Carbapenem-resistant Enterobacterales Infections Research Articles

Antibiotic Choice, Effectiveness, and Outcome Among Hospitalized Neonates with Gram-Negative Bloodstream Infection in India: A Prospective Cohort Study

Background: Neonatal sepsis is a leading cause of childhood mortality. Antimicrobial resistance complicates management in high burden countries, such as India. We sought to determine whether early use of microbiologically active antibiotics is associated with reduced mortality of neonatal Gram-negative (GN) bloodstream infections (BSI). Methods: Between May 2017 and July 2019, we recruited neonates with GN BSI admitted to three neonatal intensive care units in India. Antibiotic use, microbial data, and clinical outcomes were prospectively collected. We assessed the association between empiric therapy including an active agent, defined by in vitro susceptibility, and 30-day all-cause mortality using Cox proportional hazard models. Findings: Of 9303 neonates admitted over a 27-month period, 3107 (33%) had at least one blood culture; 263 (3%) had a GN BSI identified at a median 6 days of life (IQR 3-11). Among isolates, 196 were Enterobacterales with 73 (37%) identified as carbapenem-resistant Enterobacterales (CRE), and 46 were Acinetobacter species with 28 (61%) being carbapenem-resistant Acinetobacter species (CRAb). Overall, 52 infants received initial empiric therapy including colistin, which was active in most (169 of 263, 64%) instances, but a minority of patients with CRE (33 of 73, 45%) and CRAb (11 of 28, 39%) received an active agent. Initial use of active antibiotics was not associated with decreased 30-day mortality for CRE or CRAb infections. Interpretation: Early initiation of currently available, active antibiotics was not associated with lower mortality among neonates with GN BSI in a setting with a high burden of carbapenem-resistant organisms. Funding: U.S. Centers for Disease Control and Prevention Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was approved by the ethics committees of each participating hospital, the Johns Hopkins School of Medicine Institutional Review Board, and the Government of India Health Ministry Screening Committee.

Evaluating the clinical effectiveness of new beta-lactam/beta-lactamase inhibitor combination antibiotics: A systematic literature review and meta-analysis.

Ceftazidime/avibactam (C/A), ceftolozane/tazobactam (C/T), imipenem/relebactam (I/R), and meropenem/vaborbactam (M/V) combine either a cephalosporin (C/T and C/A) or a carbapenem antibiotic (M/V and I/R) with a β-lactamase inhibitor. They are used to treat carbapenem-resistant Enterobacterales (CRE) and/or multidrug-resistant Pseudomonas aeruginosa (MDRPA). We compared the pooled clinical success of these medications to older therapies. PubMed and EMBASE were searched from January 1, 2012, through September 2, 2020, for C/A, C/T, I/R, and M/V studies. The main outcome was clinical success, which was assessed using random-effects models. Stratified analyses were conducted for study drug, sample size, quality, infection source, study design, and multidrug-resistant gram-negative organism (MDRGNO) population. Microbiological success and 28- and 30-day mortality were assessed as secondary outcomes. Heterogeneity was determined using I2 values. Overall, 25 articles met the inclusion criteria; 8 observational studies and 17 randomized control trials. We detected no difference in clinical success comparing new combination antibiotics with standard therapies for all included organisms (pooled OR, 1.21; 95% CI, 0.96-1.51). We detected a moderate level of heterogeneity among the included studies I2 = 56%. Studies that focused on patients with CRE or MDRPA infections demonstrated a strong association between treatment with new combination antibiotics and clinical success (pooled OR, 2.20; 95% CI, 1.60-3.57). C/T, C/A, I/R, and M/V are not inferior to standard therapies for treating various complicated infections, but they may have greater clinical success for treating MDRPA and CRE infections. More studies that evaluate the use of these antibiotics for drug-resistant infections are needed to determine their effectiveness.

