Comparing the activity of broad-spectrum beta-lactams in combination with aminoglycosides against VIM-producing Enterobacteriaceae.

Metallo-beta-lactamase (MBL)-producing carbapenem-resistant Enterobacteriaceae (CRE) infections continue to pose a serious threat to healthcare. Due to their unique active site, MBLs evade the activity of many novel beta-lactam/beta-lactamase inhibitor combinations, which have been specifically targeted toward those carbapenemases with serine active sites. Furthermore, resistance to most, if not all, other clinically relevant antimicrobial classes leaves few reliable therapeutic options. Combination therapy has thus played a vital role in the treatment of MBL-producing CRE infections. In this study, we utilized the static time-kill assay to investigate clinically relevant concentrations of cefepime, piperacillin-tazobactam, and meropenem alone and in combination with either amikacin or the novel plazomicin to determine if combinations of routinely used beta-lactam therapy with an aminoglycoside would achieve bactericidal activity against eight clinically isolated Verona integron-encoded MBL (VIM)-producing CRE. Furthermore, we compared this activity to the combination of aztreonam/avibactam, which has shown potent activity against MBL-producing CRE. Both aztreonam/avibactam and meropenem with either aminoglycoside were rapidly bactericidal within 4 hours and remained bactericidal through 24 hours against all isolates with few exceptions. Combinations including cefepime and piperacillin-tazobactam were also rapidly bactericidal, but activity after 24 hours was inconsistent depending upon the partner aminoglycoside and isolate. Further investigation is warranted to elucidate optimal antibiotic exposures against MBL-producing CRE, including novel agents in the pipeline.IMPORTANCECarbapenem-resistant Enterobacterales (CRE) are one of the most pressing antimicrobial-resistant threats at present. In addition to exhibiting resistance to many, if not all, commonly used antimicrobial agents, CRE achieves these resistant phenotypes through a variety of mechanisms, each of which can uniquely affect available treatment options. The present study is an in vitro investigation of several Verona integron-encoded metallo-beta-lactamase (VIM)-producing CRE isolated from patients at our academic medical center. Because metallo-beta-lactamases (MBLs) are inherently resistant to many of the novel treatments designed to treat CRE due to their different active site composition, we tested several antimicrobial combinations containing routinely utilized broad-spectrum beta-lactams and aminoglycosides. Our results further our understanding of combination therapy options against VIM-producing CRE, including with non-carbapenem-beta-lactams cefepime and piperacillin. By optimizing combinations of existing antimicrobial agents, we hope to expand the available armamentarium against these resistant pathogens.

Changing times: The impact of gram-negative breakpoint changes over the previous decade.

We assessed breakpoint changes of 13,101 Enterobacterales and Pseudomonas aeruginosa isolates from the past decade. All ß-lactams and fluoroquinolones demonstrated decreased susceptibilities following breakpoint changes. Enterobacter cloacae experienced the largest average decrease in susceptibility amongst the Enterobacterales at 5.3% and P. aeruginosa experienced an average decrease in susceptibility of 9.3%.

Time Above All Else: Pharmacodynamic Analysis of ß-Lactams in Critically Ill Patients.

