UN assembly outlines goals for reigning in resistance

At the September 2016 High Level UN General Assembly (UNGA) meeting on antimicrobial resistance, 193 U.N. member countries agreed to a political declaration, committing them to key action steps for “the greatest and most urgent global risk.”  The declaration evolved from a platform of four agreed-upon needs:  the spurring of novel diagnostics and therapeutics to address AMR; assuring equitable access to the above by developing countries; enhancing efforts for surveillance of antibiotic use and resistance; and measures to assess progress.  The declaration encompassed commitments in the context of a One Health approach, soliciting participation by 193 national governments, 30 CEOs of global companies involved in animal protein production, and 13 pharmaceutical companies.  An ad hoc committee will be established for guidance on implementation and tasked with producing a progress report in 2018. The PEW Charitable Trusts, in conjunction with several other organizations, has formed the Conscience of Antimicrobial Resistance Accountability (CARA), which commits them to ensuring action on the meeting objectives.

APUA was represented at the UNGA meeting by Program Director, Jane Kramer.  For commentary on this momentous, unprecedented event, visit the blogs by Maryn McKenna and David Shlaes. 

CDC fuels antibiotic resistance research with $14 million; 34 projects funded

As part of the Centers for Disease Antibiotic Resistance Solutions Initiative, 34 projects will receive funding to explore novel approaches towards the antibiotic resistance problem, with a major focus on the human microbiome in prediction and prevention of drug-resistant infections. The list of awardees which includes numerous universities, two nonprofit organizations and one commercial company can be found here.

According to CDC director Tom Frieden, understanding the role of the microbiome is “key to innovative approaches to combat antibiotic resistance, protect patients, and improve antibiotic use.”  The projects will examine how antibiotics interrupt the healthy microbiome, placing patients at risk, and also explore stewardship programs to protect a healthy microbiome.

U.S. Food and Agriculture Association (FAO) releases 4-year action plan

Global antimicrobial consumption in livestock is currently estimated at 60,000 tons annually. With the anticipated doubling of antimicrobial use in pig and poultry production, The FAO has unveiled an Action Plan on Antimicrobial Resistance 2016-2020, aimed at helping governments create national strategies for tackling antimicrobial use (AMU) and resistance (AMR) in their food and agriculture sectors by mid-2017.  Key features of the plan include: 1) improving awareness of AMR issues among all stakeholders; 2) building surveillance capacities in food and agriculture for AMR and AMU; 3) strengthening governance; and 4) promoting prudent use practices in food and agriculture systems.

European animal-antibiotic sales data show downward trend

Twenty-eight European countries have contributed veterinary antibiotic sales data to a report that shows a declining trend in the total sales of food-animal antibiotics between 2011 and 2014.  While the overall decline was 2.4%, in 24 of the countries, the rate averaged 12%.  The data are collected annually by ESVAC (European Surveillance of Veterinary Antimicrobial Consumption) which maintains an interactive database, launched in 2015, that facilitates searching and data analysis.  The database has been used by the European Medicines Agency (EMA) to inform antimicrobial policy and to track responsible animal use. 

No similar records of sales data are available in the U.S. However, in May 2016, the FDA issued a final rule requiring drug makers to report quantities of antibiotics that are sold to various food-producing livestock. Total antibiotic usage for livestock reportedly rose 22% between 2009 and 2014.

 European farmers battle livestock-associated MRSA

Livestock-associated MRSA (LA-MRSA) was first reported in Denmark in 2006 and has since spread rapidly through Denmark’s swine industry, which exports breeding stock to 48 European countries. It is estimated that 63% of Danish swine are infected with LA-MRSA strain CC398 and more than 12,000 Danes are likely carriers. The strain is often asymptomatic in animals, but can be highly resistant and potentially deadly to humans.  As Danish pigs are not screened prior to export and no reporting is required, importers are unknowingly accepting contaminated stock. With a loophole in import regulations and no surveillance program, the UK is vulnerable to CC398, and the recent finding of three contaminated meat samples in UK supermarkets has raised alarm.

Norwegian “search and destroy” strategy identifies farm worker import of MRSA

While other countries such as the UK are at risk from contaminated imports, Norway is the sole country to employ a “search and destroy” strategy for eliminating livestock-associated MRSA (LA-MRSA). Through continuous monitoring and slaughtering of infected herds (including farm disinfection since 2014), Norway has become the only country to successfully eliminate MRSA from its herds.  The goal is to prevent MRSA infection in pig herds from infecting the general population.  Despite a near total ban on imports, three outbreaks were reported during a 2008-2014 survey of Norwegian farms.  An epidemiological investigation has now demonstrated for the first time that humans were likely the primary transmitters of infection to the Norwegian pigs. The outbreak strains showed genetic similarity to strains from Danish farms and are believed to be imported via foreign farm workers who had contact with pig farms in Denmark.  The finding has prompted consideration of mandatory screening of farm workers before entering Norwegian swine farms.

