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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]

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]

ABSTRACT With the introduction of ceftazidime-avibactam worldwide, the antimicrobial activity of new β-lactam/β-lactamase inhibitors (BL/BLIs) needs to be investigated. From January 2020 to June 2023, Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales were collected. With a broth microdilution test of new BL/BLIs, cross-activity test with nine combinations of BLs and new BLIs and dose-escalation titration test for non-susceptible isolates were conducted to investigate inhibitory activities of new BLIs. A total of 188 isolates was collected and most isolates (186/188, 98.9%) carried the KPC-2 gene exclusively, while two isolates (1.1%) co-harbored NDM-1. Among the 186 KPC-2-producing isolates, 184 (98.9%) were susceptible to ceftazidime-avibactam, 173 (93.0%) to imipenem-relebactam, and 184 (98.9%) to meropenem-vaborbactam. All isolates non-susceptible to imipenem-relebactam or meropenem-vaborbactam became susceptible when avibactam replaced relebactam or vaborbactam, with 7 of 11 (63.6%) imipenem-relebactam non-susceptible isolates and both (100.0%) of the meropenem-vaborbactam non-susceptible isolates. When the minimum inhibitory concentrations (MICs) of BLs were compared using log2 scales, combinations with avibactam showed statistically significant efficacy in lowering MICs compared to relebactam and vaborbactam (all P < 0.05). In the dose-escalation test of new BLIs, increasing dose of all new BLIs corresponded to increased susceptibility to BLs. Ceftazidime-avibactam exhibited excellent susceptibility against KPC-2-producing Enterobacterales unless co-harboring metallo-β-lactamase. The cross-combination test against non-susceptible isolates suggests that the inhibitory activity of avibactam was superior to those of relebactam or vaborbactam. Increasing the dose of new BLIs produced increased susceptibility to BLs, suggesting that high-concentration regimen need to be developed.IMPORTANCEThis study investigated 188 Klebsiella pneumoniae carbapenemase (KPC)-2-producing Enterobacterales collected from January 2020 to June 2023 in a tertiary care hospital of Korea. Most isolates were susceptible to ceftazidime-avibactam (98.9%) and meropenem-vaborbactam (98.9%), while susceptibility to imipenem-relebactam was lower (93.0%). The cross-combination test using nine combinations of the individual β-lactams (BLs) and new β-lactamase inhibitors (BLIs) showed that the inhibitory activity of avibactam was significantly superior to relebactam or vaborbactam when the Log2 MIC of BLs were compared for each combination with BLIs (all P < 0.05). The dose-escalation test of new BLIs demonstrated that increasing doses of new BLIs corresponded to increased susceptibility to BLs. Taken together, this study illustrates the excellent activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales and suggests further investigation into high-concentration regimens for potentially non-susceptible clinical isolates.

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]

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]

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.

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]

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 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.

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 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 The mechanism of resistance in carbapenem-resistant Enterobacteriaceae (CRE) has therapeutic implications. We comprehensively characterized emerging mechanisms of resistance in CRE between 2013 and 2016 at a health system in Northern California. A total of 38.7% (24/62) of CRE isolates were carbapenemase gene-positive, comprising 25.0% (6/24) bla OXA-48 like , 20.8% (5/24) bla KPC , 20.8% (5/24) bla NDM , 20.8% (5/24) bla SME , 8.3% (2/24) bla IMP , and 4.2% (1/24) bla VIM. Between carbapenemases and porin loss, the resistance mechanism was identified in 95.2% (59/62) of CRE isolates. Isolates expressing bla KPC were 100% susceptible to ceftazidime–avibactam, meropenem–vaborbactam, and imipenem–relebactam; bla OXA-48 like –positive isolates were 100% susceptible to ceftazidime–avibactam; and metallo β-lactamase–positive isolates were nearly all nonsusceptible to above antibiotics. Carbapenemase gene-negative CRE were 100% (38/38), 92.1% (35/38), 89.5% (34/38), and 31.6% (12/38) susceptible to ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam, and ceftolozane–tazobactam, respectively. None of the CRE strains were identical by whole genome sequencing. At this health system, CRE were mediated by diverse mechanisms with predictable susceptibility to newer β-lactamase inhibitors. Highlights • Lower than national CRE rate at this health care system located in Northern California. • KPC was not the predominant carbapenemase detected at this health care system. • Reduced porin protein levels were detected in CRE isolates by mass spectrometry. • CRE were predictably susceptible to ceftazidime–avibactam, imipenem–relebactam, and meropenem–vaborbactam. [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]

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.

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]

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]