Archive for May 7, 2017

Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing urinary tract and intraabdominal infections in Europe: report from an antimicrobial surveillance programme (2012–15)

Journal of Antimicrobial Chemotherapy May 2017 V.72 N.5

EDITOR’S CHOICE

Michael A. Pfaller; Matteo Bassetti; Leonard R. Duncan; Mariana Castanheira

Objectives:

To evaluate the in vitro activity of ceftolozane/tazobactam and comparators tested against European isolates of Enterobacteriaceae and Pseudomonas aeruginosa from hospitalized patients with urinary tract infection or intraabdominal infections.

Methods:

A total of 6553 Gram-negative organisms (603 P. aeruginosa and 5950 Enterobacteriaceae) were consecutively collected from 41 hospitals located in 17 European countries plus Israel and Turkey. The organisms were tested for susceptibility by broth microdilution methods and the results interpreted according to EUCAST and CLSI breakpoint criteria.

Results:

Ceftolozane/tazobactam [MIC50/90 0.25/1 mg/L; 93.5%/91.3% susceptible (S) (CLSI/EUCAST criteria)] and meropenem [MIC50/90 ≤0.06/≤0.06 mg/L; 98.1%/98.3% S (CLSI/EUCAST)] were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates, 1.9% were carbapenem resistant (CRE), 15.2% exhibited an ESBL non-CRE phenotype, 14.6% were MDR, 2.2% were XDR and <0.1% were pan-drug resistant (PDR). Whereas ceftolozane/tazobactam showed activity against ESBL non-CRE phenotype isolates (MIC50/90 0.5/8 mg/L), it lacked useful activity against strains with a CRE (MIC50/90 >32/>32 mg/L; 3.6% S) or PDR (MIC50 >32 mg/L; 0.0% S) phenotype. Ceftolozane/tazobactam was the most potent (MIC50/90 0.5/4 mg/L) β-lactam agent tested against P. aeruginosa isolates, inhibiting 91.7% at an MIC of ≤4 mg/L. P. aeruginosa exhibited high rates of resistance to cefepime (20.6%), ceftazidime (23.1%), meropenem (9.0%) and piperacillin/tazobactam (26.9%) (EUCAST criteria). Among these four P. aeruginosa resistant phenotypes, 61.3%–70.4% were susceptible to ceftolozane/tazobactam.

Conclusions:

Ceftolozane/tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than currently available cephalosporins and piperacillin/tazobactam when tested against Enterobacteriaceae.

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May 7, 2017 at 8:00 pm

In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria

Journal of Antimicrobial Chemotherapy May 2017 V.72 N.5

EDITOR’S CHOICE

David M. Livermore; Shazad Mushtaq; Marina Warner; Anna Vickers; Neil Woodford

Objectives:

Diazabicyclooctanes (DBOs) inhibit class A, class C and some class D β-lactamases. A few also bind PBP2, conferring direct antibacterial activity and a β-lactamase-independent ‘enhancer’ effect, potentiating β-lactams targeting PBP3. We tested a novel DBO, zidebactam, combined with cefepime.

Methods:

CLSI agar dilution MICs were determined with cefepime/zidebactam in a chequerboard format. Bactericidal activity was also measured.

Results:

Zidebactam MICs were ≤2 mg/L (mostly 0.12–0.5 mg/L) for most Escherichia coli, Klebsiella, Citrobacter and Enterobacter spp., but were >32 mg/L for Proteeae, most Serratia and a few E. coli, Klebsiella and Enterobacter/Citrobacter. The antibacterial activity of zidebactam dominated chequerboard studies for Enterobacteriaceae, but potentiation of cefepime was apparent for zidebactam-resistant isolates with class A and C enzymes, illustrating β-lactamase inhibition. Overall, cefepime/zidebactam inhibited almost all Enterobacteriaceae with AmpC, ESBL, K1, KPC and OXA-48-like β-lactamases at 1 + 1 mg/L and also 29 of 35 isolates with metallo-carbapenemases, including several resistant to zidebactam alone. Zidebactam MICs for 36 of 50 Pseudomonas aeruginosa were 4–16 mg/L, and the majority of AmpC, metallo-β-lactamase-producing and cystic fibrosis isolates were susceptible to cefepime/zidebactam at 8 + 8 mg/L. Zidebactam MICs for Acinetobacter baumannii and Stenotrophomonas maltophilia were >32 mg/L; potentiation of cefepime was frequent for S. maltophilia, but minimal for A. baumannii. Kill curve results largely supported MICs.

Conclusions:

Zidebactam represents a second triple-action DBO following RG6080, with lower MICs for Enterobacteriaceae and P. aeruginosa. Clinical evaluation of cefepime/zidebactam must critically evaluate the reliance that can be placed on this direct antibacterial activity and on the enhancer effect as well as β-lactamase inhibition.

