Mode of Action

Penicillinase-resistant penicillins exert a bactericidal action against penicillin susceptible microorganisms during the state of active multiplication. All penicillins inhibit the biosynthesis of the bacterial cell wall.

Mechanism of Resistance

Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta-lactamase, altered affinity of penicillin for target, or decreased penetration of the antibiotic to reach the target site.

Cross Resistance

Susceptibility Test Methods

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2 (broth and/or agar). The MIC values should be interpreted according to the criteria in Table 1.

Diffusion techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method.2,3. It has been determined that the most accurate method to test the susceptibility of microorganisms to penicillinase resistant penicillins, including oxacillin, by disk diffusion is achieved using disks impregnated with 30 mcg cefoxitin. Interpretation involves correlation of the diameter obtained with the cefoxitin disk test with the MIC for oxacillin2. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 microgram cefoxitin disk should be interpreted according to the following criteria in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Oxacillin

S=susceptible, I=intermediate, R=resistant

a In most staphylococcal isolates, oxacillin resistance is mediated by mecA, encoding the penicillin binding protein 2a (PBP2a, also called PBP2'). Isolates that test positive for mecA or PBP2a should be reported as oxacillin resistant."

2b Cefoxitin is used as a surrogate for oxacillin; report oxacillin susceptible or resistant based on the cefoxitin result.

2c If both cefoxitin and oxacillin are tested against S. aureus or S. lugdenensis, and either result is resistant, the organism should be reported as oxacillin resistant.

2d Oxacillin MIC interpretive criteria may overcall resistance for some coagulase-negative staphylococci (CoNS), because some non-S. epidermidis strains for which the oxacillin MICs are 0.5 to 2mcg/ml lack mecA. For serious infections with CoNS other than S. epidermidis, testing for mecA or for PBP 2a or with cefoxitin disk diffusion

A report of "Susceptible" indicates that the antimicrobial is likely to inhibit the growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3 Standard oxacillin powder should provide the following range of MIC values 1 noted in Table 2. For the diffusion technique using the 30 mcg cefoxitin disk, the criteria in Table 2 should be achieved.

Table 2. Acceptable Quality Control Ranges for Susceptibility Testing*

ATCC=American Type Culture Collection

aDespite the lack of reliable disk diffusion interpretive criteria for S. pneumoniae with certain beta-lactams, Streptococcus pneumonia ATCC® 49619 is the strain designated for QC of all disk diffusion tests with Streptococcus spp.

bDeterioration of oxacillin disk content is best assessed with QC organisms S. aureus ATCC® 25923, with an acceptable zone diameter for 18-24.

General

Oxacillin should generally not be administered to patients with a history of sensitivity to any penicillin. Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma. Whenever allergic reactions occur, penicillin should be withdrawn unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to penicillin therapy. The use of antibiotics may result in overgrowth of nonsusceptible organisms. If new infections due to bacteria or fungi occur, the drug should be discontinued and appropriate measures taken.

Prescribing Oxacillin for Injection, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Laboratory Tests

Periodic assessment of organ system function including renal, hepatic, and hematopoietic should be made during prolonged therapy with oxacillin.

Blood cultures, white blood cell, and differential cell counts should be obtained prior to initiation of therapy and at least weekly during therapy with oxacillin.

Periodic urinalysis, blood urea nitrogen, and creatinine determinations should be performed during therapy with oxacillin and dosage alterations should be considered if these values become elevated. If any impairment of renal function is suspected or known to exist, a reduction in the total dosage should be considered and blood levels monitored to avoid possible neurotoxic reactions.

AST (SGOT) and ALT (SGPT) values should be obtained periodically during therapy to monitor for possible liver function abnormalities.

DRUG INTERACTIONS

Oxacillin blood levels may be increased and prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Probenecid decreases the apparent volume of distribution and slows the rate of excretion by competitively inhibiting renal tubular secretion of penicillins.

Oxacillin-probenecid therapy should be limited to those infections where very high serum levels of oxacillin are necessary.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been conducted with these drugs. Studies on reproduction (nafcillin) in rats and rabbits reveal no fetal or maternal abnormalities before conception and continuously through weaning (one generation).

Pregnancy

Nursing Mothers

Pediatric Use

Geriatric Use

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Oxacillin for Injection contains 57.4 mg (2.5 mEq) per gram Oxacillin. At the usual recommended doses, patients would receive between 57.4 and 343.8 mg (2.5 and 15 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.

Information for Patients

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Body as a Whole

Two types of allergic reactions to penicillins are noted clinically, immediate and delayed.

Immediate reactions usually occur within 20 minutes of administration and range in severity from urticaria and pruritus to angioneurotic edema, laryngospasm, bronchospasm, hypotension, vascular collapse, and death. Such immediate anaphylactic reactions are very rare (see WARNINGS) and usually occur after parenteral therapy but have occurred in patients receiving oral therapy. Another type of immediate reaction, an accelerated reaction, may occur between 20 minutes and 48 hours after administration and may include urticaria, pruritus, and fever. Although laryngeal edema, laryngospasm, and hypotension occasionally occur, fatality is uncommon.

Delayed allergic reactions to penicillin therapy usually occur after 48 hours and sometimes as late as 2 to 4 weeks after initiation of therapy.

Manifestations of this type of reaction include serum sickness-like symptoms (i.e, fever, malaise, urticaria, myalgia, arthralgia, abdominal pain) and various skin rashes. Nausea, vomiting, diarrhea, stomatitis, black or hairy tongue, and other symptoms of gastrointestinal irritation may occur, especially during oral penicillin therapy.

Nervous System Reactions

Urogenital Reactions

Gastrointestinal Reaction

Metabolic Reactions

To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Bacteriologic studies to determine the causative organisms and their susceptibility to oxacillin should always be performed. Duration of therapy varies with the type of severity of infection as well as the overall condition of the patient; therefore it should be determined by the clinical and bacteriological response of the patient. In severe staphylococcal infections, therapy with oxacillin should be continued for at least 14 days. Therapy should be continued for at least 48 hours after the patient has become afebrile, asymptomatic, and cultures are negative. Treatment of endocarditis and osteomyelitis may require a longer duration of therapy.

With intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis.

RECOMMENDED DOSAGES FOR OXACILLIN FOR INJECTION, USP

Directions for use

For Direct Intravenous Use: Use Sterile Water for Injection, USP or Sodium Chloride Injection, USP. Add 10 mL to the 1 gram vial and 20 mL to the 2 gram vial. Withdraw the entire contents and administer slowly over a period of approximately 10 minutes.

For Administration by Intravenous Drip: Reconstitute as directed above (For Direct Intravenous Use) prior to diluting with Intravenous Solution.

STABILITY PERIODS FOR OXACILLIN FOR INJECTION, USP

IV Solution

5% Dextrose in Normal Saline

10% D-Fructose in Water

10% D-Fructose in Normal Saline

Lactated Potassic Saline Injection

10% Invert Sugar in Normal Saline

10% Invert Sugar Plus 0.3% Potassium Chloride in Water

Travert 10% Electrolyte #1

Travert 10% Electrolyte #2

Travert 10% Electrolyte #3

Only those solutions listed above should be used for the intravenous infusion of oxacillin sodium. The concentration of the antibiotic should fall within the range specified. The drug concentration and the rate and volume of the infusion should be adjusted so that the total dose of oxacillin is administered before the drug loses its stability in the solution in use.

If another agent is used in conjunction with oxacillin therapy, it should not be physically mixed with oxacillin but should be administered separately.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Do not add supplementary medication to oxacillin for injection, USP.