KPC-producing Enterobacteriaceae Research Articles

Carbapenem-resistance worldwide: a call for action - correspondence.

Carbapenem-resistance worldwide: a call for action - correspondence.

Submarine Outfalls of Treated Wastewater Effluents are Sources of Extensively- and Multidrug-Resistant KPC- and OXA-48-Producing Enterobacteriaceae in Coastal Marine Environment.

The rapid and ongoing spread of carbapenemase-producing Enterobacteriaceae has led to a global health threat. However, a limited number of studies have addressed this problem in the marine environment. We investigated their emergence in the coastal waters of the central Adriatic Sea (Croatia), which are recipients of submarine effluents from two wastewater treatment plants. Fifteen KPC-producing Enterobacteriaceae (nine Escherichia coli, four Klebsiella pneumoniae and two Citrobacter freundii) were recovered, and susceptibility testing to 14 antimicrobials from 10 classes showed that four isolates were extensively drug resistant (XDR) and two were resistant to colistin. After ERIC and BOX-PCR typing, eight isolates were selected for whole genome sequencing. The E. coli isolates belonged to serotype O21:H27 and sequence type (ST) 2795, while K. pneumoniae isolates were assigned to STs 37 and 534. Large-scale genome analysis revealed an arsenal of 137 genes conferring resistance to 19 antimicrobial drug classes, 35 genes associated with virulence, and 20 plasmid replicons. The isolates simultaneously carried 43–90 genes encoding for antibiotic resistance, while four isolates co-harbored carbapenemase genes blaKPC-2 and blaOXA-48. The blaOXA-48 was associated with IncL-type plasmids in E. coli and K. pneumoniae. Importantly, the blaKPC-2 in four E. coli isolates was located on ~40 kb IncP6 broad-host-range plasmids which recently emerged as blaKPC-2 vesicles, providing first report of these blaKPC-2-bearing resistance plasmids circulating in E. coli in Europe. This study also represents the first evidence of XDR and potentially virulent strains of KPC-producing E. coli in coastal waters and the co-occurrence of blaKPC-2 and blaOXA-48 carbapenemase genes in this species. The leakage of these strains through submarine effluents into coastal waters is of concern, indicating a reservoir of this infectious threat in the marine environment.

In vitro Combined Inhibitory Activities of β-Lactam Antibiotics and Clavulanic Acid Against bla KPC-2-Positive Klebsiella pneumoniae.

BackgroundThe spread of KPC-producing Enterobacteriaceae has triggered a global public health concern, with KPC-2-positive strains being the most prevalent in China. We hereby studied the in vitro combined inhibitory activities of three kinds of β-lactam antibiotics and clavulanic acid at different concentrations against blaKPC-2-positive Klebsiella pneumoniae to explore the antimicrobial characteristics of these combinations and alternative therapeutic regimens for infections caused by blaKPC-2-positive K. pneumoniae strains.Materials and MethodsIn this study, 153 clinically isolated blaKPC-2-positive K. pneumoniae strains from 19 provinces in China were collected from 2016 to 2018. Antimicrobial susceptibility testing of imipenem/clavulanic acid, meropenem/clavulanic acid, ceftazidime/clavulanic acid, and each antimicrobial agent alone was performed by broth microdilution technique according to the CLSI guidelines. The concentration ratios of β-lactam antibiotics to clavulanic acid were as follows: 1:1, 1:2, 1:4, 1:8, 1:16, 1:32. The antimicrobial susceptibility of the combinations was determined according to the breakpoints of Imipenem, meropenem, and ceftazidime established by the CLSI directives for Enterobacteriaceae.ResultsThe MICs of all three combinations gradually declined with increments in the proportion of clavulanic acid in the regimens, and the most significant decline in the MIC50 and MIC90 was seen in combinations at the concentration ratio of 1:1 (also 1:2 for meropenem/clavulanic acid). When the concentration of clavulanic acid was restricted to 4 mg/L, the susceptibility of more than 70% of the isolates to the regimens could be restored with imipenem MIC 2–4 mg/L, meropenem MIC 2–8 mg/L or ceftazidime MIC 8mg/L. However, the percentage decreased to 30 to 40% when the initial MIC level was higher.ConclusionThe highest combined inhibitory activity of β-lactam antibiotics/clavulanic acid at low concentration ratios against blaKPC-2-positive K. pneumoniae may offer a new way to optimize the effects of these antimicrobial regimens.

