Cloxacillin Sodium
Indications: Infection, staphylococcal, penicillinase-producing
DESCRIPTION:
Cloxacillin sodium is an antibacterial agent of the isoxazolyl penicillin series. It is a penicillinase-resistant, acid resistant semisynthetic penicillin suitable for oral administration. Cloxacillin sodium is available as an oral solution and capsules.
The molecular formula is C19H17ClN3NaO5SΒ·H2O. The molecular weight is 475.88
The chemical name is 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,6[[[3(2-chlorophenyl)-5-methyl-4-isoxazolyl]carbonyl]amino]3,3-dimethyl-7-oxo-,monosodium salt, monohydrate,2S (2alpha5alpha,6beta)-.
CLINICAL PHARMACOLOGY:
Microbiology
Penicillinase-resistant penicillins exert a bactericidal action against penicillin-susceptible microorganisms during the state of active multiplication. All penicillins inhibit the biosynthesis of the bactericidal cell wall.
The drugs in this class are highly resistant to inactivation by staphylococcal penicillinase and are active against penicillinase producing and non-penicillinase producing strains of Staphylococcus aureus . The penicillinase-resistant penicillins are active in vitro against a variety of other bacteria.
Susceptibility Testing
Quantitative methods of susceptibility testing that require measurement of zone diameters or minimal inhibitory concentration (MIC's) give the most precise estimates of antibiotic susceptibility. One such procedure has been recommended for use with discs to test susceptibility to this class of drugs.
Interpretations correlate diameters on the disc test with MIC values. A penicillinase-resistant class disc may be used to determine microbial susceptibility to cloxacillin, dicloxacillin, methicillin, nafcillin, and oxacillin. With this procedure, employing a 5 microgram methicillin sodium disc, a report from the laboratory of "susceptible" (zone of at least 14 mm) indicates that the infecting organism is likely to respond early to therapy. A report of "resistant" (zone of less than 10 mm) indicates that the infecting organism is not likely to respond to therapy. A report of "intermediate susceptibility" (zone of 10-13 mm) suggests that the organism might be susceptible if high doses of the antibiotic are used, or if the infection is confined to tissues and fluids (e.g., urine), in which high antibiotic levels are attained.
In general, all staphylococci should be tested against the penicillin G disc and against the methicillin disc. Routine methods of antibiotic susceptibility testing may fail to detect strains of organisms resistant to the penicillinase-resistant penicillins. For this reason, the use of large inocula and 48-hour incubation periods may be necessary to obtain accurate susceptibility studies with these antibiotics. Bacterial strains which are resistant to one of the penicillinase-resistant penicillins should be considered resistant to all of the drugs in the class.
Pharmacokinetics
Cloxacillin sodium is resistant to destruction by acid. Absorption of cloxacillin sodium after oral administration is rapid but incomplete. Studies with an oral dose of 1 gram gave average serum levels at 60 minutes of 14.4 mcg/ml. At four hours, average levels were 2 mcg/ml. In one study, single oral doses of cloxacillin sodium 500 mg produced peak serum concentrations of 7.5 to 14.4 mcg/ml at 1 to 1.5 hours.
Once absorbed, cloxacillin sodium binds to serum protein, mainly albumin. The degree of protein binding reported varies with the method of study and the investigator, but generally has been found to be 95.2Β±0.5%. Oral absorption of cloxacillin is delayed when the drug is administered after meals.
Cloxacillin sodium, with normal doses, has insignificant concentrations in the cerebrospinal and ascitic fluids. It is found in therapeutic concentrations in the pleural, bile, and amniotic fluids. Cloxacillin sodium is rapidly excreted as unchanged drug in the urine by glomerular filtration and active tubular secretion.
INDICATIONS AND USAGE:
The penicillinase-resistant penicillins are indicated in the treatment of infections caused by penicillinase-producing staphylococci which have demonstrated susceptibility to the drugs. Cultures and susceptibility tests should be performed initially to determine the causative organism and their sensitivity to the drug (see CLINICAL PHARMACOLOGY, Susceptibility Testing).
