January 19, 2016
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Table of Contents
  1. Response to colistin resistance begins, with MCR-1 gene detected in more countries
  2. United Nations General Assembly adopts resolution calling for high-level meeting on AMR
  3. 2016 US budget boosts CDC, NIH, and FDA funding to combat AMR
  4. President Obama unveils National Action Plan for drug-resistant tuberculosis
  5. Developments in tuberculosis diagnostics and treatment
  6. Healthcare institutions contribute to demand for antibiotic-free meat
  7. Nearly one third of deaths from foodborne illness are children according to WHO report
  8. US CDC reports cases of carbapenem-resistant Enterobacteriaceae
  9. Pipeline review on alternatives to antibiotics calls for investment of £1.5 billion pounds
  10. Doctors more likely to prescribe antibiotics to tobacco users in the US

1. Response to colistin resistance begins, with MCR-1 gene detected in more countries

Yi-Yun Liu et al.Resistance to colistin--a last-line defense against drug-resistant bacteria--has received growing attention as the prevalence of MCR-1, the plasmid-mediated resistance gene, among food animals in China became known in November 2015. As of this month, MCR-1 has been detected in at least 17 countries, with new reports being published in the Lancet Infectious Diseases of the gene's presence in Germany, Vietnam, Cambodia, Japan, Switzerland, Belgium, and Malaysia. In addition, MCR-1 has been detected in Canada, the first finding of the gene in North or South America. These results come from retrospective studies of databases containing bacterial samples generated in the last several years - from humans, animals, and retail meat.​These mounting concerns over colistin resistance have prompted several actions. The Chinese government is set to conduct a review of colistin use with the aim of removing it from animal feed. In addition. the European Medicines Agency (EMA) Committee for Veterinary Medicinal Products will reconvene an expert group to update its advice on the use of colistin in animals. Previously, the EMA group recommended that colistin be maintained for use in veterinary medicine to treat infected animals, but that all indications for preventive use be removed. Over the next 6 months, the EMA will review available information and assess whether to revise its advice on colistin. The group will take into account the importance of colistin for human and veterinary medicine, the impact of colistin resistance, the availability of alternative treatments, and possible risk management measures. 

The Alliance to Save Our Antibiotics and Medact are hosting a conference entitled "Antibiotics and Agriculture: prescriptions for reducing farm antibiotic use" on April 14, 2016 at The Institute of Child Health in London. The conference is motivated in part by the mounting evidence that animal agriculture contributes to AMR, recent reports of colistin resistance in the UK, and the continued routine preventive use of antibiotics in the European Union under current regulations that allow prophylactic use. The conference aims to unite health and agricultural stakeholders behind an effective plan to reduce the use of antibiotics in farming. The conference will bring together international stakeholders and experts, including policymakers, health professionals, livestock farmers, veterinarians, scientists, and civil society groups.

2. United Nations General Assembly adopts resolution calling for high-level meeting on AMR

The United Nations General Assembly has decided to hold a high-level meeting on antimicrobial resistance in 2016 in accordance with a resolution adopted in December 2015. The resolution, entitled "Global health and foreign policy: strengthening the management of international health crises," includes language that requests that the UN Secretary-General collaborate with the Director General of the World Health Organization (WHO) and member states to design the meeting and determine potential deliverables. The resolution recognizes that AMR threatens the sustainability of public health responses to communicable diseases, including tuberculosis, malaria, and HIV/AIDS. The resolution also encourages the WHO, Food and Agriculture Organization of the UN (FAO), and the World Organization for Animal Health (OIE) to further develop efforts towards a One Health approach. Member States will be discussing options for such a UN high-level meeting at the upcoming WHO Executive Board meeting from January 25-30.

