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High serum and bile levels of CEFOBID are attained after a single dose of the drug. Table 1 demonstrates the serum concentrations of CEFOBID 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.
Table 1: Cefoperazone Serum Concentrations
|Dose/Route||Mean Serum Concentrations (mcg/mL)|
|0*||0.5 hr||1 hr||2 hr||4 hr||8 hr||12 hr|
|1 g IV||153||114||73||38||16||4||0.5|
|2 g IV||252||153||114||70||32||8||2|
|3 g IV||340||210||142||89||41||9||2|
|4 g IV||506||325||251||161||71||19||6|
|1 g IM||32**||52||65||57||33||7||1|
|2 g IM||40**||69||93||97||58||14||4|
|* Hours post-administration,
with 0 time being the end of the infusion.
** Values obtained 15 minutes post-injection.
The mean serum half-life of CEFOBID 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 CEFOBID reversible protein binding varies with the serum concentration from 93% at 25 mcg/mL of CEFOBID to 90% at 250 mcg/mL and 82% at 500 mcg/mL.
CEFOBID achieves therapeutic concentrations in the following body tissues and fluids:
|Tissue or Fluid||Dose||Concentration|
|Ascitic Fluid||2 g||64 mcg/mL|
|Cerebrospinal Fluid (in patients with inflamed meninges)||50 mg/kg||1.8 mcg/mL to 8.0 mcg/mL|
|Urine||2 g||3,286 mcg/mL|
|Sputum||3 g||6.0 mcg/mL|
|Endometrium||2 g||74 mcg/g|
|Myometrium||2 g||54 mcg/g|
|Palatine Tonsil||1 g||8 mcg/g|
|Sinus Mucous Membrane||1 g||8 mcg/g|
|Umbilical Cord Blood||1 g||25 mcg/mL|
|Amniotic Fluid||1 g||4.8 mcg/mL|
|Lung||1 g||28 mcg/g|
|Bone||2 g||40 mcg/g|
CEFOBID 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 CEFOBID 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 CEFOBID 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 CEFOBID 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, CEFOBID may accumulate in the serum.
CEFOBID has been used in pediatrics, but the safety and effectiveness in children have not been established. The half-life of CEFOBID in serum is 6–10 hours in low birth-weight neonates.
Mechanism of Action
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 gram-negative 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 [see INDICATIONS AND USAGE].
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.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.
Quantitative methods are used to determine 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 method.1,2,3 The MIC values should be interpreted according to the criteria provided in Table 2.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.3,4 This procedure uses paper disks impregnated with 75 mcg cefoperazone to test the susceptibility of bacteria to cefoperazone. The disk diffusion interpretive criteria are provided in Table 2.
Table 2: Susceptibility Test Criteria for Cefoperazone
|Pathogen||Susceptibility Interpretative Criteria|
|Minimal Inhibitory Concentrations (MIC in mcg/mL)|
|Other non-Entobacteriaceaea||≤ 8||≥16|
|Anaerobic bacteriab||≤ 8||≥16|
criteria are based on a dose of 3 g every 6 hours or 4 g every 8 hours in
patients with normal renal function.
Methicillin-susceptible Staphylococcus spp., as determined by susceptibility to oxacillin can be considered susceptible to cefoperazone.
aThese include nonfastidious glucose-nonfermenting gram-negative bacilli with the exception of: Pseudomonas aeruginosa, Acinetobacter species, Burkholderia species and Stenotrophomonas maltophilia.
bMICs for anaerobic bacteria are determined using agar dilution methodology.
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. A report of Resistance (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the site of infection; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standardized cefoperazone powder should provide the following range of MIC values noted in Table 3. For the diffusion technique using the 75 mcg cefoperazone disk, the criteria in Table 3 should be achieved.
Table 3: Acceptable Quality Control Ranges for
|Minimum Inhibitory Ranges (MIC in mcg/mL)||Disk Diffusion Ranges (Zone Diameters in mm)|
|Bacteroides fragilis ATCC 25285||32 - 128a||--|
|Bacteroides thetaiotaomicron ATCC 29741||32 - 128a||--|
|Eubacterium lentum ATCC 43055||32 - 128a||--|
|Escherichia coli ATCC 25922||0.12 - 0.5||28 - 34|
|Pseudomonas aeruginosa ATCC 27853||2 - 8||23 - 29|
|Staphylococcus aureus ATCC 29213||1 - 4||--|
|Staphylococcus aureus ATCC 25923||--||24 - 33|
|Quality Control Ranges for Oxacillin vs. S. aureus|
|Staphylococcus aureus ATCC 29213||0.12 - 0.5||--|
|ATCC® = American Type Culture
a MICs for anaerobic bacteria are determined using agar dilution methodology. Susceptibility of staphylococci to cefotaxime may be deduced from testing only penicillin and either cefoxitin or oxacillin.
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard–Tenth Edition. CLSI document M07-A10. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
2. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Eighth Edition. CLSI document M11– A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Fifth Informational Supplement. CLSI document M 100-S25. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard - Twelfth Edition. CLSI document M02-A12. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
Last reviewed on RxList: 3/30/2015
This monograph has been modified to include the generic and brand name in many instances.
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