835. Comparison of the outcomes of patients with KPC and NDM-1-producing Enterobacteriaceae

BackgroundCarbapenemase-producing Enterobacteriaceae infections are associated with high mortality. We aimed to compare the clinical outcomes of patients with Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and those with New-Delhi-Metallo-beta-lactamase-1 (NDM-1)-producing Enterobacteriaceae.MethodsWe performed a retrospective cohort study of all adult patients (> 16 years old) with KPC or NDM-1-producing Enterobacteriaceae isolates in a 2,700-bed tertiary referral hospital in Seoul, South Korea between 2010 and 2019. Primary outcomes were infection within 30 days and 30-day mortality after the first isolation of KPC or NDM-1-producing Enterobacteriaceae.ResultsA total of 859 patients were identified during the study period. Of them, 475 (55%) were KPC group and 384 (45%) were NDM-1 group. KPC group tended to develop infection within 30 days after first isolation more frequently than NDM-1 group (31% vs. 26%; P = 0.07). Thirty-day mortality was significantly higher in KPC group compared to NDM-1 group (KPC, 17% (81/475) versus NDM-1, 9% (33/384), P < 0.001). Multivariate analysis revealed that APACHE II score (adjusted odds ratio [aOR], 1.12; P < 0.001), solid cancer (aOR, 2.56; P < 0.001), previous carbapenem therapy (aOR, 1.93; P = 0.004), development of infection of KPC or NDM-1-producing Enterobacteriaceae within 30 days (aOR, 2.63; P < 0.001), and KPC-producing Enterobacteriaceae (aOR, 1.62; P = 0.045) were independent risk factors for 30-day mortality.Table 1. Results of analyses of risk factors for 30-day mortality from initial positive culture date in patients with KPC or NDM-1- producing Enterobacteriaceae Figure 1. Kaplan–Meier survival estimates of patients with KPC or NDM-1-producing Enterobacteriaceae for 30-day mortality after first isolation: KPC (continuous line) versus NDM (dotted line). (log-rank test). ConclusionOur study suggests that KPC-producing Enterobacteriaceae is associated with poorer outcome compared to NDM-1-producing Enterobacteriaceae. Therefore, patients with KPC-producing Enterobacteriaceae colonization should be monitored carefully for development of infection, and appropriate antibiotics should be initiated as soon as possible.Disclosures All Authors: No reported disclosures

Simultaneous administration of imipenem/cilastatin/relebactam with selected intravenous antimicrobials, a stewardship approach

Imipenem/cilastatin/relebactam is a β-lactam/β-lactamase inhibitor that has been recently FDA approved for complicated intra-abdominal and urinary tract infections under the brand name Recarbrio®. It has activity against imipenem non-susceptible Pseudomonas species as well as KPC-producing Enterobacteriaceae. Optimization of PK/PD of antimicrobials particularly in critically-ill patients is essential, but unfortunately, is hindered by separate administration that requires significant resources. The objective of the study is to investigate the compatibility of Y-site administration of imipenem/cilastatin/relebactam with a wide range of antimicrobials. After admixture, physical characteristics, pH changes and turbidity were measured for each 2-drug combination at a time. With the exception of amphotericin B deoxycholate, and posaconazole, imipenem/cilastatin/relebactam was compatible with a variety of antimicrobial agents. The compatibility profile described, will facilitate incorporation into hospital protocols, contribute to therapy optimization and guide clinicians to avoid successive administration, consequently resulting in reduction of total infusion time, optimization of PK/PD, economizing nursing time and cost containment.

