Breakthroughs Blog: Antimicrobial resistance

United Nations General Assembly. Photo: UN Photo/Loey FelipeEvery year in mid-September, the world’s diplomatic corps descends upon midtown Manhattan for two weeks of snarled traffic, road closures, and general mayhem. The cause of this paralysis? The United Nations General Assembly (UNGA)—a gathering of all the highest levels of the world’s governments to address those issues so pressing that only a global response will suffice.In recent years, global development, including global health, has featured prominently on both the UNGA formal and side-event agendas. This year the bulk of the formal agenda—set by Fiji which holds the Presidency of the General Assembly—focuses on oceans, climate change, and refugees and migration. However, the assembly also includes a full-day, high-level summit on antimicrobial resistance (AMR) scheduled by the outgoing Norwegian General Assembly President. Though other global health issues may not feature on the formal agenda, there are a number of hot topics that will certainly be highlighted at side events throughout the week. Here are the major global health policy issues GHTC will be tracking:Antimicrobial Resistance A CDC scientist studies a drug resistant strain of bacteria. Photo: James Gathany With the publication of the Review on Antimicrobial Resistance (also known as the O’Neill report), which was commissioned by government of the United Kingdom to comprehensively examine the global problem of AMR, the full scale of the human and economic cost of the rise of AMR is becoming clear. Seven hundred thousand people die each year globally from AMR infections, and the United States alone spends an extra US$20 billion on health due to AMR. As a result, global attention has focused on how best to both support development of novel antibiotics and conserve antibiotics of last resort to prevent the development of further resistance. At the full-day summit on September 21, world leaders will convene to discuss how the global community can collectively address AMR. A number of organizations are also sponsoring side events and conferences devoted to the myriad ways to stem the tide. It will remain to be seen whether any political commitments or new bilateral AMR initiatives emerge. Zika/Ebola/Pandemic preparedness/Global Health Security AgendaThe West African Ebola outbreak and the ongoing Zika pandemic have focused the world’s attention on the fundamental weakness of international pandemic preparedness efforts. With the continuing international spread of Zika, strengthening the international community’s ability to prevent, detect, and respond to outbreaks remains a global priority. The gathering of so many world leaders in one place for UNGA will create a ripe environment to foster novel partnership models to strengthen health systems to stand up to future outbreaks. While not featured on the formal agenda, a number of high-level side events on health systems strengthening and partnerships could spur interesting new initiatives post-UNGA. Access to MedicinesOn Wednesday, the United Nations Secretary-General’s High-Level Panel on Access to Medicines (HLP), convened in late 2015 by Secretary-General Ban Ki-moon, published its final report offering recommendations for “remedying the policy incoherence between the justifiable rights of inventors, human rights law, trade rules, and public health in the context of health technologies.” The issues tackled in the report and the panel’s recommendations for improving access to health technologies are highly contentious with health advocates, industry, and other trade and intellectual property stakeholders holding divergent viewpoints on how best to achieve this aim. This tension is reflected in the final report itself, which though released as a consensus document, also contains six separate commentaries by HLP members advocating positions other than those taken in the report.Given the timing of this report release, it should be a central topic of discussion at UNGA as various groups choose whether to lend their support to carrying forward the recommendations or criticize the panel for going too far or not far enough. Looking further forward, this issue will also feature prominently at a March special session of the United Nations Human Rights Council.While your author expects that these will be the key global health policy issues addressed at this year’s UNGA, there are always a few last-minute surprises. Needless to say, GHTC will keep you informed of exactly what is going on in the midst of the midtown Manhattan mayhem all week long.

CDC microbiologist Brian Yoo prepares a panel of isolates. Photo: CDCThe threat of antibiotic resistance (AR) is a growing challenge around the world. Antibiotic-resistant germs—bacteria that no longer respond to the drugs designed to kill them—cause more than 2 million illnesses and 23,000 deaths each year in the United States alone. It is critical for scientists and researchers to be equipped with the right tools and the best information available to combat antibiotic resistance and improve antibiotic use. Better diagnostic tests are needed to help us characterize and identify resistant pathogens—an important component of diagnosing an infection early and accurately, and preventing spread of resistant infections. And new antibiotics are needed to more effectively treat infections with bacteria that have already developed resistance. One of the new resources available to researchers is the Antimicrobial Resistance Isolate Bank (AR Isolate Bank), which was launched in 2015 by the US Centers for Disease Control and Prevention (CDC). An AR isolate panel is removed from the freezer. Photo: CDC A collaboration between CDC and the US Food and Drug Administration (FDA), the AR Isolate Bank is a curated repository of nearly 400 unique AR pathogens pulled from CDC’s collection of more than 450,000 AR isolates and more than 18,000 characterized genomes. These curated isolate collections—called panels—provide researchers with well-characterized, resistant bacteria that can be used to develop effective and accurate next-generation diagnostics and accelerate research for new antibiotics. E.coli. Photo: CDC A timely example of the value of the AR Isolate Bank panels is its collection of E.coli isolates with the mcr-1 gene. Increasing reports of bacteria carrying mcr-1 genes have put public health experts across the globe on high alert. These genes can make bacteria containing them resistant to the crucial antibiotic colistin—a last resort drug being used to treat “nightmare bacteria” carbapenem-resistant Enterobacteriaceae. Within three weeks of identification of E.coli with the mcr-1 gene in the United States, the CDC assembled appropriate panels for the bank. Public health, industry, academic, and private labs can use these panels to calibrate their diagnostic tests so that they can ensure that bacteria carrying the mcr-1 gene are quickly and accurately identified and characterized. Findings from these calibrated tests will help public health partners ramp up targeted detection and response. The sample isolates can also help researchers build new tests to detect these types of resistance in the future—all to more quickly slow the spread of resistance.Since the launch of the AR Isolate Bank, more than 140 customers—including academic, commercial, federal, hospital and clinic, and public health laboratories—have requested panels. CDC is collaborating with FDA to support and expand use of this resource. At this time, the isolates are only available for shipment to recognized US laboratories with confirmed biosafety officers.The AR Isolate Bank is one small piece of CDC’s wide-ranging work to reduce the spread and impact of antibiotic resistant infections. CDC’s Antibiotic Resistance Solutions Initiative supports implementation of the surveillance, prevention, and stewardship activities outlined in the National Action Plan for Combating Antibiotic-Resistant Bacteria, which identifies critical actions to be taken by federal agencies to combat the emergence of resistant bacteria.