The penicillinase-resistant penicillins may be used to initiate therapy in suspected cases of resistant staphylococcal infections prior to the availability of laboratory test results. The penicillinase-resistant penicillins should not be used in infections caused by organisms susceptible to penicillin G. If the susceptibility tests indicate that the infection is due to an organism other than a resistant staphylococcus, therapy should not be continued with a penicillinase-resistant penicillin.
CONTRAINDICATIONS:
A history of hypersensitivity (anaphylactic) reaction to any penicillin is a contraindication.
WARNINGS:
Serious and occasionally fatal hypersensitivity (anaphylactic shock with collapse) reactions have occurred in patients receiving penicillin. The incidence of anaphylactic shock in all penicillin-treated patients is between 0.015 and 0.04%. Anaphylactic shock resulting in death has occurred in approximately 0.002% of the patients treated. Although anaphylaxis is more frequent following a parenteral administration, it has occurred in patients receiving oral penicillins.
When penicillin therapy is indicated, it should be initiated only after a comprehensive patient drug and allergy history has been obtained. If an allergic reaction occurs, the drug should be discontinued and the patient should receive supportive treatment, e.g., artificial maintenance of ventilation, pressor amines, antihistamines, and corticosteroids. Individuals with a history of penicillin hypersensitivity may also experience allergic reactions when treated with a cephalosporin.
PRECAUTIONS:
General: Penicillinase-resistant penicillins 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 oral route of administration should not be relied upon in patients with severe illness, or with nausea, vomiting, gastric dilation, cardiospasm, or intestinal hypermotility. Occasionally patients will not absorb therapeutic amounts of orally administered penicillin.
The use of antibiotics may result in overgrowth of nonsusceptible organisms. If new infections due to bacteria of fungi occur, the drug should be discontinued and appropriate measures taken.
Information for the Patient: Patients receiving penicillins should be given the following information and instructions by the physician:
1. Patients should be told that penicillin is an antibacterial agent which will work with the body's natural defenses to control certain types of infections. They should be told that the drug should not be taken if they have had an allergic reaction to any form of penicillin previously, and to inform the physician of any allergies or previous allergic reactions to any drugs they may have had (see WARNINGS).
2. Patients who have previously experienced an anaphylactic reaction to penicillin should be instructed to wear a medical identification tag or bracelet.
3. Because most antibacterial drugs taken by mouth are best absorbed on an empty stomach, patients should be directed, unless circumstances warrant otherwise, to take penicillin one hour before meals or two hours after eating (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
4. Patients should be told to take the entire course of therapy prescribed, even if fever and other symptoms have been stopped (see General).
5. If any of the following reactions occur, stop taking your prescription and notify the physician: shortness of breath, wheezing, skin rash, mouth irritation, black tongue, sore throat, nausea, vomiting, diarrhea, fever, swollen joints, or any unusual bleeding or bruising (see ADVERSE REACTIONS).
6. Do not take any additional medications without physician approval, including non-prescription drugs such as antacids, laxatives or vitamins.
7. Discard any liquid forms of penicillin after 7 days if stored at room temperature or after 14 days if refrigerated.
Laboratory Tests: Bacteriologic studies to determine the causative organisms and their susceptibility to the penicillinase-resistant penicillins should be performed (see CLINICAL PHARMACOLOGY, Microbiology). In the treatment of suspected staphylococcal infections, therapy should be changed to another active agent if culture tests fail to demonstrate the presence of staphylococci.
Periodic assessment of organ system function including renal, hepatic, and hematopoietic should be made during prolonged therapy with the penicillinase-resistant penicillins.
Blood cultures, white blood cell, and differential cell counts should be obtained prior to initiation of therapy and at least weekly during therapy with penicillinase-resistant penicillins.
Periodic urinalysis, blood urea nitrogen, and creatinine determinations should be performed during therapy with the penicillinase-resistant penicillins 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 (See DOSAGE AND ADMINISTRATION).
SGOT and SGPT values should be obtained periodically during therapy to monitor for possible liver function abnormalities.
