Cefoperazone

Cefoperazone, a third-generation cephalosporin, interferes with cell wall synthesis by binding to the penicillin-binding proteins (PBPs), thus preventing cross-linking of nascent peptidoglycan. Cefoperazone is stable to penicillinases and has a high degree of stability to many beta-lactamases produced by gram-negative bacteria.

Mechanisms of Resistance

There are 3 principal mechanisms of resistance to cefoperazone: mutations in the target PBPs, which occur primarily in gram-positive bacteria; production of extended spectrum beta-lactamases or over-expression of chromosomally determined beta-lactamases in gramnegative bacteria; reduced uptake or active efflux in certain gram-negative bacteria.

Interactions with Other Antimicrobials

When tested in vitro, cefoperazone has demonstrated synergistic interactions with aminoglycosides against gram-negative bacilli. The clinical significance of these in vitro findings is unknown.

Cefoperazone has been shown to be active against the following microorganisms, both in vitro and in clinical infections.

Gram-positive aerobic bacteria:

Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Streptococcus agalactiae (Group B beta-hemolytic streptococci)
Streptococcus pneumoniae
Streptococcus pyogenes (Group A beta-hemolytic streptococci)

Gram-negative aerobic bacteria:

Citrobacter species
Enterobacter species
Escherichia coli
Haemophilus influenzae
Klebsiella species
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas species
Serratia marcescens

Anaerobic gram-positive bacteria:

Gram-positive cocci (including Peptococcus and Peptostreptococcus spp.)
Clostridium species (with the exception of C. difficile)

Anaerobic gram-negative bacteria:

Bacteroides species

The following in vitro data are available, but their clinical significance is unknown. In addition, at least 90% of organisms in the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the cefoperazone susceptible breakpoint of 8 mcg/mL. However, the safety and efficacy of cefoperazone in treating clinical infections due to these bacteria have not been established in adequate well-controlled clinical trials.

Gram-negative aerobic bacteria:

Bordetella pertussis
Neisseria meningitides
Salmonella spp.
Serratia liquefaciens
Shigella spp.
Yersinia enterocolytica

Gram-positive anaerobic bacteria:

Eubacterium spp.

Gram-negative anaerobic bacteria:

Fusobacterium spp.

High serum and bile levels of cefoperazone are attained after a single dose of the drug. The following table demonstrates the serum concentrations of cefoperazone in normal volunteers following either a single 15-minute constant rate intravenous infusion of 1, 2, 3 or 4 grams of the drug, or a single intramuscular injection of 1 or 2 grams of the drug.

Cefoperazone Serum Concentrations:

* Hours post-administration, with 0 time being the end of the infusion.
** Values obtained 15 minutes post-injection.

The mean serum half-life of cefoperazone is approximately 2.0 hours, independent of the route of administration.

In a pharmacokinetic study, a total daily dose of 16 grams was administered to severely immunocompromised patients by constant infusion without complications. Steady state serum concentrations were approximately 150 mcg/mL in these patients.

In vitro studies with human serum indicate that the degree of cefoperazone reversible protein binding varies with the serum concentration from 93% at 25 mcg/mL of cefoperazone to 90% at 250 mcg/mL and 82% at 500 mcg/mL.

Cefoperazone achieves therapeutic concentrations in the following body tissues and fluids:

Cefoperazone is excreted mainly in the bile. Maximum bile concentrations are generally obtained between one and three hours following drug administration and exceed concurrent serum concentrations by up to 100 times. Reported biliary concentrations of cefoperazone range from 66 mcg/mL at 30 minutes to as high as 6000 mcg/mL at 3 hours after an intravenous bolus injection of 2 grams.

Following a single intramuscular or intravenous dose, the urinary recovery of cefoperazone over a 12-hour period averages 20–30%. No significant quantity of metabolites has been found in the urine. Urinary concentrations greater than 2200 mcg/mL have been obtained following a 15-minute infusion of a 2 g dose. After an IM injection of 2 g, peak urine concentrations of almost 1000 mcg/mL have been obtained, and therapeutic levels are maintained for 12 hours.

Repeated administration of cefoperazone at 12-hour intervals does not result in accumulation of the drug in normal subjects. Peak serum concentrations, areas under the curve (AUC’s), and serum half-lives in patients with severe renal insufficiency are not significantly different from those in normal volunteers. In patients with hepatic dysfunction, the serum half-life is prolonged and urinary excretion is increased. In patients with combined renal and hepatic insufficiencies, cefoperazone may accumulate in the serum.

Cefoperazone has been used in pediatrics, but the safety and effectiveness in children have not been established. The half-life of cefoperazone in serum is 6–10 hours in low birth-weight neonates.