New variant of LA-MRSA shared by animals and humans

A new strain of MRSA, which does not appear in Danish livestock, has now emerged in 10 Danes living in urban areas. The new variant, reported in the September issue of Clinical Infectious Diseases, is identical to strains found in poultry imported from other European countries and is believed to be transported through the food supply.  According to Lance Price, the lead US-based researcher, “We’ve known for several years that people working directly with livestock are at increased risk for MRSA infections, but this is one of the first studies providing evidence that everyday consumers are also potentially at risk.” Since inspectors currently focus primarily on Salmonella and other more typical food pathogens, it is now believed that surveillance should be expanded to include this new pathogen.  The findings underscore the ease with which bacteria travel internationally and the need for a one-health policy that will reduce antibiotic use on industrial farms globally.

PEW calls for changes to FDA Guidance for judicious use of antibiotics in animals

The U.S. FDA Guidance for Industry #213 will go into effect on Jan 2017.  The new legislation requires the supervision of a veterinarian for administration of antibiotics to food animals and also asks pharmaceutical companies to voluntarily remove indications for growth promotion use of antibiotics from its labels.  A recent analysis by the Pew Charitable Trusts has reported that 149 of 389 currently approved labels fall short of the FDA’s judicious use recommendations by inadequately specifying maximum durations or conditions of use, or by providing appropriate dosage amounts. The PEW report has requested FDA action to rectify the noted loopholes that still permit the use of medically important antibiotics.

Study finds higher levels of antimicrobial resistance in resource-poor nations

A first-of-its-kind study by the Center for Disease Dynamics, Economics & Policy (CDDEP) has demonstrated an association between the prevalence of antimicrobial resistance (AMR) and the national income status.  Using the Center’s ResistanceMap collection of antibiotic consumption and antibiotics resistance data, the group has found an inverse relationship: increasing AMR correlates with decreasing national income.  The poorest nations have the highest prevalence.

In addition, an Emerging Infectious Diseases publication has reported a study on antibiotic resistance in children hospitalized as a result of the civil war in Syria, where infrastructure and sanitation are seriously compromised.  Eighty-nine of 128 children were infected with multi-drug resistant pathogens and most of these (90%) occurred among the wounded.

The findings emphasize the need for urgent action to confront antimicrobial resistance in resource-poor settings.

ANTIMICROBIAL STEWARDSHIP: Pitfalls and Progress

  • Antibiotic prescription choices fall seriously short of recommendations

In the initial report of the Centers for Disease Control and the Pew Charitable Trusts, it was revealed that 30% of the 47 million annual outpatient antibiotic prescriptions in the U.S. are unnecessary.  Now, a second issue brief has addressed the topic of appropriate antibiotic selection. New data assembled by the CDC, PEW and other experts, and published in JAMA Internal Medicine show that, of the 44 million prescriptions issued annually for sinus infection, middle ear infections and pharyngitis, only 52% of treated patients received the recommended first-line drug (generally penicillin or amoxicillin +/- clavulanate). The most commonly prescribed antibiotic was a macrolide (e.g., azithromycin) which is a broad-spectrum drug to which there is already significant resistance in Streptococcus pneumoniae, a common agent of these infections.  

An accompanying report, posted by PEW, has set targets for improving antibiotic selections.  PEW estimates that at least 80% of outpatients should be receiving first-line antibiotics. The targets are intended to help cut inappropriate use by 50% by 2020 as outlined in the President’s National Action Plan for Combating Antibiotic Resistant Bacteria (P-CARB).

  • CDC releases new guidance for outpatient antimicrobial stewardship

In an effort to reduce a gap in its antimicrobial stewardship guidelines, the CDC has released a new publication, titled Core Elements of Outpatient Antibiotic Stewardship, designed to cover antibiotic prescribing in doctor’s offices, emergency departments and urgent care and retail clinics. The document was released to coincide with CDC’s Get Smart Week (Nov 14-20), and complements its previous stewardship guidelines released in 2014 and 2015 that cover stewardship in hospitals and nursing homes.  The guidelines, reported in MMWR, outline strategies to improve prescribing and reduce antibiotic use.  The release was complemented with a webinar given by author Katherine Fleming-Dutra from the Division of Healthcare Quality Promotion, who has said “commitment is the foundational piece.” Practical action steps and recommendations for tracking and reporting and educating physicians and patients are also included.

