Addition Of Relebactam Research Articles

Activities of aztreonam in combination with several novel β-lactam-β-lactamase inhibitor combinations against carbapenem-resistant Klebsiella pneumoniae strains coproducing KPC and NDM.

Isolates coproducing serine/metallo-carbapenems are a serious emerging public health threat, given their rapid dissemination and the limited number of treatment options. The purposes of this study were to evaluate the in vitro antibacterial activity of novel β-lactam-β-lactamase inhibitor combinations (BLBLIs) against carbapenem-resistant Klebsiella pneumoniae (CRKP) coproducing metallo-β-lactamase and serine-β-lactamase, and to explore their effects in combination with aztreonam, meropenem, or polymyxin in order to identify the best therapeutic options. Four CRKP isolates coproducing K. pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM) were selected, and a microdilution broth method was used to determine their susceptibility to antibiotics. Time-kill assay was used to detect the bactericidal effects of the combinations of antibiotics. The minimum inhibitory concentration (MIC) values for imipenem and meropenem in three isolates did not decrease after the addition of relebactam or varbobactam, but the addition of avibactam to aztreonam reduced the MIC by more than 64-fold. Time-kill assay demonstrated that imipenem-cilastatin/relebactam (ICR) alone exerted a bacteriostatic effect against three isolates (average reduction: 1.88 log10 CFU/mL) and ICR combined with aztreonam exerted an additive effect. Aztreonam combined with meropenem/varbobactam (MEV) or ceftazidime/avibactam (CZA) showed synergistic effects, while the effect of aztreonam combined with CZA was inferior to that of MEV. Compared with the same concentration of aztreonam plus CZA combination, aztreonam/avibactam had a better bactericidal effect (24 h bacterial count reduction >3 log10CFU/mL). These data indicate that the combination of ATM with several new BLBLIs exerts powerful bactericidal activity, which suggests that these double β-lactam combinations might provide potential alternative treatments for infections caused by pathogens coproducing-serine/metallo-carbapenems.

Activity of newest generation β-lactam/β-lactamase inhibitor combination therapies against multidrug resistant Pseudomonas aeruginosa

Multidrug resistant (MDR) P. aeruginosa accounts for 35% of all P. aeruginosa isolated from respiratory samples of patients with cystic fibrosis (CF). The usefulness of β-lactam antibiotics for treating CF, such as carbapenems and later generation cephalosporins, is limited by the development of antibacterial resistance. A proven treatment approach is the combination of a β-lactam antibiotic with a β-lactamase inhibitor. New β-lactam/β-lactamase inhibitor combinations are available, but data are lacking regarding the susceptibility of MDR CF-associated P. aeruginosa (CFPA) to these new combination therapies. In this study we determined MIC values for three new combinations; imipenem-relebactam (I-R), ceftazidime-avibactam (CZA), and ceftolozane-tazobactam (C/T) against MDR CFPA (n = 20). The MIC90 of I-R, CZA, and C/T was 64/4, 32/4, and 16/8 (all µg/mL), respectively. The susceptibility of isolates to imipenem was not significantly improved with the addition of relebactam (p = 0.68). However, susceptibility to ceftazidime was significantly improved with the addition of avibactam (p < 0.01), and the susceptibility to C/T was improved compared to piperacillin/tazobactam (p < 0.05) These data provide in vitro evidence that I-R may not be any more effective than imipenem monotherapy against MDR CFPA. The pattern of susceptibility observed for CZA and C/T in the current study was similar to data previously reported for non-CF-associated MDR P. aeruginosa.

Susceptibility of OXA-48-producing Enterobacterales to imipenem/relebactam, meropenem/vaborbactam and ceftazidime/avibactam

Relebactam and vaborbactam are among the newest β-lactamase inhibitors marketed. They were originally designed to inhibit the Ambler class A carbapenemase KPC. In this study, susceptibility to imipenem/relebactam and meropenem/vaborbactam was determined against a collection of OXA-48-like-producing Enterobacterales (n=407). The clonality and resistomes of the isolates were determined by whole-genome sequencing. Comparison was performed with other relevant antibiotics such as carbapenems alone, ceftazidime/avibactam and ceftolozane/tazobactam. Addition of relebactam and vaborbactam did not significantly modify the MIC50 and MIC90 values obtained for imipenem and meropenem alone. In contrast, addition of avibactam strongly restored ceftazidime susceptibility. According to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, MIC50/MIC90 values were at 2/4, 2/4, 2/8, 2/8, 32/>32 and 0.5/2 mg/L for imipenem, imipenem/relebactam, meropenem, meropenem/vaborbactam, ceftazidime and ceftazidime/avibactam, respectively. No differences were observed depending on the species. This study highlights the lack of benefit in vitro for carbapenem/inhibitor combination compared with carbapenem alone against OXA-48-producing isolates as well as the difficulties in comparing molecules since carbapenem/inhibitor combinations were not developed with the same dosage of carbapenem.

