Comparative In Vitro Activities of Relebactam, Imipenem, the Combination of the Two, and Six Comparator Antimicrobial Agents against 432 Strains of Anaerobic Organisms, Including Imipenem-Resistant Strains

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Relebactam is a novel diazobicyclooctane inhibitor that has activity in combination with imipenem against a broad range of beta-lactamases, including class A (extended-spectrum beta-lactamases [ESBLs] and KPCs) and class C enzymes, as well as carbapenemases most commonly found in Klebsiella pneumoniae (1, 2). Anaerobes are important pathogens in a variety of human infections for which carbapenems are important therapeutic choices. In a previous study, the combination of imipenem-relebactam's in vitro activity against 453 Bacteroides fragilis group species strains reported resistance rates of 0.7% (MIC₉₀s, 1 μg/ml). The authors concluded that relebactam does not add activity to that of imipenem, but did not study relebactam alone as a comparator (3). They also suggested that imipenem-relebactam does not inhibit the B. fragilis metalloenzyme (cfiA gene) and that any resistance might be due to other mechanisms, such as outer membrane proteins (Opr proteins and porins) and/or efflux (3, 4).

In order to further define the antianaerobic activity of imipenem-relebactam against a broader range of anaerobic pathogens involved in human clinical infections, we assessed its activity on a broad spectrum of clinical anaerobic isolates, many of which are beta-lactamase producers. We studied relebactam and imipenem alone as well as in combination, and other comparator agents, including ampicillin-sulbactam, piperacillin-tazobactam, moxifloxacin, clindamycin, metronidazole, and tigecycline. Clinical isolates were recovered from a variety of infections and included 131 recent isolates of Bacteroides spp., plus 17 selected strains of Bacteroides spp. with imipenem MICs ranging from 4 to >32 μg/ml. Other Gram-negative genera included Parabacteroides, Prevotella, Fusobacterium, Porphyromonas, Veillonella, Bilophila, and Desulfovibrio. Gram-positive genera included Eggerthella, Actinomyces, Eubacterium, Flavonifractor, Mogibacterium, Slackia, Solobacterium, and Clostridium. Isolates were identified by standard criteria (4, 5), and MICs were determined using the agar dilution method according to CLSI M11-A8 procedures (6). Serial 2-fold dilutions of comparators were tested, as well as relebactam. Imipenem alone and in combination with relebactam held constant at 4 μg/ml was also tested.

The results of the comparative in vitro activities of relebactam, imipenem, and the combination are shown in Table 1. Relebactam alone had MICs of ≥32 μg/ml against all isolates, including against all B. fragilis group spp., with the exception of Desulfovibrio desulfuricans (1 strain) (MIC 8 μg/ml), Porphyromonas asaccharolytica (3) and P. gingivalis (1) (8 to 16 μg/ml), Prevotella melaninogenica (1) (16 μg/ml), and Finegoldia magna (1) (4 μg/ml). Results of the combination of imipenem-relebactam showed minimal difference from those of imipenem alone for most of the strains tested with the following exceptions: 7 of 10 Bilophila wadsworthia strains were imipenem-resistant (MIC ≥ 8 μg/ml), with 6 of the strains showing a 2- to 32-fold decrease in MIC with imipenem-relebactam (range 0.25 to 4 μg/ml), and 4 of 10 F. varium strains showed a 4-fold reduction in MIC (16 to 4 μg/ml). Of the strains that were imipenem susceptible, 4 of 10 F. necrophorum strains showed a 4-fold MIC decrease, as did 2 of 24 strains of B. ovatus that showed a 4- to 16-fold decrease. Among the 13 strains of B. fragilis selected because of decreased susceptibility or resistance to imipenem, there was no enhancement of activity with the addition of relebactam. MICs for the quality-control strains were all within acceptable ranges for all drugs.

Relebactam alone had no antianaerobic activity, with MICs of >32 μg/ml for most of the organisms, with the exceptions of a very few strains of D. desulfuricans, P. asaccharolytica, P. gingivalis, P. melaninogenica, and F. magna. Relebactam had limited impact on the activity of imipenem as far as overall results for the broad spectrum of anaerobes tested. Our results for the B. fragilis group spp. are in accord with those reported by Snydman et al. (3), with MIC₉₀s occasionally differing from reported results by only one doubling dilution. Among the 13 strains of B. fragilis selected because of decreased susceptibility or resistance to imipenem (MICs > 8 μg/ml), there was no enhancement of imipenem activity with the addition of relebactam. Still, the imipenem-relebactam combination had general excellent anaerobic activity and would cover organisms present in the typical mixed infections of anaerobes and facultative organisms.

The other comparator drugs showed various results. Resistance to moxifloxacin and clindamycin was common among many species. Veillonella species (7 of 10, 70%), Desulfovibrio, and Bilophila species showed a high percentage of resistance to piperacillin-tazobactam (≥64 μg/ml). Bacteroides species (19 of 58, 33%), but not B. fragilis, showed decreased susceptibility and resistance to tigecycline (MIC₉₀ ≥8 μg/ml). Resistance to metronidazole remained infrequent among Gram-negative species. While relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, its enhanced activity against beta-lactamase-producing anaerobes was limited to Bilophila sp., two strains of B. ovatus, and four of F. varium, although no antagonism was detected for any of the species tested. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.