  • New tool may aid antimicrobial stewardship in pediatric RTIs

A new study published in the Lancet Respiratory Medicine proposes a novel decision tool that can help doctors with more appropriate treatment of children having cough and respiratory tract infection. In an examination of over 8000 children from GP offices in England, the researchers used multivariable modeling to identify 7 factors that could predict the likelihood of hospitalization:  short illness (<3days);  temperature over 100F; age under 24 months; sub-costal or intercostal recession, wheeze, asthma and vomiting— or STARWAVe for short.  The strategy is perceived as a useful antibiotic stewardship tool.  Children with low probability of hospitalization (having 0 or 1 predictors) would receive no antibiotics; those with normal risk (2 or 3 predictors) would receive no antibiotics or delayed antibiotics, and those with 4 or more (high risk) would be monitored for deterioration and re-examined in 24 hours.  The tool requires further testing in clinical settings, but is estimated to reduce overall antibiotic use by 10%.  

DIAGNOSTICS IN THE NEWS: Advances shorten delays in diagnosis

  •  Rapid diagnostics reduce MRSA transmission in emergency hospital

Using a combination of PCR diagnostics with pre-emptive isolation precautions and rigorous hygiene management, researchers at a Berlin orthopedic and trauma surgery unit reported significant reduction in nosocomial MRSA colonization rates.  Upon admission, all high-risk patients for MRSA were isolated and screened using PCR diagnostics—an  ultra-rapid technique that identifies MRSA in under two hours.  The combination approach reduced nosocomial MRSA cases from 7 per 10,000 patient-days to under 3 per 10,000 patient days.  

Generally, patients are not isolated until MRSA is identified—typically in 2-3 days using conventional screening.  The study demonstrated the critical role of this initial time period in facilitating bacterial spread, and the necessity of using the combination approach to minimize MRSA dispersion.  

  • Vietnam study shows C-reactive protein testing reduces antibiotic use

European studies have demonstrated the value of a rapid point-of-care diagnostic, i.e., the C-reactive protein test, in reducing inappropriate antibiotic use for treating outpatient respiratory tract infections (RIs).  Now, for the first time, a study (Lancet Global Health) of 2000 adults and children from a resource-constrained setting in 10 primary healthcare settings in N. Vietnam has demonstrated similar efficiency.  Using CRP diagnostic testing to rapidly distinguish between serious and self-limiting RIs, the investigators found a nearly 18% reduction in antibiotic prescriptions when compared with traditional diagnostic methods.

For more information and a discussion of this topic, see APUA’s 2015 publication, Improving outpatient antibiotic prescribing for respiratory tract infections: results of new algorithms used in European trials (J of Infect Control and Hospital Epidemiology) which emanated from an expert panel discussion organized by APUA in 2013.

 HYGIENE NEWS – advances in understanding and combating AMR infections

  • C. difficile infection found to correlate with previous patient on antibiotics

The spores of Clostridium difficile are very difficult to eradicate and known to contaminate hospital room surfaces such as beds, rails, floors and walls, resulting in exposure to incoming patients.  A large retrospective study of hospitalized patients conducted between 2010-2015 by Elaine Larson and her team, and reported in JAMA Internal Medicine, has now examined the impacts on patients who occupy the same bed in which the prior patient had received antibiotics.   After adjusting for factors that are known to cause C. difficile infection (CDI), and removing cases in which the initial patient had CDI, the study found that the risk of CDI increased by 20% for a patient whose hospital bed had been previously occupied by someone who was receiving antibiotics.  The study is considered to be a direct example of the harm imposed by antibiotics on patients who do not themselves receive antibiotics.

  • Hospital laundry and sinks found to harbor superbugs

In a FEMS Microbiology Letters study of hospital linens tested at a centralized Seattle, Washington laundry facility, researcher Marilyn Roberts and team found substantial contamination of receiving and sorting areas with the spore-forming hospital pathogen, C. difficile.  Twenty three per cent of dirty linen areas were contaminated, while only 2% of clean linen areas tested positive. According to Dr. Roberts, “…laundry facilities should be considered an extension of the healthcare environment when considering infection prevention and occupational health.”  It is estimated that 10-25% of hospitalized adults carry C. difficile.  