Non-susceptibilities to antibiotics against important Gram-negative bacteria, and imipenem-relebactam, meropenem-vaborbactam against carbapenem non-susceptible Enterobacterales and Pseudomonas aeruginosa isolates implicated in complicated intra-abdominal and urinary tract infections in Taiwan, 2019

Susceptibility of isolates of top-ranking Enterobacterales species and Pseudomonas aeruginosa implicated in complicated intra-abdominal infections (cIAI) and urinary tract infections (cUTI) to important antibiotics, including imipenem-relebactam (IMR) and meropenem-vaborbactam (MVB), in Taiwan in 2019 were evaluated. MICs to various antibiotics were determined using broth microdilution method. Susceptibility results were interpreted mainly based on the MIC breakpoints of the Clinical and Laboratory Standards Institute (CLSI) 2021, but susceptibilities of IMR and MVB were interpreted based on the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2021. Resistance genes amongst carbapenem-non-susceptible (NS) Gram-negative bacteria (GNB) were investigated using multiplex polymerase chain reaction (PCR). Escherichia coli (n=356), Klebsiella pneumoniae (n=165) and Enterobacter cloacae complex (n=42) isolates accounted for 85.3% of the 660 Enterobacterales isolates. The non-susceptibility rates of imipenem (IPM), IMR against isolates of non-Morganellaceae Enterobacterales, and meropenem (MEM), MVB against all Enterobacterales isolates were 92.2%/94.8%, 98.4-98.7%/98.4-99%, 95%/98.2% and 98.8-100%/99.4-100% for the cIAI/cUTI subgroups, respectively. Amongst the 40 IPM-NS-non-Morganellaceae Enterobacterales isolates, when the CLSI 2021 criteria were applied, 10 were NS to IMR, and four Klebsiella pneumoniae isolates (harbouring blaKPC but neither blaMBL nor blaOXA-48-like genes) were NS to IMR and MVB. Amongst the 93 Pseudomonas aeruginosa isolates under evaluation, the addition of relebactam (4mg/L) resulted in a 4-to-16-fold reduction in the MICs of IPM in all 15 IPM-NS-Pseudomonas aeruginosa isolates (including 10 porin-deficient ones) not harbouring blaMBL/blaOXA-48-like genes. Contrastingly, the addition of vaborbactam (8mg/L) improved the non-susceptibility to MEM in one (20%) of five IPM/MEM-NS Pseudomonas aeruginosa isolates. Continuous monitoring of susceptibility to clinically important GNB is warranted.

An overview of cilastatin + imipenem + relebactam as a therapeutic option for hospital-acquired and ventilator-associated bacterial pneumonia: evidence to date

ABSTRACT Introduction: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are prevalent nosocomial infections with a worrisomely increasing prevalence of multidrug-resistant causative organisms, including those with resistance to carbapenems. The addition of relebactam, a β-lactamase inhibitor, to imipenem treatment restores the antimicrobial activity against the most of multidrug-resistant Gram-negative bacteria, including some carrying β‐lactamase enzyme-type carbapenemases. Areas covered: The aim of this article is to summarize the current evidence regarding imipenem/relebactam for the treatment of HAP/VAP. The authors discuss its chemistry, pharmacokinetics/pharmacodynamics, microbiology, tolerance and clinical efficacy. The results of clinical trials have demonstrated an efficacy of imipenem/relebactam similar to that of its comparator for the treatment of patients with HAP/VAP. Different studies have also shown its good safety profile, which is better than that of the combination of other β‐lactams with other antibiotics. Expert opinion: This drug should be incorporated as a new therapeutic option for the treatment of patients with HAP/VAP, especially as an alternative treatment in patients with confirmed infections caused by multidrug-resistant Gram-negatives.

Imipenem/cilastatin/relebactam: A new carbapenem β-lactamase inhibitor combination.

