APUA HIGHLIGHTS: March 2016
APUA president Levy quoted in major media
In its Jan 15, 2016 article, “It’s the beginning of the end for meat raised with antibiotics” The Huffington Post outlines the previous 40-year trajectory for antibiotic use in food animals—a road that anticipates much stricter control by the end of 2016 when U.S. FDA regulations are imposed. The article cites the 1976 Levy farm study which first revealed the profound impacts of subtherapeutic antibiotics on the flora of chickens and humans alike. Levy remarked, “You can’t shy away from the fact that the most important risk factor of antibiotic usage in animals, people or agriculture is the emergence of resistance.” Decades later, and despite the mounting scientific evidence and public pressure from consumers and major food companies, some 32 million pounds of antibiotics are still used on food animals in the U.S. annually, signaling more work is needed before the practice is finally eliminated.
In its March 3, 2016 article “Antibiotic-free chicken chasing cage-free eggs” the Chicago Tribune highlights the public’s growing interest in poultry that hasn’t been fed growth-enhancing antibiotics. As the understanding of the dangers of antibiotic resistance grows, major poultry providers such as Purdue Farms and Tyson Food among others are responding by offering consumers antibiotic-free alternatives. APUA President Dr. Stuart Levy was among the first scientific researchers to look at the issue in the 1970s. His study found that chickens given antibiotics developed drug-resistant bacteria, findings that didn't sit well with the meat industry at the time. Decades later, Levy said he found it "fascinating" to see the meat industry come around. "Right now, I think the whole world is concerned about drug-resistant bacteria and use of antibiotics on animals is a big part of it," Levy said.
APUA supports new California legislation on antimicrobial stewardship
In 2014-2015, California State Senator Jerry Hill led several successful efforts to curb resistant infections, including laws mandating antimicrobial stewardship in California hospitals (SB 1311) and nursing homes (SB 361); continuing education for veterinarians (SB 361); and comprehensive regulation of antimicrobial use in livestock and establishment of antimicrobial stewardship in animal medicine (SB 27). APUA has now signed a letter in support of proposed legislation that would extend the antimicrobial stewardship requirement to include outpatient settings.
APUA endorses PATH Act
In a letter to members of the Senate HELP Committee (Health, Education, Labor and Pensions), APUA has joined members of S-FAR (U.S. Stakeholder Forum on Antimicrobial Resistance) in urging the slating of the bipartisan PATH Act for consideration on the Senate floor. The Promise for Antibiotics and Therapeutics for Health Act (S.185) would help encourage biomedical innovation and pave the way for establishing approval of a new drug category—the“limited population antibacterial drug (LPAD)”. The approval of LPADs would help fight serious infections affecting small patient populations for which large clinical trials are not feasible. Passage of the PATH Act would speed access and optimize safeguards for appropriate antibiotic use in these populations.
APUA lends support to UK Alliance to Save Our Antibiotics
The UK-based Alliance to Save Our Antibiotics is a 39-member coalition of EU organizations formed by the The Soil Association. The coalition has submitted a letter, supported by APUA, to the European Commission, urging it, as well as EU governments and the European Parliament, to support and implement an EU ban on the purely preventative, antibiotic treatment of groups of food animals in which no member has a diagnosable disease. The call for the ban was initiated by farmers’ unions of Denmark, Finland, Iceland, Norway and Sweden and is viewed as a unique opportunity for more responsible use of antibiotics in food animals.
APUA-Nepal issues new chapter Newsletter
APUA-Nepal has released its 12th issue of the APUA-Nepal Newsletter. The new issue updates disk susceptibility results obtained from E.coli, K. pneumoniae, Morganella andS. aureus obtained from Lumbini Zonal Hospital. It also reports the antibiotic susceptibilities of pus sample pathogens from different health centers.
ANTIBIOTIC RESISTANCE in the NEWS
New study supports APUA stance on routine antibiotics for malnutrition
In 2013, a New England Journal of Medicine article published evidence that supported routine use of antibiotic therapy (amoxicillin or cefdinir) in ready-to-use therapeutic food (RTUF) for pediatric outpatients with uncomplicated severe acute malnutrition. APUAtook issue with this position, citing the risk of antibiotic selective pressure leading to untreatable resistant infections. Alternatively, APUA suggested expansion of validated interventions, including breast feeding, probiotics and access to RTUF and clean water. Anew study by Sheila Isanaka and colleagues reported in the New England Journal of Medicine (Feb 4, 2016) provides additional validation for this viewpoint. Their double-blind study of >2400 children in Niger found no significant benefit from routine ampicillin use in recovery from severe acute malnutrition.
