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Objectives We aimed to compare the stability of the newly developed β-lactams (cefiderocol) and β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable β-lactam resistance in Pseudomonas aeruginosa. Methods We screened a collection of 61 P. aeruginosa PAO1 derivatives. Eighteen isolates displayed the most relevant mechanisms of mutational resistance to β-lactams. The other 43 constructs expressed transferable β-lactamases from genes cloned in pUCP-24. MICs were determined by reference broth microdilution. Results Cefiderocol and imipenem/relebactam exhibited excellent in vitro activity against all of the mutational resistance mechanisms studied. Aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam proved to be more vulnerable to mutational events, especially to overexpression of efflux operons. The agents exhibiting the widest spectrum of activity against transferable β-lactamases were aztreonam/avibactam and cefepime/zidebactam, followed by cefepime/taniborbactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam. However, some MBLs, particularly NDM enzymes, may affect their activity. Combined production of certain enzymes (e.g. NDM-1) with increased MexAB-OprM-mediated efflux and OprD deficiency results in resistance to almost all agents tested, including last options such as aztreonam/avibactam and cefiderocol. Conclusions Cefiderocol and new β-lactam/β-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa β-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient β-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged. [ABSTRACT FROM AUTHOR]

Background Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. Methods We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a β-lactam/β-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21–28), and late follow-up (LFU; Days 35–42). Results A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P  = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. Conclusions Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered. [ABSTRACT FROM AUTHOR]

Co-infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) and Pseudomonas aeruginosa (CRPA) is associated with poor outcomes and historically relied on combination therapy with toxic agents for management. However, several novel β-lactam/β-lactamase inhibitor combination agents have been developed, offering potential monotherapy options. Here, we compare the in vitro activity of ceftazidime-avibactam (CZA), imipenem-relebactam (IRL), and meropenem-vaborbactam (MVB) against both CRKP and CRPA clinical isolates. Minimum inhibitory concentrations (MICs) for each agent were determined using broth microdilution. Carbapenemase gene detection was performed for representative isolates of varying carbapenem resistance phenotypes. IRL demonstrated excellent activity against CRKP and CRPA with susceptibility rates at 95.8% and 91.7%, respectively. While CZA and MVB showed comparable susceptibility to IRL against CRKP (93.8%), susceptibility of CRPA to CZA was modest at 79.2%, whereas most CRPA strains were resistant to MVB. Of the 35 CRKP isolates tested, 91.4% (32/35) carried a blaKPC gene. Only 1 of 37 (2.7%) CRPA isolates tested carried a blaVIM gene, which conferred phenotypic resistance to all three agents. None of the CRKP strains were cross-resistant to all three agents. Source of infection and co-infection did not significantly influence antimicrobial activity for IRL and CZA; none of the CRPA isolates from co-infected patients were susceptible to MVB. Our results suggest that novel β-lactam agents with antipseudomonal activity and stability against carbapenemases, such as IRL and CZA, offer potential monotherapy options for the treatment of co-infection involving both CRKP and CRPA, but not MVB. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a major global health issue. Metallo-β-lactamases (MBL), in particular, are problematic because they can inactivate all classes of β-lactams except aztreonam. Unfortunately, the latter may be simultaneously inactivated by serine β-lactamases. The most dangerous known MBL is New Delhi Metallo-β-lactamase (NDM). This study aimed to test the in vitro susceptibility to aztreonam in combination with novel β-lactamase inhibitors (avibactam, relebactam, and vaborbactam) in clinical strains of Enterobacterales NDM which is resistant to aztreonam. We investigated 21 NDM isolates—including Klebsiella pneumoniae, Escherichia coli, and Citrobacter freundii—which are simultaneously resistant to aztreonam, ceftazidime/avibactam, imipenem/relebactam, and meropenem/vaborbactam. MICs for aztreonam combinations with novel inhibitors were determined using the gradient strip superposition method. The most effective combination was aztreonam/avibactam, active in 80.95% strains, while combinations with relebactam and vaborbactam were effective in 61.90% and 47.62%, respectively. In three studied strains, none of the studied inhibitors restored aztreonam susceptibility. Aztreonam/avibactam has the most significant antimicrobial potential for NDM isolates. However, combinations with other inhibitors should not be rejected in advance because we identified strain susceptible only to tested combinations with inhibitors other than avibactam. Standardization committees should, as soon as possible, develop official methodology for antimicrobial susceptibility testing for aztreonam with β-lactamase inhibitors. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the efficacy of human-simulated regimens (HSRs) of ceftazidime, ceftazidime/avibactam, imipenem, imipenem/relebactam, meropenem and meropenem/vaborbactam in a murine thigh infection model against serine carbapenemase-producing Pseudomonas aeruginosa. Methods Nine P. aeruginosa clinical isolates harbouring GES-5 (n = 1), GES-20 (n = 1), GES-5/20 (n = 1), GES-19, GES-20 (n = 3) and KPC (n = 3) were evaluated. Six mice were administered HSRs of ceftazidime 2 g q8h (2 h infusion), ceftazidime/avibactam 2.5 g q8h (2 h infusion), meropenem 2 g q8h (3 h infusion), imipenem 0.5 g q6h (0.5 h infusion), imipenem/relebactam 1.25 g q6h (0.5 h infusion) and meropenem/vaborbactam 4 g q8h (3 h infusion). Change in bacterial burden relative to baseline and the percent of isolates meeting the 1 log10 kill endpoint were assessed. Results The addition of avibactam to ceftazidime increased the percentage of isolates meeting 1 log10 kill from 33% to 100% of GES- or KPC-harbouring isolates. Imipenem/relebactam HSR produced ≥1 log10 of kill against 83% and 100% of GES- and KPC-harbouring isolates, respectively, while imipenem alone failed to reach 1 log10 kill for any isolates. Vaborbactam resulted in variable restoration of meropenem activity as 1 log10 kill was achieved in only 33% and 66% of GES- and KPC-harbouring isolates, respectively, compared with no isolates for meropenem alone. Conclusions Ceftazidime/avibactam and imipenem/relebactam were active against 100% and 89% of KPC- or GES-harbouring isolates tested in vivo. The activity of meropenem/vaborbactam was variable, suggesting this may be an inferior treatment option in this setting. Further studies to evaluate clinical outcomes in GES- and KPC-producing P. aeruginosa are warranted given their increasing prevalence worldwide. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa. Methods: MIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective β-lactam breakpoints according to EUCAST were used for BL/BLI combinations. Results: For Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs. Conclusions: Zidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates. [ABSTRACT FROM AUTHOR]