The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, efficacy, safety, and current regulatory status of imipenem/cilastatin/relebactam are reviewed. Imipenem/cilastatin/relebactam is a newly approved anti-infective combination of a well-established β-lactam and a new β-lactamase inhibitor for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intra-abdominal infections (cIAIs) caused by susceptible gram-negative bacteria in patients 18 years of age or older with limited or no alternative treatment options. The antibiotic is also indicated for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The antibiotic is active in vitro against a wide range of pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales (CRE) such as Klebsiella pneumoniae carbapenemase. The addition of relebactam does not restore the activity of imipenem against metallo-β-lactamase (MBL)-producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. Two phase 3 clinical trials of imipenem/cilastatin/relebactam were conducted. In the RESTORE-IMI 1 trial, the efficacy and safety of imipenem/cilastatin/relebactam was found to be comparable to that of imipenem/cilastatin plus colistin for the treatment of infections caused by imipenem-nonsusceptible gram-negative bacteria in patients with HABP/VABP, cUTIs, and cIAIs, with a significantly lower incidence of nephrotoxicity reported with the new antibiotic. The RESTORE-IMI 2 trial demonstrated the noninferiority of imipenem/cilastatin/relebactam to piperacillin/tazobactam for the treatment of HABP/VABP. Commonly reported adverse events in clinical trials included anemia, elevated liver enzymes, electrolyte imbalances, nausea, vomiting, diarrhea, headache, fever, phlebitis and/or infusion-site reactions, and hypertension. Imipenem/cilastatin/relebactam is a new β-lactam/β-lactamase inhibitor combination with activity against MDR gram-negative bacteria, including many CRE but excluding MBL-producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. It is approved for the treatment of cUTIs, cIAIs, and HABP/VABP.

1312. Metallo-β-lactamase-Producing Enterobacterales (MBL-EB): Is it Time to Rethink Our Assessment Tools?

BackgroundWe previously reported the potent in vivo activity of ceftazidime/avibactam human-simulated regimen (HSR) against MBL-EB despite the observed resistance in vitro and the lack of avibactam MBL-inhibitory activity (AAC 2014 Nov;58(11):7007-9). Similar to avibactam, relebactam (REL) is a diazabicyclooctane that inhibits serine β-lactamases belonging to Classes A - C but not MBLs. In the current study, we examined the in vivo activity of cefepime (FEP)/REL combination HSR against MBL-EB in a murine thigh infection model.MethodsSix clinical MBL-EB isolates expressing VIM, IMP or NDM and co-expressing at least one β-lactamase of Classes A - C (KPC, CTX-M, TEM, SHV, ACT, CMY) were utilized. MICs of FEP and FEP/REL combination (at fixed REL concentration of 4 mg/L) were determined using broth microdilution. FEP HSR (2 g q12h as 0.5 h infusion) alone and in combination with REL HSR (250 mg q6h as 0.5 h infusion) were established in the infection model. Thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 CFU/ml. Two hours later, mice were administered the FEP HSR or the FEP/REL HSR. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls.ResultsAll isolates were FEP resistant (MIC ≥ 32 mg/L). Addition of REL had no impact on the MIC of the isolates. In in vivo studies, the average bacterial burden at 0 h was 5.84 ± 0.41 log10CFU/thigh. In accordance with the in vitro susceptibility, administration of FEP HSR was associated with net bacterial growth among all isolates ranging from 0.46 ± 0.60 to 2.97 ± 0.53 log10CFU/thigh. In contrast, FEP/REL combination HSR resulted in substantial bacterial reductions among all isolates ranging from -0.73 ± 0.13 to -1.72 ± 0.14 log10CFU/thigh, indicating that REL enhanced the FEP activity in vivo.ConclusionDespite the powerful β-lactam hydrolytic capability of MBLs in vitro, FEP inactivation in the murine model was attributed predominantly to the expression of the serine β-lactamases. The in vitro/in vivo discordance in β-lactam/β-lactamase activity against MBL-EB reveals a potential flaw in the currently utilized in vitro susceptibility testing methodologies and highlights a challenge encountered during the development of new agents against these isolates.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

In vitro activity of imipenem-relebactam against resistant phenotypes of Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples - SMART Surveillance Europe 2015-2017.

