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A double ampC (AmpC G183D ) and ampD (AmpD H157Y ) genes mutations have been identified by whole genome sequencing in a Pseudomonas aeruginosa (PaS) that became resistant (PaR) in a patient treated by ceftolozane/tazobactam (C/T). To precisely characterize the respective contributions of these mutations on the decreased susceptibility to C/T and on the parallel increased susceptibility to imipenem (IMI), mutants were generated by homologous recombination in PAO1 reference strain (PAO1- AmpC G183D , PAO1-AmpD H157Y , PAO1-AmpC G183D /AmpD H157Y ) and in PaR (PaR-AmpC PaS /AmpD PaS ). Sequential time-kill curve experiments were conducted on all strains and analyzed by semi-mechanistic PKPD modeling. A PKPD model with adaptation successfully described the data, allowing discrimination between initial and time-related (adaptive resistance) effects of mutations. With PAO1 and mutant-derived strains, initial EC 50 values increased by 1.4, 4.1, and 29-fold after AmpC G183D , AmpD H157Y and AmpC G183D /AmpD H157Y mutations, respectively. EC 50 values were increased by 320, 12.4, and 55-fold at the end of the 2 nd experiment. EC 50 of PAO1-AmpC G183D /AmpD H157Y was higher than that of single mutants at any time of the experiments. Within the PaR clinical background, reversal of AmpC G183D , and AmpD H157Y mutations led to an important decrease of EC 50 value, from 80.5 mg/L to 6.77 mg/L for PaR and PaR-AmpC PaS /AmpD PaS , respectively. The effect of mutations on IMI susceptibility mainly showed that the AmpC G183D mutation prevented the emergence of adaptive resistance. The model successfully described the separate and combined effect of AmpC G183D and AmpD H157Y mutations against C/T and IMI, allowing discrimination and quantification of the initial and time-related effects of mutations. This method could be reproduced in clinical strains to decipher complex resistance mechanisms., Competing Interests: The authors declare no conflict of interest.

Streptococcus pneumoniae is an important cause of acute otitis media (AOM). The aim of this study was to evaluate trends in antibiotic resistance and circulating serotypes of pneumococci isolated from middle ear fluid of French children with AOM during the period 2001-2011, before and after the introduction of the PCV-7 (2003) and PCV-13 (2010) vaccines. Between 2001 and 2011 the French pneumococcal surveillance network analysed the antibiotic susceptibility of 6683 S. pneumoniae isolated from children with AOM, of which 1569 were serotyped. We observed a significant overall increase in antibiotic susceptibility. Respective resistance (I+R) rates in 2001 and 2011 were 76.9% and 57.3% for penicillin, 43.0% and 29.8% for amoxicillin, and 28.6% and 13.0% for cefotaxime. We also found a marked reduction in vaccine serotypes after PCV-7 implementation, from 63.0% in 2001 to 13.2% in 2011, while the incidence of the additional six serotypes included in PCV-13 increased during the same period, with a particularly high proportion of 19A isolates. The proportion of some non-PCV-13 serotypes also increased between 2001 and 2011, especially 15A and 23A. Before PCV-7 implementation, most (70.8%) penicillin non-susceptible pneumococci belonged to PCV-7 serotypes, whereas in 2011, 56.8% of penicillin non-susceptible pneumococci belonged to serotype 19A. Between 2001 and 2011, antibiotic resistance among pneumococci responsible for AOM in France fell markedly, and PCV-7 serotypes were replaced by non-PCV-7 serotypes, especially 19A. We are continuing to assess the impact of PCV-13, introduced in France in 2010, on pneumococcal serotype circulation and antibiotic resistance., (Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Hospital effluents are involved in dissemination of antibiotic-resistant integrons. We describe here a new class 3 integron, In3-5, detected in an Enterobacter cloacae isolate retrieved from a random French hospital effluent sample collected in 2009. In3-5 carries two gene cassettes: the new blaOXA -256 and an aac(6')-Ib variant, respectively conferring resistance to β-lactams and aminoglycosides. In3-5 is located on an IncQ-like backbone plasmid. Class 3 integrons could thus be involved in the dissemination of antibiotic resistance in both clinical settings and the environment, and could participate in the exchange of antibiotic-resistance genes between these two ecosystems., (©2013 The Authors Clinical Microbiology and Infection ©2013 European Society of Clinical Microbiology and Infectious Diseases.)