Objectives To determine the in vitro activity of cefiderocol in a global collection of carbapenem-resistant Pseudomonas aeruginosa including >200 carbapenemase-producing isolates. Methods Isolates (n  = 806) from the ERACE-PA Surveillance Program were assessed. Broth microdilution MICs were determined for cefiderocol (iron-depleted CAMHB) and comparators (CAMHB). Susceptibility was interpreted by CLSI and EUCAST breakpoints and reported as percent of isolates. The MIC distribution of cefiderocol in the entire cohort and by carbapenemase status was assessed. Results In the entire cohort, cefiderocol was the most active agent (CLSI 98% susceptible; EUCAST 95% susceptible; MIC50/90, 0.25/2 mg/L). Amikacin (urinary only breakpoint) was the second most active, with 70% of isolates testing as susceptible. The percentage of isolates susceptible to all other agents was low (<50%) including meropenem/vaborbactam, imipenem/relebactam, piperacillin/tazobactam and levofloxacin. Cefiderocol maintained significant activity against the most commonly encountered carbapenemases including VIM- (CLSI 97% susceptible; EUCAST 92% susceptible) and GES (CLSI 100% susceptible; EUCAST 97% susceptible)-harbouring isolates. The cefiderocol MIC distribution was similar regardless of carbapenemase status, with MIC50/90 values of 0.5/4 mg/L, 0.5/2 mg/L and 0.25/1 mg/L for MBL, serine carbapenemase and molecular carbapenemase-negative isolates, respectively. Conclusions Cefiderocol displayed potent in vitro activity in this global cohort of carbapenem-resistant P. aeruginosa including >200 carbapenemase-harbouring isolates. Cefiderocol was highly active against MBL-producing isolates, where treatment options are limited. These data can help guide empirical therapy guidelines based on local prevalence of carbapenemase-producing P. aeruginosa or in response to rapid molecular diagnostics. [ABSTRACT FROM AUTHOR]

Nosocomial central nervous system (CNS) infections with carbapenem- and colistin-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria are an increasing therapeutic challenge. Here, we review pharmacokinetic and pharmacodynamic data and clinical experiences with new antibiotics administered intravenously for the treatment of CNS infections by multi-resistant bacteria. Cefiderocol, a new siderophore extended-spectrum cephalosporin, pharmacokinetically behaves similar to established cephalosporins and at high doses will probably be a valuable addition in our therapeutic armamentarium for CNS infections. The new glycopeptides dalbavancin, telavancin, and oritavancin are highly bound to plasma proteins. Although effective in animal models of meningitis, it is unlikely that they reach effective cerebrospinal fluid (CSF) concentrations after intravenous administration alone. The β-lactam/β-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the β-lactamase inhibitor tends to be too low to achieve adequate CSF concentrations. The oxazolidinone tedizolid has a broader spectrum but a less suitable pharmacokinetic profile than linezolid. The halogenated tetracycline eravacycline does not reach CSF concentrations sufficient to treat colistin-resistant Gram-negative bacteria with usual intravenous dosing. Generally, treatment of CNS infections should be intravenous, whenever possible, to avoid adverse effects of intraventricular therapy (IVT). An additional IVT can overcome the limited penetration of many new antibiotics into CSF. It should be considered for patients in which the CNS infection responds poorly to systemic antimicrobial therapy alone. [ABSTRACT FROM AUTHOR]

The emergence of bacteria resistant to beta-lactam/beta-lactamase inhibitor combinations is insufficiently studied, wherein the role of the inoculum effect (IE) in decreased efficacy is unclear. To address these issues, 5-day treatments with doripenem and doripenem/relebactam combination at different ratios of the agents were simulated in a hollow-fiber dynamic model against carbapenemase-producing K. pneumoniae at standard and high inocula. Minimal inhibitory concentrations (MICs) of doripenem alone and in the presence of relebactam at two inocula were determined. Combination MICs were tested using traditional (fixed relebactam concentration) and pharmacokinetic-based approach (fixed doripenem-to-relebactam concentration ratio equal to the therapeutic 24-h area under the concentration-time curve (AUC) ratio). In all experiments, resistant subpopulations were noted, but combined simulations reduced their numbers. With doripenem, the IE was apparent for both K. pneumoniae isolates in combined treatments for one strain. The pharmacokinetic-based approach to combination MIC estimation compared to traditional showed stronger correlation between DOSE/MIC and emergence of resistance. These results support (1) the constraint of relebactam combined with doripenem against the emergence of resistance and IE; (2) the applicability of a pharmacokinetic-based approach to estimate carbapenem MICs in the presence of an inhibitor to predict the IE and to describe the patterns of resistance occurrence. [ABSTRACT FROM AUTHOR]

Background: Pseudomonas aeruginosa shows resistance to several antibiotics and often develops such resistance during patient treatment. Objective: Develop an in vitro model, using clinical isolates of P. aeruginosa, to compare the ability of the imipenem and imipenem/relebactam to generate resistant mutants to imipenem and to other antibiotics. Perform a genotypic analysis to detect how the selective pressure changes their genomes. Methods: The antibiotics resistance was studied by microdilution assays and e-test, and the genotypic study was performed by NGS. Results: The isolates acquired resistance to imipenem in an average of 6 days, and to imipenem/relebactam in 12 days (p value = 0.004). After 30 days of exposure, 75% of the isolates reached a MIC > 64 mg/L for imipenem and 37.5% for imipenem/relebactam (p value = 0.077). The 37.5% and the 12.5% imipenem/relebactam mutants developed resistance to piperacillin/tazobactam and ceftazidime, respectively, while the 87.5% and 37.5% of the imipenem mutants showed resistance to these drugs (p value = 0.003, p value = 0.015). The main biological processes altered by the SNPs were the glycosylation pathway, transcriptional regulation, histidine kinase response, porins, and efflux pumps. Discussion: The addition of relebactam delays the generation of resistance to imipenem and limits the cross-resistance to other beta-lactams. The clinical relevance of this phenomenon, which has the limitation that it has been performed in vitro, should be evaluated by stewardship programs in clinical practice, as it could be useful in controlling multi-drug resistance in P. aeruginosa. [ABSTRACT FROM AUTHOR]

Carbapenemase-producing in Enterobacterales (CPE) represent a critical health concern worldwide, including in Switzerland, leading to very limited therapeutic options. Therefore, our aim was to evaluate the susceptibility to the novel ß-lactam/ß-lactamase inhibitor combinations ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam of CPE isolates recovered in Switzerland from 2018 to 2020. A total of 150 clinical CPE were studied including mainly Klebsiella pneumoniae (n = 61, 40.3%) and Escherichia coli (n = 53, 35.3%). The distribution of carbapenemases was as follows: KPC-like (32%), OXA-48-like (32%), NDM-like (24%), combinations of carbapenemases (10%), VIM-1 producers (n = 2), and a single IMI-1 producer. Overall, 77% of the strains were susceptible to meropenem-vaborbactam, 63% was susceptible to ceftazidime-avibactam, and 62% susceptible to imipenem-relebactam. Those data may contribute to optimize the choice of first line therapy for treating infections due to CPE. [ABSTRACT FROM AUTHOR]