Risk factors for Healthcare-Associated Infections caused by KPC-producing Enterobacteriaceae: a case-control study

Objetivo: Evaluar los factores de riesgo para infecciones relacionadas con la asistencia sanitaria causadas por Enterobacteriaceae productoras de carbapenemas.Método: Este es un estudio retrospectivo de casos y controles que consistió en una muestra de 82 pacientes infectados y 164 controles, totalizando 246 pacientes. La recopilación de datos se realizó entre enero y mayo de 2017 mediante la búsqueda en el Sistema Automatizado de Control de Infecciones Hospitalarias y en los registros electrónicos de pacientes.Resultados: Pacientes previamente colonizados con microorganismos gramnegativos (OR: 10.7, 95% CI: 2-60, p=0.007), con cáncer (OR: 20.8, 95% CI: 4-120, p&lt;0.001), utilizando una catéter de doble luz (OR: 30.5, 95% CI: 2-382, p=0.008), con lesión por presión (OR: 136.2, 95% CI: 11- 1623, p&lt;0.001) y permanecer en la Unidad de Cuidados Intensivos (OR: 1.4, 95% CI: 1.2-1.6, p &lt;0.001) fueron más propensos a desarrollar infecciones causadas por Enterobacteriaceae productoras de carbapenemas que el grupo control. El área bajo la curva ROC mostró un buen rendimiento general (0,99; IC 95%: 0,992-0,998) del modelo de regresión logística final.Conclusión: La colonización previa, el cáncer, el uso de catéteres de doble luz, la lesión por presión y la estadía en la UCI fueron factores de riesgo muy importantes para la adquisición de infecciones en el entorno hospitalario. Objective: To evaluate the risk factors for healthcare-associated infections caused by Klebsiella pneumoniae carbapenemase producing Enterobacteriaceae. Method: This is a retrospective case-control study that consisted of a sample of 82 infected patients and 164 controls, totaling 246 patients. Data collection was performed between January and May 2017 through search in the Automated Hospital Infection Control System and in the electronic patient records.Results: Patients previously colonized with gram-negative microorganisms (OR: 10.7, 95% CI: 2-60, p=0.007), with cancer (OR: 20.8, 95% CI: 4-120, p&lt;0.001), using a double lumen catheter (OR: 30.5, 95% CI: 2-382, p=0.008), with pressure injury (OR: 136.2, 95% CI: 11- 1623, p&lt;0.001) and Intensive Care Unit stay (OR: 1.4, 95% CI: 1.2-1.6, p &lt;0.001) had a greater chance of developing Healthcare-associated Infections caused by KPC-producing Enterobacteriaceae than the control group. The area under the ROC curve showed a good overall performance (0.99, 95% CI: 0.992-0.998) of the final logistic regression model. Conclusion: Previous colonization, cancer, double lumen catheter use, pressure injury and ICU stay were very important risk factors for the acquisition of infections in the hospital environment.&#x0D;

490. High Prevalence of Rectal Carriage of blaKPC –Mediated Carbapenem-Resistant Enterobacteriaceae Among Community Food Handlers in Kuwait

BackgroundCarbapenemases are diverse enzymes which inactivate the carbapenems. KPC-producing carbapenemase-producing Enterobacteriaceae have disseminated to many regions in the world, however, anecdotal reports of KPC-producing CPE in some GCC countries excluding Kuwait. In this study we report the first emergence of the KPC producing CPE isolated from healthy food handlers in our community.MethodsRectal swabs were collected from 405 food handlers. Isolates were identified by VITEK 2 and their susceptibility to 21 antibiotics performed by MIC determination using Etest. Genes encoding carbapenemase production were characterized by PCR and clonality of isolates was determined by MLST.ResultsA total of 36 CPE were isolated from 31 participants, of which 15 (41.7%) were Escherichia coli and 8 (22.2%) Klebsiella pneumoniae. All isolates were susceptible to amikacin and tigecycline but an alarmingly high percentage (38.9%) were non-susceptible to colistin. A very high proportion of the CPE harbored blaKPC (58.3%), followed by blaOXA-48 (25%), blaNDM (5.6%) and blaVIM (2.8%). Carbapenemases were co-produced with ESBLs in 30.6% of the isolates. Sequencing of the KPC revealed that KPC-18 represented 45%, KPC-2 36% and KPC-29 18%. Considerable genetic diversity among the isolates was identified by MLST assays demonstrating the emergence of new clones. Five diverse new CPE clones were detected from three Bangladeshi citizens and 2 Indians.ConclusionOur finding demonstrates a relatively high colonization rate (8.9%) of healthy food handlers by CPE of which KPC-producing CPE were predominant; this is an unusual finding in Kuwait representing the first of such findings in our country and GCC.Disclosures All authors: No reported disclosures.