While ampicillin did reduce the risk of hospitalization, the outcomes of hospitalized children in the treated group did not differ from those in the placebo group. Thus, in regions having adequate hospital infrastructure to manage associated infections, the authors recommend eliminating the routine administration of antibiotics for children with severe acute malnutrition.
CDC issues new guidelines for upper respiratory tract infections
The CDC and the American College of Physicians have issued new guidance for doctors’ use in deciding if antibiotics are warranted for common acute respiratory tract infections (ARTI; e.g., acute bronchitis, pharyngitis, rhinosinusitis (sinus infection), and the common cold). Based on an extensive synthesis of current clinical guidelines from meta analyses, systematic reviews and randomized clinical trials, the Annals of Internal Medicine article presents best practices for antibiotic use in healthy adults andissues four summary statements of “high-value care advice”. In addition to the standard admonition against testing and/or issuing antibiotic prescriptions for the common cold and bronchitis (except in suspected pneumonia), the authors advise testing and treating patients with confirmed group A streptococcal pharyngitis and, in cases of rhinosinusitis, reserving antibiotic treatment for patients with persistent or worsening symptoms or having facial pain lasting a specified number of days. The recommendations also offer guidance on symptom relief, and provide a sample of a “symptomatic prescription pad” found on the CDC website.
Pharmaceutical biotech and diagnostics industries release declaration
On Jan 21, 2016, 85 companies and 9 industry associations signed and released theDeclaration by the Pharmaceutical, Biotechnology and Diagnostics Industries on Combating Antimicrobial Resistance at the World Economic Forum in Davos, Switzerland. Recognizing the important role they have to play in tackling the antibiotic resistance problem, the signees are committed to:
- Work to reduce the development of antimicrobial resistance through education, improved antimicrobial stewardship, by encouraging infection control, vaccination and prevention efforts and reducing environmental pollution from antibiotics
- Invest in R&D to produce new innovative diagnostics and treatments while encouraging open collaborations between industry and public researchers and working with payers and policymakers to address the unique challenges of this market and
- Improve affordable access to new and existing antimicrobials globally.The signees also called on governments to allocate funding to help create sustainable and predictable markets, and to implement local models that will achieve globally coordinated efforts.
For commentary on this declaration, see the 1/26/16 blog post by David Shlaes: Big Pharma and Antibiotic R&D – An Update
EU study reveals mismatch in public funding for antibiotic research
In a European analysis of publically funded antibiotic research performed between 2007 and 2013 (Lancet Infect Dis 2015), R. Kelly and colleagues identified 1,243 projects on antibiotic resistance, totaling €1.3 billion ($1.4 billion US) distributed between drug development (66%), transmission (15%), diagnostics (11%), interventions (4%) and environment/surveillance (3%). Top investors were Denmark, Estonia, Finland, the Netherlands, Sweden and the UK. Noting that investment currently does not correspond with the burdens imposed by antibiotic resistance, Kelly and coauthors hope the analysis will “prompt nations to pay due consideration to the existing research landscape when considering future investments.”
Latest AMR report focuses on vaccines and alternatives
The latest in a series of Antimicrobial Resistance Reports (AMR), led by Jim O’Neill (committee chair) and supported by the Wellcome Trust and the UK government, calls for wider use of vaccines and alternative approaches to combat the resistance problem. Comparing the problem of resistance to a “slow-motion car crash – one that has sadly already begun,” O’Neill calls for global coverage with the Streptococcus pneumoniae vaccine to reduce childhood deaths and prevent 11.4 million days of antibiotic use. Besides wider use of existing vaccines, the report encourages two additional interventions: sustained funding for supporting research into new vaccines and alternatives; and sustaining a viable market for needed products, including Advance Market Commitments and market entry rewards. You can view Vaccines and alternatives approaches: reducing our dependence on antimicrobials here.
WHO invites feedback on its antimicrobial resistance prevention and containment activities
The World Health Organization has released a survey to assess different stakeholders’ perceptions about the WHO’s past and present performance regarding the prevention and containment of antimicrobial resistance. As the WHO is in the process of implementing a new global action plan to contain antimicrobial resistance, the survey also aims to evaluate the expectations of the impact of the new action plan, and how the organization should move forward with its work. The anonymous survey can be found athttps://no.surveymonkey.com/r/whosurveyamr.
