ASP Scan (Weekly) for Sep 15, 2017

Promising novel assay
Transmissible Enterobacteriaceae
Additional FMT benefits
Antibiotic use and VRE infections
European AMR initiative
Antibiotic-resistant brucellosis
Drug-resistant gonorrhea Rx
ESBL bacteria in street kids
Funding for new C diff drug
Antimicrobial resistance in Africa
Antibiotics for asthmatic children
Drug resistance in the ICU

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

Novel assay could help physicians differentiate viral, bacterial infections

Results from a new study in Pediatrics confirmed high performance of a novel diagnostic test to distinguish bacterial from viral infection in febrile children.

The test is a host-signature assay that measures the levels of three proteins in the blood—tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon y-induced protein 10 (IP10), and C-reactive protein (CRP)—then calculates a bacterial/viral likelihood score.

Although a previous study had indicated that the assay could differentiate bacterial from viral infections with high sensitivity and specificity, the aim of this investigation was to independently validate performance in a double-blind, multi-center clinical study focusing on pediatric patients and emergency department arrivals aged 3 months to 18 years old. The reference standard diagnosis was based on predetermined criteria plus adjudication by experts blinded to assay results.

In total, 597 serum samples were collected from children at five pediatric emergency departments, but after exclusion of patients who failed to meet inclusion criteria, the test was performed on 361 patients, with 239 viral, 68 bacterial, and 54 indeterminate reference standard diagnoses. The infectious cohort was sex-balanced, with an average age of 4.1 years and a wide range of fever temperatures, times from symptom onset, and clinical syndromes.

Of the 361 patients in the infectious cohort, the assay classified 209 patients with a viral outcome, 99 patients with a bacterial outcome, and 53 patients with an equivocal outcome. Primary analysis of the 307 patients with either a viral or bacterial reference standard diagnosis showed that the assay distinguished between viral and bacterial patients with 93.8% sensitivity and 89.8% specificity.

When compared with laboratory parameters and diagnostic markers routinely used in clinical practice to distinguish bacterial from viral infections, the assay outperformed white blood cell count and demonstrated significantly improved sensitivity and comparable specificity to absolute neutrophil count, while also outperforming CRP and procalcitonin tests.

"Taken together with the high performance observed in other independent studies, these data support a new effective tool to help clinicians avoid missing bacterial infections or overusing antibiotics," the authors write.
Sep 13 Pediatrics abstract


Non-E coli Enterobacteriaceae found to be more transmissible in ICUs

Non–Escherichia coli Enterobacteriaceae (non-EcE) such as Klebsiella pneumoniae are nearly four times more transmissible than E coli in intensive care units (ICUs), Dutch scientists report in Clinical Infectious Diseases.

In the post-hoc analysis of a multicenter study conducted in 13 European ICUs, the researchers used prospective surveillance data from more than 11,000 patients and a mathematical model to estimate the transmission capacities of extended-spectrum cephalosporin-resistant E coli and non-EcE, which have become an increasing problem in hospitals in recent years. Understanding the transmission dynamics of these pathogens is considered essential for designing effective infection control measures.

Among the 11,420 patients in the study with at least one culture result, 637 patients were found to be colonized with E coli and 1,184 with non-EcE (including Klebsiella, Enterobacter, Serratia, and Citrobacter species). The admission prevalence was 3.8% for non-EcE (74% of which were K pneumoniae). Acquisition rates were 7.4 and 2.6 per 100 admissions at risk for non-EcE and E coli, respectively. The estimated transmission capacity of non-EcE was 3.7 times higher than that of E coli, with single admission reproduction numbers of 0.17 for non-EcE and 0.047 for E coli.

The authors of the study say the finding that the reproduction numbers were below the critical threshold of 1 suggests that outbreaks in ICUs typically remain small with current infection control policies. But they warn that if problems emerge, such as an outbreak of colistin-resistant Enterobacteriaceae, "more measures are needed to control a K pneumoniae outbreak than are needed to control an E coli outbreak."
Sep 15 Clin Infect Dis abstract


Study finds FMT may have additional benefits for gut microbiome

In another study yesterday in Clinical Infectious Diseases, Canadian investigators report that fecal microbiota transplantation (FMT), a non-pharmacologic approach to treating recurrent Clostridium difficile infection (CDI), may be a novel strategy for removing additional drug-resistant bacteria from the gut microbiome.

