In Vitro and In Vivo Activities of OP0595, a New Diazabicyclooctane, against CTX-M-15-Positive Escherichia coli and KPC-Positive Klebsiella pneumoniae

Abstract

Gram-negative bacteria are evolving to produce ␤-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine ␤-lactamase inhibitor which acts also as an antibiotic and as a ␤-lactamase-independent ␤-lactam "enhancer" against Enterobacteriaceae. Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, in in vitro time-kill studies and an in vivo infection model against five strains of CTX-M-15-positive Escherichia coli and five strains of KPC-positive Klebsiella pneumoniae. An OP0595 concentration of 4 g/ml was found to be sufficient for an effective combination with all three ␤-lactam agents. In both in vitro time-kill studies and an in vivo model of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all ␤-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a ␤-lactam agent is important to exert the antimicrobial functions of OP0595.T he global increase in antibiotic-resistant Gram-negative bacteria in recent years is posing a serious medical problem. In many cases, the mechanism underlying bacterial resistance involves the production of ␤-lactamase. As of 2012, roughly 1,300 ␤-lactamases had been identified, including many that are not inhibited by established ␤-lactamase inhibitors such as tazobactam and clavulanic acid and several that hydrolyze carbapenems, which were previously regarded as "␤-lactamase stable" (1).␤-Lactamases can be classified according to several schemes. The most fundamental one is the Ambler classification, which is based on amino acid sequence and subdivides the serine ␤-lactamases into class A, including the common TEM, SHV, CTX-M, and KPC types, class C (e.g., AmpC, CMY, etc.), and class D (OXA). Class B comprises metalloenzymes (e.g., IMP, NDM, etc.) that require divalent cations, generally zinc, for substrate hydrolysis (2).The spread of extended-spectrum TEM, SHV, and CTX-M ␤-lactamases has led to increased clinical dependence on carbapenems; however, carbapenemase-producing Enterobacteriaceae spp. are spreading rapidly worldwide (3). The most prevalent types of carbapenemase vary geographically; for example, KPC types are dominant in North and South America, China, Israel, and parts of southern Europe, whereas OXA-48 is prevalent in the Middle East (except Israel) and NDM is common in south Asia (4). Bacteria expressing these enzymes can cause severe infections, and the fatality rate in cases of bloodstream infections involving carbapenemase-producing Klebsiella pneumoniae is high (5).As a result, new and effective ␤-lactamase inhibitors are urgently needed, and diazabicyclooctanes such as avibactam, relebactam (MK-7655), and OP0595 are under clinical development for this role (6, 7). Diazabicyclooctanes represent a new class of ␤-lactamase ...

Efficacy and Pharmacokinetics of the Combination of OP0595 and Cefepime in a Mouse Model of Pneumonia Caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae

“…(7)(8)(9). In a neutropenic mouse model of thigh infection, the number of bacteria decreased in an FEP dose-dependent manner in combination with OP0595, and the action of OP0595 in the combination therapy was considered to be as a beta-lactamase inhibitor and beta-lactam enhancer (9). In our mouse model of pneumonia as well, OP0595 in the combination therapy might act as both a beta-lactamase inhibitor and a beta-lactam enhancer.…”

“…In the previous study, the 50% inhibitory concentrations (IC 50 s) of OP0595 for the class A and C beta-lactamases were similar to or slightly higher than those of avibactam (8). OP0595 also improved the MICs of beta-lactams in a dose-dependent manner as avibactam does (7)(8)(9). In this study, the MICs of FEP against KEN-11 markedly improved in combination with 0.5, 1.0, and 2.0 mg/liter of OP0595 (Table 1).…”

“…The number of bacteria in the blood significantly decreased in the combination therapy group compared with the other groups (P Ͻ 0.001 versus the control, P Ͻ 0.05 versus the OP0595 treatment group, and P Ͻ 0.01 versus the FEP treatment group). (7)(8)(9). In a neutropenic mouse model of thigh infection, the number of bacteria decreased in an FEP dose-dependent manner in combination with OP0595, and the action of OP0595 in the combination therapy was considered to be as a beta-lactamase inhibitor and beta-lactam enhancer (9).…”

“…The combination of OP0595 and beta-lactams showed good in vitro activity against ESBL-, AmpC-, and carbapenemase-producing pathogens, including those producing OXA-48-class betalactamases (7)(8)(9). Additionally, the combination of OP0595 and cefepime (FEP) showed a dose-dependent effect in a neutropenic murine thigh infection model (9). However, the effect of the combination therapy against severe infections, such as pneumonia or bacteremia, remains unknown.…”

“…In addition to the inhibition of beta-lactamases, OP0595 showed antimicrobial activity by inhibiting penicillin binding protein 2 (PBP2) and enhanced the antimicrobial activity of the beta-lactams that bind to PBP3 (7,8). The combination of OP0595 and beta-lactams showed good in vitro activity against ESBL-, AmpC-, and carbapenemase-producing pathogens, including those producing OXA-48-class betalactamases (7)(8)(9). Additionally, the combination of OP0595 and cefepime (FEP) showed a dose-dependent effect in a neutropenic murine thigh infection model (9).…”