833. Characteristics and Utilization Patterns of Colistin Compared with Newer Agents in Gram-Negative Infections

BackgroundColistin has resurfaced in light of Gram-negative (GN) resistance. New antibiotics to treat antibiotic resistant GN infections (eg, ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam [new agents]), have recently been approved but their use vs colistin is unclear. We compared the overall use of colistin and new agents from 2014 to 2018 in patient days on therapy (PDOT).MethodsData on non-cystic fibrosis patients from the Premier Healthcare Database was used. PDOT was tabulated quarterly for Premier hospitals and projected to the US population. A subset of data from 2016 to 2018 with microbiologically confirmed GN (MCGN) infections was selected for adult inpatients receiving ≥3 days of therapy with colistin, new agents, carbapenems, or extended-spectrum cephalosporins. The index infection was defined either as the first carbapenem-resistant (CR) or -sensitive infection if no CR infection occurred. Patients could be treated with ≥1 antibiotic per infection. Utilization was examined by pathogen and patient characteristics.ResultsPDOT with colistin decreased from 2015 to 2018, while new agents have increased (Figure). During 2015–2018, colistin and any of 3 new agents were used by 3,320 and 5,781 inpatients, respectively, of whom, 649 (20%) and 1,284 (22%) had MCGN pathogens. Colistin-treated patients were sicker than patients treated with new agents (Table), underlying renal disease was present in 34.5% vs 36.3 %, and median length of stay of 17 vs 15 days, respectively. Mean total hospital cost was $93,815 vs $84,013 for colistin and new agents, respectively. Mortality was greater in colistin patients (18% vs 12%; p< 0.0001). CR infections constituted similar proportions of colistin and new agent use (79% vs 75%). Colistin accounted for 15.2% of CR Acinetobacter treatments and 9.7% of CR Enterobacterales (CRE) treatments compared with 4.5% and 12.8%, respectively, for new agents.Figure. Projected Inpatient PDOT Table. ConclusionColistin use has decreased simultaneously with the introduction and increased use of new agents in the USA. Colistin was used more frequently in sicker patients and for Acinetobacter spp. infections than for CRE infections. Patients on colistin have worse outcomes, probably due to baseline differences in their health status.DisclosuresStephen Marcella, MD, Shionogi Inc. (Employee) Casey Doremus, MS, Shionogi Inc. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

Evaluation of Intravenous Fosfomycin Disodium Dosing Regimens in Critically Ill Patients for Treatment of Carbapenem-Resistant Enterobacterales Infections Using Monte Carlo Simulation.

There are limited intravenous fosfomycin disodium (IVFOS) dosing regimens to treat carbapenem-resistant Enterobacterales (CRE) infections. This study aimed to use Monte Carlo simulation (MCS) for evaluation of IVFOS dosing regimens in critically ill patients with CRE infections. The dosing regimens in critically ill patients with various creatinine clearance were evaluated with MCS using minimum inhibitory concentration (MIC) distributions of fosfomycin against CRE clinical isolates in Thailand and the 24 h area under the plasma drug concentration–time curve over the minimum inhibitory concentration (AUC0-24/MIC) of ≥21.5 to be a target for IVFOS. The achieved goal of the probability of target attainment (PTA) and a cumulative fraction of response (CFR) were ≥90%. A total of 129 non-duplicated CRE clinical isolates had MIC distributions from 0.38 to >1024 mg/L. IVFOS 8 g every 8 h, 1 h, or 4 h infusion, could achieve approximately 90% PTA of AUC0-24/MIC target to treat CRE infections with MICs ≤ 128 mg/L. According to PTA target, an IVFOS daily dose to treat carbapenem-resistant Escherichia coli based on Clinical Laboratory Standards Institute (CLSI) breakpoints for urinary tract infections and one to treatment for CRE infections based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were 16 g/day and 8 g/day, respectively. All dosing regimens of IVFOS against CRE achieved CFR ≤ 70%. This study proposes the IVFOS dosing regimens based on CLSI and EUCAST breakpoints for the treatment of CRE infections. However, further clinical studies are needed to confirm the results of these findings.

In Vitro Pharmacodynamics of Fosfomycin against Carbapenem-Resistant Enterobacter cloacae and Klebsiella aerogenes.

The increase of carbapenem-resistant Enterobacterales (CRE) and lack of therapeutic options due to the scarcity of new antibiotics has sparked interest toward the use of intravenous fosfomycin against systemic CRE infections. We aimed to investigate the in vitro pharmacodynamics of fosfomycin against carbapenem-resistant Enterobacter cloacae and Klebsiella aerogenes Time-kill studies and population analysis profiles were performed with eight clinical CRE isolates, which were exposed to fosfomycin concentrations ranging from 0.25 to 2,048 mg/liter. The 24-h mean killing effect was characterized by an inhibitory sigmoid maximum effect (Emax) model. Whole-genome sequencing was performed to elucidate known fosfomycin resistance mechanisms. Fosfomycin MICs ranged from 0.5 to 64 mg/liter. The isolates harbored a variety of carbapenemase genes including blaIMP, blaKPC, and blaNDM Five out of eight isolates harbored the fosA gene, while none harbored the recently discovered fosL-like gene. Heteroresistant subpopulations were detected in all isolates, with two out of eight isolates harboring heteroresistant subpopulations at up to 2,048 mg/liter. In time-kill studies, fosfomycin exhibited bactericidal activity at 2 to 4 h at several fosfomycin concentrations (one isolate at ≥16 mg/liter, two at ≥32 mg/liter, two at ≥64 mg/liter, two at ≥128 mg/liter, and one at ≥512 mg/liter). At 24 h, bactericidal activity was only observed in two isolates (MICs, 0.5 and 4 mg/liter) at 2,048 mg/liter. From the Emax model, no significant bacterial killing was observed beyond 500 mg/liter. Our findings suggest that the use of fosfomycin monotherapy may be limited against CRE due to heteroresistance and rapid bacterial regrowth. Further optimization of intravenous fosfomycin dosing regimens is required to increase efficacy against such infections.