Urban wastewater treatment plants (UWTPs) are among the main sources of antibiotics' release into the environment. The occurrence of antibiotics may promote the selection of antibiotic resistance genes (ARGs) and antibiotic resistant bacteria (ARB), which shade health risks to humans and animals. In this paper the fate of ARB and ARGs in UWTPs, focusing on different processes/technologies (i.e., biological processes, advanced treatment technologies and disinfection), was critically reviewed. The mechanisms by which biological processes influence the development/selection of ARB and ARGs transfer are still poorly understood. Advanced treatment technologies and disinfection process are regarded as a major tool to control the spread of ARB into the environment. In spite of intense efforts made over the last years to bring solutions to control antibiotic resistance spread in the environment, there are still important gaps to fill in. In particular, it is important to: (i) improve risk assessment studies in order to allow accurate estimates about the maximal abundance of ARB in UWTPs effluents that would not pose risks for human and environmental health; (ii) understand the factors and mechanisms that drive antibiotic resistance maintenance and selection in wastewater habitats. The final objective is to implement wastewater treatment technologies capable of assuring the production of UWTPs effluents with an acceptable level of ARB., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Bacteria harbouring the novel qnrA plasmid-mediated mechanism of quinolone resistance have been described in different countries, but the frequency of their occurrence has not been investigated. In total, 1,468 clinical isolates of Enterobacteriaceae with quinolone resistance or extended-spectrum beta-lactamase (ESBL) phenotypes were collected from eight teaching hospitals in France during 2002-2005 and screened for qnrA. Overall, 28 isolates (22 Enterobacter cloacae, three Klebsiella pneumoniae, one Citrobacter freundii, one Klebsiella oxytoca and one Proteus mirabilis) were positive for qnrA, representing 1.9% of all isolates, 3.3% of ESBL-producing isolates (22% of the E. cloacae isolates) and 0% of non-ESBL-producing isolates. The prevalence of qnrA among consecutive ESBL-producing isolates in 2004 from the eight hospitals was 2.8% (18/639). Of the qnrA-positive isolates, 100% were intermediately-resistant or resistant to nalidixic acid, and 75% to ciprofloxacin. Twenty-one of the 22 qnrA-positive E. cloacae isolates were obtained from two hospitals in the Paris area, and molecular typing and plasmid content analysis showed clonal relationships for five, three and two isolates, respectively. The qnrA genetic environment was similar to that of the In36 integron. The remaining two isolates had qnrA variants (30 and 29 nucleotide differences, respectively, compared with the original sequence) and an unknown genetic environment. The ESBL gene associated with qnrA was bla(SHV-12) in most of the isolates, but bla(PER-1) and bla(SHV-2a) were found in two isolates. In France, it appears that qnrA-positive isolates are predominantly E. cloacae isolates producing SHV-12, and may be associated with the dissemination of an In36-like integron.

Data on the use of antibiotics were collected by means of a questionnaire from 49 hospitals in south-western France. Use was expressed as a usage density rate: number of defined daily doses (DDDs) per 1000 patient-days. The average use of antibiotics amounted to 402 DDDs per 1000 patient-days and varied between 60 and 734. In acute-care wards, the amount of antibiotic use increased with the size of the hospital: 461 DDDs per 1000 patient-days for group A (<100 beds), 510 DDDs per 1000 patient-days for group B (more than 100 and less then 300 beds) and 676 DDDs per 1000 patient-days for group C (>300 beds). The rate of use differed among different types of hospital areas and varied from 58 for psychiatry departments to more than 1273 DDDs per 1000 patient-days for the infectious diseases departments. Broad-spectrum penicillins were the most frequently prescribed antibiotics. Fluoroquinolone and third-generation cephalosporin use were relatively uniform in the three size categories. This study shows that it is possible for a hospital to benchmark its consumption with other hospitals that are similar in size. In this way, surveillance of antibiotic use can aid hospitals in targeting infection control efforts.