3. 2016 US budget boosts CDC, NIH, and FDA funding to combat AMR

Washington Post
The Consolidated Appropriations Act, passed on December 18, 2015 by the US Congress, sets aside increased funding for antibiotic resistance efforts in the 2016 US government budget. The budget gives $160 million to the Centers for Disease Control and Prevention (CDC) to strengthen state and local health department monitoring of antibiotic resistant outbreaks and regional lab capacity. The budget allocates $8.7 million for the Combating Antibiotic Resistant Bacteria initiative. The budget also gives $100 million to the National Institutes of Health for research and development on AMR. BARDA (Biomedical Advanced Research and Development Authority), which has been engaged in public-private partnerships with AstraZeneca and GlaxoSmithKline to develop new antibiotics, will receive $96 million.This month, the NIH has announced research funding awards of $5 million over 2 years for 24 projects exploring alternatives to antibiotics. These projects involve 18 academic institutions and 3 industrial companies. Antibiotics typically target the pathways for bacteria cell wall and protein synthesis to kill bacteria or inhibit growth. Some of the projects involve the therapeutic use of "good bacteria" found in or added to the human microbiome to control harmful bacteria. Another research area is phage therapy, which involves the use of viruses to attack harmful bacteria while preserving the normal microbiota of a patient. Other projects include adding decoy targets to prevent bacteria from producing disease, enhancing the human immune response, and creating drugs that reduce the ability of pathogens to adapt and compete. These alternative approaches are also detailed by the National Institute of Allergy and Infectious Diseases (NIAID) Antibacterial Resistance Program.

The Food and Drug Administration (FDA) received $104.5 million out of the $109.5 million requested to fund the Food Safety Modernization Act (FSMA). To date, the FDA has published finalized 5 of 7 FSMA rules, having released since last year food safety rules on human food, animal food, produce, supplier verification for imported food, and accredited third-party certification. This funding represents a significant increase from the amount FDA received in 2015 for enacting FSMA of $27.5 million. The budget also includes $1 billion in funding for the USDA Food Safety and Inspection Service (FSIS) to support mandatory inspection activities, which was $1.6 million below the 2015 level, but $3.3 million above what was requested by President Obama.

However, the 2016 budget does not include the $77 million for USDA requested in the President's Budget. Lance Price of the Antibiotic Resistance Action Center noted that there is a "funding dead zone" for research linking the agricultural use of antibiotics to AMR in humans. In November 2015, the Pew Charitable Trusts, Infectious Diseases Society of America, Bon Appetit Management Company, McDonald's USA, Tyson Foods, and WalMart sent a letter to the Congressional Appropriations Subcommittee on Agriculture, Rural Development, FDA, and Related Agencies. That letter urged Congress to increase funding for research, surveillance, and information dissemination on antibiotic use in animal agriculture.

4. President Obama unveils National Action Plan for drug-resistant tuberculosis

White HouseIn late December, the Obama Administration released its National Action Plan for Combating Multidrug-Resistant Tuberculosis, which recommends interventions against MDR-TB with specific milestones over 1, 3, and 5 years. The World Health Organization has reported that TB kills 1.5 million people each year. More than 2 billion people in the world are estimated to be currently infected with latent TB, which puts them at risk of developing the disease. Though TB is curable, fewer than 20 percent of people with MDR-TB receive the drugs they need; and of that 20 percent, fewer than half are cured. The combination of under-resourced public health systems, inaccurate diagnosis, and inability to access or complete treatment leads to preventable deaths, further transmission of MDR-TB, and the development of extensively drug-resistant TB (XDR-TB). According to the CDC, the cost to treat a patient in the US is $17,000 for drug-susceptible TB, $150,000 for MDR-TB, and $482,000 for XDR-TB. Reducing the prevalence of drug resistant TB could therefore prevent severe effects on human life and health systems.The National Action Plan sets out three goals to be carried out among healthcare providers, public health departments and TB control programs, governments, nongovernmental organizations, private sector organizations, community groups, civil society organizations, funding organizations, and TB survivors and advocates:
  1. Strengthen domestic capacity. The National Action Plan calls on the CDC to work with the National Tuberculosis Controllers Association (a medical professional society) and other partner organizations to establish a "National TB Stockpile" to prevent shortages of medicines and diagnostics, conduct rapid surveillance of TB drug resistance patterns, build capacity for investigation and control of TB disease and latent infections, and improve treatment of patients with MDR-TB.
  2. Improve international capacity and collaboration. The main objectives for this goal are to improve access to high-quality, patient-centered diagnostic and treatment services globally and to strengthen national TB laboratory networks to diagnose TB.
  3. Accelerate basic and applied research and development. The National Action Plan calls for developing options for preventing active TB, latent TB infection, and TB transmission. Such options would include optimization of infection control, prophylactic treatments to prevent latent TB from progressing to active drug-resistant TB, and ideally, development of a vaccine. Currently, there is no effective vaccine against TB in adults, and the BCG vaccine available in most high-burden countries only partially protects children.
The National Action Plan for MDR-TB was developed in response to recommendations put forth by the US National Action Plan for Combating Antibiotic Resistant Bacteria released in March 2015 and builds on the US Government Global Tuberculosis Strategy 2015-2019.

