ASP Scan (Weekly) for Sep 14, 2018

UK-India diagnostics effort
Probiotics and antibiotic use in kids
Candida auris in New York
Resistance and rising temps
European One Health AMR plan
India bans combo drugs
MDR bacteria in farmed salmon
Resistant E coli in dogs
Essential-antibiotic price hike
Antibiotics and cough
Piperacillin-tazobactam trial results
Double antibiotic for pneumonia
C diff in food animals
Accessible antimicrobial resistance data

UK-India effort explores diagnostics solutions to AMR in India

A 3-year, £3 million ($3.9 million) collaboration between UK and India researchers seeks to create rapid diagnostics to help address the growing problem of antimicrobial resistance (AMR) in India, according to a news release yesterday from the University of Edinburgh, one of the project partners.

The program, called Diagnostics for One Health and User Driven Solutions for AMR (DOSA), will involve nine academic institutions, five from India and four from Britain. Medical researchers, diagnostic innovators, economists and social scientists will create cutting edge, rapid diagnostic solutions to fight AMR in settings as diverse as community healthcare, dairy farms, and aquaculture, according to the release. Project experts will meet Sep 24 and 25 at Indian Institute of Technology Delhi to kick off the venture.

The project is jointly funded by UK Research and Innovation/Economic and Social Research Council, the Newton Fund, and Government of India's Department of Biotechnology.

"DOSA gives us the exceptional possibility to create a deep understanding between user needs and diagnostics innovation," said Till Bachmann, PhD, UK project coordinator and deputy head of the Division of Infection and Pathway Medicine at the University of Edinburgh. "The project will focus on community settings in India. It is here where the big drivers of AMR are located, where AMR is a huge burden and where it is exceptionally difficult to implement rapid diagnostics."
Sep 13 University of Edinburgh news release
DOSA project abstract


Systematic review finds probiotics tied to lower antibiotic use in children

Just a week after two small studies panned probiotics for restoring the gut microbiome, a new meta-analysis has found probiotic use to be associated with a reduced need for antibiotics in infants and children, according to a study today in the European Journal of Public Health.

Probiotics are live microorganisms taken to balance the gut microbiota and for other health benefits. The study—a review of 17 randomized controlled trials—included studies that used 13 probiotic formulations, all of which contained Lactobacillus and Bifidobacterium either alone or in combination.

An analysis of the pooled data from the studies found that infants and children who received probiotics to prevent acute illnesses like respiratory tract infections had a 29% lower incidence of being prescribed antibiotics compared with those who took placebos. And when the researchers honed in on the five studies with a low risk of bias, probiotics were associated with a 54% lower risk of being prescribed antibiotics.

In a University of Georgetown press release, senior author Daniel Merenstein, MD, of Georgetown's Department of Family Medicine, said, "We already have evidence that consuming probiotics reduces the incidence, duration, and severity of certain types of common acute respiratory and gastrointestinal infections. The question is whether that reduction is solidly linked to declining use of antibiotics, and we see that there is an association."

By using "association," Merenstein refers to a link between probiotics and antibiotic use, meaning the study did not show that the first definitively caused the latter.

"More studies are needed in all ages, and particularly in the elderly, to see if sustained probiotic use is connected to an overall reduction in antibiotic prescriptions," said the study's lead author, Sarah King, PhD, from Cambridge, United Kingdom. "If so, this could potentially have a huge impact on the use of probiotics in general medicine and consumers in general."
Sep 14 Eur J Public Health study
Sep 14 University of Georgetown news release
Sep 7 CIDRAP News scan "Studies find probiotics lacking for restoring gut microbiome"


Investigation provides details on Candida auris outbreak in New York

Originally published by CIDRAP News Sep 13

A study published yesterday in Emerging Infectious Diseases describes the outbreak of the multidrug-resistant fungal infection Candida auris in New York healthcare facilities.

Since C auris was first detected in the United States in 2016, New York has consistently reported the highest number of cases. Of the 391 confirmed and probable cases reported to the Centers for Disease Control and Prevention (CDC) in 11 states as of Aug 17, 213 are in New York. To better understand the spread of C auris in New York healthcare facilities, researchers from the New York State Department of Health, New York City Department of Health and Mental Hygiene, and the CDC conducted an epidemiologic investigation that included review of clinical cases reported by Apr 30, 2017, contract tracing and screening, and collection of environmental samples from facilities where case-patients resided.

The investigators detected 51 cases in 19 healthcare facilities, all but one of which were in New York City. Of these case-patients, 31 (61%) had lived in long-term care facilities before being admitted to the hospital where the infection was diagnosed. The 90-day mortality rate among these cases was 45% (23/51), although the number of deaths attributable to C auris is unknown. Exploration of epidemiologic links revealed a large, interconnected web of affected healthcare facilities throughout New York City.

