ASP Scan (Weekly) for Mar 03, 2017

Antibiotic development incentives
De-escalation to ertapenem
NDM-1 in Ethiopia
MRSA, VRE in infants
Drug resistance in UTIs
Antibiotic resistance poll
Rising UK colistin use
Drug-resistant TB plea
MDR infections in organ transplants
Stewardship app

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

GAO urges more FDA guidance on new antibiotic development

A new report from the US Government Accountability Office (GAO) says the Food and Drug Administration (FDA) needs to provide more guidance to drug companies on how to use incentives to develop new antibiotics.

The incentives are part of the 2012 Generating Antibiotic Incentives Now (GAIN) Act, which made new antibiotics eligible for fast-track and priority review status and gave drug companies an extra 5 years of market exclusivity for those antibiotics if they were eligible under the qualified infectious disease products (QIDP) designation. The hope was that these incentives would spur antibiotic development.

So far, the FDA has taken steps to implement the GAIN Act. According to the GAO, the FDA granted 101 of 109 requests for QIDP designation from 2012 through 2015 and approved six drugs with QIDP designation for market in the United States. The agency has also released 14 updated or new guidance documents on antibiotic development and QIDP designation.

But in reviewing the FDA's efforts and in speaking with drug sponsors that have applied for QIDP designation, the GAO also found that half of the agency's updated or new guidance documents are in draft form and may not necessarily reflect scientific developments and the agency's current thinking. Several of the drug sponsors expressed concern over whether they could rely on these documents for guidance and suggested written guidance was needed for the QIDP designation.

"The lack of clarity on the role of draft guidance for and the lack of written guidance on the QIDP designation create uncertainty for drug sponsors about how much reliance they should place on these draft documents and could diminish the likelihood that drug sponsors apply for the designation because they do not fully understand its requirements and benefits," the report states.

The GAO recommends that the FDA clarify how drug sponsors should use draft guidance documents and develop written guidance on the QIDP designation and its incentives.
Mar 2 GAO report


Study: De-escalation to ertapenem is safe, effective in ESBL pathogens

A new study indicates ertapenem can be used as a de-escalation therapy for extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae infections, particularly urinary tract and bloodstream infections.

In the randomized controlled trial published in BMC Infectious Diseases, 66 patients being treated at a hospital in Thailand for documented ESBL-producing Enterobacteriaceae infections from 2011 to 2014 were assigned to two groups: A control group of 34 patients who continued receiving standard group 2 carbapenems (imipenem, meropenem, doripenem, and biapenem) as empirical therapy, and an intervention group of 32 patients who were de-escalated to ertapenem, a narrower-spectrum group 1 carbapenem. The patients primarily had urinary tract infections and bacteremia.

The primary outcome was clinical cure rate at end of therapy. Secondary outcomes included microbiological eradication rate, superimposed infection rate during study treatment, 28-day mortality rate, and adverse drug reactions.

By using a 15% predefined margin, ertapenem was considered non-inferior to the control group regarding the clinical cure rate (% change = 14.0) the microbiological eradication rate (% change = 4.1), and the superimposed infection rate (% change = −16.5). Patients in the de-escalation group also had a significantly lower 28-day mortality rate (9.4% vs. 29.4%; P  = .05), a significantly shorter median length of stay (16.5 days vs. 20.0 days P  = .04), and a significantly lower defined daily dose of carbapenem use (12.9 ± 8.9 vs. 18.4 ± 12.6; P  = .05).

"These findings confirm the efficacy of ertapenem and are consistent with the findings previously documented in many observational cohort studies," the authors write, adding that a study in the cost-effectiveness of de-escalation to ertapenem would also be useful. 
Mar 1 BMC Infect Dis study


NDM-1-producing A baumanni identified in Ethiopia

A new study in BMC Infectious Diseases describes the identification of three Acinetobacter baumanniisolates carrying the carbapenem-resistance gene NDM-1 in Ethiopia. It's the first time organisms carrying the gene have been found in the country.

