KPC-producing Carbapenem-resistant Enterobacteriaceae Research Articles

An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of Meropenem-Vaborbactam.

Carbapenem-resistant gram-negative pathogens remain an urgent public health threat, and safe, effective treatment options are limited. Although several agents are now available to combat these infections, meropenem-vaborbactam was the first to combine a novel, cyclic, boronic acid-based, β-lactamase inhibitor with a carbapenem backbone. Vaborbactam emanated from a discovery program specifically designed to identify candidate β-lactamase inhibitors with biochemical, microbiologic, and pharmacologic properties optimized for use in conjunction with a carbapenem. Meropenem was selected as the ideal carbapenem given its broad-spectrum in vitro activity, well established safety profile, and proven efficacy in the treatment of serious gram-negative infections. The combination has demonstrated potent in vitro activity against resistant gram-negative pathogens, particularly KPC-producing Klebsiella pneumoniae (MIC50 values typically ≤ 0.06 mg/l). Importantly, the pharmacokinetic (PK) profiles of the two agents are well matched, and the approved optimized dosing regimen of 4 g every 8 h (Q8h) as a 3-h infusion provides reliable probability of target attainment against the majority of commonly encountered carbapenem-resistant Enterobacteriaceae (CRE). Robust in vitro and in vivo PK/pharmacodynamic (PD) data support the ability of this dosing regimen to achieve specified PK/PD targets for both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. This concerted effort into optimizing the PK and PD parameters of both the β-lactam and β-lactamase inhibitor alone and in combination contributed to the clinical success of meropenem-vaborbactam demonstrated in phase 3 trials in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections. As the use of meropenem-vaborbactam increases concomitantly with the prevalence of KPC-producing CRE, continued pharmacovigilance and antimicrobial stewardship efforts will be of upmost importance to ensure that these PK/PD efforts translate into improved patient outcomes.

Harnessing Next-Generation Sequence Technology to Elucidate Healthcare-Associated Infection Transmission Pathways

Background: Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant bacteria that persist in healthcare environments, particularly in wastewater reservoirs where they can pose risks for patients. Healthcare-associated outbreaks of carbapenemase-producing (CP) CRE can be propagated via a single bacterial strain and/or mobile genetic element (MGEs) harboring a carbapenemase gene. Unlike chromosomally encoded carbapenemases, CP-MGEs can rapidly facilitate the spread of these carbapenemase genes across bacterial strains. From July 2017 to December 2018, the Florida Department of Health in Orange County investigated an outbreak of patients colonized with various bacterial genera of CP-CRE carrying the Klebsiella pneumoniae carbapenemase gene (blaKPC), indicating a potential MGE reservoir. WGS was performed to identify transmission pathways and linked cases, beyond what traditional testing provides. Methods: We selected a subset of blaKPC-harboring isolates for WGS on short- and long-read platforms (MiSeq, PacBio, MinION) to achieve high quality, complete genome and plasmid assemblies. Laboratory, clinical, and epidemiological data were combined to identify possible transmission events, common sources, and common MGEs. Results: Eleven clinical isolates from 5 genera (Citrobacter, Enterobacter, Klebsiella, Morganella, Providencia, and Serratia), and 10 environmental isolates collected from the pharmacy and medication room, ICU, and patient rooms and comprising 4 genera (Citrobacter, Enterobacter, Klebsiella, and Serratia) underwent WGS. Although short-read WGS elucidated additional subsets of closely related strains, high genomic diversity was also observed within some species: Citrobacter freundii: 13,483 single-nucleotide variants (SNVs), 67% core genome; Enterobacter spp: 3–18,563 SNVs; 34%; and K. pneumoniae: 8–18,460 SNVs, 80%. Further analysis using long-read hybrid assemblies revealed 2 unique blaKPC-harboring plasmids. The first plasmid, pDHQP20145-KPC3 (50 kb), contained the blaKPC-3 gene and was detected in both patient and environmental isolates across 3 of the 5 sequenced genera. The second plasmid, pDHQP201745-KPC2 (180 kb), contained the blaKPC-2 gene, and was found across 2 CP-CRE genera isolated from both patients and the environment, including isolates from the medication room sink drain and a patient who received compounded oral medications. Conclusion: WGS identified 2 blaKPC-harboring plasmids, including pDHQP20145-KPC3, which was found across 3 genera of CP-CRE isolated from patients and the environment, supporting prolonged transmission of KPC-producing CRE in this facility, and a CP-MGE driving transmission. The rapid spread of emerging, potentially mobile, antimicrobial resistance has increased our need to further explore the genomic environment of promiscuous MGEs. WGS can contribute to infection control beyond traditional subtyping methods, such as pulsed-field gel electrophoresis (PFGE), as MGEs increasingly represent an important driver of transmission.Funding: NoneDisclosures: None

Meropenem–vaborbactam for adults with complicated urinary tract and other invasive infections

ABSTRACTIntroduction: Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat among uropathogens with significant morbidity and mortality. Meropenem–vaborbactam is a novel carbapenem and cyclic boronic acid-based beta-lactamase inhibitor combination with potent activity against subtypes of CRE.Areas covered: This article reviews mechanisms of carbapenem resistance, existing treatment options for CRE, and the current evidence to support the use of meropenem–vaborbactam for the treatment of infections caused by subtypes of CRE including complicated urinary tract infections.Expert commentary: Meropenem–vaborbactam is a superior treatment option for infections secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. It is associated with higher rates of treatment success and lower rates of toxicity than traditional agents and demonstrates a potentially higher barrier to acquired antimicrobial resistance than ceftazidime–avibactam. At present, meropenem–vaborbactam should be regarded as a preferred treatment option for invasive infections secondary to KPC-producing CRE.