5. Developments in tuberculosis treatment for children and diagnostics

Learn more by watching the TB Alliance video on new child Tuberculosis drug
The first TB drug designed for children, with a sweet flavor and child-appropriate dosage in a dissolvable tablet, will enter the market early this year. The drug was developed through a partnership between the TB Alliance, WHO, and US government. The drug will be a combination of the existing TB drugs rifampicin, isoniazid, and pyrazinamide. Macleods, an Indian pharmaceutical company, will manufacture the drug. As reported by SciDevNet, Kenya will likely be one of the first markets for the drug according to the TB manager in the Kenya Aids NGOs Consortium. This child TB drug could mitigate the risks associated with practices involving care providers and parents crushing or chopping adult pills for children. Having to divide the adult dose pill for pediatric use could otherwise negatively impact drug adherence and health outcomes and facilitate the development of drug resistance. ​Researchers in Australia have created a diagnostic test for tuberculosis (TB) with the potential to serve as a reliable low-cost, accurate, and rapid test in low-resource settings. In their proof of concept paper, the researchers claim that their test would cost $3 and take 75 minutes. Such a test would enable healthcare providers to make timely and informed first-line decisions about appropriate treatment for patients. The diagnostic test uses a nucleic acid amplification assay that selectively clones Mycobacterium tuberculosis DNA. Two aspects of the test make it potentially well-suited for point of care diagnosis. First, the test uses an isothermal method, so it does not rely on thermal cycling to heat DNA. Second, the test uses cheap disposable electrodes to read the presence of TB DNA with the naked eye rather than with a possibly costly fluorescence-based detection platform. Conventional TB tests, which include the tuberculin skin test and sputum smear microscopy, do not allow for point-of-care diagnosis, and suffer from poor sensitivity and specificity. Advances have been made for nucleic acid amplification tests, but tools like the Xpert MTB/RIF, endorsed by the WHO in 2010, still pose challenges related to cost, maintenance, and reliance on thermal cycling. However, this diagnostic test does not yet screen for resistance to the antibiotic Rifampicin, which the Xpert MTB/RIF does. Nonetheless, the researchers suggest that their diagnostic test could still provide a cost-effective, point of care, first-pass diagnostic tool.

6. Healthcare institutions contribute to demand for antibiotic-free meat

NPR: A dish with antibiotic-free beef at Overlake Medical CenterMore than 400 US hospitals are working to make 20% of their meat purchases antibiotic-free, according to Practice Greenhealth, a non-profit that works towards increasing environmental sustainability in healthcare institutions. As reported by NPR, a dozen hospitals have made the majority of their chicken purchases antibiotic-free. One such hospital profiled by the NPR article is Hackensack University Medical Center in New Jersey, where 100% of the chicken served there is now antibiotic-free. It took several years for the hospital to work with its distributor and a group purchasing organization to fulfil a supply of antibiotic-free chicken from Perdue. Perdue, one of the largest poultry producers in the US, committed to reduce the antibiotics in its chicken production. Kyle Tafuri, senior sustainability adviser at Hackensack reports that the hospital pays 30% more for Perdue’s antibiotic-free chicken (marketed under its Harvestland brand). He also stated that Hackensack is seeking antibiotic-free pork and beef, which are currently more expensive and difficult to source.There is growing evidence that antibiotic-free meat may be a safer product. For instance, in 2015, Consumer Reports tested retail ground beef samples and found that compared to sustainably produced ground beef (antibiotic-free and/or grassfed), conventionally-produced ground beef samples were twice as likely to contain multidrug-resistant bacteria. Such pathogens could lead to drug-resistant infections when consumed, especially if the meat is not cooked properly.