According to the study, the three A baumanni isolates were among 224 gram-negative isolates obtained from clinical infections and routine clinical specimens at a hospital in Jimma City, Oromiya regional state, between January 2014 and June 2015. Antimicrobial susceptibility testing and molecular characterization revealed that the isolates, which came from three different patients, were meropenem-resistant and NDM-1 positive. Two of the patients survived their infections, and the third died.

Genetic sequencing identified the three isolates' sequence type as ST957, suggesting a different origin from an NDM-1-positive A baumanni strain that had caused an outbreak in Kenya and was, to this point, the only other documented NDM-1-positive A baumanni in East Africa. The authors note that this finding argues against the regional spread of NDM-1-positive organisms and potentially indicates independent import of strains from other regions.

None of the other bacterial isolates analyzed in the study have been found to harbor the NDM-1 gene so far, and attempts to see if the A baumanni isolates could transfer the gene to strains of Escherichia coliwere not successful under laboratory conditions. But the authors warn that natural transmission to other bacteria is likely, "given the evident lack of hygienic precautions due to limited resource settings."

"It is further likely, that the detected isolates are solely the tip of the iceberg regarding the presence of NDM-1 producing organisms in the region, as only a limited number of bacterial isolates could be evaluated," the authors write.
Mar 1 BMC Infect Dis study


Study identifies risk factors for MRSA, VRE in NICU patients

Originally published by CIDRAP News Mar 2

Surgery and prolonged antimicrobial treatment can increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) colonization in infants prior to neonatal intensive care unit (NICU) discharge, according to a study yesterday in the Journal of the Pediatric Infectious Diseases Society.

For the study, New York researchers identified 1,320 infants younger than 7 days of age who had been hospitalized for more than 2 weeks at four children's hospitals from 2009 to 2012 and had been swabbed for surveillance cultures for MRSA and VRE within 7 days of NICU discharge. Although it's known that infants hospitalized in the NICU can be at risk of infection with one of these pathogens and can serve as a reservoir for them, MRSA and VRE colonization rates preceding NICU discharge have not been well studied.

The results of the surveillance cultures showed that, among the 1,320 infants, 58 (4%) were colonized with MRSA and 17 (1%) were colonized with VRE within 7 days of NICU discharge. Final multivariable models revealed that surgical procedures were a statistically significant predictor of MRSA colonization (OR, 2.83, P = .01), while 10 days or more of treatment with oxacillin (OR, 23.40, P  < .01) or penicillin/ampicillin (OR, 6.26, P < .01) was a statistically significant predictor of VRE colonization.

The authors conclude that while the study found only a small percent of infants harbor MRSA and VRE prior to NICU discharge, the findings "have potential implications for dissemination of these potential pathogens, particularly MRSA, into long-term care facilities, other hospital units, and the communities."
Mar 1 J Pediatric Infect Dis study


Study: Prior antibiotic use may raise risk of resistant urinary tract infections

Originally published by CIDRAP News Mar 1

Receiving two or more antibiotic regimens is associated with an increased risk of gram-negative pathogens in patients with hospital-onset urinary tract infections (UTIs), according to a study yesterday in BMC Infectious Diseases.

The retrospective, observational study examined discharge data on hospital patients who had a positive urine culture for gram-negative bacteria and received an antibiotic against gram-negative bacteria from January 2012 through March 2013. The researchers were looking to determine if prior antibiotic exposure in these UTI patients affected the distribution and non-susceptibility patterns of key gram-negative pathogens.

The gram-negative organisms of interest were Escherichia coliKlebsiella pneumoniaePseudomonas aeruginosa, and other members of the Enterobacteriaceae family. Organisms were assessed for susceptibility to fluoroquinolones, carbapenems, and piperacillin/tazobactam.

A total of 5,574 unique UTI episodes were included in the analysis (2,027 in patients with prior antibiotic exposure, 3,547 in patients with no prior antibiotic exposure) and 6,093 pathogens were isolated from urine cultures. The most commonly isolated pathogens were E coli (49.5%), K pneumoniae (17.1%), and P aeruginosa (8.2%). P aeruginosa was isolated significantly more often from patients who had at least two prior antibiotic exposures (12.6%) than in patients with no prior antibiotic exposure (8.2%) or with one prior exposure (7.9%). Distribution trends for other pathogens were not affected by the presence or absence of antibiotics.