728. Activity of Eravacycline Against Contemporary Gram-Negative Clinical Isolates From New York City Hospitals

BackgroundAntibiotic-resistant Gram-negative bacteria, including KPC-producing Enterobacteriaceae and carbapenem-resistant A. baumannii, have been problematic hospital pathogens in NYC and other areas. Eravacycline (ERV), a fluorocycline antibiotic released in the USA in 2018, has demonstrated in vitro activity against many of these strains. We tested the activity of ERV against a recent collection of clinical isolates from NYC hospitals.MethodsFor a 3-month period in 2017, all unique patient isolates of E. coli, K. pneumoniae, Enterobacter spp., and A. baumannii were collected from 7 hospitals in Brooklyn, NY. MICs were performed by broth microdilution for ERV and Tigecycline (TGC) and agar dilution for other antibiotics according to CLSI methodology. Cephalosporin-resistant isolates were screened by PCR for common carbapenemases.ResultsThe susceptibility results for tetracycline and ERV are listed in the Table. Overall, 95% of the Enterobacteriaceae were inhibited by ≤ 0.5 μg/mL of ERV, the FDA-suggested breakpoint. Of 1,876 isolates of E. coli, 4 possessed KPC. ERV MICs for these 4 isolates were 0.125–0.25 μg/mL. Of 518 isolates of K. pneumoniae, 20 possessed KPC. The ERV MIC50 and MIC90 for these isolates were 1 and 1 μg/mL, respectively. Of 172 isolates of Enterobacter spp., 3 possessed KPC. ERV MICs for these 3 isolates were 0.5–1 μg/mL. Of 45 isolates of A. baumannii, 11 isolates possessed a carbapenemase (OXA23 in 8, OXA24 in 2, and KPC in 1). The ERV MIC50 and MIC90 for these isolates were 1 and 2 μg/mL, respectively. Overall, ERV MICs were two-fold lower than TGC MICs for A. baumannii.ConclusionERV possesses significant in vitro activity against contemporary clinical isolates of Enterobacteriaceae and A. baumannii from NYC, including many carbapenemase producing strains. Disclosures All authors: No reported disclosures.

Present and Future of Carbapenem-resistant Enterobacteriaceae (CRE) Infections.

Carbapenem-resistant Enterobacteriaceae (CRE) have become a public health threat worldwide. There are three major mechanisms by which Enterobacteriaceae become resistant to carbapenems: enzyme production, efflux pumps and porin mutations. Of these, enzyme production is the main resistance mechanism. There are three main groups of enzymes responsible for most of the carbapenem resistance: KPC (Klebsiella pneumoniae carbapenemase) (Ambler class A), MBLs (Metallo-ß-Lactamases) (Ambler class B) and OXA-48-like (Ambler class D). KPC-producing Enterobacteriaceae are endemic in the United States, Colombia, Argentina, Greece and Italy. On the other hand, the MBL NDM-1 is the main carbapenemase-producing resistance in India, Pakistan and Sri Lanka, while OXA-48-like enzyme-producers are endemic in Turkey, Malta, the Middle-East and North Africa. All three groups of enzymes are plasmid-mediated, which implies an easier horizontal transfer and, thus, faster spread of carbapenem resistance worldwide. As a result, there is an urgent need to develop new therapeutic guidelines to treat CRE infections. Bearing in mind the different mechanisms by which Enterobacteriaceae can become resistant to carbapenems, there are different approaches to treat infections caused by these bacteria, which include the repurposing of already existing antibiotics, dual therapies with these antibiotics, and the development of new ß-lactamase inhibitors and antibiotics.

Efficacy and Safety of Meropenem-Vaborbactam Versus Best Available Therapy for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Patients Without Prior Antimicrobial Failure: A Post Hoc Analysis.