ß-Lactams are the most commonly used antibiotics in intensive care units (ICUs). As critically ill patients often experience pharmacokinetic aberrations, and rates of antimicrobial resistance vary between hospital settings, reliance on tertiary sources or package labeling to guide empiric dosing often results in suboptimal ß-lactam exposure. The primary objective was to identify ß-lactam regimens capable of achieving ≥90% cumulative fraction of response (CFR) against 7 Gram-negative pathogens within 4 ICUs at our institution. Unit-specific minimal inhibitory concentration (MIC) distribution data was used in combination with published pharmacokinetic parameters in critically ill patients to perform Monte Carlo simulations. The percentage of time for which the unbound concentration of antibiotic remained above the MIC (%ƒT > MIC) was used as the pharmacodynamic target: 70%ƒT >MIC for cefepime, 40%ƒT > MIC for meropenem, and 50%ƒT > MIC for piperacillin/tazobactam. Regimens were modeled to determine the likelihood of achieving ≥90% CFR. Overall, intermittently dosed cefepime, meropenem, and piperacillin/tazobactam failed to achieve ≥90% CFR for every organism. Cefepime 2 g intermittent bolus every 8 hours failed to achieve ≥90% CFR for Klebsiella pneumoniae or Enterobacter cloacae despite susceptibility rates exceeding 90%. Piperacillin/tazobactam 4.5 g prolonged infusion (PI) every 6 hours achieved <85% CFR for Pseudomonas aeruginosa and <50% CFR for Acinetobacter baumannii in every ICU. Meropenem 2 g PI every 8 hours and meropenem 2 g PI every 6 hours were the only regimens capable of achieving ≥90% CFR for P aeruginosa in all units. Use of Monte Carlo simulations, with incorporation of local MIC distribution data, provides a mechanism to effectively predict optimal agent and dose selection within specific hospital systems, thereby enhancing pharmacokinetic/pharmacodynamic optimization and improving clinical efficacy.

In vitro activity of eravacycline compared with tigecycline against carbapenem-resistant Enterobacteriaceae.

Eravacycline has been shown to have broad-spectrum activity against Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). We compared the activity of eravacycline with that of tigecycline in CRE isolates cultured from patients at an academic medical centre. Eravacycline was more potent than tigecycline [mean minimum inhibitory concentration (MIC) ratio = 0.76, 95% confidence interval 0.66-0.87]; however, the MIC90 observed for eravacycline was higher than previously reported at 4 µg/mL. Future studies are necessary to elucidate the mechanism driving this difference.

Plazomicin: a new aminoglycoside in the fight against antimicrobial resistance.

OBJECTIVE: To review the mechanism of action, mechanisms of resistance, in vitro activity, pharmacokinetics, pharmacodynamics, and clinical data for a novel aminoglycoside. DATA SOURCES: A PubMed search was performed from January 2006 to August 2019 using the following search terms: plazomicin and ACHN-490. Another search was conducted on clinicaltrials.gov for published clinical data. References from selected studies were also used to find additional literature. STUDY SELECTION AND DATA EXTRACTION: All English-language studies presenting original research (in vitro, in vivo, pharmacokinetic, and clinical) were evaluated. DATA SYNTHESIS: Plazomicin has in vitro activity against several multi-drug-resistant organisms, including carbapenem-resistant Enterobacteriaceae. It was Food and Drug Administration (FDA) approved to treat complicated urinary tract infections (cUTIs), including acute pyelonephritis, following phase II and III trials compared with levofloxacin and meropenem, respectively. Despite the FDA Black Box Warning for aminoglycoside class effects (nephrotoxicity, ototoxicity, neuromuscular blockade, and pregnancy risk), it exhibited a favorable safety profile with the most common adverse effects being decreased renal function (3.7%), diarrhea (2.3%), hypertension (2.3%), headache (1.3%), nausea (1.3%), vomiting (1.3%), and hypotension (1.0%) in the largest in-human trial. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Plazomicin will likely be used in the treatment of multi-drug-resistant cUTIs or in combination to treat serious carbapenem-resistant Enterobacteriaceae infections. CONCLUSIONS: Plazomicin appears poised to help fill the need for new agents to treat infections caused by multi-drug-resistant Enterobacteriaceae.

In vitro activity of plazomicin compared to other clinically relevant aminoglycosides in carbapenem-resistant Enterobacteriaceae.

We evaluated the in vitro activity of plazomicin against other aminoglycosides in 122 clinical carbapenem-resistant Enterobacteriaceae isolates using several clinical susceptibility breakpoints. Plazomicin had excellent in vitro activity with 98% overall susceptibility. Amikacin was the next most active with 86% overall susceptibility. This dropped to 55% when switching from Clinical Laboratory and Standards Institute to US Committee on Antimicrobial Susceptibility Testing breakpoints.

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.

Staggering the administration of polymyxin B and meropenem in time-kill against carbapenem-resistant Enterobacteriaceae exhibiting a wide range of meropenem MICs.

