Archive for March 5, 2016

Novel Aminoglycoside Resistance Transposons and Transposon-Derived Circular Forms Detected in Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

Antimicrobial Agents and Chemotherapy March 2016 V.60 N.3 P.1801-1818;

Nabil Karah, Chinmay Kumar Dwibedi, Karin Sjöström, Petra Edquist, Anders Johansson, Sun Nyunt Wai, and Bernt Eric Uhlin

aDepartment of Molecular Biology, Laboratory for Molecular Infection Medicine Sweden, and Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden

bDepartment of Clinical Microbiology and Laboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden

cUnit for Antibiotic Resistance and Respiratory Bacterial Infections, Public Health Agency of Sweden, Solna, Sweden

Acinetobacter baumannii has emerged as an important opportunistic pathogen equipped with a growing number of antibiotic resistance genes.

Our study investigated the molecular epidemiology and antibiotic resistance features of 28 consecutive carbapenem-resistant clinical isolates of A. baumannii collected throughout Sweden in 2012 and 2013. The isolates mainly belonged to clonal complexes (CCs) with an extensive international distribution, such as CC2 (n = 16) and CC25 (n = 7).

Resistance to carbapenems was related to blaOXA-23 (20 isolates), blaOXA-24/40-like (6 isolates), blaOXA-467 (1 isolate), and ISAba1-blaOXA-69 (1 isolate). Ceftazidime resistance was associated with blaPER-7 in the CC25 isolates.

Two classical point mutations were responsible for resistance to quinolones in all the isolates. Isolates with high levels of resistance to aminoglycosides carried the 16S rRNA methylase armA gene. The isolates also carried a variety of genes encoding aminoglycoside-modifying enzymes.

Several novel structures involved in aminoglycoside resistance were identified, including Tn6279, ΔTn6279, Ab-ST3-aadB, and different assemblies of Tn6020 and TnaphA6. Importantly, a number of circular forms related to the IS26 or ISAba125 composite transposons were detected.

The frequent occurrence of these circular forms in the populations of several isolates indicates a potential role of these circular forms in the dissemination of antibiotic resistance genes.



March 5, 2016 at 11:23 am

Comparison of Verona Integron-Borne Metallo-β-Lactamase (VIM) Variants Reveals Differences in Stability and Inhibition Profiles

Antimicrobial Agents and Chemotherapy March 2016 V.60 N.3 P.1377-1384

Anne Makena, Azer Ö. Düzgün, Jürgen Brem, Michael A. McDonough, Anna M. Rydzik, Martine I. Abboud, Ayşegül Saral, Ayşegül Ç. Çiçek, Cemal Sandalli, and Christopher J. Schofield

aChemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom

bDepartment of Genetics and Bioengineering, Gümüşhane University, Gümüşhane, Turkey

cDepartment of Biology, Coruh University, Artvin, Turkey

dDepartment of Medical Microbiology, Recep Tayyip Erdoğan University, Rize, Turkey

eDepartment of Biology, Recep Tayyip Erdoğan University, Rize, Turkey

Metallo-β-lactamases (MBLs) are of increasing clinical significance; the development of clinically useful MBL inhibitors is challenged by the rapid evolution of variant MBLs.

The Verona integron-borne metallo-β-lactamase (VIM) enzymes are among the most widely distributed MBLs, with >40 VIM variants having been reported. We report on the crystallographic analysis of VIM-5 and comparison of biochemical and biophysical properties of VIM-1, VIM-2, VIM-4, VIM-5, and VIM-38.

Recombinant VIM variants were produced and purified, and their secondary structure and thermal stabilities were investigated by circular dichroism analyses. Steady-state kinetic analyses with a representative panel of β-lactam substrates were carried out to compare the catalytic efficiencies of the VIM variants.

Furthermore, a set of metalloenzyme inhibitors were screened to compare their effects on the different VIM variants. The results reveal only small variations in the kinetic parameters of the VIM variants but substantial differences in their thermal stabilities and inhibition profiles.

Overall, these results support the proposal that protein stability may be a factor in MBL evolution and highlight the importance of screening MBL variants during inhibitor development programs.


March 5, 2016 at 11:22 am

β-Lactamase Characterization of Gram-Negative Pathogens Recovered from Patients Enrolled in the Phase 2 Trials for Ceftazidime-Avibactam: Clinical Efficacies Analyzed against Subsets of Molecularly Characterized Isolates

Antimicrobial Agents and Chemotherapy March 2016 V.60 N.3 P.1328-1335

Rodrigo E. Mendes, Mariana Castanheira, Leanne Gasink, Gregory G. Stone, Wright W. Nichols, Robert K. Flamm, and Ronald N. Jones

aJMI Laboratories, North Liberty, Iowa, USA

bAstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA

The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized β-lactam resistance mechanisms from complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials. Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MICs of ≥2 μg/ml (69 isolates) and nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥16 μg/ml were characterized for their narrow- and extended-spectrum β-lactamase (ESBL) content. Enterobacteriaceae (one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥2 and ≥16 μg/ml, respectively, were tested for carbapenemases. All cUTI E. coli had the lineage background investigated (ST131-like versus non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test of cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen positive). All screen-positive cUTI pathogens were CTX-M-producing E. coli, except for one E. cloacae isolate with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other β-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBL Enterobacteriaceae isolate was recovered at the baseline visit. When an ESBL Enterobacteriaceae isolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-like E. coli isolate was recovered at baseline, as when a non-ST131-like isolate was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.


March 5, 2016 at 11:21 am


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