Background: Carbapenem-resistant bacteria are an increasing problem in clinical practice; thus, it is important to identify β-lactamase inhibitors (e.g., relebactam) that can restore carbapenem susceptibility. We report analyses of relebactam enhancement of imipenem activity against both imipenem-nonsusceptible (NS) and imipenem-susceptible (S) Pseudomonas aeruginosa and Enterobacterales. Gram-negative bacterial isolates were collected for the ongoing Study for Monitoring Antimicrobial Resistance Trends global surveillance program. Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MIC) were used to determine the imipenem and imipenem/relebactam antibacterial susceptibilities of P. aeruginosa and Enterobacterales isolates. Results: Between 2018 and 2020, 36.2% of P. aeruginosa (N = 23,073) and 8.2% of Enterobacterales (N = 91,769) isolates were imipenem-NS. Relebactam restored imipenem susceptibility in 64.1% and 49.4% of imipenem-NS P. aeruginosa and Enterobacterales isolates, respectively. Restoration of susceptibility was largely observed among K. pneumoniae carbapenemase-producing Enterobacterales and carbapenemase-negative P. aeruginosa. Relebactam also caused a lowering of imipenem MIC among imipenem-S P. aeruginosa and Enterobacterales isolates from chromosomal Ambler class C β-lactamase (AmpC)–producing species. For both imipenem-NS and imipenem-S P. aeruginosa isolates, relebactam reduced the imipenem MIC mode from 16 μg/mL to 1 μg/mL and from 2 μg/mL to 0.5 μg/mL, respectively, compared with imipenem alone. Conclusions: Relebactam restored imipenem susceptibility among nonsusceptible isolates of P. aeruginosa and Enterobacterales and enhanced imipenem susceptibility among susceptible isolates of P. aeruginosa and isolates from Enterobacterales species that can produce chromosomal AmpC. The reduced imipenem modal MIC values with relebactam may result in a higher probability of target attainment in patients. [ABSTRACT FROM AUTHOR]

Background In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making. Methods A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment. Results Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment. Conclusions This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL. Clinical Trials Registration NCT02493764. [ABSTRACT FROM AUTHOR]

Background: Ceftazidime-avibactam was approved by the FDA to treat infections caused by Enterobacterales carrying blaKPC-2. However, variants of KPC-2 with amino acid substitutions at position 179 have emerged and confer resistance to ceftazidime-avibactam. Methods: The activity of imipenem-relebactam was assessed against a panel of 19 KPC-2 D179 variants. KPC-2 and the D179N and D179Y variants were purified for biochemical analyses. Molecular models were constructed with imipenem to assess differences in kinetic profiles. Results: All strains were susceptible to imipenem–relebactam, but resistant to ceftazidime (19/19) and ceftazidime-avibactam (18/19). KPC-2 and the D179N variant hydrolyzed imipenem, but the D179N variant's rate was much slower. The D179Y variant was unable to turnover imipenem. All three β-lactamases hydrolyzed ceftazidime at varying rates. The acylation rate of relebactam for the D179N variant was ~2.5× lower than KPC-2. Poor catalytic turnover by the D179Y variant precluded the determination of inhibitory kinetic parameters. Acyl-complexes with imipenem and ceftazidime were less prevalent with the D179N variant compared to the D179Y variant, supporting the kinetic observations that the D179Y variant was not as active as the D179N variant. Relebactam was slower to form an acyl-complex with the D179Y variant compared to avibactam. The D179Y model with imipenem revealed that the catalytic water molecule was shifted, and the carbonyl of imipenem was not within the oxyanion hole. Conversely in the D179N model, imipenem was oriented favorably for deacylation. Conclusions: Imipenem–relebactam overcame the resistance of the D179 variants, suggesting that this combination will be active against clinical isolates harboring these derivatives of KPC-2. [ABSTRACT FROM AUTHOR]

The role of β-lactamases in reduced susceptibility or resistance to cefiderocol has been supported by recent reports. The purpose of this study was to investigate the in vitro impact of clinically available β-lactamase inhibitors on cefiderocol activity against characterized carbapenemase-producing Gram-negative isolates. A collection of 39 well-characterized Gram-negative isolates obtained from various clinical sources and countries were included. Cefiderocol antimicrobial susceptibility was evaluated via reference broth microdilution. The chequerboard microdilution method and time–kill assays were used to determine the synergy of tazobactam, avibactam, vaborbactam and relebactam in combination with cefiderocol. MICs of cefiderocol presented a 4- to 256-fold reduction against Klebsiella pneumoniae carbapenemase (KPC)-producing Gram-negative isolates (predominantly K. pneumoniae) when avibactam, vaborbactam and relebactam were combined individually. Notably, the KPC-inhibitors led to a 4- to 32-fold reduction in cefiderocol MICs in the four cefiderocol-resistant KPC-producing K. pneumoniae isolates, showing restoration of cefiderocol susceptibility (MIC ≤ 2 mg/L) in ten out of twelve cases. Tazobactam led to a 4- to 64-fold decrease in cefiderocol MICs only in K. pneumoniae strains harbouring blaKPC-41, blaKPC-31, blaKPC-53 and blaKPC-66. The synergistic effect of all serine-β-lactamase inhibitors on cefiderocol activity was also shown in OXA-48-like-producing Enterobacterales strains. Conversely, a combination of β-lactamases inhibitors with cefiderocol was not synergistic with all OXA-23-like-producing strains and most metallo-β-lactamases producers. In conclusion, the addition of clinically available serine β-lactamase inhibitors to cefiderocol might represent an important development in the formulation to increase its spectrum and therapeutic efficacy, and to limit in vivo resistance emergence. [ABSTRACT FROM AUTHOR]

Purpose: Cefmetazole (CMZ), a cephamycin antibiotic, is primarily used as a definitive therapy for Extended Spectrum β-Lactamase (ESBL)-producing Escherichia coli infections. However, the mechanism of CMZ resistance in E. coli is still unknown. To elucidate the resistance mechanism and to determine combined drugs for prevention of resistance acquisition. Methods: Clinical isolates of 14 ESBL-producing E. coli and non-producing 12 isolates were used in in vitro testing of CMZ resistance acquisition. After 10-day of CMZ exposure (1st subculture), these strains were incubated in an antibacterial-free medium for 14-day. These strains were again exposed to CMZ for 10-day (2nd subculture) and confirmed for changes in MIC. For each strain detected after 1st subculture, each mRNA expression level of porin, chromosomal ampC, and drug-efflux pump was measured using real-time RT-PCR. Relebactam (REL) has the potency to recover antimicrobial activity against carbapenem-resistant Enterobacterales that has porin deficiency. REL was added to the CMZ dilution series, and MIC changes and those of porin were confirmed. Results: Of these 26 strains, 15 strains (57.7%) acquired resistance after 1st subculture, but after passage culture on the antibacterial-free medium, 11 strains recovered susceptibility. These 11 strains showed resistance after 2nd subculture. The expression levels of ompF and ompC were significantly decreased in these strains (P< 0.05). When REL was added, all strains suppressed resistance acquisition after 1st subculture. The mechanism was the activation of ompF. Conclusion: Our results showed that the mRNA expression levels of genes encoding porin were decreased in the strains that acquired resistance due to CMZ exposure, and that ompF and ompC in particular were thought to be involved in the acquisition of resistance. The CMZ acquisition of resistance was also suppressed by the concomitant use of REL and actually suppressed the decrease in mRNA expression in ompF. It was confirmed that porin reactivated by REL. [ABSTRACT FROM AUTHOR]

Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature. [ABSTRACT FROM AUTHOR]

The inoculum effect (IE) is a well-known phenomenon with beta-lactams. At the same time, the IE has not been extensively studied with carbapenem/carbapenemase inhibitor combinations. The antibiotic-to-inhibitor concentration ratio used in susceptibility testing can influence the in vitro activity of the combination. To explore the role of these factors, imipenem/relebactam and doripenem/relebactam MICs were estimated against six Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae strains at standard inocula (SI) and high inocula (HI) by two methods: with a fixed relebactam concentration and with a fixed, pharmacokinetic-based carbapenem-to-relebactam concentration ratio. The combination MICs at HI, compared to SI, increased with most of the tested strains. However, the IE occurred with only two K. pneumoniae strains regardless of the MIC testing method. The relationship between the MICs at SI and the respective inoculum-induced MIC changes was observed when the MICs were estimated at pharmacokinetic-based carbapenem-to-relebactam concentration ratios. Thus, (1) IE was observed with both carbapenem/relebactam combinations regardless of the MIC testing method; however, IE was not observed frequently among tested K. pneumoniae strains. (2) At HI, carbapenem/relebactam combination MICs increased to levels associated with carbapenem resistance. (3) Combination MICs determined at pharmacokinetic-based carbapenem-to-inhibitor concentration ratios predict susceptibility elevations at HI in KPC-producing K. pneumoniae. [ABSTRACT FROM AUTHOR]

Antibiotic-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Staphylococcus aureus, and Enterobacterales infections are serious global health problems, and class A β-lactamases are one mechanism that leads to antibiotic resistance. QPX7728, relebactam, and enmetazobactam are new β-lactamase inhibitors to combat β-lactam resistance. in silico approach was used in the current study to find which of the three inhibitors would be more effective for all class A β-lactamases and to reveal molecular insights into the differences between their binding energies. The mutations in conserved residues of the active sites of β-lactamases were defined using BLDB and Clustal Omega. FastME and MMseq2 were used for cluster and phylogeny analysis. 3D protein structure models for β-lactamases were built using SWISS-MODEL. ERRAT and Galaxy Web Server were used to verify 42 β-lactamase protein structures. QPX7728, relebactam, and enmetazobactam were docked to β-lactamases by using AutoDock 4.2. The TEM76-relebactam, CTX-M-81-relebactam, TEM-76-enmetazobactam, and CTX-M-200-enmetazobactam complexes were simulated by molecular dynamics method for 500 ns. Based on molecular docking results, relebactam and QPX7728 were more favorable inhibitors for serine A β-lactamases. A 2D representation of the interactions between ligands and β-lactamases showed that S235, hydrogen bonded with TEM-76, might play a role in inhibitor design. A 500-ns MD analysis of complexes indicated that distance from S70, stability in the enzyme active cavity, and high atomic displacement would account for a significant difference in inhibitor binding affinity. [ABSTRACT FROM AUTHOR]

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Background and Objectives: Imipenem/relebactam (IMP/R) is a newly FDA approved β-lactam/β-lactamase inhibitor combination. Relebactam ability to restore IMP activity could differ according to the cause of imipenem non-susceptibility. Therefore, we investigated the in-vitro activity of IMP/R against Klebsiella pneumoniae with different mechanisms of imipenem non-susceptibility. Materials and Methods: Imipenem-nonsusceptible (IMP-NS) K. pneumoniae isolates were collected and characterized for β-lactamase encoding genes by multiplex PCR. For IMP-NS carbapenemase-negative isolates, study of Ompk35 & Ompk36 gene expression was performed by reverse transcription-PCR while efflux pump activity was studied by minimum inhibitory concentration (MIC) reduction assay using efflux pump inhibitor. Susceptibility testing of K. pneumoniae to IMP and IMP/R were achieved by broth microdilution (BMD) method. Results: During the study period, 140 isolates of IMP-NS K. pneumoniae were collected. BMD method showed that relebactam restored IMP susceptibility in 100%, 60% and 49% of isolates that only harbor AmpC, extended spectrum beta lactamase (ESBL) and carbapenemases, respectively. IMP/R was most potent against all bla KPC and 50% of blaOXA-48 _producing isolates. No demonstrable activity of IMP/R against K. pneumoniae harboring metallo-β-lactamases (MBLs). Out of 18 isolates with IMP non-suceptibility due to porins loss with overproduction of ESBL and/or AmpC, 14 (77.7%) isolates were IMP/R susceptible. IMP/R showed no activity against isolates with only efflux pump hyperactivity. Conclusion: Relebactam could restore IPM activity in KPC or AmpC-producing IMP/NS K. pneumoniae but with no activity against MBL- producing isolates. Relebactam activity against isolates harbouring-bla OXA-48 or with altered Ompk35 & Ompk36 gene expression and efflux pump hyperactivity need further studies. Therefore, using IMP/R antibiotic in the treatment of infections caused by IMP/NS K. pneumoniae should be based on its molecular profile of IMP resistance to optimize the utility of IMP/R. [ABSTRACT FROM AUTHOR]

Recarbrio is a novel antibiotic approved by US-FDA. It was initially found to be useful in treating various resistant gram negative infections. A recent investigation revealed lack of methodological and scientific integrity behind the process of FDA approval for this drug. This incident is a lesson for us that we shall not consider FDA clearance as the gold standard before approving any drug in the Indian market or start using it before having adequate data from our own clinical settings. [ABSTRACT FROM AUTHOR]

Objective: This article critically evaluates common Pseudomonas aeruginosa resistance mechanisms and the properties newer β-lactam antimicrobials possess to evade these mechanisms.Data Sources: An extensive PubMed, Google Scholar, and ClinicalTrials.gov search was conducted (January 1995 to July 2020) to identify relevant literature on epidemiology, resistance mechanisms, antipseudomonal agents, newer β-lactam agents, and clinical data available pertaining to P aeruginosa.Study Selection and Data Extraction: Relevant published articles and package inserts were reviewed for inclusion.Data Synthesis: Therapeutic options to treat P aeruginosa infections are limited because of its intrinsic and acquired resistance mechanisms. The goal was to identify advances with newer β-lactams and characterize improvements in therapeutic potential for P aeruginosa infections.Relevance To Patient Care and Clinical Practice: Multidrug-resistant (MDR) P aeruginosa isolates are increasingly encountered from a variety of infections. This review highlights potential activity gains of newer β-lactam antibacterial drugs and the current clinical data to support their use. Pharmacists will be asked to recommend or evaluate the use of these agents and need to be aware of information specific to P aeruginosa, which differs from experience derived from Enterobacterales infections.Conclusions: Newer agents, including ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and cefiderocol, are useful for the treatment of MDR P aeruginosa infections. These agents offer improved efficacy and less toxicity compared with aminoglycosides and polymyxins and can be used for pathogens that are resistant to first-line antipseudomonal β-lactams. Selection of one agent over another should consider availability, turnaround of susceptibility testing, and product cost. Efficacy data specific for pseudomonal infections are limited, and there are no direct comparisons between the newer agents. [ABSTRACT FROM AUTHOR]