IntroductionInfections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are associated with increased morbidity and high mortality. Meropenem–vaborbactam (MV) is a novel β-lactam/β-lactamase inhibitor combination active against KPC-producing Enterobacteriaceae. The aim of this post hoc analysis of the TANGO-II randomized controlled trial was to assess the efficacy of MV versus best available therapy (BAT) in the subgroup of patients without prior antimicrobial failure.MethodsThe primary outcome measure was clinical cure at the test of cure (TOC). Secondary outcome measures included (1) clinical cure at the end of therapy (EOT), (2) microbiological cure at TOC, (3) microbiological cure at EOT, and (4) 28-day all-cause mortality.ResultsFirst-line MV was associated with a 42.9% absolute increase in clinical cure rate at TOC (95% confidence intervals [CI] 13.7–72.1) in comparison with first-line BAT. A 49.3% absolute increase in clinical cure rate at EOT (95% CI 20.8–77.7), a 42.6% absolute increase in microbiological cure rate at EOT (95% CI 13.4–71.8), and a 36.2% absolute increase in microbiologic cure rate at TOC (95% CI 5.9–66.6) were also observed, in addition to a 29.0% absolute reduction in mortality (95% CI − 54.3 to − 3.7). Overall, fewer adverse events were observed in the MV group than in the BAT group.ConclusionMV was superior to BAT in the subgroup of patients with serious carbapenem-resistant Enterobacteriaceae (CRE) infections and no prior antimicrobial failure, with very high rates of clinical success, and was well tolerated. Post approval and real-world studies remain essential to clearly define the most appropriate population for early, empirical MV coverage, in accordance with antimicrobial stewardship principles.FundingThe Medicines Company.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-00981-y) contains supplementary material, which is available to authorized users.

In Vitro Effectiveness of Meropenem and Cefmetazole Combination Treatment Against KPC-2-Producing Enterobacteriaceae.

Purpose: Optimal treatment regimens are yet to be established for carbapenemase-producing Enterobacteriaceae (CPE). We assessed the in vitro efficacy of meropenem (MEM) and cefmetazole (CMZ) combination treatment against blaKPC-2-positive Enterobacteriaceae, in comparison with that of double-carbapenem therapy using ertapenem (ERT). Materials and Methods: We performed checkerboard assay for 10 blaKPC-2-positive clinical isolates and Klebsiella pneumoniae BAA-1705 (possessing blaKPC-2), with synergistic effect being defined by a fractional inhibitory concentration index of ≤0.5. Subsequently, we conducted time-kill assays using K. pneumoniae BAA-1705 with an initial inoculum of 104-107 colony forming unit (CFU)/mL. Bactericidal effect was defined as the reduction of initial bacterial count by ≥103 CFU/mL in 24 hr. Finally, we applied scanning electron microscopy to observe morphological changes induced by the combination of MEM and CMZ. Results: Checkerboard assays revealed a synergistic effect in 7 out of 11 blaKPC-2 -positive Enterobacteriaceae when the MEM and CMZ combination was used, and no effect when the MEM and ERT combination was used. The minimum inhibitory concentration of MEM decreased 4-8-fold when combined with CMZ. Time-kill assays with an initial inoculum of 5 × 105 CFU/mL revealed regrowth under the combination of MEM and ERT (0.25 × minimum inhibitory concentration [MIC] each), whereas the combination of 0.25 × MIC each of MEM and CMZ exhibited bactericidal effect. Scanning electron microscopy results demonstrated that the combination of 0.5 × MIC MEM and 0.5 × MIC CMZ facilitated bacterial cell lysis compared with each antibiotic alone. Conclusion: The combination therapy using MEM and CMZ potentially has bactericidal effect against KPC-producing Enterobacteriaceae.

1251. Contaminated Sinks May be an Environmental Source for Serial Transmission of Carbapenem-Resistant Enterobacteriaceae (CRE) to ICU Patients