The push to install hospital sinks in patient rooms in recent years has been an effort to facilitate hand hygiene and to help prevent infection transmission. As a result of recent nosocomial outbreaks however, this bedrock of hospital hygiene has come under scrutiny for the stubborn biofilms that lurk there.  Biofilms are notoriously difficult to eradicate and pose a serious threat to post-surgical or immunocompromised individuals.  While CDC studies of contaminated drains found no evidence of bacterial transfer from sink to hands, serious outbreaks have provoked more intensive investigation and have targeted gooseneck faucets as a culprit.  Because of the downward direct pressure and force, this faucet style can cause splash-back of micro-droplets onto nearby porous surfaces where staff prepare medical equipment used in patient care. When sinks were covered or removed, the offending outbreaks of drug-resistant infections stopped.  The findings have led to investigation of better sink designs that minimize splash-back  and also towards promotion of a switch to alcohol gel when hands are not visibly soiled.

NOVEL ANTIMICROBIALS: mining exotic sites yields new compounds

  • Antibacterial peptides found in marsupial milk

In a recent issue of the APUA Highlights, we reported on the potent antibacterial activity of an ancient Kisameet healing clay uncovered from British Columbia, Canada. In examining another exotic source, researchers at Sydney University in Australia have found antibacterial peptides in the milk of Tasmanian devils, wallabies and opossums. Whereas humans have just one cathelicidin peptide in their milk, the marsupials have between six and twelve cathelicidin compounds, which protect them from infection during gestation in the mother’s pathogen-laden pouch.  Researchers K. Belov and team extracted the cathelicidin DNA sequences and created artificial peptides which they then tested against bacteria and fungi. Two of these, Saha-CATH5 and Saha-CATH6, demonstrated broad-spectrum activity and were potent against both MRSA (methicillin-resistant Staphylococcus aureus) and VREF (vancomycin-resistant Enterococcus faecium).  At concentrations toxic to bacteria, Saha-CATH5 and Saha-CATH6 are non-injurious to human cells and thus are considered as promising candidates for drug development.

  • Human gut bacteria secrete antimicrobial

Researchers at Rockefeller and Rutgers Universities have tapped into the non-culturable populations of the human gut microbiome to mine for new antimicrobial compounds. In a departure from classic methodologies for discovering new antibiotics, they used DNA sequence technologies to identify unique codes for large peptide molecules that could have antimicrobial properties.  From 25 such sequences that they used to create synthetic compounds, they found two—derived from Rhodococcus spp  and named humimycin A and humimycin B)—that  were antimicrobial against pathogens and commensal strains.   While active against MRSA, humimycin became even more potent when used in combination with the β-lactam class of antibiotics.  In mice lethally infected with MRSA, and treated with humimycin alone, only 50% (5 of 10) survived.  However, survival increased to 100% when both drugs were given.  Researchers believe the findings will open a new pathway towards discovering additional antimicrobials in our own human microbiome.

  • Antibacterial compounds found in maggots

Maggots have a long history of use for debriding infected wounds and speeding healing. (See YouTube video on the benefits of maggot therapy here).  Now researchers from Swansea University’s Maggot Research Group in Wales have investigated anecdotal evidence of actual bacterial killing by maggots. They extracted maggot secretions of the common green bottle flyand isolated the responsible molecules, which they have trademarked as Seraticin. The next step is an elucidation of the actual molecules responsible for the antimicrobial activity, which they hope to synthesize and test against known antibiotic-resistant strains.

  • Cranberry compounds may help reduce dependence on antibiotics

Proanthocyanodins (PACs) from the American cranberry have previously been shown to possess anti-oxidant, anti-adhesion and antimicrobial qualities.  Now, investigators at McGill University in Quebec have hypothesized that PACs could be utilized to interfere with the infection process.  Using fruit flies infected with Pseudomonas aeruginosa, they were able to show protection, which was mediated by the cranberry extract’s ability to interfere with bacterial quorum sensing activity, i.e., the ability of bacteria to communicate with one another.  Specifically, the PACs reduce the level of N-Acyl homoserine lactones in gram-negative species.

The cranberry compounds reduced infection severity, allowing the flies to live longer. The researchers envision the cranberry compounds as a future component of the arsenal to reduce overall dependence on antibiotics.

  • Novel agar platform demonstrates microbial evolution

Utilizing a novel 4ft by 3ft petri dish platform, evolutionary scientists at MIT and Harvard Medical School have succeeded in visualizing the abstract idea of microbial evolution.  The agar platform contains an antibiotic gradient seeded with sensitive, motile bacteria.  Using time-lapse photography, the bacteria are seen mutating and growing towards the higher concentrations of antibiotic – essentially evolving into “superbugs” over a two-week time span. 

Besides dramatically demonstrating the concept of evolution, the experiment revealed an unexpected aspect of bacterial mutation.  It visualized the significance and role of the spatial dimension—a concept that has been difficult to study classically.   As the faster growing, resistant mutants moved towards a fresh food source, they essentially thwarted the growth of slower, mutant colonies—creating a physical blocking of mutational lineages, which occurs in biofilm formation. The platform allows reconstruction of phenotypic and genotypic evolutionary histories.

