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When evaluating antimicrobial agents, in vitro microbiologic activity and pharmacokinetics are important factors, but these data are usually not assessed simultaneously. The purpose of the study was to compare cefoxitin, cefotetan, ceftizoxime, cefotaxime (CT), desacetylcefotaxime (DACT), and CT/DACT (1:1 ratio) by integrating their microbiologic activity against clinical isolates of Bacteroides fragilis with their pharmacokinetic properties. Minimal inhibitory concentrations (MIC) were determined by the agar dilution method. Steady-state serum concentration--time profiles were simulated for 2-gm doses in a 70-kg patient using ADAPT software and pharmacokinetic data from published studies. Serum protein binding (%) of each agent was also obtained from published studies and used to calculate the unbound serum concentration--time profiles. As estimates of pharmacodynamic activity, time below the MIC (T less than MIC) and percentage of the dosing interval below the MIC (% INT less than MIC) were calculated for individual isolates using total and unbound serum concentrations. Data analysis included MIC50, MIC90, range, breakpoint susceptibility, and analysis of variance for T less than MIC and % INT less than MIC (Scheffé post-hoc test, P less than 0.05). The MIC90 of cefotetan was at least a twofold dilution lower than the other agents. However, using unbound (pharmacologically active) serum concentrations, T less than MIC and % INT less than MIC for ceftizoxime (at a simulated eight-hour dosing interval) were significantly smaller than with the other antibiotic regimens. Integration of in vitro and pharmacokinetic data may provide additional information to assist in the evaluation of antimicrobials. For B fragilis from our institution, the pharmacodynamic profile of unbound ceftizoxime is superior to the other antianaerobic cephalosporins/cephamycins tested.

The in vitro activity of certain beta-lactam agents against aerobic and anaerobic bacteria is influenced by the method and medium used for susceptibility testing. The in vitro activity of ceftizoxime and cefoxitin against Bacteroides fragilis group strains varies when either the broth microdilution or agar dilution method is used. In general, minimal inhibitory concentration values from broth microdilution are two- to fourfold lower than those from agar dilution. Broth microdilution test results with ceftizoxime have recently been shown to correlate more closely with clinical outcome in patients than those from agar dilution testing. Broth microdilution has become the recommended method of the National Committee for Clinical Laboratory Standards for testing ceftizoxime. Using broth microdilution testing, the in vitro activity of ceftizoxime has been shown to be as good as or better than that of cefoxitin, cefotetan, and cefotaxime against anaerobes, including the B fragilis group. Ceftizoxime also had good activity against B fragilis group strains resistant to cefoxitin or cefotetan. Time-kill kinetic studies have shown that the bactericidal activity of ceftizoxime is equal to or greater than that of cefoxitin or cefotetan against both cefoxitin-susceptible or cefoxitin-resistant strains of the B fragilis group.

Standardized in vitro susceptibility testing criteria and quality-control guidelines for cefotetan have been well documented in the scientific literature. Cefotetan and cefoxitin differ in their in vitro spectrums of activity and cannot be used interchangeably for in vitro tests. In vitro susceptibility information failed to correlate with clinical or bacteriologic responses of treated patients when 314 anaerobic bacteria from 145 patients were evaluated. All cefotetan-resistant anaerobic bacteria were eradicated by cefotetan therapy, and 93 percent of patients with resistant strains were clinically curved. Most members of the Bacteroides distasonis-ovatus-thetaiotaomicron group of pathogens were resistant in vitro, but only one strain persisted after cefotetan therapy for a 96.6 percent cure rate. There was better correlation when 2,336 aerobic bacteria from 1,630 infected body sites were considered. Microorganisms susceptible or moderately susceptible by in vitro tests were equally responsive to therapy (95 percent of patients clinically cured and 94 percent of isolates eradicated). However, strains that were resistant by in vitro test criteria were less likely to respond clinically. Development of resistance during therapy or superinfections (1.7 percent) were not found to be clinically important problems with cefotetan chemotherapy.