In addition, the results showed that among all the pathogens of interest, two or more prior antibiotic exposures were associated with slightly higher incidences of fluoroquinolone nonsusceptibility, multidrug resistance, and extended-spectrum beta lactamase phenotypes than were one or no previous antibiotic exposures. This trend, the researchers note, was largely driven by susceptibility pattern changes observed in K pneumoniae isolates.

Although the findings could not substantiate prior antibiotic exposure as an independent risk factor for drug-resistant UTIs, the authors argue that it is an easily identifiable variable that can be used to guide empirical therapy.
Feb 28 BMC Infect Dis study 


Poll shows most Americans know little about superbugs

Originally published by CIDRAP News Mar 1

A new poll shows that more than two thirds of Americans are in the dark about the threat of antibiotic-resistant "superbugs," and more than half think antibiotics are effective against viral infections.

The poll, conducted online Feb 6 through 8 by HealthDay News and The Harris Poll, included 2,202 adults. In the poll, 69% of respondents said they know little or nothing about the superbug problem, while 53% said antibiotics work against viral infections, 40% said they work against the common cold, and 48% said that antibiotics can be used against the flu. The numbers were even higher for younger respondents.

"This poll shows that public ignorance is a huge part of the problem," Humphrey Taylor, chairman emeritus of the Harris Poll, told HealthDay News. "Millions of patients continue to believe that antibiotics will help them recover from colds, flu, and other viral infections."

On a positive note, HealthDay News reports that when asked to pick from a list of possible causes of antibiotic resistance, roughly two thirds of respondents selected inappropriate antibiotic prescriptions. And 90% said the public "bears some responsibility" in fighting antibiotic resistance.

Research by the US Centers for Disease Control and Prevention and the Pew Charitable Trusts shows that at least 30% of outpatient antibiotic prescriptions in the United States are inappropriate. The data show that most unnecessary antibiotics are prescribed for respiratory conditions caused by viruses, including common colds, bronchitis, and sinus and ear infections. 
Feb 27 HealthDay News article


Report: Sharp rise seen in colistin prescriptions in English hospitals

Originally published by CIDRAP News Mar 1

Prescriptions for the last-resort antibiotic colistin rose by 40% from 2014 to 2015 in English hospitals, according to a story by the Bureau of Investigative Journalism.

Data from Public Health England obtained by the bureau showed that defined daily doses of colistin rose from 346,143 in 2014 to 485,024 in 2015, and have been on the rise every year since 2010.

Medical experts tell the bureau that the rise in colistin prescriptions is an indication that multidrug-resistant infections—such as carbapenem-resistant Enterobacteriaceae—are becoming more common. Colistin, which was introduced in the early 1970s and then withdrawn because it can cause damage to the kidneys, is considered a last option for treatment of infections that don't respond to other antibiotics.

Concerns about emerging colistin resistance have been growing since late 2015, when researchers discovered a highly mobile gene (known as MCR-1) that confers resistance to colistin in E coli samples from humans, pigs, and pork products. Since then, the MCR-1 gene has been identified in various human and animal bacteria in more than 30 countries, including the United Kingdom.

Michael Weinbren, MD, an infectious disease expert with the Chesterfield Royal Hospital NHS Foundation Trust, told the bureau that growing use of colistin in human medicine will aid the spread of MCR-1. "The one thing you can be sure of is that the organisms will develop resistance," he said.

The bureau also reports that the UK's Veterinary Medicines Directorate last year licensed three new products containing colistin for use on British farms. The emergence and spread of the MCR-1 gene in China, which had widely used colistin in food-animal production, prompted Chinese officials to ban the drug as an animal feed additive in 2016.
Feb 24 Bureau of Investigative Journalism story 


WHO calls for R&D into drug-resistant tuberculosis treatment

Originally published by CIDRAP News Feb 28

The World Health Organization (WHO) issued a statement today reaffirming the need for more research and development on new antibiotics for multidrug-resistant tuberculosis (MDR-TB).

