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Chemistry – A third generation cephalosporin, cefoperazone sodium contains a piperazine side chain giving it antipseudomonal activity. It occurs as white, crystalline powder and is freely soluble in water and poorly soluble in alcohol. At room temperature, cefoperazone sodium has a maximum solubility in compatible IV solutions of 475 mg/ml (at concentrations >333 mg/ml vigorous and prolonged shaking may be required). Reconstituted solutions of the drug have a pH from 4.5 – 6.5. One gram contains 1.5 mEq of sodium.
Storage/Stability/Compatibility – The sterile powder for injection should be stored at temperatures less than 25°C and protected from light. Once reconstituted, solutions do not need to be protected from light.
After reconstitution, cefoperazone sodium is generally stable for 24 hours at room temperature and 5 days when refrigerated in a variety of IV solutions (e.g., sterile or bacteriostatic water for injection, dextrose in water/saline/LRS solutions, lactated Ringer’s injection, Normasol R, and saline IV solutions). When frozen at -2 to -10°C in dextrose, sodium chloride or sterile water for injection, cefoperazone sodium is stable for 3 weeks (dextrose solutions) to 5 weeks (water or saline solutions).
Cefoperazone sodium is reportedly compatible with cimetidine HCl, clindamycin phosphate, furosemide and heparin sodium, acyclovir sodium, cyclophosphamide, esmolol HCl, famotidine, hydromorphone HCl, magnesium sulfate, and morphine sulfate. It is reportedly incompatible with some TPN mixtures, doxapram HCl, gentamicin sulfate, hetastarch, labetolol HCl, meperidine HCl, odansetron HCl, perphenazine, promethazine, and sargostim. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references (e.g., Handbook on Injectable Drugs by Trissel; see bibliography) for more specific information.
Pharmacology – Cefoperazone is a third generation injectable cephalosporin agent. For more information, refer to the monograph: Cephalosporins, General Information.
Uses/Indications – Cefoperazone is used to treat serious infections, particularly against susceptible Enterobacteriaceae not susceptible to other less expensive agents or when aminoglycosides are not indicated (due to their potential toxicity).
Pharmacokinetics – Cefoperazone is not absorbed after oral administration and must be given parenterally. It is widely distributed throughout the body; CSF levels are low if meninges are not inflamed. Cefoperazone crosses the placenta and enters maternal milk in low concentrations; no documented adverse effects to offspring have been noted. Unlike most cephalosporins, cefoperazone is principally excreted in the bile and elimination half-lives are approximately 2 hours in humans. Dosage adjustments generally are not required for patients with renal insufficiency.
Contraindications/Precautions/Reproductive Safety – Only prior allergic reaction to cephalosporins contraindicates cefoperazone’s use. In humans documented hypersensitive to penicillin, up to 16% may also be allergic to cephalosporins. The veterinary significance of this is unclear. Because cefoperazone is excreted in the bile, patients with significant hepatic disease or biliary obstruction may have their serum half-lives increase 2 – 4 times above normal. Dosage adjustment may be necessary. Cefoperazone should be used with caution in patients with preexisting bleeding disorders. It contains a thiomethyltetrazole side-chain which has been associated with causing coagulation abnormalities.
No teratogenic effects were demonstrated in studies in pregnant mice, rats, and monkeys given up to 10 times labeled doses of cefoperazone.
Adverse Effects/Warnings – Cefoperazone is a relatively safe agent. Rarely, hypersensitivity reactions could potentially occur in animals. Because of its thiomethyltetrazole side-chain it may also rarely cause hypoprothrombinemia. Diarrhea secondary to changes in gut flora have been reported. Some human patients demonstrate mild, transient increases in liver enzymes, serum creatinine and BUN. Clinical significance of these effects is in doubt. If administered via the IM route, pain at the injection site has also been noted.
Overdosage/Acute Toxicity – No specific antidotes are available. Overdoses should be monitored and treated symptomatically and supportively if required.
Drug Interactions – A disulfiram-like reaction (anorexia, nausea, vomiting) has been reported in humans who have ingested alcohol with 48-72 hours of receiving beta-lactam antibiotics with a thiomethyltetrazole side-chain (e.g.,cefamandole, cefoperazone, moxalactam, cefotetan). Because these antibiotics have been associated with bleeding, they should be used cautiously in patients receiving oral anticoagulants. Synergism against some Enterobacteriaceae (e.g., Pseudomonas aeruginosa) may be attained if using cefoperazone with a beta-lactamase inhibitor such as clavulanic acid or with an aminoglycoside (e.g., gentamicin, amikacin). Do not mix cefoperazone in same syringe or IV bag with aminoglycosides as inactivation may occur. Synergy may be unpredictable however and although there have been no reports of additive nephrotoxicity with cefoperazone, some cephalosporins may increase the nephrotoxic potential of aminoglycosides. Probenecid does not have an effect on cefoperazone elimination.
Laboratory Considerations – When using Kirby-Bauer disk diffusion procedures for testing susceptibility, a specific 75 micrograms cefoperazone disk should be used. A cephalosporin-class disk containing cephalothin should not be used to test for cefoperazone susceptibility. An inhibition zone of 21 mm or more indicates susceptibility; 16-20 mm, intermediate; and 15 mm or less, resistant.
When using a dilution susceptibility procedure, an organism with a MIC of 16 micrograms/ml or less is considered susceptible and 64 micrograms/ml or greater is considered resistant. With either method, infections caused by organisms with intermediate susceptibility may be effectively treated if the infection is limited to tissues where the drug is concentrated (e.g., urine, bile) or if a higher than normal dose is used.
In some human patients receiving cefoperazone, a positive direct antiglobulin (Coombs’) test has been reported.
Cefoperazone, like most other cephalosporins, may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e.g., Clinitest®).
For susceptible infections: 30 – 50 mg/kg q8-12h IV or IM (Note: This is a human dose and should be used as a general guideline only) (Walker 1992)
Monitoring Parameters – 1) Efficacy; 2) PT’s, CBC if bleeding occurs
Client Information – Because cefoperazone use is generally associated with inpatient therapy, little client monitoring is required. They should be alert to either bleeding problems or symptoms associated with hypersensitivity.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times –
Veterinary-Approved Products: None
Cefoperazone Sodium Powder for Injection in 1g, 2g vials. Also available in 1 or 2 gram piggyback containers and in pre-mixed frozen in 50 ml plastic containers Cefobid ® (Roerig); (Rx)