BackgroundWe performed an investigation after noting an increase in hospital-onset (HO) KPC-producing Enterobacteriaceae (KPC-E) infections in patients admitted to a tertiary referral hospital in North Carolina.MethodsWe defined pre-outbreak (January 1, 2017–June 30, 2017), outbreak (July 1, 2017–October 31, 2017), and post-outbreak (November 1, 2017–March 31, 2018) phases. A clinical case was defined as any positive clinical culture for KPC-E. HO was defined as a positive clinical or surveillance culture collected on hospital day ≥3. Patients were mapped in space and time to inform targeted environmental sampling. Whole-genome sequencing (WGS) was performed on selected KPC K. pneumoniae environmental and patient isolates to determine relatedness.In October 2017, a CRE prevention bundle was implemented that included daily communication of CRE patient movement, increased audits/feedback of HCW compliance with hand hygiene, enhanced cleaning and disinfection in CRE rooms and high-risk units with bleach and UVC disinfection, and weekly rectal surveillance screens in four adult ICUs.Results0.67 clinical cases of KPC-E per month were observed during the pre-outbreak period compared with 3.75 clinical cases of KPC-E per month during the outbreak period. K. pneumoniae was the most common species (Figure 1). Mapping of patients revealed probable direct and indirect transmission between patients in multiple hospital units (Figure 2). three patients who were non-sequentially admitted to the same ICU room over a 12-week span acquired KPC K. pneumoniae (Figure 2). Environmental cultures from the in-room sink drain and P-trap grew KPC K. pneumoniae that was related to the patient isolates by WGS; the sink was removed. Although no additional clinical cases of KPC-E occurred after full implementation of the bundle and sink removal, we continued to observe acquisition of KPC-E rectal colonization in all four ICUs (Figure 3).ConclusionWe describe a multispecies outbreak of KPC-E that was mitigated through evidence-based CRE control measures and removal of a colonized sink. However, ongoing low-level presumed transmission of KPC points to persistent environmental sources. Additional study is needed to understand the prevalence of CRE in hospital sinks, factors that drive drain colonization, and contribution of CRE in a sink to nosocomial transmission. Disclosures All authors: No reported disclosures.

Dialysis drains as a possible source for carbapenem-resistant pathogens causing an ICU outbreak.

We describe a case series of patients colonized with KPC-producing Enterobacteriaceae related to dialysis drains at patient's bedside. The study was set at the intensive care unit (ICU) of a tertiary referral hospital. In March 2016, we discovered four ICU patients to be colonized with KPC-producing Enterobacteriaceae in routine screening. All of these patients had already received contact isolation, and all of them were treated with continuous veno-venous dialysis. Environmental examinations showed KPC-producing Enterobacteriaceae in dialysis drains in different ICU rooms and even in rooms not hosting KPC-colonized patients. Based on our findings, we suspected the dialysis drains as a reservoir of KPC-producing Enterobacteriaceae with a potential risk for the patients. Therefore, we decided to change the dialysis waste management. As a result, no KCP-producing Enterobacteriaceae were detected during the following weekly screening of the patients. Installation of dialysis connection units including a drain system at the patient's bedside is a comfortable way to provide water supply. In many ICUs, such dialysis drains are installed near the patients' head and directly besides the infusion systems. When the drains are not used properly, in our opinion, they pose a risk of transmission of pathogens from the drain to the patient. Our findings support the need of specific precautions.

Killing activity of meropenem in combination with amikacin against VIM- or KPC-producing Enterobacteriaceae that are susceptible, intermediate, or resistant to amikacin

Amikacin is administered with a carbapenem to treat serious infections caused by carbapenem-resistant Enterobacteriaceae (CRE). The varying degrees of activity of the individual agents correspond to differences in activity of the 2 in combination. Amikacin and meropenem are not bactericidal against amikacin-resistant CRE.

Meropenem-vaborbactam for the treatment of complicated urinary tract infections including acute pyelonephritis

ABSTRACTIntroduction: Meropenem-vaborbactam is a new beta-lactam/beta-lactamase inhibitor combination that combines a carbapenem antibiotic with a first-in-class, boronic acid pharmacophore, serine beta-lactamase inhibitor which has potent inhibitory activity against class A carbapenemases, especially Klebsiella pneumoniae carbapenemases (KPC), in addition to other class A and class C beta-lactamases. The US Food and Drug Administration has recently approved meropenem-vaborbactam for the treatment of adult patients with complicated urinary tract infections including acute pyelonephritis.Areas covered: A PubMed search was performed to gather the most current and relevant articles regarding meropenem-vaborbactam. In this review the authors discuss the chemistry, mechanism of action, pharmacokinetics, pharmacodynamics, antimicrobial spectrum, and efficacy and safety of meropenem-vaborbactam for the treatment of complicated urinary tract infections including acute pyelonephritisExpert opinion: Although meropenem-vaborbactam is approved for treatment for complicated urinary tract infections including acute pyelonephritis, it is unlikely, at this point, to be utilized widely beyond cases that are caused by KPC-producing Enterobacteriaceae. It may also be a potential treatment option for complicated urinary tract infections caused by KPC-producing Enterobacteriaceae that are resistant to ceftazidime-avibactam. Long-term safety data with this novel beta-lactamase inhibitor is still needed although early data suggests that it will be safe and well tolerated.