Carcinogenesis, Mutagenesis, and 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 Category B: Reproduction studies performed in the mouse, rat, and rabbit have revealed no evidence of impaired fertility or harm to the fetus due to the penicillinase-resistant penicillins. Human experience with the penicillins during pregnancy has not shown any positive evidence of adverse effects on the fetus. There are, however, no adequate or well-controlled studies in pregnant women showing conclusively that harmful effects of these drugs on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: Penicillins are excreted in breast milk. Caution should be exercised when penicillins are administered to a nursing woman.
Pediatric Use: Because of incompletely developed renal function in newborns, penicillinase-resistant penicillins (especially methicillin) may not be completely excreted, with abnormally high blood resulting. Frequent blood levels are advisable in this group with dosage adjustments when necessary. All newborns treated with penicillins should be monitored closely for clinical and laboratory evidence of toxic or adverse effects (see DOSAGE AND ADMINISTRATION).
DRUG INTERACTIONS:
Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of penicillin and concurrent use of these drugs should be avoided.
ADVERSE REACTIONS:
Body as a Whole: The reported incidence of allergic reactions to penicillin ranges from 0.7-10% (see WARNINGS). Sensitization is usually the result of treatment but some individuals have had immediate reactions to penicillin when first treated. In such cases, it is thought that the patients may have had prior exposure to the drug via trace amounts present in milk and vaccines.
Two types of allergic reactions to penicillin are noted clinically, immediate and delayed.
Immediately 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: Neurotoxic reactions similar to those observed with penicillin G may occur with large intravenous doses of the penicillinase-resistant penicillins especially in patients with renal insufficiency.
Urogenital Reactions: Renal tubular damage and interstitial nephritis have been associated with the administration of nafcillin and oxacillin. Manifestations of this reaction may include rash, fever, eosinophilia, hematuria, proteinuria, and renal insufficiency. Methicillin-induced nephropathy does not appear to be dose-related and is generally reversible upon prompt discontinuation of therapy.
Metabolic Reactions: Agranulocytosis, neutropenia, and bone marrow depression have been associated with the use of methicillin sodium, nafcillin, oxacillin, and cloxacillin. Hepatotoxicity, characterized by fever, nausea, and vomiting associated with abnormal liver function tests, mainly elevated SGOT levels, has been associated with the use of oxacillin and cloxacillin.
DOSAGE AND ADMINISTRATION:
The penicillinase-resistant penicillins are available for oral administration and for intramuscular and intravenous injection. The sodium salts of methicillin, oxacillin, and nafcillin may be administered parenterally and the sodium salts of cloxacillin, dicloxacillin, oxacillin, and nafcillin are available for oral use.
Bacteriologic studies to determine the causative organisms and their sensitivity to the penicillinase-resistant penicillins should always be performed. Duration of therapy varies with the type and 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 penicillinase-resistant penicillins 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. The treatment of endocarditis and osteomyelitis may require a longer term of therapy.
Concurrent administration of the penicillinase-resistant penicillins and probenecid increases and prolongs serum penicillin levels. Probenecid decreases the apparent volume of distribution and slows the rate of excretion by competitively inhibiting renal tubular secretion of penicillin. Penicillin-probenecid therapy is generally limited to those infections where very high serum levels of penicillin are necessary.
Oral preparations of the penicillinase-resistant penicillins should not be used as initial therapy in serious, life-threatening infections (see PRECAUTIONS, General). Oral therapy with the penicillinase-resistant penicillins may be used to follow-up the previous use of a parenteral agent as soon as the clinical condition warrants. For intramuscular gluteal injections, care should be taken to avoid sciatic nerve injury. With intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis.
TABLE 1 Recommended Dosages for Cloxacillin Sodium in Mild to Moderate and Severe Infections
Drug
Adults
Children
Mild to moderate
Severe
Mild to moderate
Severe
Cloxacillin
250 mg every 6 hours
500 mg or higher every 6 hours
50 mg/kg/day* in equally divided doses
100mg/kg/day* or higher in equally divided doses every 6 hours
* Patients weighing less than 20 kg (44 lbs).
Directions for Dispensing Oral Solution: Prepare solution at the time of dispensing. For ease in preparation, add the water in two portions, shaking well after each addition. Add the total amount of water as directed on the labeling of the package being dispensed. Refrigerated, the solution is stable for 14 days.