Ceftazidime–avibactam (CZA), meropenem–vaborbactam (MVB) and imipenem–relebactam (I–R) are combinations of old ß-lactams with novel non-ß-lactam ß-lactamase inhibitors (BLBLIs) able to inhibit some carbapenemases, such as the KPC-type, thus are becoming the standard for difficult-to-treat carbapenemase-producing Enterobacterales (CPE); a practical question is whether these novel BLBLIs should be used as monotherapy or as part of a combination regimen with other antibiotics, and if so, with which ones, to reduce the emergence of resistant strains and to optimize their efficacy. In this short review, we assessed clinical outcomes in patients with CPE-infections treated with the novel BLBLIs as mono- or combo-regimens, and laboratory studies on the synergistic effects with other antimicrobials. Available evidence on combination therapy is scarce and mainly limited to retrospective studies involving 630 patients treated with CZA: aminoglycosides were used in 39.6% of 336 patients treated with combo-regimens, followed by polymyxin B/colistin (24.4%), tigecycline (24.1%), carbapenems (13.4%) and fosfomycin (5.4%). Aminoglycosides could be useful in case of bloodstream and severe urinary infections. Pneumonia is a risk factor for CZA-resistance emergence: fosfomycin, due to favorable lung pharmacokinetics/pharmacodynamics, could represent an interesting partner; fosfomycin could be added also for osteomyelitis. Tigecycline could be preferred for intrabdominal and skin-soft tissue infections. Due to nephrotoxicity and lack of in vitro synergy, the association CZA/colistin seems not optimal. MVB and I–R were mostly used as monotherapies. Currently, there is no definitive evidence whether combinations are more effective than monotherapies; further studies are warranted, and to date only personal opinions can be provided. [ABSTRACT FROM AUTHOR]

The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single‐dose, double‐blind (relebactam only), randomized, placebo‐ and positive‐controlled, 3‐period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open‐label positive control), and IV placebo. Least squares mean and 2‐sided 90% confidence interval for change from baseline in population‐derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population‐derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150‐mg supratherapeutic dose (4.6‐fold above the 250‐mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a β‐lactamase inhibitor in antimicrobial therapy. [ABSTRACT FROM AUTHOR]

Imipenem‐cilastatin‐relebactam (IMI‐REL) is a novel β‐lactam–β‐lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β‐lactamase inhibitor with the ability to inhibit a broad spectrum of β‐lactamases such as class A and class C β‐lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem‐resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI‐REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem‐resistant bacteria. In a phase III trial comparing IMI‐REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30‐minute infusion of imipenem 500 mg–cilastatin 500 mg–relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI‐REL represents another important step in the ongoing fight against multidrug‐resistant gram‐negative pathogens. [ABSTRACT FROM AUTHOR]

Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes. Optimal treatment strategies for CRE infections continue to evolve. A lack of pediatric-specific comparative effectiveness data, uncertain pediatric dosing regimens for several agents, and a relative lack of new antibiotics with pediatric indications approved by the US Food and Drug Administration (FDA) collectively present unique challenges for children. In this review, we provide a framework for antibiotic treatment of CRE infections in children, highlighting relevant microbiologic considerations and summarizing available data related to the evaluation of FDA-approved antibiotics (as of September 2019) with CRE activity, including carbapenems, ceftazidime-avibactam, meropenem-vaborbactam, imipenem/cilastatin-relebactam, polymyxins, tigecycline, eravacycline, and plazomicin. [ABSTRACT FROM AUTHOR]

Objectives: Imipenem is one of the recommended β-lactams for the treatment of Mycobacterium abscessus pulmonary infections in spite of the production of BlaMab β-lactamase. Avibactam, a second-generation β-lactamase inhibitor, was previously shown to inactivate BlaMab, but its partner drug, ceftazidime, is devoid of any antibacterial activity against M. abscessus. Here, we investigate whether relebactam, a novel second-generation inhibitor developed in combination with imipenem, improves the activity of this carbapenem against M. abscessus.Methods: The impact of BlaMab inhibition by relebactam was evaluated by determining MICs, time-kill curves and M. abscessus intracellular proliferation in human macrophages. Kinetic parameters for the inhibition of BlaMab by relebactam were determined by spectrophotometry using nitrocefin as the substrate. The data were compared with those obtained with avibactam.Results: Combination of relebactam (4 mg/L) with β-lactams led to >128- and 2-fold decreases in the MICs of amoxicillin (from >4096 to 32 mg/L) and imipenem (from 8 to 4 mg/L). In vitro, M. abscessus was not killed by the imipenem/relebactam combination. In contrast, relebactam increased the intracellular activity of imipenem, leading to 88% killing. Relebactam and avibactam similarly potentiated the antibacterial activities of β-lactams although BlaMab was inactivated 150-fold less effectively by relebactam than by avibactam.Conclusions: Inhibition of BlaMab by relebactam improves the efficacy of imipenem against M. abscessus in macrophages, indicating that the imipenem/relebactam combination should be clinically considered for the treatment of infections due to M. abscessus. [ABSTRACT FROM AUTHOR]

Objectives: Imipenem/relebactam, an investigational β-lactam/β-lactamase inhibitor combination for treatment of Gram-negative infections, and comparators including ceftazidime/avibactam, piperacillin/tazobactam and colistin were tested for activity against representative carbapenemase-producing Enterobacteriaceae (CPE) isolates.Methods: MICs of the antimicrobial agents were determined using standard broth microdilution methodology for CPE isolates collected from Indiana patients, primarily during the time frame of 2013-17 (n = 199 of a total of 200 isolates). Inhibitors were tested at 4 mg/L in all combinations.Results: Of the CPE in the study, 199 produced plasmid-encoded KPC class A carbapenemases; 1 Serratia marcescens isolate produced the SME-1 chromosomal class A carbapenemase. MIC50/MIC90 values of imipenem/relebactam were ≤0.25/0.5 mg/L, whereas MIC50/MIC90 values of ceftazidime/avibactam were 1/2 mg/L. Resistance to colistin was observed in 54% (n = 97) of 180 non-Serratia isolates tested (MIC50 of 4 mg/L). Colistin resistance mechanisms included production of a plasmid-encoded mcr-1-like gene (n = 2) or an inactivated mgrB gene.Conclusions: Imipenem/relebactam was the most potent agent tested against CPE in this study and may be a useful addition to the antimicrobial armamentarium to treat infections caused by these pathogens. [ABSTRACT FROM AUTHOR]