New diagnostic differentiates between viral and bacterial infections
Researchers at Duke University have developed a 10-hour blood test with 87% accuracy for classifying patients with influenza viruses, rhinoviruses, streptococcal and other common infections. The test is based on a patient’s unique and quantifiable response to these different infectious and non-infectious stressors and utilizes microarray technology to measure changes in gene expression. Researchers are actively working to reduce the assay time so that it can become a point-of-care diagnostic that could significantly reduce unnecessary antibiotic prescribing. The test improves markedly on the current procalcitonin test, which has an accuracy of 78%.
New weapons offer optimism in the battle against resistant bacteria
In the search for new approaches to the antibiotic resistance problem, several promising investigations are worth noting:
In a recent mBio publication, Julian Davies and his team at the University of British Columbia have reported on finding antibacterial activity from a rare Kisameet mineral clay, (trademarked as Kisolite), which was first used by early aboriginal tribes for treating assorted maladies. Extracts of the ancient clay, which to date have no reported toxicity to humans and no observable resistance, demonstrated biocidal activity against 16 strains of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterspecies). Said Davies, “… to our great surprise, the clay … was very, very active against most of the bacteria that we tested. It was a very strong antibiotic.” In other reports the clay also demonstrated prevention and dispersion of S. aureus and P. aeruginosa biofilms as well as antifungal properties.
Similar antibacterial activity against S. aureus has been reported in blue volcanic clay utilized medicinally by early Australian aboriginal societies.
Animal and human clinical trials will be needed to elevate the clay compounds from “naturopathic” status to an approved therapeutic in the U.S.
In another development, Spanish researchers Maria Getino and colleagues have found that chemicals called tanzawaic acids may inhibit the bacterial mating process known as conjugation. First isolated in 1997 from Penicillium spp, a dozen different forms of the acids have been discovered. After the testing of over 1600 marine microbe extracts, two members of the tanzawaic acid group — A and B —were shown to prevent conjugation and plasmid passage of resistance genes between E. coli. Importantly, compound B was found non-toxic to human cells, paving the way for investigations into potentially reducing resistance transfer and spread in human infections and also on farm environments. The findings were reported in PlosOne.
A new review in the Journal of Applied Microbiology provides greater insights into the potential applications of nisin, a bacteriocin derived from Lactococcus andStreptococcus species. Long-used commercially as a food biopreservative and for control of mastitis infection, nisin has been found to exhibit both anti-cancer and antibacterial properties. Study authors J.M. Shin et al examined nisin’s effects on infections of the skin, respiratory system and abdomen and in oral health. The compound proved effective against both MRSA and biofilms with no reports to date of bacterial resistance to the drug. Clinical trials in humans will be needed to determine its usefulness against antibiotic resistant infections, cancer and periodontal disease.
Look for an overview on the status and future of bacteriocins as therapy in APUA’s upcoming spring edition of the APUA Newsletter.
It is known that metal nanoparticles (e.g., gold and silver) are effective biocides, but also inflict collateral damage to surrounding cells. Now scientists at the University of Colorado at Boulder have described light-activated nanoparticles that can kill drug-resistant cells in vitro, while leaving monolayer cells intact. These “quantum dots” resemble the tiny semiconductors in consumer electronics, and when exposed to light, the normally inactive particles become photo-excited, transforming them into highly specific weapons for altering and killing superbugs. Importantly, the nanotherapy can be quickly modified to adapt to evolving resistance.
The push to legitimize bacteriophage therapy in the west has intensified. As an integral part of the U.S. White House national plan to fight drug resistance, a rigorously designedclinical trial to treat Staph aureus rhinosinusitis is now underway by AmpliPhi Biosciences Corp. in Richmond Va.
Another trial is pending in 2017 by TechnoPhage for treatment of diabetic foot ulcer. Anongoing trial by Phagoburn in 11 hospitals across Belgium, France and Switzerland is actively testing bacteriophages on Pseudomonas aeruginosa and E. coli infections in burn wounds. The phages for this study, which are derived from hospital sewage runoff and local rivers, are pretested for toxicity in miniature pigs and for efficacy in E. coli-infected mice prior to application in burn patients.
For an update on bacteriophage therapy, see the feature article by Drs. A. Sulakvelidze and J. G. Morris in the 2015 spring issue of the APUA Newsletter.
MRSA worsened by first-line antibiotics?