In Vitro Activity of Imipenem-Relebactam and Ceftolozane-Tazobactam against Resistant Gram-Negative Bacilli.

Understanding which antimicrobial agents are likely to be active against Gram-negative bacilli can guide selection of antimicrobials for empirical therapy as mechanistic rapid diagnostics are adopted. In this study, we determined the MICs of a novel β-lactam-β-lactamase inhibitor combination, imipenem-relebactam, along with ceftolozane-tazobactam, imipenem, ertapenem, meropenem, ceftriaxone, and cefepime, against 282 drug-resistant isolates of Gram-negative bacilli. For isolates harboring blaKPC (n = 110), the addition of relebactam to imipenem lowered the MIC50/MIC90 from 16/>128 μg/ml for imipenem alone to 0.25/1 μg/ml. For isolates harboring blaCTX-M (n = 48), the MIC50/MIC90 of ceftolozane-tazobactam were 0.5/16 μg/ml (83% susceptible). For isolates harboring blaCMY-2 (n = 17), the MIC50/MIC90 of ceftolozane-tazobactam were 4/8 μg/ml (47% susceptible). Imipenem-relebactam was active against most KPC-producing (but not NDM- or IMP-producing) Enterobacteriaceae and is an encouraging addition to the present antibiotic repertoire.

In vitro activity of meropenem combined with vaborbactam against KPC-producing Enterobacteriaceae in China.

Vaborbactam is a novel inhibitor of serine β-lactamases, including KPCs, which predominate in China. It is being developed in combination with meropenem. Using the broth microdilution method, the in vitro activity of meropenem/vaborbactam against 128 KPC-producing Enterobacteriaceae from China was investigated. Meropenem alone showed no activity (MIC50 and MIC90 >64 mg/L), but the addition of vaborbactam potentiated meropenem in a dose-dependent manner with MIC90 decreasing from >64 to 0.5 mg/L in the presence of increasing concentrations of vaborbactam. MIC50 and MIC90 of meropenem with 8 mg/L vaborbactam (MV8) were reduced to 0.5 and 8 mg/L, respectively. MV8 (4 mg/L meropenem) inhibited 76.6% of Klebsiella pneumoniae and 100% of Escherichia coli isolates. Seventy-three (77.7%) of the K. pneumoniae isolates belonged to ST11; the remaining 22.3% of isolates were represented by 12 different STs. Of the ST11 and non-ST11 isolates, 71.2% and 95.2%, respectively, were inhibited by MV8 (4 mg/L meropenem). In 14 strains characterized for intrinsic resistance mechanisms, MV8 MIC was increased in isolates with defects in both OmpK35 and OmpK36. The highest MV8 MIC was observed in the strain that had both non-functional porins and increased expression of blaKPC and acrB. Our findings suggest that meropenem/vaborbactam has good activity against KPC-producing Enterobacteriaceae from China. However, a higher percentage of K. pneumoniae isolates for which MV8 MIC was elevated compared with other geographical areas is noteworthy. This might be due to clonal dissemination of ST11 KPC-producing isolates that are defective in both major porins, OmpK35 and OmpK36.

Clearance of carbapenemase-producing Enterobacteriaceae (CPE) carriage: a comparative study of NDM-1 and KPC CPE