Objectives: Relebactam is a diazabicyclooctane non-β-lactam inhibitor of Ambler class A and C β-lactamases that is in clinical development in combination with imipenem/cilastatin. The current study evaluated the in vitro activity of imipenem/relebactam against 5447 isolates of Pseudomonas aeruginosa submitted to the SMART global surveillance programme in 2015-17 by 67 clinical laboratories in 22 European countries.Methods: MICs were determined using the CLSI broth microdilution reference method (Eleventh Edition: M07, 2018). Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. MICs were interpreted using EUCAST clinical breakpoints (version 8.1); imipenem breakpoints were applied to imipenem/relebactam.Results: Rates of susceptibility to imipenem and imipenem/relebactam (MIC ≤4 mg/L) were 69.4% and 92.4%, respectively, for all isolates of P. aeruginosa. Over one-third of all isolates (34.9%, 1902/5447) were MDR; lower respiratory tract isolates (38.3%, 1327/3461) were more frequently MDR than were intraabdominal (28.5%, 355/1245) or urinary tract (29.7%, 212/714) isolates. Of all MDR isolates, 78.2% were susceptible to imipenem/relebactam, a rate that was 50-77 percentage points higher than the rate of susceptibility to imipenem or any other β-lactam tested; rates of susceptibility to imipenem/relebactam were similar for MDR isolates from lower respiratory tract (77.8% susceptible), intraabdominal (80.3%) and urinary tract (76.4%) infections. Overall, relebactam restored imipenem susceptibility to 75.2% (1254/1668) of imipenem-non-susceptible isolates of P. aeruginosa and to 69.6% (947/1361) of imipenem-non-susceptible isolates with an MDR phenotype.Conclusions: Relebactam restored in vitro susceptibility to imipenem for most imipenem-non-susceptible and MDR clinical isolates of P. aeruginosa from European patients. [ABSTRACT FROM AUTHOR]

Relebactam is a β-lactamase inhibitor of class A and class C β-lactamases, including carbapenemases. We evaluated the ability of relebactam to restore imipenem susceptibility against a collection of Klebsiella pneumoniae isolates from Greek hospitals. We tested 314 non-MBL carbapenemase-producing K. pneumoniae consecutive clinical strains isolated from unique patients at 18 hospitals in Greece, between November 2014 and December 2016. Susceptibility testing of imipenem, imipenem-relebactam, meropenem, doripenem, gentamicin, and colistin was performed using broth microdilution. Additionally, MICs of ceftazidime-avibactam, fosfomycin, and tigecycline were determined by MIC Test Strips. MICs were interpreted per EUCAST breakpoints. Imipenem-relebactam MICs were interpreted using the breakpoints proposed for imipenem. Carbapenemase genes were detected using PCR. Whole genome sequencing was performed for selected isolates. Imipenem-relebactam inhibited 98.0% of the KPC-producing isolates at ≤ 2 mg/L (MIC50/90, 0.25/1 mg/L) and was considerably more active than imipenem (MIC50/90, 32/> 64 mg/L). Reduced activity of imipenem-relebactam was rarely detected (2%) and was associated with chromosomal factors (ompK35 disruption and/or mutated ompK36). Only ceftazidime-avibactam showed in vitro activity comparable to imipenem-relebactam (99.6% susceptible). Relebactam provided only weak potentiation of imipenem activity against K. pneumoniae with class D OXA-48-like enzymes. Relebactam exhibited strong potential for restoring the in vitro activity of imipenem against KPC-producing K. pneumoniae, lowering the imipenem MIC50 and MIC90 from 32 to 0.25 mg/L, and from > 64 to 1 mg/L, respectively. Production of KPC carbapenemase represents the main cause of carbapenem resistance among K. pneumoniae in Greek hospitals (66.5%), and this carbapenemase appears to be very well inhibited by relebactam. [ABSTRACT FROM AUTHOR]

Background: Carbapenem-resistant Gram-negative bacteria are a major clinical concern as they cause virtually untreatable infections since carbapenems are among the last-resort antimicrobial agents. β-Lactamases implicated in carbapenem resistance include KPC, NDM, and OXA-type carbapenemases. Antimicrobial combination therapy is the current treatment approach against carbapenem resistance in order to limit the excessive use of colistin; however, its advantages over monotherapy remain debatable. An alternative treatment strategy would be the use of carbapenem/β-lactamase inhibitor (βLI) combinations. In this study, we assessed the in vitro and in vivo phenotypic and molecular efficacies of three βLIs when combined with different carbapenems against carbapenem-resistant Gram-negative clinical isolates. The chosen βLIs were (1) Avibactam, against OXA-type carbapenemases, (2) calcium-EDTA, against NDM-1, and (3) Relebactam, against KPC-2. Methods: Six Acinetobacter baumannii clinical isolates were screened for bla OXA-23-like, bla OXA-24/40, bla OXA-51-like, bla OXA-58, and bla OXA-143-like, and eight Enterobacteriaceae clinical isolates were screened for bla OXA-48, bla NDM-1, and bla KPC-2. The minimal inhibitory concentrations of Imipenem (IPM), Ertapenem (ETP), and Meropenem (MEM) with corresponding βLIs for each isolate were determined. The efficacy of the most suitable in vitro treatment option against each of bla OXA-48, bla NDM-1, and bla KPC-2 was assessed via survival studies in a BALB/c murine infection model. Finally, RT-qPCR was performed to assess the molecular response of the genes of resistance to the carbapenem/βLI combinations used under both in vitro and in vivo settings. Results: Combining MEM, IPM, and ETP with the corresponding βLIs restored the isolates' susceptibilities to those antimicrobial agents in 66.7%, 57.1%, and 30.8% of the samples, respectively. Survival studies in mice revealed 100% survival rates when MEM was combined with either Avibactam or Relebactam against bla OXA-48 and bla KPC-2, respectively. RT-qPCR demonstrated the consistent overexpression of bla OXA-48 upon treatment, without hindering Avibactam's activity, while bla NDM-1 and bla KPC-2 experienced variable expression levels upon treatment under in vitro and in vivo settings despite their effective phenotypic results. Conclusion: New carbapenem/βLI combinations may be viable alternatives to antimicrobial combination therapy as they displayed high efficacy in vitro and in vivo. Meropenem/Avibactam and Meropenem/Relebactam should be tested on larger sample sizes with different carbapenemases before progressing further in its preclinical development. [ABSTRACT FROM AUTHOR]

Novel β‐lactamase inhibitors have extended the reach of new and existing β‐lactams against multidrug‐resistant bacteria expressing β‐lactamases. The efficacy of these combination therapeutics relies on a complex two‐component pharmacodynamic (PD) system where the β‐lactamase inhibitor inactivates the bacterial β‐lactamase enzyme and frees the companion β‐lactam to act against its penicillin‐binding protein target. Despite considerable investigation into the pharmacokinetics (PK) and pharmacodynamics of β‐lactams, the pharmacology of their companion β‐lactamase inhibitors has only recently been rigorously explored. This review describes the diversity of β‐lactamase enzymes, mechanisms of enzyme inhibition, and factors impacting the efficacy of clinically available β‐lactamase inhibitors. Relevant PK differences among available inhibitors and the PK/PD properties of these agents are described independently of their companion β‐lactams. In the modern era of antibiotic resistance, a comprehensive understanding of the pharmacology, PK, and PD of β‐lactamase inhibitors is paramount to maximizing the therapeutic efficacy of existing β‐lactam/β‐lactamase inhibitor combinations and protecting novel agents in the drug development pipeline. [ABSTRACT FROM AUTHOR]