Screening cultures performed for 572 patients in the 19 facilities where cases were identified revealed an additional 61 patients who were colonized with C auris. Environmental samples were positive for C auris at 15 of 20 facilities, with contamination of surfaces and objects in case-patient rooms and mobile equipment outside those rooms common. Assessment of infection control found that adherence to recommended practices—including hand hygiene, implementation of contact precautions, use of personal protective equipment, and environmental cleaning with proper disinfectants—varied.

The investigators say the reasons for the preponderance of C auris cases in New York City are unknown. The possibilities include a true higher prevalence from multiple introductions into the city, more detection from aggressive case finding, the presence of a large, interconnected network of healthcare facilities, or a combination of all three factors. The infection prevention and control lapses observed by investigators have since prompted intensive improvement efforts.

"The goals are delaying endemicity, preventing outbreaks within facilities, reducing transmission and geographic spread, and blunting the effect of C auris in New York and the rest of the United States," the investigators write.
Sep 12 Emerg Infect Dis article


Analysis of European data finds link between warmer temps, resistance

Originally published by CIDRAP News Sep 13

A team of researchers that earlier this year identified a link between antibiotic resistance and warmer temperatures across the United States is reporting similar findings in an analysis of European data.

In a study yesterday on the preprint server bioRxiv, the researchers from Harvard, Boston Children's Hospital, and Statens Serum Institut in Denmark performed an ecological analysis of country-level antibiotic resistance prevalence in three common bacterial pathogens—Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus—across 28 European countries. They used multivariable models to evaluate associations with minimum temperature and other predictors, including antibiotic consumption and population density, over a 17-year period (2000-2016), then quantified those effects on the rate of change of antibiotic resistance across geographies.

The results of the analysis showed that countries with warmer ambient minimum temperatures were experienced faster increases in antibiotic resistance over time for most pathogens and antibiotic classes, even after accounting for rates of antibiotic consumption and population density. Specifically, a 10°C (18°F) increase in the average minimum temperature was associated with an increased rate of change in resistance to aminoglycosides, third-generation cephalosporins, and fluoroquinolones in E coli and K pneumoniae—ranging from 0.33% per year to 1.2% per year.

The researchers also found, however, that the rate of S aureus resistance to methicillin decreased by 0.4% a year as minimum temperatures increased, a finding they argue reflects widespread declines in methicillin-resistant S aureus across Europe over the study period.

As in their previous study, the researchers note that their findings do not show that increasing temperatures are causing antibiotic resistance rates to rise, but that temperature may be playing a role in modulating the rate of change of antibiotic resistance in a region and deserves further exploration. They conclude, "We hope this work will drive further avenues of research to investigate the role of climate as well as other sociodemographic factors on the distribution and transmission of antibiotic resistance."
Sep 12 bioRxiv abstract
May 23 CIDRAP News story "Study finds antibiotic resistance rise tied to hotter temps"


European Parliament representatives adopt One Health AMR action plan

Originally published by CIDRAP News Sep 13

Stressing the need to take into account that human, animal, and environmental health are interlinked, members of the European Parliament (MEPs) today voted to adopt a One Health action plan against antimicrobial resistance.

In the non-binding resolution, adopted with 589 votes for and 12 against, MEPs urged the European Union (EU) Commission and EU member states to restrict the sale of antibiotics by human and animal health professionals and to remove any incentives for prescribing them. The resolution also called for penalties for illegal sales, and sales without prescriptions, of antibiotics.

"We have to start looking at the whole cycle, because people's and animal health are interconnected," rapporteur Karin Kadenbach, an MEP from Austria, said in a European Parliament press release. "Diseases are transmitted to people from animals and vice versa, and that is why we support the holistic approach of the 'One Health' initiative."

MEPs also recommended that the EU Commission draft a list of priority pathogens for humans and animals that could be used to guide future antibiotic research and development efforts, and they emphasized the need for cheaper rapid diagnostic tests to determine whether infections or bacterial or viral.  
Sep 13 European Parliament press release


India bans 328 combination drugs, including antibiotics

Originally published by CIDRAP News Sep 13

In a blow to pharmaceutical firms but with antimicrobial stewardship ramifications, the government of India has banned 328 combination drugs, Reuters reported today.

The Indian government in 2016 had banned 350 such drugs, called fixed-dose combinations (FDCs), but a scientific advisory board was reviewing the ban after industry groups mounted a legal challenge. The country's Supreme Court ordered the review.