Ex Vivo Characterization of Effects of Renal Replacement Therapy Modalities and Settings on Pharmacokinetics of Meropenem and Vaborbactam.

The combination product meropenem-vaborbactam, with activity against KPC-producing carbapenem-resistant Enterobacteriaceae, is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem-vaborbactam during continuous venovenous hemofiltration (CVVH). An ex vivo model was used to examine the effects of a matrix of operational settings. Vaborbactam did not adsorb to AN69 (acrylonitrile and sodium methallylsulfonate copolymer) ST100 (surface area, 1 m2) hemofilter; the mean (±standard deviation [SD]) meropenem adsorption was 9% (±1%). The sieving coefficients (mean ± SD) with AN69 ST100 and ST150 (surface area, 1.5 m2) filters ranged from 0.97 ± 0.16 to 1.14 ± 0.12 and from 1.13 ± 0.01 to 1.53 ± 0.28, respectively, for meropenem and from 0.64 ± 0.39 to 0.90 ± 0.14 and 0.78 ± 0.18 to 1.04 ± 0.28, respectively, for vaborbactam. At identical settings, vaborbactam sieving coefficients were 25% to 30% lower than for meropenem. Points of dilution, blood flow rates, or effluent flow rates did not affect sieving coefficients for either drug. However, doubling the effluent flow rate resulted in >50 to 100% increases in filter clearance for both drugs. Postfilter dilution resulted in 40 to 80% increases in filter clearance at a high effluent flow rate (4,000 ml/h), compared with ∼15% increases at a low effluent flow rate (1,000 ml/h) for both drugs. For all combinations of setting and filters tested, vaborbactam clearance was lower than that of meropenem by ∼20 to 40%. Overall, meropenem-vaborbactam is efficiently cleared in CVVH mode.

Clinical factors predicting persistent carriage of Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae among patients with known carriage

Information on the natural duration of carbapenem-resistant Enterobacteriaceae (CRE) carriage and factors associated with persistence of carriage is limited. To evaluate the clinical variables associated with persistent carriage of Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. Data for patients admitted between June 2015 and December 2016 who were identified as KPC-producing CRE carriers by either rectal swabs or clinical cultures were reviewed retrospectively. Patients with follow-up culture data for three months after initial acquisition were included. Regression models were used to evaluate the clinical variables associated with persistence of carriage. Of the 100 eligible patients, 50 patients (50%) experienced spontaneous decolonization within three months. Among the 50 patients (50%) who remained culture positive after three months, 26 patients carried KPC-producing CRE after six months. Multi-variable analysis revealed that re-admission [adjusted odds ratio (aOR) 9.96; 95% confidence interval (CI) 1.13-87.98; P=0.039], duration of hospitalization (aOR 1.03; 95% CI 1.01-1.05; P=0.003), positive clinical culture (aOR 6.26; 95% CI 1.28-30.54; P=0.023) and carbapenem use (OR 9.15; 95% CI 1.85-45.27; P=0.007) were predictive for persistent carriage after six months. The results suggest that patients with KPC-producing CRE in clinical specimens who are using carbapenem, particularly those with multiple and prolonged hospitalizations, are more likely to remain carriers after six months of initial acquisition. This information is useful for coordinating strategies for pre-emptive isolation by predicting the CRE carriage status appropriately, and ensuring active surveillance through risk factor stratification.

Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae.

ABSTRACTVaborbactam (formerly RPX7009) is a new beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of beta-lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with beta-lactamases cloned from various classes and a panel of Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent inhibitor of class A carbapenemases, such as KPC, as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to the potencies of vaborbactam in combination with other antibiotics against strains producing the KPC beta-lactamase. Consistent with broad-spectrum beta-lactamase inhibition, vaborbactam reduced the meropenem MICs for engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of extended-spectrum beta-lactamase production, class C beta-lactamase production, and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC had a minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency showed that vaborbactam at 8 μg/ml results in meropenem MICs of ≤2 μg/ml in the most resistant engineered strains containing multiple mutations. Vaborbactam is a highly active beta-lactamase inhibitor that restores the activity of meropenem and other beta-lactam antibiotics in beta-lactamase-producing bacteria, particularly KPC-producing carbapenem-resistant Enterobacteriaceae.

Rectal Swabs Are Suitable for Quantifying the Carriage Load of KPC-Producing Carbapenem-Resistant Enterobacteriaceae

It is more convenient and practical to collect rectal swabs than stool specimens to study carriage of colon pathogens. In this study, we examined the ability to use rectal swabs rather than stool specimens to quantify Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE). We used a quantitative real-time PCR (qPCR) assay to determine the concentration of the bla(KPC) gene relative to the concentration of 16S rRNA genes and a quantitative culture-based method to quantify CRE relative to total aerobic bacteria. Our results demonstrated that rectal swabs are suitable for quantifying the concentration of KPC-producing CRE and that qPCR showed higher correlation between rectal swabs and stool specimens than the culture-based method.