Carbapenems are considered as last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. With the increasing use of carbapenems in clinical practice, the emergence of carbapenem-resistant pathogens now poses a great threat to human health. Currently, antibiotic options for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) are very limited, with polymyxins, tigecycline, fosfomycin, and aminoglycosides as the mainstays of therapy. The need for new and effective anti-CRE therapies is urgent. Here, we describe the current understanding of issues related to CRE and review combination therapeutic strategies for CRE infections, including high-dose tigecycline, high-dose prolonged-infusion of carbapenem, and double carbapenem therapy. We also review the newly available antibiotics which have potential in the future treatment of CRE infections: ceftazidime/avibactam, which is active against KPC and OXA-48 producers; meropenem/vaborbactam, which is active against KPC producers; plazomicin, which is a next-generation aminoglycoside with in vitro activity against CRE; and eravacycline, which is a tetracycline class antibacterial with in vitro activity against CRE. Although direct evidence for CRE treatment is still lacking and the development of resistance is a concern, these new antibiotics provide additional therapeutic options for CRE infections. Finally, we review other potential anti-CRE antibiotics in development: imipenem/relebactam and cefiderocol. Currently, high-dose and combination strategies that may include the new β-lactam/β-lactamase inhibitors should be considered in severe CRE infections to maximize treatment success. In the future, when more treatment options are available, therapy for CRE infections should be individualized and based on molecular phenotypes of resistance, susceptibility profiles, disease severity, and patient characteristics. More high-quality studies are needed to guide effective treatment for infections caused by CRE. [ABSTRACT FROM AUTHOR]

Traditionally, the antibacterial activity of β-lactam antibiotics in the presence of β-lactamase inhibitors is determined at the fixed inhibitor concentration. This traditional approach does not consider the ratio of antibiotic-to-inhibitor concentrations achieved in humans. To explore whether an alternative pharmacokinetically based approach to estimate MICs in combinations is predictive of antimicrobial efficacy, the effects of imipenem and doripenem alone and in combination with relebactam were studied in time-kill experiments against carbapenemase-producing Klebsiella pneumoniae. The carbapenem-to-relebactam concentration ratios in time-kill assays were equal to the therapeutic 24-h area under the concentration-time curve (AUC) ratios of the drugs (1.5/1). The simulated levels of carbapenem and relebactam were equal to their concentrations achieved in humans. When effects of combined regimens were plotted against respective C/MICs, a sigmoid relationship was obtained only with MICs determined by pharmacokinetically based method. The effectiveness of both carbapenems in the presence of relebactam was comparable by the results of time-kill experiments. These findings suggest that (1) antibiotic/inhibitor MICs determined at a pharmacokinetically based concentration ratio allow an adequate assessment of carbapenem susceptibility in carbapenemase-producing K. pneumoniae strains and can be used to predict antibacterial effects; (2) in time-kill experiments, the effects of imipenem and doripenem in the presence of relebactam are comparable. [ABSTRACT FROM AUTHOR]

(1) Purpose of this study: determination of adsorption and transmembrane clearances (CLTM) of imipenem and relebactam in ex vivo continuous hemofiltration (CH) and continuous hemodialysis (CHD) models. These clearances were incorporated into a Monte Carlo Simulation (MCS), to develop drug dosing recommendations for critically ill patients requiring continuous renal replacement therapy (CRRT); (2) Methods: A validated ex vivo bovine blood CH and CHD model using two hemodiafilters. Imipenem/relebactam and urea CLTM at different ultrafiltrate/dialysate flow rates were evaluated in both CH and CHD. MCS was performed to determine dose recommendations for patients receiving CRRT; (3) Results: Neither imipenem nor relebactam adsorbed to the CRRT apparatus. The CLTM of imipenem, relebactam, and urea approximated the effluent rates (ultrafiltrate/dialysate flow rates). The types of hemodiafilter and effluent rates did not influence CLTM except in a dialysis flow rate of 1 L/h and 6 L/h in the CHD with relebactam (p < 0.05). Imipenem and relebactam 200 mg/100 mg every 6 h were sufficient to meet the standard time above the MIC pharmacodynamic targets in the modeled CRRT regimen of 25 kg/mL/h. (4) Conclusions: Imipenem and relebactam are not removed by adsorption to the CRRT apparatus, but readily cross the hemodiafilter membrane in CH and CHD. Dosage adjustment of imipenem/relebactam is likely required for critically ill patients receiving CRRT. [ABSTRACT FROM AUTHOR]

The growing emergence of drug-resistant bacterial strains is an issue to treat severe infections, and many efforts have identified new pharmacological agents. The inhibitors of β-lactamases (BLI) have gained a prominent role in the safeguard of beta-lactams. In the last years, new β-lactam–BLI combinations have been registered or are still under clinical evaluation, demonstrating their effectiveness to treat complicated infections. It is also noteworthy that the pharmacokinetics of BLIs partly matches that of β-lactams companions, meaning that some clinical situations, as well as renal impairment and renal replacement therapies, may alter the disposition of both drugs. Common pharmacokinetic characteristics, linear pharmacokinetics across a wide range of doses, and known pharmacokinetic/pharmacodynamic parameters may guide modifications of dosing regimens for both β-lactams and BLIs. However, comorbidities (i.e., burns, diabetes, cancer) and severe changes in individual pathological conditions (i.e., acute renal impairment, sepsis) could make dose adaptation difficult, because the impact of those factors on BLI pharmacokinetics is partly known. Therapeutic drug monitoring protocols may overcome those issues and offer strategies to personalize drug doses in the intensive care setting. Further prospective clinical trials are warranted to improve the use of BLIs and their β-lactam companions in severe and complicated infections. [ABSTRACT FROM AUTHOR]

Background Carbapenem-resistant Gram-negative bacteria are important nosocomial pathogens, and therapeutic options are often limited. Methods Clinical isolates were gathered during a surveillance study in 2017 involving 7 hospitals in Brooklyn, NY. Isolates underwent susceptibility testing using the agar dilution method; for the combination of imipenem-relebactam and ceftolozane-tazobactam, the concentrations of relebactam and tazobactam were fixed at 4 µg/mL. Breakpoints were defined according to CLSI criteria; for imipenem-relebactam, the breakpoint of imipenem was utilized. Isolates were screened by PCR for common carbapenemases. Results Overall susceptibility patterns are given in the Table. Of 1805 isolates of E. coli (including 4 with bla KPC), 100% were susceptible to imipenem and imipenem-relebactam. Of 503 isolates of K. pneumoniae (including 19 isolates with bla KPC), all were susceptible to imipenem-relebactam. Of 171 isolates of Enterobacter spp. (including 3 with bla KPC), 100% were susceptible to imipenem-relebactam. Of 260 isolates of P. aeruginosa , 96% were susceptible to imipenem-relebactam and nearly all to ceftolozane-tazobactam. Against A. baumannii , the activity of imipenem-relebactam was the same as imipenem and the ceftolozane-tazobactam MIC was ≤ 4 µg/mL in 65% of isolates. Conclusion Imipenem-relebactam possesses promising activity against multidrug-resistant Enterobacteriaceae endemic to New York City. Ceftolozane-tazobactam demonstrated excellent activity against P. aeruginosa , including isolates resistant to carbapenems. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new β-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) Acinetobacter clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam. Sulbactam/relebactam was able to restore sulbactam susceptibility in 40% of the isolates. In addition, the susceptibility testing using twenty-three A. baumannii AB5075 knockout strains revealed potential sulbactam and/or sulbactam/avibactam target genes. We observed that diazabicyclooctanes (DBOs) β-lactamase inhibitors combined with sulbactam restore sulbactam susceptibility against carbapenem-resistant Acinetobacter clinical isolates. However, relebactam was not as effective as avibactam when combined with sulbactam. Exploring novel combinations may offer new options to treat Acinetobacter spp. infections, especially for widespread oxacillinases and metallo-β-lactamases (MBLs) producers. [ABSTRACT FROM AUTHOR]

