Microbiology

Enterococcal Infections

Although cefoperazone has been shown to be clinically effective in the treatment of infections caused by enterococci in cases of peritonitis and other intra-abdominal infections, infections of the skin and skin structures, pelvic inflammatory disease, endometritis and other infections of the female genital tract, and urinary tract infections,1 the majority of clinical isolates of enterococci tested are not susceptible to cefoperazone but fall just at or in the intermediate zone of susceptibility, and are moderately resistant to cefoperazone. However, in vitro susceptibility testing may not correlate directly with in vivo results. Despite this, cefoperazone therapy has resulted in clinical cures of enterococcal infections, chiefly in polymicrobial infections. Cefoperazone should be used in enterococcal infections with care and at doses that achieve satisfactory serum levels of cefoperazone.

Combination Therapy

Synergy between CEFOBID and aminoglycosides has been demonstrated with many gram-negative bacilli. However, such enhanced activity of these combinations is not predictable. If such therapy is considered, in vitro susceptibility tests should be performed to determine the activity of the drugs in combination, and renal function should be monitored carefully. (See PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections.)

Hypersensitivity Reactions

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING BETA-LACTAM ANTIBACTERIALS, INCLUDING CEFOPERAZONE. THESE REACTIONS ARE MORE APT TO OCCUR IN INDIVIDUALS WITH A HISTORY OF HYPERSENSITIVITY REACTIONS TO MULTIPLE ALLERGENS. BEFORE THERAPY WITH CEFOBID IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS, CARBAPENEMS OR OTHER DRUGS. IF AN ALLERGIC REACTION OCCURS, CEFOPERAZONE SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED.

Severe and occasionally fatal skin reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and exfoliative dermatitis have been reported in patients on CEFOBID therapy. If a severe skin reaction occurs CEFOBID should be discontinued and appropriate therapy should be initiated (see ADVERSE REACTIONS).

Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CEFOBID, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Hemorrhage

Serious hemorrhage cases, including fatalities, have been reported with cefoperazone. Monitor for signs of bleeding, thrombocytopenia, and coagulopathy. Discontinue CEFOBID if there is persistent bleeding and no alternative explanations are identified.

Encephalopathy

Encephalopathy (with or without seizures) has been reported with the use of CEFOBID. Most cases occurred in patients with renal impairment. If encephalopathy occurs, discontinuation of CEFOBID should be considered and appropriate supportive measures should be taken.

General

Prescribing CEFOBID in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Although transient elevations of the BUN and serum creatinine have been observed, CEFOBID alone does not appear to cause significant nephrotoxicity. However, concomitant administration of aminoglycosides and other cephalosporins has caused nephrotoxicity.

CEFOBID is extensively excreted in bile. The serum half-life of CEFOBID is increased 2–4 fold in patients with hepatic disease and/or biliary obstruction. In general, total daily dosage above 4 g should not be necessary in such patients. If higher dosages are used, serum concentrations should be monitored.

Because renal excretion is not the main route of elimination of CEFOBID (see CLINICAL PHARMACOLOGY), patients with renal failure require no adjustment in dosage when usual doses are administered. When high doses of CEFOBID are used, concentrations of drug in the serum should be monitored periodically. If evidence of accumulation exists, dosage should be decreased accordingly.

The half-life of CEFOBID is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period. In patients with both hepatic dysfunction and significant renal disease, CEFOBID dosage should not exceed 1–2 g daily without close monitoring of serum concentrations.

As with other antibacterial drugs, vitamin K deficiency resulting in coagulopathy has occurred in patients treated with CEFOBID. The mechanism is probably related to the suppression of gut flora which normally synthesize this vitamin. Those at risk include patients with a poor nutritional status, malabsorption states (e.g., cystic fibrosis), alcoholism, and patients on prolonged hyper-alimentation regimens (administered either intravenously or via a naso-gastric tube). Hypoprothrombinemia with or without bleeding has been reported. Prothrombin time should be monitored in these patients, and patients receiving anticoagulant therapy, and exogenous vitamin K administered as indicated.

A disulfiram-like reaction characterized by flushing, sweating, headache, and tachycardia has been reported when alcohol (beer, wine) was ingested within 72 hours after CEFOBID administration. Patients should be cautioned about the ingestion of alcoholic beverages following the administration of CEFOBID.

Prolonged use of CEFOBID may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

CEFOBID should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Information for Patients

Patients should be counseled that antibacterial drugs including CEFOBID should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CEFOBID is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treated by CEFOBID or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibacterial drugs which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, 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 antibacterial drug. If this occurs, patients should contact their physician as soon as possible.

Drug/Laboratory Test Interactions

A false-positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. The maximum duration of CEFOBID animal toxicity studies is six months. In none of the in vivo or in vitro genetic toxicology studies did CEFOBID show any mutagenic potential at either the chromosomal or subchromosomal level. CEFOBID produced no impairment of fertility and had no effects on general reproductive performance or fetal development when administered subcutaneously at daily doses up to 500 to 1000 mg/kg prior to and during mating, and to pregnant female rats during gestation. These doses are 10 to 20 times the estimated usual single clinical dose. CEFOBID had adverse effects on the testes of prepubertal rats at all doses tested. Subcutaneous administration of 1000 mg/kg per day (approximately 16 times the average adult human dose) resulted in reduced testicular weight, arrested spermatogenesis, reduced germinal cell population and vacuolation of Sertoli cell cytoplasm. The severity of lesions was dose dependent in the 100 to 1000 mg/kg per day range; the low dose caused a minor decrease in spermatocytes. This effect has not been observed in adult rats. Histologically the lesions were reversible at all but the highest dosage levels. However, these studies did not evaluate subsequent development of reproductive function in the rats. The relationship of these findings to humans is unknown.

Usage in Pregnancy

Reproduction studies have been performed in mice, rats and monkeys at doses up to 10 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to CEFOBID. Cefoperazone crosses the placental barrier. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Usage in Nursing Mothers

Only low concentrations of CEFOBID are excreted in human milk. Although CEFOBID passes poorly into breast milk of nursing mothers, caution should be exercised when CEFOBID is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established. For information concerning testicular changes in prepubertal rats (see Carcinogenesis, Mutagenesis, Impairment of Fertility).

Geriatric Use

Clinical studies of CEFOBID® (sterile cefoperazone sodium) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Clinical Trials Experience

In clinical studies the following adverse effects were observed and were considered to be related to CEFOBID therapy or of uncertain etiology:

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of CEFOBID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Coagulopathy, thrombocytopenia, hypoprothrombinaemia (see PRECAUTIONS)

Immune System Disorders: Anaphylactic reaction including shock and fatal cases (see WARNINGS)

Hepatobiliary Disorders: Jaundice, hepatic dysfunction

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, pruritus

Vascular Disorders: Hemorrhage (see WARNINGS)

Nervous System Disorders: Encephalopathy (with or without seizures) (see WARNINGS)

General Reconstitution Procedures

CEFOBID sterile powder for intravenous or intramuscular use may be initially reconstituted with any compatible solution mentioned above in Table 3. Solutions should be allowed to stand after reconstitution to allow any foaming to dissipate to permit visual inspection for complete solubilization. Vigorous and prolonged agitation may be necessary to solubilize CEFOBID in higher concentrations (above 333 mg cefoperazone/mL). The maximum solubility of CEFOBID sterile powder is approximately 475 mg cefoperazone/mL of compatible diluent.

Preparation for Intravenous Use