For the study, the researchers performed whole-metagenome DNA sequencing on stool specimens from eight donor-recipient pairs, both prior to FMT and at six visits following FMT. They were looking to characterize changes in microbiota composition and antimicrobial resistance gene carriage following the procedure, in which healthy donor feces is transplanted into the intestinal tract of patients who have recurrent CDI. The purpose of the investigation was to replicate previous reports of several types of multidrug-resistant bacterial pathogens being eliminated in patients who had undergone FMT for recurrent CDI.

Sequencing of the 64 total metagenomics data sets indicated significant changes in the intestinal microbiota of the FMT recipients. Normal commensal bacteria (BacteroidesEubacterium) increased in abundance, while opportunistic pathogens like K pneumoniae decreased. In addition, the researchers found that a total of 95 resistance genes—including clinically relevant quinolone, beta-lactamase, extended-spectrum beta-lactamase (ESBL), and vancomycin-resistant genes—were depleted in the FMT recipients.

They also, however, found evidence that 37 resistance genes (conferring ESBL and quinolone resistance) had been transferred from donors to recipients via FMT. The authors say this finding is not surprising, since some resistance genes are endogenous to commensal bacteria, but they note that it underscores the importance of selecting and screening for healthy FMT donors.

"FMT may be a non-pharmacologic approach to managing patients colonized with or at risk from infections due to multidrug-resistant bacteria," the authors write. "It is still not clear how effective or durable this approach could be, but it seems promising."
Sep 15 Clin Infect Dis abstract


Specific antibiotics linked to risk of hospital-acquired VRE infections

Originally published by CIDRAP News Sep 14

German researchers have found indications that the risk of acquiring healthcare-associated vancomycin-resistant enterococci (HA-VRE) is linked to the use of specific antimicrobial agents, according to a study yesterday in Antimicrobial Resistance and Infection Control.

The study, conducted at a hospital in Berlin from January 2014 through December 2015, included data on more than 200,000 patients from 61 wards, including surgical wards, medical wards, intensive care units (ICUs), and hemato-oncology wards. VRE isolates, both from clinical infection samples and colonized patients, were labeled as HA-VRE if they were identified 3 days or later after hospital admission, and otherwise as community-acquired (CA-VRE). The researchers also collected data on all antibacterials for systemic use to calculate ward-specific antibiotic consumption

Overall, 1,430 VRE cases were identified, with 409 (28.6%) considered hospital-acquired. The highest HA-VRE rates were observed in ICUs, and the lowest rates were on medical wards. Median antibiotic use on all wards was 76.8 defined daily doses (DDD) per 100 patient-days (PD), with use of broad-spectrum antibiotics (carbapenems, third-generation cephalosporins, and glycopeptides) 3 to 13-fold higher on ICUs compared with medical wards.

Using a multivariable regression model, the researchers determined that carbapenem use in the current month and glycopeptide use in the previous month increased the risk for HA-VRE by 1% per 1 DDD/100 PD and 3% per 1 DDD/100 PD, respectively. When just clinical VRE samples were considered, only glycopeptide use showed a statistically significant association. Detection of at least one patient on a ward with CA-VRE in the current month was found to nearly double the risk of having HA-VRE, a finding that suggests person-to-person transmission.

The authors say the study indicates that a multifaceted approach to lowering HA-VRE rates is required, "including prudent use of antimicrobial agents as well as implementation of and strict compliance to infection control measures to prevent VRE transmission."
Sep 13 Antimicrob Resist Infect Control study


EU initiates Joint Action to combat resistance continent-wide

Originally published by CIDRAP News Sep 14

A European Union Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EU-JAMRAI) was launched yesterday at the French Ministry of Health in Paris. More than 44 partners and 22 collaborating stakeholders participated, according to a news release from the EU Consumers, Health, Agriculture and Food Executive Agency (CHAFEA).