ObjectivesThe aim of this study was to compare clearance rates and related characteristics of patients carrying KPC-producing carbapenemase-producing Enterobacteriaceae (CPE) with those of patients carrying NDM-1-producing CPE. MethodsFrom November 2010 to October 2016, consecutive patients whose clinical or surveillance cultures yielded CPE were prospectively identified and followed in a 2700-bed tertiary referral hospital. CPE control protocols included strict single-room isolation, contact precautions and weekly surveillance cultures. CPE clearance was defined as three or more consecutive CPE-negative cultures without relapse. We compared patients carrying NDM-1 CPE and KPC and those with and without clearance. The time to CPE clearance or discharge was assessed using the Kaplan–Meier method and NDM-1 CPE and KPC CPE groups were compared. ResultsA total of 147 patients carrying CPE, 106 with NDM-1 and 41 with KPC, were included in the study. At the time of hospital discharge, 12 of the 106 patients carrying NDM-1 CPE were clear of CPE, whereas none of the KPC CPE patients were (NDM-1, 11.3% (12/106) versus KPC, 0% (0/41), p 0.02). There was no significant association between CPE clearance and factors such as an immunocompromised condition, antibiotic usage, or species of colonizing organism. Among 40 patients who were readmitted, CPE non-clearance was significantly higher in patients carrying KPC CPE (NDM-1, 36.7% (11/30) versus KPC, 80.0% (8/10), p 0.03). ConclusionsCompared with NDM-1 CPE patients, patients carrying KPC CPE had a significantly lower probability of clearance during hospitalization. Furthermore, KPC CPE carriage persisted for a substantial period of time following patient discharge.

Effect of Porins and blaKPC Expression on Activity of Imipenem with Relebactam in Klebsiella pneumoniae: Can Antibiotic Combinations Overcome Resistance?

Imipenem with relebactam is a novel β-lactam-β-lactamase inhibitor that has activity against most KPC-producing Enterobacteriaceae. Using 10 isolates of KPC-possessing Klebsiella pneumoniae, we assessed the relationship between imipenem-relebactam minimum inhibitory concentrations (MICs) and mechanisms known to contribute to antimicrobial resistance. The effect of adding a second agent was assessed by time-kill experiments. Mutations affecting the genes encoding porins ompK35 and ompK36 and identification of β-lactamases were assessed by PCR. Expression of blaKPC and acrB was assessed by real-time reverse-transcriptase (RT)-PCR, and production of OmpK36 by SDS-PAGE. Time-kill studies were performed using combinations of imipenem-relebactam with polymyxin B, amikacin, or tigecycline. Seven isolates having a disruption in a single porin, or in neither porin, remained susceptible to imipenem-relebactam. The addition of a second agent did not improve the activity of imipenem-relebactam for these isolates, although the addition of tigecycline was antagonistic for three isolates. Three isolates had major disruptions in both ompK35 and ompK36 that correlated with reduced activity of imipenem-relebactam (MICs 2/4, 8/4, and 512/4 μg/mL). Two of these isolates also had overexpression of blaKPC, including the isolate with the highest MIC. These isolates were also resistant to polymyxin B and amikacin. The addition of amikacin provided both synergistic and bactericidal activity for the two more resistant isolates. The activity of imipenem-relebactam against K. pneumoniae is affected by major disruptions of both ompK35 and ompK36 and by expression of the KPC gene. Combining imipenem-relebactam with an aminoglycoside may be a promising approach for isolates with reduced susceptibility to imipenem-relebactam.

Dissemination of KPC-2-Encoding IncX6 Plasmids Among Multiple Enterobacteriaceae Species in a Single Chinese Hospital.

Forty-five KPC-producing Enterobacteriaceae strains were isolated from multiple departments in a Chinese public hospital from 2014 to 2015. Genome sequencing of four representative strains, namely Proteus mirabilis GN2, Serratia marcescens GN26, Morganella morganii GN28, and Klebsiella aerogenes E20, indicated the presence of blaKPC-2-carrying IncX6 plasmids pGN2-KPC, pGN26-KPC, pGN28-KPC, and pE20-KPC in the four strains, respectively. These plasmids were genetically closely related to one another and to the only previously sequenced IncX6 plasmid, pKPC3_SZ. Each of the plasmids carried a single accessory module containing the blaKPC-2/3-carrying ΔTn6296 derivatives. The ΔTn6292 element from pGN26-KPC also contained qnrS, which was absent from all other plasmids. Overall, pKPC3_SZ-like blaKPC-carrying IncX6 plasmids were detected by PCR in 44.4% of the KPC-producing isolates, which included K. aerogenes, P. mirabilis, S. marcescens, M. morganii, Escherichia coli, and Klebsiella pneumoniae, and were obtained from six different departments of the hospital. Data presented herein provided insights into the genomic diversity and evolution of IncX6 plasmids, as well as the dissemination and epidemiology of blaKPC-carrying IncX6 plasmids among Enterobacteriaceae in a hospital setting.