Adjunctive antimicrobial therapy for complicated appendicitis: bacterial overkill by combination therapy.

Although single antimicrobials with broad-spectrum aerobic and anaerobic coverage are effective in patients with appendicitis, many general surgeons continue to use multiple agents. A prospective, double-blind, randomized trial was designed to detect any clinical correlate of in vitro susceptibility advantage of multiple antimicrobials as adjunctive therapy for 114 patients undergoing operation for complicated appendicitis. There was clinical resolution of intraabdominal infections with no occurrence of postoperative infectious complications in 90% (36 of 40) of the cefotetan group and 86% (31 of 36) of the clindamycin/amikacin group (p = 0.11). The number of patients who had changes in antibiotic therapy due to postoperative complications was higher in the clindamycin/amikacin group: five (12.5%), compared to one (2.8%) in the cefotetan group (p = 0.07). Although Bacteroides fragilis group organisms resistant to cefotetan were identified, none was responsible for the postoperative infections. Adverse drug events in 28% of the cefotetan group and 26% of the clindamycin/amikacin group consisted primarily of transient elevations of liver function tests. Monotherapy with a second-generation, broad-spectrum cephalosporin, such as cefotetan, given twice a day is an economical and effective adjunctive regimen in patients with complicated appendicitis for which operation is the definitive treatment. Aminoglycosides and other, more potent antimicrobials should be reserved for resistant organisms or nosocomial infections.

Lack of predictability of cefotetan in vitro susceptibility tests against cefotetan-resistant anaerobic bacteria in determining clinical and bacteriologic efficacies.

Interpretive criteria for cefotetan in vitro susceptibility testing appear to be clinically relevant when applied to aerobic bacteria. To determine whether the same was true for anaerobic bacteria, we conducted a retrospective analysis of intraabdominal, gynecologic, and skin and skin structure infections treated with cefotetan. Of the infections, 202 contained at least one anaerobe isolate. Of the 51 patients, 47 (92.9%) from whom one or more cefotetan-resistant anaerobes were isolated were clinically cured or showed improvement. Similarly, cefotetan was efficacious for 95.4% of the patients harboring only cefotetan-susceptible anaerobes. Favorable bacteriologic responses were observed in 94.1% and 97.4% of these patient groups, respectively. The data suggests that the therapeutic utility of cefotetan against anaerobic bacteria cannot be accurately predicted on the basis of in vitro susceptibility test results alone but may be explained by a variety of factors, as discussed in this report.

Quality control guidelines for testing cefotetan in the reference agar dilution procedure for susceptibility testing of anaerobic bacteria.

Reference values for quality control of in vitro susceptibility tests with cefotetan against anaerobic bacteria were determined in two independent multilaboratory studies with the approved National Committee for Clinical Laboratory Standards agar dilution method and three control strains (Bacteroides fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741, and Clostridium perfringens ATCC 13124). The results of the two studies were in agreement. The recommended MIC control limits for B. fragilis ATCC 25285 and B. thetaiotaomicron ATCC 29741 are 4.0 to 16 micrograms/ml and 32 to 128 micrograms/ml, respectively. MICs for C. perfringens ATCC 13124 were too variable to be useful for controlling tests with cefotetan.

A multicenter study of the in vitro antianaerobic activity of cefotetan compared with other antimicrobial agents.

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.

Mutational resistance as the mechanism of acquired drug resistance to aminoglycosides and antibacterial agents in Mycobacterium fortuitum and Mycobacterium chelonei. Evidence is based on plasmid analysis, mutational frequencies, and aminoglycoside-modifying enzyme assays.

Possible mechanisms of drug resistance of Mycobacterium fortuitum and Mycobacterium chelonei to antibacterial agents were investigated. Single-step mutational frequencies were low (generally less than or equal to 10(-7] for cefoxitin, doxycycline, erythromycin, and sulfamethoxazole and relatively high (10(-4) to 10(-7] for kanamycin and amikacin. Aminoglycoside-susceptible strains of both species contained an aminoglycoside acetyltransferase (3)-III or IV. No additional enzymes were seen with laboratory or clinically acquired aminoglycoside resistance. Plasmids of several sizes were present in some susceptible isolates of both species, but acquired resistance was not associated with a change in the apparent size or number of these plasmids. Isolates with acquired resistance to amikacin were resistant to the other 2-deoxystreptamine aminoglycosides but showed little or no change in minimal inhibitory concentrations to streptomycin, suggesting either a difference in cellular uptake between the 2 groups of drugs or, more likely, different binding sites on the ribosome. In 59 patients treated with 63 courses of therapy with a single agent for 1 month or longer, the development of resistance was observed only twice (3%). Both isolates had high mutational frequencies (10(-4) and 10(-5]. These studies support mutational resistance as the mechanism of acquired resistance to antibacterial agents in M. fortuitum and M. chelonei.

Presence of aminoglycoside acetyltransferase and plasmids in Mycobacterium fortuitum. Lack of correlation with intrinsic aminoglycoside resistance.

Isolates of the 3 biovariants of Mycobacterium fortuitum exhibited 3 patterns of resistance when tested against 9 aminoglycosides. Examination of cell lysates from the 3 groups revealed 15/15 isolates to contain an aminoglycoside acetyltransferase (AAC) resembling AAC (3)-III or (3)-IV found in bacterial species. The enzyme did not appear to confer resistance, as its activity did not correlate with any pattern of resistance. The DNA extraction revealed plasmids in only 2 of 8 isolates tested, suggesting no relationship of plasmids to intrinsic aminoglycoside resistance or the presence of the AAC. These studies, combined with current knowledge of ribosomal resistance, suggest altered cellular transport or permeability as the mechanism of intrinsic aminoglycoside resistance in this species, although the patterns of resistance are different from those observed in other bacteria with nonenzymatic aminoglycoside resistance. This is the first demonstration of specific aminoglycoside-modifying enzymes among mycobacterial species and the first report of plasmids in M. fortuitum.

Rapid detection of yeast enzymes by using 4-methylumbelliferyl substrates.

In a preliminary study with a limited number of isolates, the usefulness of 17 4-methylumbelliferyl substrates for identifying yeast isolates was investigated. Substrates to detect acid phosphatase, glucosidase, and pyrophosphate diesterase showed promise.