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May 7, 2017 at 7:58 pm

REVIEW – DNA replication proteins as potential targets for antimicrobials in drug-resistant bacterial pathogens

Journal of Antimicrobial Chemotherapy May 2017 V.72 N.5

Erika van Eijk; Bert Wittekoek; Ed J. Kuijper; Wiep Klaas Smits

With the impending crisis of antimicrobial resistance, there is an urgent need to develop novel antimicrobials to combat difficult infections and MDR pathogenic microorganisms. DNA replication is essential for cell viability and is therefore an attractive target for antimicrobials. Although several antimicrobials targeting DNA replication proteins have been developed to date, gyrase/topoisomerase inhibitors are the only class widely used in the clinic. Given the numerous essential proteins in the bacterial replisome that may serve as a potential target for inhibitors and the relative paucity of suitable compounds, it is evident that antimicrobials targeting the replisome are underdeveloped so far. In this review, we report on the diversity of antimicrobial compounds targeting DNA replication and highlight some of the challenges in developing new drugs that target this process.

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May 7, 2017 at 7:57 pm

Antimicrobials and QT prolongation

Journal of Antimicrobial Chemotherapy May 2017 V.72 N.5

Jay W. Mason

Solithromycin, a ketolide/macrolide antibiotic, has recently been reported to be free of the expected QT-prolonging effect of macrolides. It appears that its keto substitution provides a structural basis for this observation, as the other two tested ketolides also have minimal QT effect.

Among non-cardiovascular therapies, antimicrobials probably carry the greatest potential to cause cardiac arrhythmias. This is a result of their propensity to bind to the delayed rectifier potassium channel, IKr, inducing QT prolongation and risk of torsades de pointes ventricular tachycardia, their frequent interference with the metabolism of other QT prolongers and their susceptibility to metabolic inhibition by numerous commonly used drugs.

Unfortunately, there is evidence that medical practitioners do not take account of the QT/arrhythmia risk of antimicrobials in their prescribing practices. Education on this topic is sorely needed. When a macrolide is indicated, a ketolide should be considered in patients with a QT risk.

PDF

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May 7, 2017 at 7:56 pm

Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature.

Clin Microbiol Infect. 2016 Dec 9. pii: S1198-743X(16)30610-3

Grabein B1, Graninger W2, Rodríguez Baño J3, Dinh A4, Liesenfeld DB5.

Author information

1 Department of Clinical Microbiology and Hospital Hygiene, Munich University Hospital, Munich, Germany.

2 Institute for Infectiology, Karl Landsteiner Society, Vienna, Austria.

3 Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitarios Virgen Macarena y Virgen del Rocío, Departamento de Medicina, Universidad de Sevilla-IBIS, Sevilla, Spain; Spanish Network for Research in Infectious Diseases, Instituto de Salud Carlos III, Madrid, Spain.

4 Infectious Disease Unit, R. Poincaré University Hospital, Garches, AP-HP, Versailles Saint Quentin University, Garches, France.

5 InfectoPharm Arzneimittel und Consilium GmbH, Heppenheim, Germany. Electronic address: david.liesenfeld@infectopharm.de

Abstract

OBJECTIVES:

We conducted a systematic review and meta-analysis to summarize the clinical evidence and usage patterns of intravenous fosfomycin from its development to the present time.

METHODS:

PubMed, the Cochrane Library and local journals were searched for relevant studies reporting aggregated data of intravenous fosfomycin use in adults and children, with no restrictions regarding study design. Single case reports were excluded. Data were systematically abstracted for all included studies. Clinical and microbiological efficacy from randomized controlled and comparative observational studies were synthesized using meta-analysis to calculate pooled effect sizes.

RESULTS:

In all, 128 studies on intravenous fosfomycin in 5527 patients were evaluated. Fosfomycin was predominantly used for sepsis/bacteraemia, urinary tract, respiratory tract, bone and joint, and central nervous system infections. No difference in clinical (OR 1.44, 95% CI 0.96-2.15) or microbiological (OR 1.28, 95% CI 0.82-2.01) efficacy between fosfomycin and other antibiotics was observed in comparative trials. The pooled estimate for resistance development during fosfomycin monotherapy was 3.4% (95% CI 1.8%-5.1%). Fosfomycin showed a favourable safety profile, with generally mild adverse events not requiring discontinuation of treatment. Included studies explored intravenous fosfomycin as an anti-staphylococcal agent in monotherapy and combination therapy, whereas studies from 1990 focused on combination therapy (fosfoymcin + β-lactams or aminoglycosides) for challenging infections frequently caused by multidrug-resistant organisms.

CONCLUSION:

Intravenous fosfomycin can play a vital role in the antibiotic armamentarium, given its long history of effective and safe use. However, well-designed randomized controlled trials are still desired.

PDF

http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(16)30610-3/pdf

May 7, 2017 at 2:55 pm

A Case of Septic Arthritis of the Shoulder Due to Yersinia enterocolitica with Review of the Literature.

Open Forum Infect Dis. 2014 Aug 2;1(2):ofu054

BRIEF REPORT

Chan J1, Gandhi RT1.

Author information

1 Infectious Diseases Division , Massachusetts General Hospital , Boston, MA.

Abstract

Yersinia enterocolitica infection rarely can cause extra-intestinal infections. We present a case of septic arthritis of the shoulder due to this organism in an elderly man with liver and cardiac disease. We review previously published cases of Y. enterocolitica septic arthritis, and discuss risk factors and management.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281793/pdf/ofu054.pdf

May 7, 2017 at 2:53 pm


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