Introduction. Infections attributable to carbapenem-resistant Gram-negative bacilli are increasing globally. New antimicrobial agents are urgently needed to treat patients with these infections.Aim. To describe susceptibility to the novel carbapenem-β-lactamase inhibitor combination imipenem-relebactam and comparators of clinical isolates of non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa from intraabdominal infections (IAIs) and urinary tract infections (UTIs).Methods. Broth microdilution MICs were determined for isolates collected in 22 European countries in 2015-2017 and interpreted using EUCAST breakpoints; imipenem-relebactam MICs were interpreted using imipenem breakpoints.Results. For NPE, 98.4 % of isolates from IAIs (n=10,465) and 98.5 % of UTI isolates (n=7,446) were susceptible to imipenem-relebactam, as were 42.4 % of imipenem-nonsusceptible (n=474), 98.6 % of Klebsiella pneumoniae carbapenemase (KPC)-positive (n=138), and 93.9 % of multidrug-resistant (MDR) isolates (n=4,424) from IAIs and UTIs combined. Molecular analysis demonstrated that two-thirds of imipenem-nonsusceptible isolates rendered susceptible by relebactam carried KPCs; 96 % (261/271) of imipenem-nonsusceptible isolates of NPE that remained nonsusceptible in the presence of relebactam carried metallo-β-lactamase (MBL)-type and/or OXA-48-like carbapenemases. Among P. aeruginosa, 94.4 % of IAI (n=1,245) and 93.0 % of UTI isolates (n=714) were susceptible to imipenem-relebactam, as were 74.4 % of imipenem-nonsusceptible (n=469) and 79.8 % of MDR isolates (n=595) from IAIs and UTIs combined. Among the 120 isolates of P. aeruginosa that remained nonsusceptible to imipenem upon addition of relebactam, 72 % carried MBLs. The distribution of NPE and P. aeruginosa carrying carbapenemases varied substantially across Europe, as did resistance to imipenem and imipenem-relebactam.Conclusions. Continued surveillance of antimicrobial resistance and resistance mechanisms, including the study of imipenem-relebactam as it approaches regulatory approval, appears warranted.

1385. Mechanism-Based, In Vitro Inhibition of Mycobacterium abscessus: Assessing β-Lactam Therapy

Background M. abscessus (Mab) is an emerging pathogen, a highly drug-resistant rapidly-growing nontuberculous mycobacteria. Mab L, D transpeptidases (LdtMab 1–5), D,D carboxypeptidase and BlaMab β-lactamase are important targets. Herein, we tested the susceptibility of ceftaroline (TAR) and imipenem (IMI) alone and in combinations with two diazabicyclooctanone β-lactamase inhibitors (BLI), relebactam (REL) and avibactam (AVI), against representative clinical isolates belonging to the Mab complex and assessed the mechanism of inhibition using mass spectrometry (QTOF-MS)MethodsMinimum inhibitory concentrations (MICs) of TAR and IMI with or without AVI and REL and a TAR-IMI combination with and without REL were determined using microdilution. Approximately 5 x 105 colony-forming units (CFU) per milliliter were inoculated into Middlebrook 7H9 broth supplemented with 10% (vol/vol) oleic albumin dextrose catalase and 0.05% (vol/vol) Tween 80. AVI or REL were added at fixed concentration of 4 µg/mL to serial dilutions of TAR or IMI. For the TAR-IMI combinations, IMI at 1 µg/mL, and serial dilutions of TAR were used. Mab isolates were incubated with test agents at 30°C for 48 h, and MIC was defined as lowest antibiotic concentration that prevented visible bacterial growth. (QTOF-MS) was used to assess intermediates of BlaMab, LdtMab1 and LdtMab2 with TAR, IMI, AVI, and RELResults In-vitro susceptibility testing on representative clinical Mab strains (table). MIC90 was > 128 μg/mL for TAR and 8 μg/mL for IMI. Combination of TAR and IMI lowered MIC’s of all clinical isolates to <0.06 μg/mL. Addition of REL or AVI lowered TAR MICs but had minimal or no impact on IMI or TAR-IMI MICs. Mass spectrometry analyses of BlaMab, LdtMab (1–2) alone and incubated with IMI, TAR, REL and AVI (figure). BlaMab β-lactamase bound the AVI and REL, but acyl complexes with TAR or IMI were not detected. LdtMab (1–2) form stable acyl complexes with AVI, REL, TAR, and IMI.ConclusionAddition of IMI to TAR lowers MICs of TAR against Mab to therapeutically achievable concentrations. It would be welcome news for clinicians who are treating patients with highly resistant Mab infection that the combination of TAR and IMI is commercially available and thus might be considered as part of a rescue regimen. Disclosures All authors: No reported disclosures.

Potentiation of imipenem by relebactam for Pseudomonas aeruginosa from bacteraemia and respiratory infections.