Hilary Bisnett, a food expert for Practice Greenhealth and Health Care Without Harm, attributes these successes in part to the fact that hospitals like Hackensack had not entered into contracts with a large food service management company. Contracts with these companies, such as Aramark, Sodexo, and Compass, offer less flexibility in changing vendors or supply to allow for sourcing antibiotic-free meat. Bisnett emphasizes that the food service sector should “get more involved with this issue”, given that one third of hospitals in the US have food services managed by these three companies.

7. Nearly one third of deaths from foodborne illness are children according to new WHO report

World Health OrganizationThe World Health Organization (WHO) Foodborne Disease Burden Epidemiology Reference Group published its first-ever estimates of the global burden of foodborne diseases in a report that intends to aid policymakers by filling in data gaps on the health and economic costs of foodborne illness. Most strikingly, 30% of all deaths from foodborne diseases are in children under the age of 5, despite making up only 9% of the world population. The report estimates the disease burden of 31 foodborne agents, including bacteria, viruses, parasites, toxins, and chemicals - the WHO found that 600 million people per year, almost 1 in 10 individuals, get sick from eating contaminated food, and 420,000 die as a result. The WHO found that foodborne illness was responsible for 33 million Disability Adjusted Life Years (years lost due to poor health, disability or early death).Diarrheal disease agents were the most frequent cause of foodborne illness, especially norovirus (12 million cases) and Campylobacter (96 million cases). Foodborne diarrheal disease caused 230,000 of the 420,000 overall deaths due to foodborne illness. Non-typhoidal Salmonella enterica accounted for 59,000 of these 230,000 deaths, and enteropathogenic E. coli for 37,000, and enterotoxigenic E. coli for 26,000 deaths. The report noted that the low- and middle-income countries experience the most severe disease burden due to unsafe water, poor hygiene, inadequate conditions in food production and storage, lower levels of education, and insufficient food safety legislation or legislation enforcement. The highest burdens by region were in the WHO African Region, with 91 million illnesses and 137,000 deaths, and South-East Asia Region, with 150 million illnesses and 175,000 deaths per year. The WHO emphasized the necessity of multi-sectoral responses from governments, international organizations, and stakeholders in the food chain - including enforcing food safety standards and managing effective surveillance networks.

8. US CDC reports cases of carbapenem-resistant Enterobacteriaceae

The US Centers for Disease Control and Prevention (CDC) reported 43 cases of patients with highly resistant carbapenem-resistant Enterobacteriaceae (CRE) that produce OXA-48 carbapenemase between 2010 and 2015. OXA-48 carbapenemase is an enzyme that allows bacteria to be resistant against penicillins and carbapenems, a last-resort antibiotic. The gene coding for OXA-48 carbapenemase is spread through a plasmid mechanism, which allows for rapid dissemination in the same way as MCR-1, a plasmid-based resistance mechanism against colistin, another last-resort antibiotic. CRE strains like OXA-48 are often resistant to most classes of antibiotics, causing healthcare-associated infections with high mortality rates. The CDC report found that isolates from 5 of the 43 patients contained both OXA-48 and NDM-1. Among the 29 patients with available travel histories, 19 had traveled internationally during the year before specimen collection, and 16 were hospitalized outside the US for at least 1 night. India was the most frequent destination, with 11 of the 19 patients having traveled there, and 9 of the 16 hospitalizations occurring there.The CDC report emphasizes the urgent importance of delaying the spread of CRE. CREs have the potential to spread globally, especially in light of the spread of CRE that produce Klebsiella pneumoniae carbapenemase (KPC) and CRE that produce New Delhi metallo-β-lactamase (NDM-1). In addition, resistance to Ceftazidime-Avibactam, a combination-therapy antibiotic introduced in early 2015 for treatment of patients infected with CREs, was reported in a July 2015 study. In that study, researchers found a KPC-producing K. pneumoniae isolate resistant to the new drug from a patient who had not been treated with it previously. OXA-48-like carbapenemases were first identified in Turkey in 2001 and then reported in 2013 in the US. The CDC noted challenges in identifying resistant organisms expressing OXA-48-like genes due to limited testing in US laboratories. However, the CDC expects that the sensitivity of testing will improve due to a modification of the CDC's CRE surveillance definitions in January 2015 to include organisms that are resistant to ertapenem or that contain a carbapenemase gene.

