Comparative activity of beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with beta-lactams against beta-lactamase-producing anaerobes

Abstract

The in vitro activities of the P-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with six P-lactams against 88 ,-lactamase-producing anaerobes were determined. When combined with the ,-lactams, the three ,-lactamase inhibitors showed no synergy against the 10 Bacteroides fragilis homology group II strains. When the B-lactams were combined with the inhibitors, their geometric mean MICs against the remaining 78 strains were reduced from 4.2 to 150.2 ,ug/ml to 0.2 to 12.9 ,ug/ml. The activity of the P-lactams combined with the P-lactamase inhibitors was significantly greater than that of the ,-lactams alone against all groups except B. fragilis homology group II, with 76 to 100% of the strains susceptible to ampicillin plus inhibitor and .90% susceptible to the other combinations.Although the antimicrobial susceptibility spectrum of anaerobes has remained relatively stable, P-lactamasemediated resistance to penicillin and other P-lactams has been described for species in the Bacteroides fragilis group and for other Bacteroides spp., Fusobacterium nucleatum, and Clostridium butyricum (3,7,15,18,19). Several studies have demonstrated that the ,-lactamase inhibitors clavulanate and sulbactam act synergistically in vitro with ,-lactams against P-lactamase-positive, but not P-lactamase-negative, anaerobic organisms (2,4,5,16,20,21). YTR 830 is a new ,-lactamase inhibitor (1) with activity comparable to that of clavulanate and superior to that of sulbactam against ,1-lactamase-producing members of the family Enterobacteriaceae (6, 10). The purpose of this study was to compare the in vitro activities of six P-lactams (ampicillin, ticarcillin, mezlocillin, piperacillin, apalcillin, and cefoperazone) The presence of 3-lactamase was detected by a chromogenic cephalosporin method on growth from enriched blood agar plates by using nitrocefin disks (BBL Microbiology Systems, Cockeysville, Md.), in accordance with standard practice (4, 10). Organisms were stored at -70°C in thioglycolateglycerol (85:15, vol/vol) and were subcultured on enriched blood agar plates before testing.Laboratory reference powders of the following agents were used: ticarcillin and clavulanate (Beecham Laboratories, Bristol, Tenn.); mezlocillin (Miles Laboratories, Inc., West Haven, Conn.); piperacillin (Lederle Laboratories, Pearl River, N.Y.); apalcillin (Wyeth Laboratories, Philadelphia, Pa.); cefoperazone and sulbactam (Pfizer Inc., New York, N.Y.); ampicillin (Bristol-Myers Laboratories, Wallingford, Conn.); cefoxitin (Merck Sharpe & Dohme, West Point, Pa.); and YTR 830 (Taiho Pharmaceuticals, Tokyo, Japan). The powders were dissolved and diluted in accordance with the instructions of the manufacturers, and the potency of the agents was checked by determination of the MICs for quality control strains.Susceptibility testing of the isolates was performed by agar dilution on Wilkins-Chalgren agar (Difco Laboratories, Detroit, Mich.) (14,17). Plates contained serial doubling dilutions of the 3-lactams (ampicillin, 0.125 to 256 ,ug/...

Genotypic identification of two groups within the species Bacteroides fragilis by ribotyping and by analysis of PCR-generated fragment patterns and insertion sequence content

“…A different group, called DNA homology group II, has been described previously within the species B. fragilis (15), and this group also could not be distinguished phenotypically (16). Strains of this group have been reported to be less susceptible to ␤-lactams combined with penicillinase inhibitors and to cefoxitin and more susceptible to broad-spectrum penicillins and cefoperazone than the strains of homology group I (3,43), to which most B. fragilis strains belong (15).…”

“…65 to 70% intergroup and 80 to 90% intragroup homology (15,16). Strains belonging to group II have been reported to be less susceptible than those of group I to the synergistic inhibitory effect of clavulanic acid and ␤-lactam antibiotics (3,43).…”

A recent fixation of cfiA genes in a monophyletic cluster of Bacteroides fragilis is correlated with the presence of multiple insertion elements

“…This difference might reflect the existence of two, most likely closely related cfiA-type genes. In the cfiA-positive strains that were isolated as such and that hybridize strongly (22,23), the gene is capable of conferring a high-level resistance to the carbapenems as well as resistance to most ␤-lactamase inhibitors, while in the weakly cfiA-positive strains of DNA homology group II (11), only the latter type of resistance is known to occur (2,40).…”

“…About 80% of B. fragilis strains isolated in clinical studies can be assigned to homology group I (11). Although strains from homology groups I and II are phenotypically indistinguishable (12), strains of homology group II lack susceptibility to the synergistic effect of such ␤-lactamase inhibitors as clavulanic acid, sulbactam, and tazobactam (2,40), which are potent inhibitors of the vast majority of the ␤-lactamases produced by clinical isolates of B. fragilis (3,4,10,20,40). These are active-site serine enzymes, loosely related to those of Ambler's class A (1,17,28).…”

Comparative Activity of Several Antimicrobial Agents against Nosocomial Gram‐Negative Rods Isolated across Canada

“…Ta zo bac tam is a re cently stud ied peni cil lanic acid sul fone that in hib its a wide va ri ety of lac ta mases (17)(18)(19)(20)(21). The com bina tion of ta zo bac tam with peni cil lins and broad spec trum cepha lo sporins has dem on strated broad an ti mi cro bial ac tiv ity (19,20).…”