Normal volunteers and patients were studied to determine the relative importance of NMTT and patient risk factors in the production of hypoprothrombinemia. The normal volunteers demonstrated in vivo NMTT production, but the order of magnitude (cefoperazone, moxalactam, and cefotetan in descending order) was different from the usual order of clinical risk. In patients, there was not a NMTT-concentration-versus-effect relationship. Patients who were vitamin K deficient were more sensitive to lower NMTT concentrations than those with normal vitamin K status. In surveillance studies, NMTT-containing antibiotics were nor more frequently associated with hypoprothrombinemia or bleeding than antibiotics that lack this moiety.

The in vitro antianaerobic activity of cefotetan was compared with that of chloramphenicol, clindamycin, cefoxitin, and penicillin in a multicenter study. Both agar dilution and broth microdilution testing procedures, as described by the National Committee for Clinical Laboratory Standards (NCCLS), were employed; a total of 1,377 strains were examined. Results were interpreted using the U.S. Food and Drug Administration- and NCCLS-recommended criteria. This study indicates that Bacteroides fragilis, Clostridium difficile, and most other clinically significant anaerobic bacteria are susceptible to cefotetan.

In 93 hospitalized patients, 111 bacterial infections were treated with moxalactam. Eighty-three infections responded well to therapy, nine infections failed to respond to therapy or relapsed, and nine infections showed superinfection with resistant bacteria. The great majority of bacteria isolated had mean inhibitory concentrations below levels readily achieved in plasma, cerebrospinal fluid, bile, abscess fluid, and peritoneal fluid. Among the commonly identified bacteria, only Pseudomonas aeruginosa, enterococci, and Staphylococcus epidermidis had variable sensitivity to moxalactam.

Activity of cefotaxime, ceftriaxone, cefotetan, and latamoxef against Escherichia coli was evaluated in whole human blood. At subinhibitory levels no effect was seen. At concentrations at or exceeding the MIC, cefotaxime was rapidly bactericidal, and latamoxef was the second most active compound. With ceftriaxone and cefotetan, the organism grew better in blood containing the antibiotic than in blood alone.

Cefotetan (formerly ICI 156834 and YM09330) is a 7-methoxy cephalosporin possessing some advantageous antimicrobial spectrum, safety, and pharmacokinetic characteristics compared with other so-called second-generation cephalosporins. The published literature was reviewed and the cefotetan quantitative susceptibility testing data from nearly 31,000 isolates was tabulated. Against 15,769 enteric bacilli, cefotetan was observed to have a potency and spectrum more closely resembling a third-generation cephalosporin and markedly superior to cefoxitin. The mean of all MIC 90s reported for the Enterobacteriaceae ranged from 0.06 to 13 micrograms/ml except for citrobacter species, E. cloacae, Enterobacter species, and C. freundii. The mean MIC 50 for all 22 recorded species was in the susceptible range. Cefotetan was very effective against B. catarrhalis, H. influenzae, and pathogenic Neisseria species. However, cefotetan and cefoxitin were not active against Pseudomonas species, Acinetobacter species, and some rarely isolated species. Cefotetan was moderately active against the staphylococci (mean MIC 50, 7.6 to 26 micrograms/ml) and streptococci (mean MIC 50, 0.9 to 6.6 micrograms/ml). The coagulase-negative staphylococcus species generally had higher cefotetan and cefoxitin minimum inhibitory concentrations compared with the S. aureus isolates. Oxacillin-resistant staphylococci were resistant to cefotetan. The enterococci, JK group diphtheroids, Corynebacterium species, and L. monocytogenes isolates were resistant. A review of 4,751 strict anaerobes showed cefotetan to have a very comparable activity and spectrum to cefoxitin. The 1,291 B. fragilis strains had a mean MIC 50 and MIC 90 of 5.4 and 23 micrograms/ml, respectively. These values were slightly superior to cefoxitin when tested in parallel. More elevated minimum inhibitory concentrations were observed for other B. fragilis group species for cefoxitin and cefotetan. The mean cefotetan MIC 90 for all other anaerobic bacteria except the Eubacterium species and Lactobacillus species predict favorable clinical efficacy. The beta-lactamase stability of cefotetan is very similar to that of other 7-methoxy cephalosporins. Cefotetan also inhibits Type Ia cephalosporinases with high enzyme affinity and is an inducer of these beta-lactamases, although cefotetan is not rapidly hydrolyzed. Synergy between cefotetan and numerous other antibiotics has been reported, but antagonism has also been occasionally observed.