ASP Scan (Weekly) for Feb 10, 2017

From tolerance to resistance
CPE in France
Stewardship in Pediatric EDs
Stewardship in nursing homes
MCR-1 increase in China
Resistant Acinetobacter
Bacteremia treatment

Our weekly wrap-up of antimicrobial stewardship & antimicrobial resistance scans

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 pneumoniaeE 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


Study: Nurses can play a key role in nursing home stewardship efforts

Originally published by CIDRAP News Feb 9

A study yesterday in the American Journal of Infection Control indicates that an online course on infection control can help nurses become more knowledgeable and more aware of their role as antibiotic stewards in nursing homes.

The results are from a survey completed by 103 nurses before and after they took an online course comprising six 30-minute interactive modules on signs and symptoms of infection in older adults. The course was aimed at nurses working in infection control and long-term care settings. The surveys were designed to assess respondents' knowledge about the care of nursing home residents with infections and their attitudes and beliefs regarding antibiotic stewardship.

Matched surveys showed that after the respondents participated in the online course, the proportion of questions answered correctly on the 12-item knowledge assessment improved from 75% (9 out of 12 questions) to 86% (10.4 out of 12 questions). In addition, the results showed an increased agreement among the respondents that their awareness of a resident's baseline status, their assessment of that status, and their communication with residents, families, and providers could influence whether a resident receives antibiotics.

"Our results suggest that online education for RNs and LPNs about the principles of antimicrobial stewardship may be a viable component in multifaceted efforts to reduce inappropriate antibiotic use in the nursing home setting," the authors write.

According to the US Centers for Disease Control and Prevention (CDC), an estimated 70% of nursing home residents receive one or more courses of antibiotics during a year. In October 2016, the Centers for Medicare and Medicaid Services finalized a rule that will require nursing homes to have antibiotic stewardship program. 
Feb 8 Am J Infect Control study


Chinese study finds increasing rate of MCR-1 carriage in humans

Originally published by CIDRAP News Feb 8

A new study out of China indicates that human fecal carriage of MCR-1-positive, multidrug-resistant Enterobacteriaceae is on the rise.

For the study, posted yesterday on the preprint server bioRxiv, Chinese investigators tested 8,022 human fecal samples collected from three hospitals in Guangdong from April 2011 through March 2016. They were looking for the presence of the MCR-1 gene, which was first identified in Escherichia coli samples from pigs, pork products, and humans in China in 2015.

MCR-1 has since become a major health concern because it confers resistance to colistin, a last-resort antibiotic used in the treatment of multidrug-resistant infections. An additional concern is the co-existence of the gene, which is carried on mobile pieces of DNA called plasmids, with other resistance mechanisms.

Of the 8,022 fecal samples, the investigators found that 497 (6.2%) were MCR-1 positive, and 182 (2.3%) were MCR-1 positive and resistant to cefotaxime, a broad-spectrum cephalosporin. From the fecal samples harboring MCR-1-positive/cefotaxime-resistant Enterobacteriaceae, the team identified 187 distinct Enterobacteriaceae isolates from 179 individuals. The vast majority of the isolates (173) were E coli.

The rate of MCR-1 gastrointestinal carriage noted in the study is significantly higher than previous studies have found. The investigators also found that the MCR-1-positive and MCR-1-positive/cefotaxime-resistant samples increased significantly over the 5 years of the study, with a specific increase after January 2014. In addition, genetic analysis showed that the MCR-1 gene is spreading through a diverse set of genetic mechanisms (including strains, plasmids, and insertion sequences) that are helping contribute to its dissemination and could help facilitate its persistence.

"Our genetic analyses suggest the rapid emergence of several major plasmid vectors of mcr-1 within numerous multidrug-resistant E. coli strains carried by humans, and highlight the significant degree of plasticity in these plasmid vectors harbouring mcr-1 over short periods of time," the authors write.

The study has not yet been peer-reviewed.
Feb 8 bioRxiv abstract 


Report notes high levels of highly resistant Acinetobacter in Nepal

Originally published by CIDRAP News Feb 8

Almost all isolates of Acinetobacter baumannii in Nepal were found to be resistant to multiple antibiotics, according to a small study yesterday in Antimicrobial Resistance & Infection Control.

Nepalese researchers analyzed 44 isolates of A baumannii, an increasingly important pathogen. The found that 43 (98%) were resistant to carbapenems, an important tool for combating antibiotic-resistant bacteria. The same number of isolates were multidrug resistant, but all were susceptible to colistin. The bla-OXA-23 gene was detected in all of the isolates, while the New Delhi Metallo-beta-lactamase-1 (NDM-1) gene was identified in 6 (14%).

The authors conclude, "Systemic network surveillance should be established for monitoring and controlling the spread of these resistant strains."
Feb 7 Antimicrob Resist Infect Control study


Inappropriate antibiotic therapy tied to poor bacteremia outcomes

Originally published by CIDRAP News Feb 7

A new study out of Denmark shows that inappropriate empiric antibiotic therapy (EAT) in bacteremia patients is associated with an increased risk of recurrence and long-term mortality but has no impact on short-term mortality.

The retrospective population-based cohort study, published yesterday in BMC Infectious Diseases, analyzed the data of 6,483 Danish patients diagnosed with incident bacteremia—the presence of bacteria in the bloodstream—in 2007-08, with follow-up of recurrence and vital status conducted through 2009. The investigators considered three different study outcomes: recurrence, 2-to-30-day mortality, and 31-to-365-day mortality.

Because antibiotic treatment for bacteremia cannot await identification of the microorganisms causing the infection, clinicians have to initiate therapy on an empirical basis. EAT was defined as appropriate if given intravenously (except fluoroquinolones, metronidazole, and fluconazole) and if all blood isolates were susceptible to one or more of the antibiotics used. EAT was considered inappropriate if it did not fulfill these criteria, and it was considered unknown if the antibiotic treatment was unrecorded.

Of the 6,483 patients, 3,778 (58%) received appropriate EAT, 1,290 (20%) received inappropriate EAT, and 1,415 (22%) had unknown EAT. Within 1 year of the initial episode, 712 patients (11%) had recurrent bacteremia. When compared with appropriate EAT, inappropriate EAT was independently associated with recurrence (hazard ratio, 1.25). The 2-to-31 day mortality was 15.1% in patients who received appropriate EAT and 17.4% in those who received inappropriate EAT, for an adjusted odds ratio (OR) of 0.85. But 31-to-365 day mortality was 22.3% in patients given appropriate EAT compared with 30.7% in those given inappropriate EAT, for an adjusted OR of 1.35.

"These findings have clinical importance and highlight the importance of vigilance in the identification and antibiotic treatment of bacteraemia," the authors write. "Identification of patients and characteristics associated with inappropriate EAT may contribute to empirical prescribing guidelines and thereby improve EAT."
Feb 6 BMC Infect Dis study

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