In vitro activity of N-formimidoyl thienamycin, moxalactam, and other new beta-lactam agents against Bacteroides fragilis: contribution of beta-lactamase to resistance

Abstract

N-Formimidoyl thienamycin (N-F-thienamycin) and moxalactam were compared with other currently available and investigational antibiotics against 100 clinical isolates of Bacteroides fragilis by an agar dilution method. N-F-thienamycin was the most active among the beta-lactam agents tested, with a minimal inhibitory concentration for 90% of isolates (MIC90) of 0.25 micrograms/ml. Moxalactam was next in activity, with an MIC90 of 4 micrograms/ml. N-F-thienamycin was somewhat more active, and moxalactam was slightly less active, than metronidazole and clindamycin. An increase in inoculum size caused an increase in the MIC of N-F-thienamycin, cefoperazone, and cefotaxime. This inoculum effect could influence the usefulness of these drugs in certain clinical conditions. The minimal bactericidal concentration was less than two times the MIC for most agents and less than four times the MIC for all beta-lactam agents at each inoculum size tested. Investigation of the mechanism of resistance to beta-lactam agents demonstrated a correlation between the level of resistance and beta-lactamase activity in each strain tested. N-F-thienamycin and cefoxitin were not hydrolyzed, and moxalactam was less susceptible to hydrolysis than the other beta-lactam antibiotics. Moxalactam and N-F-thienamycin may prove to be useful against infections with B. fragilis.

In vitro comparison of N-formimidoyl thienamycin (MK0787) and Azlocillin with three aminoglycosides and ticarcillin against Pseudomonas aeruginosa

“…For 24 strains of P. aeruginosa with known mechanisms of resistance for amikacin, tobramycin, or both, all but one strain was inhibited by <8 ,ug/ ml of N-formimidoyl thienamycin (Table 2). Of these 24 strains resistant to azlocillin (MIC 364 ,ug/ml) 14 were susceptible to z 8 ,ug/ml of Nformimidoyl thienamycin.Our data compare closely with published studies which included smaller numbers of P. aeruginosa strains (4,8,9,11,12,15 …”

“…Our data compare closely with published studies which included smaller numbers of P. aeruginosa strains (4,8,9,11,12,15 …”

“…Our data compare closely with published studies which included smaller numbers of P. aeruginosa strains (4,8,9,11,12,15). Of special interest in the present study was the activity of N-formimidoyl thienamycin against strains of P. aeruginosa resistant to one, more than one, or all of the reference antibiotics used in this study.…”

Resistance to -Lactam Antibiotics in Bacteroides Spp.

“…Further characterisation of the common P-lactamases from B. fragilis has shown them to have a molecular mass of 30-40 kDa, and to be inhibited by cloxacillin, pCMB and clavulanic acid [55-571. Cefoxitin, latamoxef and imipenem are typically resistant to hydrolysis by these enzymes [58]. P-Lactamases from B. fragilis, B. thetaiotaomicron, B. vulgatus and B. uniformis show species-specific differences in terms of substrate profile and PI values that range between 4.9 for B. fragilis and 4.25 for B. thetaiotaomicron [59].…”

Cefoxitin inactivation by Bacteroides fragilis

“…Of the currently available beta-lactam antibiotics, cefoxitin has the best in vitro activity (4,19). The enhanced activity of cefoxitin against these pathogens has been attributed to the resistance of the drug to the beta-lactamases of B. fragilis (3,5,7,11,22). Although there have been rare reports documenting the inactivation of the drug, the most common reported mechanism of cefoxitin resistance in this group of organisms has been the failure of the drug to penetrate through the outer membrane (6).…”