"The Joint Action EU-JAMRAI aims to bring together the participating EU member states and international organizations, institutes, universities in order to contribute towards tackling antimicrobial resistance and healthcare-associated infections," CHAFEA said in the release. "It will capitalize on existing initiatives and propose concrete steps to reduce the burden of antimicrobial resistance."

EU-JAMRAI will identify the best programs for combating antimicrobial resistance (AMR) currently in use and examine how cooperation at the EU level can improve national AMR-related policies, according to a Science/Business story. The effort will also identify and test evidence-based measures to address AMR and hospital-acquired infections in different contexts and provide recommendations to policymakers.

EU-JAMRAI has a €4 million ($4.8 million) budget to support EU member states in developing and implementing national strategies, ensure a common approach in Europe to the global AMR action plan, and produce guidance documents and tools for member states, among other goals, the story said.
Sep 6 CHAFEA news release
Sep 12 Science/Business story
Sep 13 agenda of kickoff meeting


Antibiotic-resistant brucellosis case tied to raw milk

Originally published by CIDRAP News Sep 14

A person who consumed raw milk from the K-Bar Dairy in Paradise, Texas, is hospitalized with brucellosis, caused by a rifampin/penicillin-resistant strain of RB51 Brucella, the Centers for Disease Control and Prevention (CDC) said in a Health Alert Network (HAN) statement yesterday. The Texas Department of State Health Services and the CDC are investigating the case.

According the CDC, milk samples from the dairy tested positive for the RB51 Brucella strain. People who consumed milk from the dairy between Jun 1 and Aug 7 should receive appropriate post-exposure prophylaxis, which is a combination of doxycycline and trimethoprim/sulfamethoxazole, for 21 days, the agency said.

Brucellosis is a serious infection that can lead to swelling of the heart, liver, and spleen. It commonly causes fever, sweating, malaise, and joint pain. 
Sep 13 CDC HAN statement


Study finds no link between US antibiotic prescribing, resistant gonorrhea

Originally published by CIDRAP News Sep 13

Although overuse of antimicrobials is a known contributor to antimicrobial resistance in general, researchers reported yesterday they could find no association between numbers of US antimicrobial prescriptions during a recent 8-year period and resistance in the bacteria that causes gonorrhea.

The researchers, from the Centers for Disease Control and Prevention (CDC) and several other institutions, note that Neisseria gonorrhoeae has developed resistance to every antimicrobial prescribed for it over the years and has been declared an urgent resistance threat by the CDC.

Writing in Emerging Infectious Diseases, the team said it is unclear to what extent antimicrobial use contributes to the emergence of gonococcal resistance in the United States.

To investigate the question, they gathered county-level antimicrobial susceptibility data from the CDC's Gonococcal Isolate Surveillance Project (GISP), county-level antimicrobial consumption data from the private company IMS Health, and demographic data from the US Census Bureau. The study covered the years 2005 to 2013.

The research included susceptibility test results for 43,852 N gonorrhoaea isolates taken from men treated for gonococcal urethritis at clinics for sexually transmitted infections. The isolates were tested against azithromycin, ceftriaxone, ciprofloxacin, penicillin, spectinomycin, and tetracycline. The IMS Health data covered more than 70% of all outpatient prescriptions during the study period.

Using multivariable statistical models, the team found no associations between N gonorrhoeae susceptibility and the numbers of prescriptions of any of the studied drugs.

Writing on what might explain the results, the authors speculated that factors other than population-level prescribing rates, such as importation of resistant strains, might contribute to gonococcal resistance. Or, they said, their data sources or methods might not have been sensitive enough to detect a relationship between prescribing and resistance.

The findings "suggest that population-wide domestic antimicrobial drug prescribing rates might not play a prominent role in the emergence of gonococcal resistance in the United States," they conclude. "Other means, such as importation from other countries, might play larger roles. Through this lens, enhanced surveillance for and public health capacity to respond to imported resistant strains are important strategies." 
Sep 12 Emerg Infect Dis report


High levels of resistant bacteria found in Tanzanian street children

Originally published by CIDRAP News Sep 13

A study yesterday in PLoS One found a high incidence of fecal carriage of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae among street children in Mwanza city, Tanzania, a port city of almost 3 million people.