Little is known regarding the appropriate timing and sequencing of a carbapenem and polymyxin in combination against carbapenem-resistant Enterobacteriaceae. Meropenem and polymyxin B were administered simultaneously or 1 agent 2 h prior to the other, in vitro. The carbapenem should be administered prior to the polymyxin when used in combination.

Compound-Specific Isotope Analyses to Assess TCE Biodegradation in a Fractured Dolomitic Aquifer.

The potential for trichloroethene (TCE) biodegradation in a fractured dolomite aquifer at a former chemical disposal site in Smithville, Ontario, Canada, is assessed using chemical analysis and TCE and cis-DCE compound-specific isotope analysis of carbon and chlorine collected over a 16-month period. Groundwater redox conditions change from suboxic to much more reducing environments within and around the plume, indicating that oxidation of organic contaminants and degradation products is occurring at the study site. TCE and cis-DCE were observed in 13 of 14 wells sampled. VC, ethene, and/or ethane were also observed in ten wells, indicating that partial/full dechlorination has occurred. Chlorine isotopic values (δ37 Cl) range between 1.39 to 4.69‰ SMOC for TCE, and 3.57 to 13.86‰ SMOC for cis-DCE. Carbon isotopic values range between -28.9 and -20.7‰ VPDB for TCE, and -26.5 and -11.8‰ VPDB for cis-DCE. In most wells, isotopic values remained steady over the 15-month study. Isotopic enrichment from TCE to cis-DCE varied between 0 and 13‰ for carbon and 1 and 4‰ for chlorine. Calculated chlorine-carbon isotopic enrichment ratios (ϵCl /ϵC ) were 0.18 for TCE and 0.69 for cis-DCE. Combined, isotopic and chemical data indicate very little dechlorination is occurring near the source zone, but suggest bacterially mediated degradation is occurring closer to the edges of the plume.

Initial experience using an endoscopic simulator to train surgical residents in flexible endoscopy in a community medical center residency program.

INTRODUCTION: The importance of training surgical residents in GI endoscopy has been recognized for years. Despite advice from SAGES and the RRC, few programs have managed to incorporate effective flexible endoscopy training into their curriculum, making it difficult for their graduates to be credentialed in GI endoscopy. Prior to October 2001, our residents obtained their entire clinical experience in the endoscopy unit with staff surgical endoscopists. Attendance was inconsistent because of their many other responsibilities, and residents often used much of their clinical endoscopic exposure gaining basic familiarity with the equipment, precluding the development of therapeutic facility. Since October 2001, we have used the Simbionix endoscopic simulator to supplement resident training in GI endoscopy. With the advent of virtual-reality simulators, and studies validating their effectiveness in teaching fundamental technical skills, we report our initial success in implementing a formal GI endoscopy curriculum using a virtual reality endoscopic simulator to provide basic experience before the clinical endoscopic experience begins. METHODS: Residents are given monthly assignments of simulated cases on the GI Mentor simulator. Junior residents complete the diagnostic case modules; senior residents complete the therapeutic modules. Data were accumulated over the course of two years with a total of five PGY-I and eight senior surgical residents completing assigned cases on the simulator. Objective criteria were measured from their performance on the simulator to determine the efficiency of the examination for each case completed. RESULTS: Preliminary data collected over the course of two years indicates that residents improve the efficiency of their endoscopic examinations over time as measured by objective criteria. Junior surgery residents attained an aggregate average of 59% efficiency in their examinations whereas senior surgical residents who had previous experience with the simulator, attained an aggregate efficiency of 80%. CONCLUSIONS: A formal flexible endoscopy curriculum enhances surgical resident training and positively impacts careers in general and gastrointestinal surgery. Endoscopic simulators allow surgical residents to master the technical aspects of GI endoscopy quickly, thereby permitting them more benefit from their clinical exposure in the endoscopy unit. We anticipate that our formal curriculum in GI endoscopy training will prepare our graduates well for careers that include flexible endoscopy as a component of their clinical practices, and position them to be credentialled in GI endoscopy upon graduation.