"Addressing drug-resistant TB research is a top priority for WHO and for the world," WHO Director-General Margaret Chan, MD, MPH, said in a press release. "More than US $800 million per year is currently necessary to fund badly needed research into new antibiotics to treat TB."

The statement comes a day after the agency released a list of antibiotic-resistant "priority pathogens" for which new antibiotics are urgently needed. WHO officials said in a press conference yesterday that although drug-resistant TB is the most important priority for development of new antibiotics, it was not included on that list because it is already recognized as a top public health threat and is targeted by dedicated programs.

The WHO estimates there were 580,000 cases of MDR-TB globally in 2015 and 250,000 related deaths. Only two new antibiotics to treat MDR-TB have completed phase 2B trials in the past 50 years, the agency said, and both are still in phase 3 trials. 
Feb 28 WHO press release


Study details drug-resistant bloodstream risks in organ transplants

Originally published by CIDRAP News Feb 28

A study yesterday in BMC Infectious Diseases details the factors most associated with mortality in abdominal organ transplant recipients with multidrug-resistant bloodstream infections.

In the retrospective study, investigators analyzed all episodes of multidrug-resistant gram-negative bacteremia (MDR-GNB) in abdominal solid organ transplant (ASOT) recipients at two Chinese hospitals from 2003 to 2016. Although the emergence of MDR-GNB in organ transplant recipients has been documented, information on risk factors for mortality has been scarce. To identify those risk factors, the investigators compared two groups of patients: those who survived and those who died within 30 days after the first episode of MDR-GNB.

During the 13-year study period, 2,169 patients underwent ASOT, and 99 MDR gram-negative samples (4.6%) were isolated from 91 patients with bloodstream infections. Of the 99 MDR-GNB isolates, 29 (29.3%) were E coli, 24 (24.2%) were A baumanni, 11 (11.1%) were Escherichia cloacae, and 10 (10.1%) were K pneumoniae. The incidence of MDR-GNB was higher in liver recipients (12.3%) than in kidney recipients (2.6%). MDR-GNB-related 30-day mortality after the first episode of MDR-GNB was 39.6% (36 deaths).

Comparison of the two groups of patients showed that nosocomial origin, presence of other concomitant bloodstreams infections, increased creatinine level, and septic shock were the main risk factors for MDR-GNB–related mortality in ASOT recipients. Septic shock led to a 160-fold increase in mortality and was the strongest predictor of outcomes in multivariate models.

"Recognition of these factors is useful in identifying individuals who are at risk of mortality," the authors write.
Feb 27 BMC Infect Dis study


Researchers say antibiotic stewardship app boosted compliance

Originally published by CIDRAP News Feb 28

A study today in the Journal of Antimicrobial Chemotherapy reports that converting antimicrobial stewardship policies to a smartphone app modestly boosted compliance with prescribing policy at three hospitals in London, England.

The study looked at the 3 years before and after the 2011 rollout of the Imperial antibiotic prescribing policy application (IAPP), which was launched at the three main hospitals of Imperial College Healthcare Trust Hospitals in west London. The hospitals already had a multimodal antimicrobial stewardship program (ASP) in place; the purpose of IAPP was to make antimicrobial prescribing policy available at the point of care.

To measure the impact on antimicrobial prescribing pre- and post-IAPP adoption, the investigators chose three proxy indicators: adherence of choice of antimicrobial to local policy or microbiology/infectious disease team recommendation, documentation of stop or review dates on medication charts, and documentation of indication on medication charts. Data from general medical and surgical patients were analyzed separately.

The results of the interrupted time series analysis showed that compliance with policy increased in both medicine and surgery after IAPP was implemented, although the change in level of compliance was statistically significant only in surgery. IAPP also improved the documentation of the stop/review date in both medical and surgical specialties, but the improvement was not significant. Documentation of indication for prescribing, however, decreased significantly in both medicine and surgery after IAPP was implemented. 

In conclusion, the authors note that the addition of IAPP to a multifaceted ASP did not demonstrate significant change in antimicrobial prescribing trends. The added value, they write, is in the "reach and access to the antimicrobial prescribing policy among a wider range of staff across our organization."      
Feb 28 J Antimicrob Chemother study

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