Between 30-80% of patients with MRSA are inappropriately treated—frequently with beta-lactam antibiotics. From investigations of MRSA infections in mice that were treated with beta-lactam antibiotics (Cell Host Microbe. 2015;18), researchers from Cedars-Sinai Medical Center found activation of a gene called mecA. MecA subsequently activates an alternative pathway for cell wall synthesis, allowing cell survival. In mice, it caused more severe skin infections by triggering a harmful inflammatory response. According to study co-author George Liu, “Individuals infected with MRSA who receive a beta-lactam antibiotic…could end up being sicker than if they received no treatment at all.” While the findings need confirmation in human trials, they emphasize the need for early diagnosis and avoidance of certain contraindicated antibiotics.
Antiseptic baths do not cause high levels of resistance
Chlorhexidine (CHG) bathing of patients for the prevention of hospital-acquired MRSA infection is a widespread hospital practice, but the long-term effects of this practice are unknown. In a retrospective study of >500 MRSA isolates from ICU patients, David Warren and colleagues report no significant changes in the prevalence of the qacA/B genes that lead to CHG resistance in MRSA, suggesting that CHG baths are effective for long-term use.
E-cigarettes boost superbugs
Scientist Crotty Alexander and colleagues at the University of California have reportednegative impacts from e-cigarette vapor, which include marked changes in Staph aureus virulence among other effects, such as suppression of immune defenses and alterations in inflammation. In mouse pneumonia models, mice infected with normal MRSA survived their infection, while 25% of those infected with vapor-exposed MRSA succumbed. The vapor-exposed Staphylococcus aureus was more adept at forming biofilms, invasion of airway cells and resisting human immune defenses.
Europe: resistance runs high in foodborne infections
A new European report (issued from the European Food safety Authority [EFSA] and the European Centers for Disease Control [ECDC]) shows increasing resistance to ciprofloxacin, reaching high to extremely high levels (69.8%) in Campylobacter from broiler chickens and in human Campylobacter infections (60.2%), the most common foodborne illness. Similarly, multidrug resistant Salmonella appeared in 25-30% of poultry and 26% of human isolates, further suggesting a linkage in animal antibiotic usage and antibiotic resistance in humans. Rates were highest in southern and eastern Europe, and lowest in northern Europe where antimicrobial use in food-animals is low.
In contrast to the above, Campylobacter resistance has declined to 11% in the U.S. and 2% in Australia. It is surmised that the differences may relate to the location of the ciprofloxacin manufacturer (Bayer—a German-based company) and to unequal access/usage between countries.
PUBLICATIONS AND EVENTS OF INTEREST:
Funding opportunity: Combating Antibiotic Resistant Bacteria (CARB) Biopharmaceutical Accelerator; Opp ID: 164267 | Collaboration or Cooperative Agreement |U.S. Dept. of Health and Human Services (HHS); deadline: April 15
The Boston Bacterial Meeting (BBM) brings together Boston-area bacteriologists from either academic or industrial settings. This year's keynote address will be delivered by Dr. Martin Blaser, APUA's 2009 Leadership Award Recipient. The event will be held June 14-15, 2016 at the Massachusetts Institute of Technology.
Health matters: antimicrobial resistance, published by Public Health England (Dec 10, 2015). This document summarizes the rising antibiotic consumption and resistance problem in England and the desire of PHE to achieve reduction in resistant infections. It lays out the known effective strategies for improving antimicrobial stewardship.
Alternatives to antibiotics—a pipeline portfolio review, by L. Czaplewski et al. The Lancet 2016; 16:239-251. This article covers non-compound approaches that target bacteria, or any approach that targets the host, including costs, challenges and outlook.
Use of antibiotics in animals and people by C. Nunan and R. Young, Veterinary Record 2016; 178:22 This letter to the editor responds to the question of whether the transfer of resistance plasmids from farm animal to human E. coli is of any ‘real significance’. The authors cite the most compelling evidence in recent publications that show identity or near identity between bacterial plasmids found in farm animals and human infections.
Carbapenem resistance: overview of the problem and future perspectives by G. Meletis. Ther Adv Infect Dis 2016; Feb 3(1):15-21. A review of key points related to carbapenem resistance.
Triton Hodge Test: improved protocol for Modified Hodge Test for enhanced detection of NDM and other carbapenemase producers, by F. Pasteran et al. J. Clin Microbiol 2015; 54(3):640-9. This article describes a simple, inexpensive test incorporating Triton X-100, which displays >90% sensitivity against NDM-producing isolates.
Find APUA’s recent feature articles on the worldwide threat to carbapenems in the 2013, Vol 31 No.2 issue of the APUA Newsletter.
Why infectious bacteria are winning by Keith Collins. Quartz. Animated infographics tell the story of antibiotics, their use and diminishing efficacy.