49% of the absorbed dose was hydrolyzed to penicilloic acids which are microbiologically inactive.23 Oxacillin is also hydroxylated to a small extent to a microbiologically active metabolite which appears to be slightly less active than oxacillin.27

Oxacillin and its metabolites are rapidly excreted in urine mainly by tubular secretion and glomerular filtration.1,5,10,27,70 Following oral administration of a single 500-mg dose of oxacillin in adults with normal renal function, 17-24% of the dose is excreted in urine as unchanged drug and active metabolites within 6 hours;13,23,31 approximately 21% of the antibacterial activity in urine is represented by the active metabolite.27 Following IM administration of a single 500-mg or 1-g dose of oxacillin in adults with normal renal function, 40-70% of the dose is excreted in urine as unchanged drug and active metabolites within 6 hours.31

In one study, serum clearance of oxacillin averaged 380 mL/minute per 1.73 m² in adults with normal renal function.45

Serum concentrations of oxacillin may be higher and the serum half-life slightly prolonged in patients with impaired renal function.7,15,18,28,45 The serum half-life of the drug is reportedly 0.5-2 hours in patients with creatinine clearances less than 10 mL/minute per 1.73 m².7,15,18,45

In one study in children 1 week to 2 years of age, the elimination half-life of oxacillin ranged from 0.9-1.8 hours.26 Serum concentrations of oxacillin are generally higher and the serum half-life is longer in neonates than in older children.10 The serum half-life of oxacillin reportedly is 1.6 hours in neonates 8-15 days of age and 1.2 hours in neonates 20-21 days of age.70

Oxacillin is only minimally removed by hemodialysis10,15,22,28,56 or peritoneal dialysis.10,18,22,56

Chemistry and Stability

Chemistry

Oxacillin is a semisynthetic penicillinase-resistant penicillin.4,5,9,10,46,58,70,64 Oxacillin, like cloxacillin (no longer commercially available in the US) and dicloxacillin, is an isoxazolyl penicillin.4,5,14,46,70

Oxacillin is commercially available as the monohydrate sodium salt.1,68 Potency of oxacillin sodium is expressed in terms of oxacillin.1,64,68 Each mg of oxacillin sodium contains 815-950 mcg of oxacillin.68 Oxacillin sodium occurs as a fine, white, crystalline powder which is odorless or may have a slight odor.68 The drug is freely soluble in water.68 Oxacillin sodium has a pK_a of approximately 2.8.75

Each gram of commercially available oxacillin sodium powder for injection contains approximately 2.5 mEq of sodium and is buffered with 20 mg of dibasic sodium phosphate.1

Commercially available frozen oxacillin sodium in dextrose injection are sterile, nonpyrogenic, iso-osmotic solutions of the drug; about 1.5 or 0.3 g of dextrose has been added to the 1- or 2-g injection of oxacillin sodium, respectively, to adjust osmolality to about 300 mOsm/kg.64 Frozen oxacillin sodium in dextrose injection also contains sodium citrate as a buffer and hydrochloric acid and/or sodium hydroxide to adjust pH to 6-8.5.64

Stability

Commercially available oxacillin sodium powder for IM or IV injection should be stored at controlled room temperature;68 the pharmacy bulk package containing 10 g of the drug should be stored at 15-30°C.2

When oxacillin sodium powder for injection is reconstituted with sterile water for injection, solutions for IM injection containing 167 mg of oxacillin per mL (250 mg/1.5 mL) are stable for 3 days at room temperature or 7 days when refrigerated.1 When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions prepared from ADD-Vantage^® vials of the drug are stable for 4 days or 6 hours, respectively, at room temperature.63

At concentrations of 0.5-4 mg/mL, oxacillin loses less than 10% of its activity within 6 hours at room temperature in the following IV solutions: 5% dextrose and 0.9% sodium chloride; 10% fructose or 10% fructose and 0.9% sodium chloride; 10% invert sugar and 0.9% sodium chloride or 0.3% potassium chloride; or 10% invert sugar with electrolytes (Travert^® 10% with Electrolytes No. 1, 2, or 3).1