India's health ministry said yesterday that the board of experts had found "no therapeutic justification for the ingredients contained in 328 FDCs and that these FDCs may involve risk to human beings." The ministry is immediately prohibiting the manufacture, sale, and use of the drugs in people. The Times of India reports that two of the drugs are the antibiotic Lupidiclox and the antibacterial Taxim AZ.

Health advocates have cheered the ban over concern about antibiotic resistance because of the misuse of FDCs, Reuters said.

The president of the Indian Drug Manufacturers' Association, Deepnath Roychowdhury, said the order would affect drugs worth about 16 billion rupees ($222 million) a year, but he said the industry would respect the verdict. 
Sep 13 Reuters news story
Sep 13 Times of India report


Chilean study finds multidrug-resistant gut bacteria in farmed salmon

Originally published by CIDRAP News Sep 12

Chilean scientists have found that extensive use of the antibiotics oxytetracycline and florfenicol leads to the selection of multidrug-resistant (MDR) bacteria in the gut microbiota of farmed salmon, according to a study yesterday in PLoS One.

To demonstrate the impact of antibiotic use in Chile's salmon farms, where more than 5,500 tons of antibiotics have been used over the last 10 years to help prevent and treat infections caused by the bacterium Piscirickettsia salmonis, the scientists selected 15 healthy Atlantic salmon from four salmon farms, then isolated and tested bacteria from fecal matter and intestines. They were particularly interested in oxytetracycline and florfenicol, because those are the two most administered antibiotics in salmon farming, mainly delivered through medicated feed.

In total, 47 bacterial isolates resistant to florfenicol and 44 resistant to oxytetracycline were isolated from the fish, with 38.3% showing a high degree of resistance to florfenicol and 34.1% showing a high degree of resistance to oxytetracycline. In addition, 6 of the 91 isolates were resistant to six other antibiotics—chloramphenicol, tetracycline, erythromycin, ampicillin, ciprofloxacin, and kanamycin—and were characterized as "super-resistant." Molecular analysis of the isolates identified several genes that confer resistance to florfenicol and oxytetracycline, which corroborated the phenotypic resistance that was observed.

"The information collected in the present study clearly indicate that using large amounts of antibiotics to treat industrially farmed animals has the consequence of selecting for multiresistant bacteria in the intestinal microbiota, which then have undeniable advantages when liberated into the environment through the feces," the authors write, warning that the release of feces with antibiotic resistance genes into the marine environment could increase the risk of fish pathogens acquiring those resistance elements and becoming untreatable.
Sep 11 PLoS One study


UK study: Common antibiotics boost risk of drug-resistant E coli in dogs

Originally published by CIDRAP News Sep 12

The use of broad-spectrum antibiotics for the treatment of bacterial infections in dogs can create a reservoir of antibiotic-resistant E coli within the canine gastrointestinal tract, UK researchers reported yesterday in the Journal of Antimicrobial Chemotherapy.

In the study, the researchers examined fecal samples from 127 dogs before treatment, immediately after treatment, and 1 month and 3 months post-treatment with one of five antibiotics—cefalexin, amoxicillin/clavulanate, cefovecin, clindamycin, or a fluoroquinolone. All confirmed E coli isolates then underwent antibiotic susceptibility testing, and resistant isolates were further analyzed for phenotypic extended-spectrum beta-lactamase (ESBL) and AmpC production and for the presence of resistance genes. The impact of treatment group per point in time and other factors on the presence of resistance were investigated using multilevel modeling.

The results showed that treatment with beta-lactams or fluoroquinolones was significantly associated with the detection of third-generation cephalosporin-resistant, AmpC-producing, MDR and/or fluoroquinolone-resistant E coli immediately after treatment. But at 1 month post-treatment, only amoxicillin-clavulanate was significantly associated with the detection of third-generation cephalosporin-resistant E coli. There was no significant difference at 3 months post-treatment for any of the antibiotics used. The detection of ESBL-producing E coli was not associated with use of any of the antibiotics administered at any time during the study.

The authors say the findings are important because they suggest that treatment with commonly used antibiotics can affect the commensal fecal flora of dogs, causing a shift toward a more resistant population of E coli that could be shared within households and healthcare settings and may cause extra-intestinal infections.

They conclude, "This information can be used to design biosecurity guidelines that limit transfer of such bacteria to in-contact individuals or to the environment, including barrier nursing, appropriate disposal of dog waste, and strict hand hygiene."
Sep 12 J Antimicrob Chemother study


Pharma CEO defends 400% essential antibiotic price hike

Originally published by CIDRAP News Sep 12

Nirmal Mulye, chief executive officer of the small Missouri-based drug company Nostrum Laboratories, said he hiked the cost of bottle of nitrofurantoin, an essential antibiotic, from  $474.75 to $2,392 last month because there was a "moral requirement to sell the product at the highest price."

