Study shows how tolerant bacteria enable the development of resistance
Researchers from the Hebrew University of Jerusalem and the Massachusetts Institute of Technology have uncovered an alternative method by which bacteria can become resistant to antibiotics.
In a study published yesterday in Science, researchers describe in vitro experiments in which they exposed three different Escherichia coli strains to daily doses of ampicillin. They were looking to build on previous research that had shown that E coli populations, when exposed to intermittent daily doses of the drug, can develop mutations that extend their lag phase—a dormant period in which individual bacteria are maturing and not yet able to divide. This extended lag phase enabled the bacteria to tolerate intermittent exposure to ampicillin. But the tolerance would end once the bacteria started growing again.
To understand how tolerance might relate to resistance, the researchers exposed the three E coli strains to ampicillin until the bacteria became resistant, isolated the first resistant clone established in each population, and then used whole-genome sequencing to understand how the resistance mutations evolved.
What they found was that subpopulations of the bacteria first developed tolerance mutations, which enabled them to survive the daily doses of ampicillin until they developed resistance mutations. The researchers also found that resistance mutations developed more quickly on tolerant bacteria.
"The reservoir of tolerant bacteria extends the window of opportunity for rarer mutations to occur," the authors write. "In addition, we found that tolerance specifically enhances the establishment of resistance mutations by the epistasis between tolerance and partial resistance to the treatment."
The authors say that since clinical bacterial isolates are not tested for tolerance, the emergence of resistance preceded by the acquisition of tolerance might go undetected, and that testing for tolerance could affect the choice of antibiotics used against a pathogen. In addition, they suggest that the development of new antibiotics that target tolerant bacteria could help slow the development of resistance.
Feb 9 Science study
CPE on the rise in France
The number of enterobacterial isolates with decreased susceptibility to carbapenems doubled in France from 2012 to 2014 and the proportion of carbapenemase producers rose by more than 50% during that period, French researchers reported yesterday in Eurosurveillance.
From January 2012 to December 2014, 6,682 enterobacterial isolates recovered from clinical and screening specimens in France and French overseas territories were tested for carbapenem activity at the French Associated National Reference Center for Antibiotic Resistance. Isolates with reduced susceptibility to at least one carbapenem (ertapenem, meropenem, or imipenem) were further evaluated for carbapenemase activity. Polymerase chain reaction (PCR) testing was used to identify the carbapenemase genes.
The results of the testing showed 99% of the enterobacterial isolates were nonsusceptible to at least one carbapenem and that the number of isolates with decreased susceptibility rose from 1,485 in 2012 to 2,972 in 2014. The percentage of carbapenemase-producing enterobacteria (CPE) among those isolates rose from 23.1% in 2012 to 36.2% in 2014. The three main enterobacterial species with decreased susceptibility to carabapenems were Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp.
The number of carbapenemase producers in E coli was five times higher in 2014 compared with 2012, a finding the authors say "hints toward a possible future endemic spread of carbapenemase-producing E coli in the community."
PCR testing identified OXA-48 as the main carbapenemase type, with an increase in OXA-48 variants and NDM producers. The number of KPC producers decreased over the same period of time. The authors suggest the dissemination of OXA-48 is likely linked to population movement between North Africa, where the OXA-48 producers are endemic, and France. In addition, identification of NDM-producing isolates and OXA-48 variants was associated with travel to the Indian subcontinent, the Middle East, Southeast Asia, North Africa, and tropical regions of Africa.
"Although the origin of colonization with a CPE producer was not always documented, it is likely that acquisition abroad is fueling the growing number of CPE identified in France," the authors wrote.
"Based on our own experience and the results of this study, we advocate for a systematic screening of at-risk patients to identify carriers of CPE."
Feb 9 Eurosurveill report
Pediatric emergency departments not involved in stewardship, study finds
A new survey of children's hospitals indicates that antimicrobial stewardship efforts in pediatric emergency departments (EDs) are limited.
The cross-sectional survey included 37 children's hospitals belonging to the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) collaborative, an effort to share best practices and relevant data for pediatric antimicrobial stewardship. Each hospital had two respondents: a hospital antimicrobial stewardship program (ASP) leader, and an ED medical director. The survey items assessed antimicrobial stewardship activities and ED involvement in those activities. The overall response rate was 91.9%.
The survey found that while the majority of ASP leaders (97.8%) and ED directors (93.7%) agreed that the creation of ED-based ASPs was necessary, pediatric emergency medicine specialists were rarely represented in ASPs. Of the 36 hospitals with ASPs, the ED was represented in only 3 (8.3%) and outpatient pediatricians in just 1 (2.8%). ED specialists were infrequently involved in the creation of clinical care guidelines, and no ASP monitored outpatient antibiotic prescribing for children discharged from the ED. In addition, efforts to improve ED provider prescribing, such as audit and feedback, were uncommon.
The authors note that the findings are a particular concern given the fact that 250 million antibiotic prescriptions are written from hospital EDs each year, and at least 30% of those prescriptions are unnecessary.
"Although ASP and ED leaders agree that implementation of antimicrobial stewardship in the ED setting is feasible and necessary, there is a clear lack of ED presence in pediatric hospital–based ASPs with respect to the creation of recommendations, prescription monitoring, and regulation of ED antibiotic prescribing," they wrote.
The survey results were published in Infection Control and Hospital Epidemiology.
Feb 8 Infect Control Hosp Epidemiol study