The commercially available preparations of frozen oxacillin sodium in dextrose injection should be stored at -20°C or lower64 and are stable for at least 90 days from the date of shipment when stored at -20°C.65 The frozen injection should be thawed at room temperature (25°C) or under refrigeration (5°C) and, once thawed, should not be refrozen.64 Thawed solutions of the commercially available frozen injection are stable for 48 hours at room temperature (25°C) or 21 days when refrigerated at 5°C.64,65 The commercially available frozen injections of the drug are provided in a plastic container fabricated from specially formulated multilayered plastic PL 2040 (Galaxy^®).64 Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.64

Oxacillin sodium is potentially physically and/or chemically incompatible with some drugs, including aminoglycosides and tetracyclines, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).8 For information on the in vitro and in vivo incompatibility of penicillins and aminoglycosides, see Drug Interactions: Aminoglycosides, in the Penicillinase-Resistant Penicillins General Statement 8:12.16.12. Specialized references should be consulted for specific compatibility information.8

Additional Information

For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of oxacillin sodium, see the Penicillinase-Resistant Penicillins General Statement 8:12.16.12.

1. Apothecon. Oxacillin sodium for injection for intramuscular or intravenous injection prescribing information. Princeton, NJ; 2001 Jan.

2. Apothecon. Oxacillin sodium for injection, USP pharmacy bulk package prescribing information. Princeton, NJ; 1998 Mar.

3. Apothecon. Oxacillin sodium for oral solution, USP prescribing information. Princeton, NJ; 1998 Mar.

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

5. Marcy SM, Klein JO. The isoxazolyl penicillins: oxacillin, cloxacillin, and dicloxacillin. Med Clin North Am . 1970; 52:1127-43.

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

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

8. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2003.

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

10. Neu HC. Antistaphylococcal penicillins. Med Clin North Am . 1982; 66:51-60. [PubMed 7038340]

11. Cherubin CE, Corrado ML, Sierra MF. Susceptibility of gram-positive cocci to various antibiotics, including cefotaxime, moxalactam, and n-formimidoyl thienamycin. Antimicrob Agents Chemother . 1981; 20:553-5. [PubMedCentral][PubMed 6282200]

12. McAllister TA. Piperacillin against clinical isolates: antimicrobial profile and clinical role. J Antimicrob Chemother . 1982; 9(Suppl B):75-84. [PubMed 6460736]

13. Hammerstrom CF, Cox F, McHenry MC et al. Clinical, laboratory, and pharmacological studies of dicloxacillin. Antimicrob Agents Chemother . 1966:69-74.

14. Kirby WM, Rosenfeld LS, Brodie J. Oxacillin: laboratory and clinical evaluation. JAMA . 1962; 181:739-44. [PubMed 14456243]

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

16. Tetzlaff TR, Howard JB, McCracken GH et al. Antibiotic concentrations in pus and bone in children with osteomyelitis. J Pediatr . 1978; 92:135-40. [PubMed 619056]

17. Kolczun MC, Nelson CL, McHenry MC et al. Antibiotic concentrations in human bone. J Bone Joint Surg . 1974; 56A:305-9.

18. Ruedy J. The effects of peritoneal dialysis on the physiological disposition of oxacillin, ampicillin and tetracycline in patients with renal disease. Can Med Assoc J . 1966; 94:257-61. [PubMedCentral][PubMed 5903164]

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

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

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

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

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

24. Fitzgerald RH, Kelly PJ, Snyder RJ et al. Penetration of methicillin, oxacillin, and cephalothin into bone and synovial tissue. Antimicrob Agents Chemother . 1978; 14:723-6. [PubMedCentral][PubMed 727762]