Researcher Tami Leiberman sees the demonstration as a useful one. “Getting more people to understand how quickly bacteria evolve antibiotic resistance might help people understand why they shouldn’t be prescribed antibiotics.  The drug resistance is not some abstract threat.  It’s real.”

APUA HEADQUARTERS NEWS

  • APUA supports bill to track superbug infections in California

A September report issued by the news agency, Reuters, has documented evidence that large numbers of infection-related deaths are going unreported in the U.S.  In 24 states plus Washington, D.C., seven of the most serious superbugs—VRE, Acinetobacter, C. difficile, MRSA, CRE, VISA and VRSA—are not counted.  Even in the states that do tally their counts, the numbers were starkly lower than those found by the Reuters independent investigators.

In California, the nation’s most populous state, Reuters has identified more than 20,000 deaths linked to antibiotic-resistant infections between 2003 and 2014.  While the state currently tracks 80 different types of communicable diseases (including AIDS, Hepatitis C and TB), it does not track antibiotic-resistant infections or the deaths resulting from them. Currently the CDC and state health departments lack the political, legal and financial clout to address the problem of unreported superbugs.  The reasons are varied, but include ignorance of the importance of accurate reporting; delays in acquiring test results; confounding by other serious medical conditions; and institutional resistance against disclosing failures in infection containment.

In December 2016, Sen. Gerry Hill (D-CA) will reintroduce legislation to make resistant infections reportable, and collect data that will help monitor trends, identify high risk areas and address the efficacy of prevention and control measures.  APUA has joined multiple stakeholders in supporting the proposed legislation. The bill follows a successful bid in 2014 (SB1311) by Sen. Hill to mandate the establishment of antibiotic stewardship programs in California hospitals.  However, the concurrent provision to track resistant infections was stripped out due to concerns over cost and reporting standards.  

  • APUA joins effort to adopt “Cures/Innovations” package

With the fast-approaching final window for passage of two important congressional bills related to the antimicrobial resistance problem, APUA has participated in a final push to raise awareness on Capitol Hill.  In responding to an effort led by S-FAR (U.S. Stakeholder Forum on Antimicrobial Resistance), APUA is one of ten organizations that has submitted a letter in support of the PATH and ADAPT acts.

Last year, the House approved the much-needed limited population antibacterial drug (LPAD) approval pathway at FDA as part of the 21st Century Cures Act (H.R.6).  The Senate HELP Committee followed this year with approval of a companion bill—the Promise for Antibiotics and Therapeutics for Health (PATH) Act, S. 185—as part of its own biomedical innovations package.  The bipartisan bills would help allow more feasible and efficient clinical trials for the most urgently needed antibiotics and promote appropriate use of these new antibiotics.

In its letter, APUA stated the importance of moving the Cures/Innovation package forward to a final vote as soon as possible. In the event of failure, APUA has asked that PATH/LPAD be advanced through another vehicle before Congress adjourns.   

EVENTS CALENDAR

November 30 - December 3, 2016: 16th Asia-Pacific Congress of Clinical Microbiology and Infection (APCCMI), Melbourne, Australia

December 11-14, 2016 ASM Conference on Antibacterial Development, Washington, DC

February 23-25, 2017: Antimicrobials 2017

February 25-26, 2017: StaphPath (inaugural meeting) Australian Society for Antimicrobials 18th Annual Scientific Meeting, Adelaide, Australia

February 26 - March 3, 2017: Antimicrobial Peptides Gordon Research Conference. Ventura, California

February 27, 2017: 7th Euro Global Summit on Clinical Microbiology, Amsterdam, The Netherlands

March 20-21, 2017: SMI’s 19th Annual Conference: Superbugs and Superdrugs - a focus on antibacterials.  London, UK

March 22–25, 2017: ASM Conference on Innovative Microbial Ecology for Mitigation of Antibiotic Resistance and Bacterial Diseases, Crystal City, VA

April 22-23, 2017: Global Health and Innovation Conference. Yale University, New Haven, Connecticut

April 22 – 25, 2017: 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Vienna, Austria

June 1-5, 2017: ASM Microbe 2017. New Orleans, LA, USA

June 14-16, 2017: Association for Professionals in Infection Control and Epidemiology (APIC) Annual Conference. Portland, Oregon, USA

 June 20 – 23, 2017: ICPIC 2017, 4th International Conference on Prevention and Infection Control, Geneva Switzerland

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