9. Pipeline review on alternatives to antibiotics calls for investment of £1.5 billion pounds 

Twenty-four scientists from academia and industry have published a pipeline portfolio review of 19 alternatives to antibiotics in The Lancet Infectious Diseases. The review covers various approaches to target bacterial infections that do not rely on the conventional antibacterial compound. The review found that the approaches that have advanced the most down the R&D pipeline are antibodies, probiotics, and vaccines in phase 2 and 3 trials. This "first wave" of alternatives will most likely serve as therapy used for prevention or in combination with antibiotics. Based on the costs of bringing new therapies to market, the review estimates that funding of £1.5 billion pounds spent over 10 years is required to sustain the development of 10 high priority alternatives to antibiotics. The review argues that in addition to monetary investment, translational expertise is needed to validate these alternatives in phase 2 trials in clinical settings. These actions, they argue, would then catalyze engagement and investment by the pharmaceutical and biotech industries.

10. Doctors more likely to prescribe antibiotics to tobacco users in the US

Science TimesThrough an analysis of the CDC-conducted National Ambulatory Medical Care Survey, researchers at Rutgers University found that tobacco users in the US were 20 to 30 percent more likely to receive antibiotics than non-tobacco users. The study sample consisted of patients over the age of 18 diagnosed with an infection for which antibiotics may be clinically indicated for the years of 2006 to 2010, which amounted to a sample of 8,307 visits. The researchers chose to focus on respiratory infections since antibiotics are most commonly prescribed for such infections, and tobacco smoke increases susceptibility to respiratory infections. The study also found that primary care physician encounters were more likely to result in a prescription of antibiotics, perhaps due to the expectations between primary care providers and patients. Patients with private insurance and white patients received antibiotics at higher rates, which points to a need for further study on the effect of socioeconomic status on prescription patterns for antibiotics.The study's findings are consistent with prior studies in Europe that showed higher rates of antibiotic use among smokers (60%) compared to non-smokers (53%) with respiratory conditions, with smokers having a 44% higher chance of being prescribed antibiotics. Another study found that smokers with increasing cigarette consumption tended to be prescribed broad-spectrum antibiotics. Higher antibiotic use may explain results in studies where ex-smokers had a higher probability of nasal carriage of Staphylococcus aureus, and a higher rate of resistant organisms was found in a small study of smokers. Another study found that exposure to maternal smoke could increase the risk of MRSA colonization for infants. Together, these studies provide evidence that smokers may serve as a reservoir for antibiotic-resistant bacteria. Given the lack of evidence to suggest tobacco users should receive more antibiotics, this study highlights the need to address a "clinical custom" among healthcare providers that facilitates the development of antibiotic resistance.

Note: The ARC Newsletter will periodically capture key meetings and developments, as well as news and resources, on antibiotic resistance for Coalition members and partners. This newsletter is prepared and published through ReAct North America/Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health. The ARC Declaration on Antibiotic Resistance can be found here. Please share items for consideration for inclusion in future newsletters by writing to Reshma Ramachandran at rramach9@jhu.edu.