25. Bass JW, Bruhn FW, Merritt WT et al. Comparison of oral penicillinase-resistant penicillins: contrasts between agents and assays. South Med J . 1982; 75:408-10. [PubMed 7041278]

26. Burckart GJ, Evans WE, Whitington GL. Comparison of antibiotic serum concentrations after intramuscular oxacillin and oral cloxacillin in children. Am J Hosp Pharm . 1978; 35:1380-2. [PubMed 707507]

27. Thijssen HH, Mattie H. Active metabolites of isoxazolylpenicillins in humans. Antimicrob Agents Chemother . 1976; 10:441-6. [PubMedCentral][PubMed 825029]

28. Bulger RJ, Lindholm DD, Murray JS et al. Effect of uremia on methicillin and oxacillin blood levels. JAMA . 1964; 187:83-6.

29. Rutenburg AM, Greenberg HL. Oxacillin in staphylococcal infections: clinical evaluation of oral and parenteral administration. JAMA . 1964; 187:127-32.

30. Gravenkempter CF, Sweedler DR, Brodie JL et al. Cloxacillin: comparison of oral and parenteral forms with oxacillin and methicillin. Antimicrob Agents Chemother . 1964:237-49.

31. Prigot A, Froix CJ, Rubin E. Absorption, diffusion, and excretion of a new penicillin, oxacillin. Antimicrob Agents Chemother . 1962:402-10.

32. Bunn PA, Amrerg J. Initial clinical and laboratory experiences with methyl phenyl isoxazolyl penicillin (P-12). NY State J Med . 1961; 61:4158-62.

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

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

35. Dismukes WE. Oxacillin-induced hepatic dysfunction. JAMA . 1973; 226:861-3. [PubMed 4800332]

36. Onorato IM, Axelrod JL. Hepatitis from intravenous high-dose oxacillin therapy: findings in an adult inpatient population. Ann Intern Med . 1978; 89:497-500. [PubMed 697229]

37. Goldstein LI, Granoff M, Waisman J. Hepatic injury due to oxacillin administration. Am J Gastroenterol . 1978; 70:171-4. [PubMed 717369]

38. Pollack AA, Berger SA, Simberkoff MS et al. Hepatitis associated with high-dose oxacillin therapy. Arch Intern Med . 1978; 138:915-7. [PubMed 646563]

39. Bruckstein AH, Attia AA. Oxacillin hepatitis: two patients with liver biopsy, and review of the literature. Am J Med . 1978; 64:519-22. [PubMed 637061]

40. Carpenter J. Neutropenia induced by semisynthetic penicillin. South Med J . 1980; 73:745-7. [PubMed 7394597]

41. Homayouni H, Gross PA, Setia U et al. Leukopenia due to penicillin and cephalosporin homologues. Arch Intern Med . 1979; 139:827-8. [PubMed 454076]

42. Isbister JP. Penicillin allergy: a review of the immunological and clinical aspects. Med J Aust . 1971; 1:1067-74. [PubMed 4398272]

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

44. Havener WH. Ocular pharmacology. 4th ed. St. Louis: The CV Mosby Company; 1978:144-58.

45. Kind AC, Tupasi TE, Standiford HC et al. Mechanisms responsible for plasma levels of nafcillin lower than those of oxacillin. Arch Intern Med . 1970; 125:685-90. [PubMed 5437893]

46. Chambers HF. Penicillins. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000: 261-74.

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

48. Parker RH, Fossieck BE. Intravenous followed by oral antimicrobial therapy for staphylococcal endocarditis. Ann Intern Med . 1980; 93:832-4. [PubMed 7447189]

49. Armstrong EP, Rush DR. Treatment of osteomyelitis. Clin Pharm . 1983; 2:213-24. [PubMed 6349907]

50. Wilson WR, Karchmer AW, Dajani AS et al and the Committee on Rheumatic Fever et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA . 1995; 274:1706-13. [PubMed 7474277]