Background Drug resistance in Gram-negative bacteria is of particular concern in children. Relebactam, a novel diazabicyclooctane inhibitor, coupled with imipenem has broad-spectrum activity against β-lactamase producing organisms. Here, we compare the in vitro activity of imipenem-relebactam to 10 standard comparator drugs against resistant Gram-negative isolates from two US pediatric hospitals. Methods We tested 100 isolates (50 per site) from pediatric clinical specimens tested during 2015–2017. All isolates were extended-spectrum cephalosporin-resistant (ESC-R); more than half were multidrug resistant (67%). Selected ESC-R isolates included Escherichia coli (90), Klebsiella pneumoniae (8), Klebsiella oxytoca (1), and Enterobacter cloacae (1) that were resistant or intermediate to ≥1 cephalosporins and/or aztreonam. A 0.5 McFarland suspension was prepared from colonies grown on blood agar plates (Thermo Scientific) at 35 ± 1°C for 18–24 hours. A final inoculum of 5 × 105 CFU/mL was prepared in Mueller–Hinton broth. Sensititre plates (Thermo Fisher Scientific) containing graded concentrations of imipenem/relebactam and 10 comparator drugs were inoculated and incubated at 35 ± 1°C for 18–24 hours. The minimum inhibitory concentration (MIC) was determined using the Sensititre Vizion system (Thermo Fisher Scientific) and endpoints were interpreted using CLSI (2019) breakpoint criteria, with the exception of colistin (EUCAST 2019). Results Selected ESC-R isolates had high rates of resistance to cephalosporins (64%–97%), aztreonam (80%), and levofloxacin (61%). All isolates were susceptible to imipenem/relebactam, imipenem and meropenem (MIC, ≤1 μg/mL for all). The imipenem/relebactam MIC50 (0.06 μg/mL) and MIC90 (0.12 μg/mL) values for ESC-R isolates were within one dilution of MICs of imipenem alone (0.12 μg/mL and 0.25 μg/mL). Among the comparators, colistin, amikacin, and piperacillin/tazobactam demonstrated comparable activities with 100%, 99%, and 94% susceptibilities, respectively. Conclusion Meropenem, imipenem alone and in combination with relebactam exhibited 100% susceptibilities against ESC-R Enterobacteriaceae isolated from pediatric specimens, demonstrating the high potency of carbapenems. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

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) Methods Minimum 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 REL Results 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. Conclusion Addition 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. [ABSTRACT FROM AUTHOR]

Background Ceftolozane-tazobactam (C/T) is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor. The combination was cleared by FDA and EMA and is approved in the United States and over 60 countries worldwide. Relebactam (REL) is an inhibitor of class A and C β-lactamases that is in clinical development in combination with imipenem (IMI). Using clinical isolates collected in the United States as part of the global SMART surveillance program, we compared the activity of C/T and IMI/REL against P. aeruginosa (PA) isolates. Methods In 2016–2018, 29 clinical laboratories from the United States collected up to 250 consecutive, aerobic or facultatively anaerobic, gram-negative pathogens (GNP) from blood, intra-abdominal, urinary, and lower respiratory tract infections. A total of 14,606 GNP were collected, of which 2,774 were PA. MICs were determined using CLSI broth microdilution and interpreted with CLSI 2019 breakpoints; IMI breakpoints were used for IMI/REL. Results The activity of C/T and IMI/REL against 2,774 PA is shown (table). Among all PA, 1.8% of isolates were nonsusceptible (NS) to both agents; 4.4% were susceptible (S) to C/T but not to IMI/REL, and 2.9% were susceptible to IMI/REL but not to C/T. Among the subset of isolates collected from patients in ICUs (n = 827), 87.3% were susceptible to both C/T and IMI/REL, 2.7% were nonsusceptible to both agents, 5.8% of isolates were susceptible only to C/T, and 4.2% of isolates were susceptible only to IMI/REL. Among all C/T-NS isolates (all patient locations, n = 132), 61.4% were IMI/REL-S and <30% were susceptible to all other studied β-lactams and fluoroquinolones. Among all IMI/REL-NS isolates (n = 173), 70.5% were C/T-S and <36% were susceptible to all other studied β-lactams and fluoroquinolones. Of the tested agents, only amikacin and colistin exceeded the activity of C/T or IMI/REL against these NS subsets. Conclusion Resistance to C/T or IMI/REL was not common among recent clinical isolates of PA collected in the United States, and both agents promise to be important treatment options. A significant proportion of isolates nonsusceptible to one agent was susceptible to the other, especially among isolates from patients in ICUs. The data suggest that susceptibility to both agents should be tested at hospitals. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Although beta-lactam allergies are an emerging focus of stewardship programs and interventions, less is publicly released regarding allergies to beta-lactamase inhibitors. This review presents and evaluates the data regarding allergic reactions with beta-lactamase inhibitors. Clavulanate, sulbactam, and tazobactam are beta-lactam-based beta-lactamase inhibitors that are combined with several penicillins or cephalosporins in order to preserve antimicrobial activity in the presence of beta-lactamases. Avibactam, relebactam, and vaborbactam are non-beta-lactam beta-lactamase inhibitors that are combined with cephalosporins or carbapenems in order to expand the antimicrobial activity against broader-spectrum beta-lactamases. Case reports document hypersensitivity reactions to clavulanate, sulbactam, and tazobactam, but not to avibactam, relebactam, or vaborbactam. Based on these reports and considering the chemical structures, cross-allergenicity with beta-lactams is likely with sulbactam and tazobactam. Considering the slightly altered beta-lactam structure, cross-allergenicity is less likely with clavulanate, but still possible. It appears that cross-allergenicity between beta-lactam antimicrobials and the newer, non-beta-lactam beta-lactamase inhibitors is unlikely. It is important for clinicians to perform allergy testing to both the beta-lactam and the beta-lactamase inhibitor in order to confirm the specific allergy and reaction type. [ABSTRACT FROM AUTHOR]