Mulye was quoted in the Financial Times. Nostrum Laboratories makes a liquid version of the antibiotic, which was first developed in 1953 and used to treat bladder infections. The drug is considered an essential antibiotic by the World Health Organization (WHO).

Mulye said the decision to raise the price was a direct response to a similar raise by Casper Pharma, which prices a bottle of their branded antibiotic at $2,800.

"The point here is the only other choice is the brand at the higher price. It is still a saving regardless of whether it is a big one or not," said Mulye in the Financial Times.

Food and Drug Administration (FDA) Commissioner Scott Gottlieb, MD, said on Twitter that "there's no moral imperative to price gouge and take advantage of patients," in reference to the story.  He also noted that there is no shortage of nitrofurantoin.
Sep 11 Financial Times story
Scott Gottlieb Twitter account


Study: Antibiotics do not reduce hospitalization risk for cough

Originally published by CIDRAP News Sep 11

A study published in the British Journal of General Practice yesterday shows that prescribing antibiotics to children with coughs does not reduce the risk of subsequent hospitalization.

The study involved researchers from the Universities of Bristol, Southampton, Oxford, and Kings College London, and looked at data on adverse outcomes in 8,320 children (ages 3 months to 15 years) who presented to their general practitioner (GP) with acute cough and other respiratory infection symptoms.

Immediate antibiotics were prescribed to 2,313 (27.8%) and delayed antibiotics to 771 (9.3%). Only 65 children (0.8%) children were hospitalized, and 350 (4.2%) revisited their GP for worsening of symptoms. Of the 65 children hospitalized, 25 (38.5%) had been prescribed an antibiotic.

"Compared with no antibiotics, there was no clear evidence that antibiotics reduced hospitalisations," the authors wrote. The immediate antibiotic risk ratio (RR) was 0.83 (95% confidence interval [CI], 0.47 to 1.45); delayed RR was 0.70 (95% CI, 0.26 to 1.90; overall P = 0.44).

"These results provide reassurance that, when faced with a child and uncertain prognosis, delayed prescribing can be a safe and effective method to reduce the child's probability of reconsulting with deterioration and can act as part of safety-netting strategies for parents," the authors concluded.
Sep 10 Br J Gen Pract 


Clinical trial doesn't support piperacillin-tazobactam for resistant BSIs

Originally published by CIDRAP News Sep 11

The results of a randomized clinical trial published today in JAMA indicate that the combination therapy piperacillin-tazobactam should not be used as carbapenem-sparing therapy in patients with bloodstream infections caused by ceftriaxone-resistant E coli or K pneumoniae.

The noninferiority trial, the results of which were reported in April at the European Congress of Clinical Microbiology and Infectious Disease, included hospitalized patients with ceftriaxone-resistant E coli or K pneumoniae from 26 sites in nine countries. Patients were randomly assigned 1:1 to receive either 4.5 grams of piperacillin-tazobactam—a beta lactam/beta lactamase inhibitor combination—every 6 hours, or 1 gram of meropenem every 8 hours. The primary outcome was all-cause mortality at 30 days after randomization, with a 5% noninferiority margin.

A total of 378 participants completed the trial and were assessed for the primary outcome. Of the 187 patients randomized to piperacillin-tazobactam, 23 (12.3%) met the primary outcome of mortality at 30 days, compared with 7 of 191 (3.7%) patients randomized to meropenem. Results were consistent in an analysis of the per-protocol population, with 30-day mortality in the piperacillin-tazobactam patients significantly higher than those treated with meropenem (10.6% vs. 3.8%). In addition, serious adverse events occurred in 5 of 188 patients (2.7%) treated with piperacillin-tazobactam, compared with 3 of 191 patients (1.6%) in the meropenem group.

"Among patients with E coli or K pneumoniae bloodstream infections and ceftriaxone resistance definitive treatment with piperacillin-tazobactam compared with meropenem did not result in noninferior 30-day mortality," the authors concluded. "These findings do not support the use of piperacillin-tazobactam in this setting."
Sep 11 JAMA abstract
Apr 24 CIDRAP News story "Combo antibiotic found inferior for MDR bloodstream infections"


Data show non-inferiority for combo antibiotic for serious pneumonia

Originally published by CIDRAP News Sep 11

Merck today announced that its antibiotic Zerbaxa (ceftolozane combined with tazobactam) was shown non-inferior to meropenem for adult patients who had either ventilated hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP), the company said in a news release.