51. Dunkle LM, Brock N. Long-term follow-up of ambulatory management of osteomyelitis. Clin Pediatr . 1982; 21:650-5.

52. Kaplan SL, Mason EO, Feigin RD. Clindamycin versus nafcillin or methicillin in the treatment of Staphylococcus aureus osteomyelitis in children. South Med J . 1982; 75:138-42. [PubMed 7036354]

53. Cheigh JS. Drug administration in renal failure. Am J Med . 1977; 62:555-63. [PubMed 851131]

54. Appel GB, Neu HC. The nephrotoxicity of antimicrobial agents (first of three parts). N Engl J Med . 1977; 296:663-70. [PubMed 402574]

55. Waldvogel FA, Vasey H. Osteomyelitis: the past decade. N Engl J Med . 1980; 303:360-70. [PubMed 6993944]

56. Bennett WM, Aronoff GR, Morrison G et al. Drug prescribing in renal failure: dosing guidelines for adults. Am J Kidney Dis . 1983; 3:155-93. [PubMed 6356890]

57. McCracken GH, Eikenwald HF. Antimicrobial therapy in infants and children. Part II. Therapy of infectious conditions. J Pediatr . 1978; 93:357-77. [PubMed 357692]

58. US Food and Drug Administration. Penicillinase-resistant penicillin human prescription drugs class labeling guideline for professional labeling. [Notice of availability published in: Fed Regist . 1982; 47:41636.] Available from: Professional Labeling Branch, Division of Drug Advertising and Labeling, Food and Drug Administration, Rockville, MD.

59. Records RE. Human intraocular penetration of sodium oxacillin. Arch Ophthalmol . 1967; 77:693-5. [PubMed 6022741]

60. Records RE, Ellis PP. The intraocular penetration of ampicillin, methicillin, and oxacillin. Am J Ophthalmol . 1967; 64:135-43. [PubMed 6028624]

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

62. Kiss J, Farago E, Fabian E. Study of oxacillin levels in human serum and lung tissue. Ther Hung . 1974; 22:55-9. [PubMed 4214521]

63. Apothecon. Oxacillin for injection (for intravenous injection only) in ADD-Vantage^® drug delivery system prescribing information. Princeton, NJ; 2001 Jan.

64. Baxter. Oxacillin injection, USP in plastic container for intravenous use only Galaxy^® container prescribing information. Deerfield, IL; 1998 Sept.

65. Baxter Healthcare Corporation. Descriptive information on premixed products. Deerfield, IL; 1994 Feb 21.

66. Anon. The choice of antibacterial drugs. Med Lett Drugs Ther . 2001; 43:69-78. [PubMed 11518876]

67. Committee on Infectious Diseases, American Academy of Pediatrics. 2000 Red book: report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997:514-26,651,660.

68. The United States pharmacopeia, 26th rev, and The national formulary, 21st ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2003:597-8,1261-3,1355-7,2571-2.

69. Ferrieri P, Gewitz MH, Gerber MA et al and the Committee on Rheumatic Fever et al. Unique features of infective endocarditis in childhood. Circulation . 2002; 105:2115-27. [PubMed 11980694]

70. Kucers A, Crowe S, Grayson ML et al, eds. The use of antibiotics. A clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Jordan Hill, Oxford: Butterworth-Heinemann; 1997: 3-226.

71. Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 16th ed. Philadelphia: WB Saunders Company: 2000.

72. Gunn VL, Nechyba C, eds. The Harriet Lane handbook: a manual for pediatric house officers. 16th ed. Philadelphia, PA: Mosby: 2002:660,766,786.

73. Mermel LA, Farr BM, Sherertz J et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis . 2001; 32:1249-72. [PubMed 11303260]

74. Barza M, Weinstein L. Some determinants of the distribution of penicillins and cephalosporins in the body: practical and theoretical considerations. Ann NY Acad Sci . 1974; 235:613-20. [PubMed 4527978]

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