The researchers analyzed stool samples obtained from 107 street children in 2015 and found ESBL-producing Enterobacteriaceae (EPE) in 34 of them (32%). Out of 36 isolates from the 34 children, 36 (100%), 35 (97%), 25 (69%), and 16 (44%) were resistant to tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin, and gentamicin, respectively.

The CTX-M-15 ESBL gene was detected in 27 isolates, or 75%. About 83% of the resistant pathogens were E coli.

The authors say their study "highlights the need for multidisciplinary approaches to understand the epidemiology and drivers of antimicrobial resistance in low-income countries."
Sep 12 PLoS One study


BARDA provides $32 million for new C difficile drug candidate

Originally published by CIDRAP News Sep 12

The Biomedical Advanced Research and Development Authority (BARDA) has awarded drug maker Summit Therapeutics $32 million over the next 2 years for development of a new antibiotic for C difficile infection (CDI).

The money will enable UK-based Summit to conduct phase 3 clinical trials of Ridinilazole, an orally administered small-molecule antibiotic that specifically targets C difficile bacteria while leaving beneficial gut bacteria alone, according to a news release yesterday from the Department of Health and Human Services (HHS), BARDA's parent agency. A phase 2 proof-of-concept clinical trial showed that the drug was highly preserving of the microbiome of patients compared the standard of care, vancomycin, and substantially reduced rates of recurrent C difficile.

CDI occurs in patients as a result of prolonged use of wide-spectrum antibiotics, which kill the body's beneficial gastrointestinal flora and allow C difficile bacteria to flourish. Treatment with wide-spectrum antibiotics further disrupts the gut microbiome, which can lead to recurrence. Recurrent CDI occurs in 20% to 30% of patients, with increasing rates of recurrence with each subsequent episode. The Centers for Disease Control and Prevention estimates that C difficile causes nearly half a million infections and 15,000 deaths each year.

Ridinilazole has received Qualified Infectious Disease Product designation from the Food and Drug Administration (FDA), which puts the drug on a fast track for FDA review.

BARDA, an agency within the HHS Office of the Assistant Secretary for Preparedness and Response, is funding the development of Ridinilazole as part of its efforts to develop drugs that treat biothreats such as anthrax and tularemia. Anthrax and tularemia infections require 60 or more days of antibiotic treatment, which can put patients at risk for CDI.

"To save lives from biothreats, whether it's anthrax or tularemia, doctors must be able to treat not just the biothreat itself but also opportunistic secondary infections that may occur,” BARDA director Rick Bright, PhD, said in the HHS release. "Partnering to develop drugs that treat biothreats as well as common, serious infections has proven to be an innovative, sustainable business model for industry and the federal government."
Sep 11 HHS press release
Sep 11 Summit Therapeutics press release


High levels of antimicrobial resistance, dearth of data found in Africa

Originally published by CIDRAP News Sep 12

A systematic review of studies on antimicrobial resistance (AMR) in Africa has found high levels of resistance to commonly prescribed antibiotics. Of greater concern, however, is a lack of recent AMR data for more than 40% of the continent, a finding that highlights the significant knowledge gaps hindering efforts to fully understand the global magnitude of the problem.

The review, published yesterday in BMC Infectious Diseases, identified 144 studies on AMR prevalence and surveillance in Africa published from 2013 through 2016; the selected studies analyzed samples from a total of 149,733 patients. The highest percentage of studies (40.9%) were from countries in East Africa, and the fewest studies (4.2%) were from countries in the South African region. No studies were identified in 23 of 54 (42.6%) countries.

In the 144 studies analyzed, 13 gram-negative and 5 gram-positive bacteria were tested against 37 different antibiotics. Overall resistance to commonly used drugs like amoxicillin (median resistance [MR], 72.9%) and trimethoprim/sulfamethoxazole (MR, 75%), the first-line drugs for urinary tract infections, was high. MR of E coli, the most common gram-negative bacterium reported, to amoxicillin and trimethoprim was 88.1% and 80.7%, respectively. Among gram-positive bacteria, penicillin resistance in Streptococcus pneumoniae was reported in 14 of 144 studies, with an MR of 26.7%.