In vitro efficacy of ceftazidime-avibactam, aztreonam-avibactam and other rescue antibiotics against carbapenem-resistant Enterobacterales from the Arabian Peninsula

ObjectivesOur aim was to assess the susceptibility of carbapenem-resistant Enterobacterales (CRE) from the Arabian Peninsula to a broad spectrum of antibiotics, including fosfomycin, ceftazidime-avibactam, and aztreonam-avibactam. Methods1192 non-repeat CRE isolated in 2009–2017 from 33 hospitals in five countries of the Arabian Peninsula were tested. The minimum inhibitory concentration of 14 antibiotics was determined. Carbapenemase and 16S methylase genes were detected by PCR. Clonality was assessed by PFGE. ResultsThe highest rate of susceptibility was detected to aztreonam-avibactam (95.5%) followed by colistin (79.8%), fosfomycin (71.8%) and tigecycline (59.9%). Isolates co-producing two carbapenemases (12.4%) were the least susceptible. Aminoglycoside susceptibility was affected by the frequent production of a 16S methylase. Susceptibility to ceftazidime-avibactam was impacted by the high rate of metallo-beta-lactamase producers (46.3%), while aztreonam-avibactam resistance occurred mostly in clonally unrelated, carbapenemase non-producing Escherichia coli. ConclusionOf the currently available drugs: colistin, tigecycline, and ceftazidime-avibactam co-administered with aztreonam appear to be the most effective to treat CRE infections. However, the presence of non-clonal CRE isolates, in which avibactam does not lower the aztreonam MIC below the clinical breakpoint, is of notable concern. Based on the relatively high rate of fosfomycin susceptibility, it would be desirable to license parenteral fosfomycin in the region.

Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β-Lactamases.

Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward β-lactam antibiotics. The hydrolytic enzymes called β-lactamases are responsible for a large proportion of the resistance phenotype. β-Lactamase inhibitors (BLIs) can be administered in combination with β-lactam antibiotics to negate the action of the β-lactamases, thereby restoring activity of the β-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) β-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon–carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine β-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant Enterobacterales infections.

Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study

Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA. CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227. 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45-71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20-28) of these patients had died. Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales. National Institutes of Health.

A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales

PurposeIn the Phase III Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE), plazomicin was studied for the treatment of critically ill patients with infections caused by carbapenem-resistant Enterobacterales. Initial plazomicin dosing was guided by creatinine clearance (CrCl) and subsequent doses adjusted by therapeutic drug monitoring to achieve AUC0–24 exposures within a target range (210–315 mg∙h/L). We applied the Hartford nomogram to evaluate whether this clinical tool could reduce plazomicin troughs levels and increase the proportion of patients within the target AUC range. MethodsThirty-seven patients enrolled in cohorts 1 or 2 of CARE were eligible for analyses. Observed 10-hour concentrations after the initial dose were plotted on the Hartford nomogram to determine an eligible dosing interval group (q24h, q36h or q48h). On the basis of baseline CrCl, a 15- or 10-mg/kg dose was simulated with the nomogram-recommended dosing interval. The proportion of patients in each dosing interval group with a trough ≥3 mg/L (trough threshold associated with serum creatinine increases ≥0.5 mg/dL in product label) was quantified. Simulated interval-normalized AUC0–24 was compared with the target AUC range. FindingsAmong the 28 patients with a CrCl ≥60 mL/min, the nomogram recommended every-24-hour dosing in 61% and an extended-interval (q36h or q48h) in 39% of patients. For patients with a CrCl ≥30–59 mL/min (n = 9), the nomogram recommended every-24-hour dosing and an extended-interval in 22% and 78% of patients, respectively. Among both renal function cohorts, exposure simulation with the nomogram significantly reduced the proportion of patients with trough concentrations ≥3 mg/L (CrCl ≥60 mL/min cohort: 91% vs 9%, P < 0.001; CrCl ≥30–59 mL/min cohort, 100% vs 0%, P < 0.001). Relative to the observed mean (SD) AUC0–24 of 309 mg∙h/mL (96 mg∙h/mL), simulation of extended intervals resulted in a mean interval-normalized AUC0–24 of 210 mg∙h/mL (40 mg∙h/mL) in all patients eligible for an extended interval, resulting in a similar proportion (49% vs 54%) of patients within the target AUC0–24 range after the first dose. ImplicationsApplication of the Hartford nomogram successfully reduced the likelihood of elevated plazomicin trough concentrations while improving AUC exposures in these patients with carbapenem-resistant Enterobacterales infections.