Imipenem resistance in Pseudomonas aeruginosa most often entails loss of the 'carbapenem-specific' porin OprD; more rarely it reflects acquired carbapenemases. Loss of OprD only confers resistance to imipenem if AmpC β-lactamase is expressed, and we investigated whether this mechanism was overcome by relebactam, a developmental diazabicyclooctane β-lactamase inhibitor. Consecutive P. aeruginosa isolates causing bacteraemia or hospital-onset lower respiratory tract infections were collected between 2014 and 2016 under the aegis of the BSAC Resistance Surveillance Programme. Imipenem MICs were determined centrally by BSAC agar dilution, with relebactam at a fixed concentration (4 mg/L). For most imipenem-susceptible P. aeruginosa (726/759, 95.7%), the MICs of imipenem alone were 0.5-2 mg/L and were decreased 3- to 4-fold by addition of relebactam, as based on geometric means or modes. For most imipenem-resistant P. aeruginosa (82/92, 89%), imipenem MICs were 8-16 mg/L, and were reduced to 1-2 mg/L by relebactam. These patterns applied regardless of whether the isolates were susceptible to penicillins and cephalosporins or had phenotypes suggesting derepressed AmpC or up-regulated efflux. Imipenem MICs for five P. aeruginosa with MBLs remained high (≥16 mg/L) regardless of relebactam. Potentiation of imipenem by relebactam was almost universal, in accordance with the view that endogenous pseudomonal AmpC ordinarily protects against this carbapenem to a small degree. Imipenem MICs were reduced to the current breakpoint, or lower, except for MBL producers. Potentiation was not compromised by derepression of AmpC or up-regulation of efflux.

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

Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, but alone it has no antianaerobic activity, with most anaerobes having MICs of ≥32 μg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem-resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.

Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations.

Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC). Little is known about the potential for relebactam or vaborbactam to select for resistance; however, inactivation of the porin protein OmpK36 in K. pneumoniae has been reported to confer resistance to both imipenem-relebactam and meropenem-vaborbactam. The addition of relebactam significantly improves the activity of imipenem against most species of Enterobacteriaceae [by lowering the minimum inhibitory concentration (MIC) by 2- to 128-fold] depending on the presence or absence of β-lactamase enzymes. Against Pseudomonas aeruginosa, the addition of relebactam also improves the activity of imipenem (MIC reduced eightfold). Based on the data available, the addition of relebactam does not improve the activity of imipenem against Acinetobacter baumannii, Stenotrophomonas maltophilia and most anaerobes. Similar to imipenem-relebactam, the addition of vaborbactam significantly (2- to>1024-fold MIC reduction) improves the activity of meropenem against most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzymes. Limited data suggest that the addition of vaborbactam does not improve the activity of meropenem against A. baumannii, P. aeruginosa, or S. maltophilia. The pharmacokinetics of both relebactam and vaborbactam are described by a two-compartment, linear model and do not appear to be altered by the co-administration of imipenem and meropenem, respectively. Relebactam's approximate volume of distribution (V d) and elimination half-life (t ½) of~18L and 1.2-2.1h, respectively, are similar to imipenem. Likewise, vaborbactam's V d and t½ of~18L and 1.3-2.0h, respectively, are comparable to meropenem. Like imipenem and meropenem, relebactam and vaborbactam are both primarily renally excreted, and clearance correlates with creatinine clearance. In vitro and in vivo pharmacodynamic studies have reported bactericidal activity for imipenem-relebactam and meropenem-vaborbactam against various Gram-negative β-lactamase-producing bacilli that are not inhibited by their respective carbapenems alone. These data also suggest that pharmacokinetic-pharmacodynamic parameters correlating with efficacy include time above the MIC for the carbapenems and overall exposure for their companion β-lactamase inhibitors. Phase II clinical trials to date have reported that imipenem-relebactam is as effective as imipenem alone for treatment of complicated intra-abdominal infections and complicated urinary tract infections, including acute pyelonephritis. Imipenem-relebactam is currently in two phase III clinical trials for the treatment of imipenem-resistant bacterial infections, as well as hospital-associated bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). A phase III clinical trial has reported superiority of meropenem-vaborbactam over piperacillin-tazobactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. Meropenem-vaborbactam has recently demonstrated higher clinical cure rates versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), as well as for HABP and VABP. The safety and tolerability of imipenem-relebactam and meropenem-vaborbactam has been reported in various phase I pharmacokinetic studies and phase II and III clinical trials. Both combinations appear to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date. In conclusion, relebactam and vaborbactam serve to broaden the spectrum of imipenem and meropenem, respectively, against β-lactamase-producing Gram-negative bacilli. The exact roles for imipenem-relebactam and meropenem-vaborbactam will be defined by efficacy and safety data from further clinical trials. Potential roles in therapy for these agents include the treatment of suspected or documented infections caused by resistant Gram-negative bacilli-producing ESBL, KPC, and/or AmpC β-lactamases. The usage of these agents in patients with CRE infections will likely become the standard of care. Finally, increased activity of imipenem-relebactam against P. aeruginosa may be of clinical benefit to patients with suspected or documented P. aeruginosa infections.

Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae

We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidime-avibactam MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum β-lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo-β-lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (P < 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (P = 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (P < 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.