Among other significant findings, ciprofloxacin resistance in Salmonella Typhi was rare, and no documented ceftriaxone resistance was reported in Neisseria gonorrhea. Ampicillin resistance in Haemophilus influenzae was high (MR, 100%). Carbapenem resistance was common in Acinetobacter spp and Pseudomonas aeruginosa but uncommon in Enterobacteriaceae. Vancomycin showed the lowest resistance pattern for all tested gram-positive bacteria.

The authors of the study highlight the overall lack of AMR data and note that the lack of consistency in measurement and reporting of susceptibility data makes it difficult to compare findings among different countries. They suggest that standardizing AMR methods and interpretation guidelines "could allow for better comparability of results and improved resistance tracking."
Sep 11 BMC Infect Dis study


More children with asthma getting unnecessary antibiotics, study finds

Originally published by CIDRAP News Sep 11

New research presented today at the annual meeting of the European Respiratory Society (ERS) indicates that children with asthma are more likely to be prescribed antibiotics than those without a diagnosis of asthma, even though antibiotics are not recommended for asthma treatment.

The study, presented by Esme Baan, MD, of Erasmus University in the Netherlands, compared antibiotic prescription data for 1.5 million children from the United Kingdom, including 150,000 with asthma, and 375,000 from the Netherlands, including approximately 30,000 with asthma. The patients, ages 5 to 18 years, were identified from population-based primary care databases in both countries.

Baan and her co-authors found that 197 antibiotic prescriptions were dispensed per 1,000 children with asthma per year in the Netherlands, compared with 126 prescriptions per 1,000 children without asthma. The United Kingdom saw 374 antibiotic prescriptions per 1,000 children with asthma annually, compared with 250 prescriptions per 1,000 children without asthma. In both countries, amoxicillin was the most commonly prescribed antibiotic.

Baan said in a news release that their analysis found most of the antibiotic prescriptions in the asthmatic children were linked to asthma exacerbations or bronchitis—conditions often caused by a virus.

"It can be difficult for a GP [general practitioner] to differentiate between a deterioration in asthma symptoms and a bacterial respiratory infection," Baan said. "We think this might be leading to more antibiotic prescriptions in children with asthma."

The Netherlands and the United Kingdom both follow the same international guidelines on asthma treatment, which state that antibiotics should not be given for deterioration in asthma symptoms. Baan says she suspects the situation may be similar in other countries.
Sep 11 ERS International Congress 2017 news release
Sep 11 MedPage Today story


Environmental hygiene cited as key to combating resistant bacteria in ICU

Originally published by CIDRAP News Sep 11

Clinicians in Spain were able to combat a simultaneous intensive care unit (ICU) outbreak of OXA-48–producing Enterobacteriaceae (OXA-48-PE) and multidrug-resistant Acinetobacter baumannii (MRAB) by focusing on environmental hygiene and other measures, according to a new study in the American Journal of Infection Control.

The authors describe on outbreak from July to October 2015 that involved 13 patients colonized or infected by OXA-48-PE and 18 by MRAB in an ICU. Interventions included patient isolation, daily hygiene with 4% chlorhexidine soap, and contact precautions. An in-depth cleaning of the ICU was performed with a chlorine solution, followed by decontamination with vaporized hydrogen peroxide (VHP). Researchers obtained environmental samples before and after the decontamination.

The cumulative incidence of OXA-48-PE and MRAB was 3.48% and 4.81%, respectively, before interventions. In the period after the intervention, the rates were 0.8% and 0%, respectively. Before the VHP biodecontamination, 4.5% of environmental samples were positive for OXA-48-PE and none for MRAB. After biodecontamination, 1.4% of samples were positive for OXA-48-PE and none for MRAB.

The authors conclude, "This study emphasizes the importance of environmental hygiene in the control of outbreaks caused by microorganisms of high environmental impact. The rapid effect after the VHP treatment suggests an influence of this measure in eradication."
Sep 8 Am J Infect Control study

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