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Evaluation of the In Vitro Activity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates.

ABSTRACT: The novel fluorocycline antibiotic eravacycline is in development for use in the treatment of serious infections caused by susceptible and multidrug-resistant (MDR) aerobic and anaerobic Gram-negative and Gram-positive pathogens. Eravacycline and 11 comparator antibiotics were tested against recent anaerobic clinical isolates, including MDR Bacteroides spp. and Clostridium difficile Eravacycline was potent in vitro against all the isolates tested, including strains with tetracycline-specific resistance determinants and MDR anaerobic pathogens resistant to carbapenems and/or ?-lactam-?-lactamase inhibitor combinations.

SUBMITTER: Snydman DR

PROVIDER: S-EPMC5923129 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Evaluation of the In Vitro Activity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates.

Snydman David R DR McDermott Laura A LA Jacobus Nilda V NV Kerstein Kathryn K Grossman Trudy H TH Sutcliffe Joyce A JA

Antimicrobial agents and chemotherapy 20180426 5

The novel fluorocycline antibiotic eravacycline is in development for use in the treatment of serious infections caused by susceptible and multidrug-resistant (MDR) aerobic and anaerobic Gram-negative and Gram-positive pathogens. Eravacycline and 11 comparator antibiotics were tested against recent anaerobic clinical isolates, including MDR Bacteroides spp. and Clostridium difficile Eravacycline was potent in vitro against all the isolates tested, including strains with tetr ...[more]

PMID: 29483114

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Project description:Lytic bacteriophages (or phages) drive bacterial mortality by elaborating exquisite abilities to bind, breach, and destroy bacterial cell membranes and subjugate critical bacterial cell functions. These antimicrobial activities make phages ideal candidates to serve as, or provide sources of, biological control measures for bacterial pathogens. In this study, we isolated the Myoviridae phage vB_BanS_Bcp1 (here referred to as Bcp1) from landfill soil, using a Bacillus anthracis host. The antimicrobial activities of both Bcp1 and its encoded endolysin, PlyB, were examined across different B. cereussensu lato group species, including B. cereussensu stricto, Bacillus thuringiensis, and Bacillus anthracis, with pathogenic potential in humans and multiple different uses in biotechnological applications. The Bcp1 phage infected only a subset (11 to 66%) of each B. cereussensu lato species group tested. In contrast, functional analysis of purified PlyB revealed a potent bacteriolytic activity against all B. cereussensu lato isolates tested (n = 79). PlyB was, furthermore, active across broad temperature, pH, and salt ranges, refractory to the development of resistance, bactericidal as a single agent, and synergistic with a second endolysin, PlyG. To confirm the potential for PlyB as an antimicrobial agent, we demonstrated the efficacy of a single intravenous treatment with PlyB alone or combination with PlyG in a murine model of lethal B. anthracis infection. Overall, our findings show exciting potential for the Bcp1 bacteriophage and the PlyB endolysin as potential new additions to the antimicrobial armamentarium.IMPORTANCE Organisms of the Bacillus cereussensu lato lineage are ubiquitous in the environment and are responsible for toxin-mediated infections ranging from severe food poisoning (B. cereussensu stricto) to anthrax (Bacillus anthracis). The increasing incidence of many of these infections, combined with the specter of antibiotic resistance, has created a need for novel antimicrobials with potent activity, including bacteriophages (or phages) and phage-encoded products (i.e., endolysins). In this study, we describe a broadly infective phage, Bcp1, and its encoded endolysin, PlyB, which exhibited a rapidly bacteriolytic effect against all B. cereussensu lato isolates tested with no evidence of evolving resistance. Importantly, PlyB was highly efficacious in a mouse model of lethal bacteremia with B. anthracis Both the Bcp1 phage and the PlyB endolysin represent novel mechanisms of action compared to antibiotics, with potential applications to address the evolving problem of antimicrobial resistance.

Project description:QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

Project description:BACKGROUND:In China multidrug-resistant bacteria pose a considerable threat to public health. Antimicrobial resistance has weakened the effectiveness of many medicines widely used today. Thus, discovering new antibacterial drugs is paramount in the effort to treat emerging drug-resistant bacteria. METHODS:Eravacycline, tigecycline and other clinical routine antibiotics were tested by reference broth micro-dilution method against 336 different strains collected from 11 teaching hospitals in China between 2012 and 2016. These isolates included Enterobacteriaceae, non-fermentative, Staphylococcus spp., Enterococcus, and a number of fastidious organisms. The strains involved in this study possess the most important drug resistance characteristics currently known in China. Drug resistant bacteria such as those producing extended spectrum ?-lactamases (ESBL) and carbapenemases (KPC-2 and NDM-1), and those exhibiting colistin resistance (mcr-1) and tigecycline were included in this study. Additionally, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), ?-lactamase positive Haemophilus influenzae, and penicillin resistant Streptococcus pneumoniae (PRSP) were also included. RESULTS:Eravacycline exhibited good efficacy against all the strains tested, especially for organisms with ESBLs, carbapenemases, and mcr-1 gene compared with tigecycline and other antibiotics tested. The MIC values of eravacycline against carbapenemase producing Enterobacteriaceae and OXA-23-producing A. baumannii were much lower than the MIC values of other antibiotics. MRSA, VRE, ?-lactamase positive Haemophilus influenza, and PRSP were sensitive to eravacycline in every strain tested. Furthermore, in most strains tested, the MICs of eravacycline were two to four-fold lower than the MICs of tigecycline. CONCLUSIONS:Eravacycline has shown potent antibacterial activity against common and clinically important antibiotic-resistant pathogens. The MIC distribution of eravacycline was generally lower than that of tigecycline which demonstrates that this new drug is potentially more effective than the existing medications.

Dataset Information

Evaluation of the In Vitro Activity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates.

Publications

Evaluation of the <i>In Vitro</i> Activity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates.

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