This prospective, randomized, double-blind, multicenter phase 3 study assessed the safety and efficacy of Zerbaxa compared with meropenem in 726 adults with either ventilated HABP or VABP requiring intravenous antibiotic therapy. In the study, Zerbaxa was administered in an investigational 3-gram dose (compared with 1 gram of meropenem), and both drugs were given intravenously every 8 hours for 8 to 14 days, or for 14 days for Pseudomonas aeruginosa infection. Meropenem is an approved broad-spectrum injectable antibiotic widely used to treat serious infections.

Zerbaxa met the pre-specified primary end points, demonstrating non-inferiority to meropenem in day 28 all-cause mortality and in clinical cure rate. Zerbaxa is currently indicated in US adults for treating complicated urinary tract infections caused by certain gram-negative bacteria and for complicated intra-abdominal infections caused by certain gram-negative and gram-positive bacteria. Merck is based in Kenilworth, N.J.

Based on the study results, Merck plans to submit supplemental new drug applications to the FDA and European Medicines Agency (EMA) for this new indication.

"HABP and VABP are serious and life-threatening hospital related pulmonary infections, especially in patients with severe underlying medical conditions," said Roy Baynes, MD, PhD, senior vice president with Merck. 
Sep 11 Merck news release


Study shows little connection between C diff in food animals, humans

Originally published by CIDRAP News Sep 11

After observing a rise in Clostridioides difficile (formerly Clostridium difficile) infections in the central part of the state, Minnesota investigators discovered a 0% prevalence of C difficile in retail metal samples in the area and a 9% rate in animal fecal samples, but the isolates did not match human isolates well, demonstrating that neither meat nor food animals are an important source of infection in that area, according to a study yesterday in the Journal of Food Protection.

C difficile infection (CDI) can cause a serious, typically healthcare-associated infection. But community-associated CDI (CA-CDI) now accounts for about 50% of CDI cases in central Minnesota, the study authors write.

They said that, from November 2011 to July 2013, they cultured retail meat products and fecal samples from food-producing and companion animals in central Minnesota for the pathogen using standard methods. They recovered no C difficile from 342 retail meat samples but 51 (9.1%) from 559 fecal samples from food-producing animals.

They then compared the 51 livestock isolates with 30 archived local veterinary C difficile isolates and 208 human CA-CDI case isolates from central Minnesota from 2012 from the Minnesota Department of Health. "Overall," the researchers write, "the 81 animal source isolates and 208 human source isolates were highly diverse genetically." Only 5 human isolates were classified as animal source.

"These data do not support meat products or food-producing and companion animals as important sources of CA-CDI in the central Minnesota study region," the authors conclude.
Sep 10 J Food Prot abstract


Report identifies actions for making pharmaceutical AMR data public

Originally published by CIDRAP News Sep 10

The Wellcome Trust has released a set of recommendations from a pilot project to make human AMR data generated and collected by the pharmaceutical industry publicly accessible.

The 90-day pilot project, funded by Wellcome and led by the Open Data Institute, with input and advice from a steering group composed of representatives of industry, public health, and academia, aimed to come up with plans for making AMR data from pharmaceutical companies openly available for researchers, health professionals, and AMR surveillance systems. Pharmaceutical companies typically generate AMR data for their own development of antibiotics and publish papers with summarized data but do not make their complete datasets publicly accessible. Advocates believe these data can boost global AMR surveillance efforts.

The project began with a landscape analysis of the industry-generated AMR data that are currently available, based on a questionnaire sent to 11 companies. The analysis found that datasets held by pharmaceutical companies currently cover clinical isolates collected in laboratories from 93 countries, including countries where robust AMR surveillance data is limited. The analysis also found that the quality of data from industry was good, but that standardization could be improved, and that the data could be made more relevant to medical and public health professionals.

To make the AMR data from the pharmaceutical industry publicly available, and unlock the value of the data, participants at a workshop held at the end of the 90-day research phase came up with four recommendations: (1) Develop a public-private partnership among industry, public health agencies, and other AMR initiatives to provide a more informative, coherent, and openly accessible data landscape; (2) enable open innovation and data sharing within the AMR community by encouraging reuse of AMR data from the industry; (3) facilitate the development of common methodologic standards and data governance frameworks to enable data use by the scientific and public health professionals; and (4) launch an online data portal managed and governed by an independent party.

A post-project report concludes, "There is both a well-defined problem that needs solving and a community of stakeholders with the determination and commitment to do so. We recommend building on this momentum to make open pharmaceutical AMR surveillance data a reality." 
September 2018 Wellcome Trust/Open Data Institute report 

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