The US National Institutes of Health (NIH) announced the Antimicrobial Resistance Diagnostic Challenge last week, a competition which will award US$20 million for the development of rapid, point-of-care diagnostics to combat antimicrobial resistance. The competition will be funded by NIH's National Institute of Allergy and Infectious Diseases and the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, while the US Centers for Disease Control and Prevention and the US Food and Drug Administration will provide scientific and regulatory expertise. Eligible diagnostics are those that either test for drug-resistant bacteria or differentiate between viral and bacterial infections, critical tools to reduce ineffective and unnecessary antibiotic prescriptions. The recently launched Coalition for Epidemic Preparedness Innovations (CEPI) will fund early stage human clinical trials and stockpile vaccine candidates for the viruses most likely to cause the next major epidemic. CEPI will collaborate with product developers and the World Health Organization (WHO) to facilitate regulatory review of vaccine candidates and to ensure that large scale clinical trials can be rapidly rolled out in the case of an outbreak. Eligible vaccine candidates will target viruses identified by the WHO as the greatest threats, including Crimean Congo hemorrhagic fever, Ebola and Marburg, Lassa fever, Rift Valley fever, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), and Nipah virus. The coalition was formed by the governments of India and Norway, philanthropic organizations the Wellcome Trust and the Bill & Melinda Gates Foundation, and the World Economic Forum and will be housed at the Norwegian Institute for Public Health in Oslo. The International Vaccine Institute (IVI) is partnering with Xiamen Innovax Biotech Co., Ltd. (Innovax) to expand access to the world’s first and only vaccine against Hepatitis E—a viral disease that causes 20 million infections and results in 70,000 deaths and 3,000 stillbirths each year. The vaccine, Hecolin®, was developed by Innovax and is only licensed for use in China. The Gates Foundation will support an assessment of the vaccine to determine its eligibility for WHO prequalification—a process that evaluates the safety, efficacy, and quality of a specific health tool produced by a specific manufacturer and that enables the product to be purchased by United Nations agencies. Hecolin® offered complete protection against hepatitis E in a phase 3 clinical trial with more than 100,000 participants. Pharmaceutical company Takeda has initiated a phase 3 clinical trial of its vaccine candidate against dengue fever, a mosquito-borne infection caused by four closely related viruses. Last year, pharmaceutical company Sanofi launched the world’s first dengue vaccine, however, new research suggests that the vaccine could actually increase the severity of infections in children who have never been exposed to dengue. This is due to antibody-dependent enhancement, in which protective antibodies against a virus (in this case, one strain of dengue virus) can actually help related viruses (the other three strains of dengue virus) attack human cells. Consequently, the antibodies produced by children receiving the vaccine could actually exacerbate the symptoms of future infections. In phase 1 and 2 trials, Takeda’s vaccine candidate appeared to be safe and resulted in the production of antibodies against all four strains of the virus. For its phase 3 trial, Takeda plans to enroll 20,000 children in dengue-endemic nations in Latin America and Asia. The trial will evaluate safety and efficacy against all four strains of dengue and in children with and without prior exposure to the virus.

The Toxoplasma gondii parasite is infamous for consuming brain tissue, causing brain cancer, and even altering the behavior of infected individuals. However, new research suggests that it could be modified and used to treat ovarian cancer. The team of scientists at Dartmouth University created a weakened version of T. gondii, removing the genes that enable the parasite to take over its host’s cells. Next, mice with aggressive ovarian cancer were inoculated with the weakened parasite. The study demonstrated that the presence of T. gondii, along with certain proteins excreted by the parasite, resulted in an enhanced immune response to ovarian cancer tumors. While none of the mice were completely cured—which could in part be attributable to the late stage of cancer at the time of treatment—those treated with the weakened parasite survived an additional 40 days on average. The World Health Organization (WHO) has issued new treatment guidelines for chlamydia, gonorrhea, and syphilis, as the three sexually transmitted infections (STIs) grow increasingly resistant to antibiotics. While resistant strains of chlamydia and syphilis are rare, multidrug-resistant gonorrhea has emerged in at least ten countries, and resistance to six classes of antibiotics has been reported. The WHO is calling for enhanced surveillance of drug-resistant strains of gonorrhea, and recommends that national treatment guidelines be determined based on local patterns of resistance. While syphilis is curable with a single dose of benzathine penicillin, the supply of the drug is low, and stock outs have been reported in a number of countries. While early stages of these three STIs are often asymptomatic, they can cause significant long-term damage, including pelvic inflammatory disease and infertility. Furthermore, they can be transmitted from mother-to-child during pregnancy and childbirth, and can increase the risk of ectopic pregnancy, miscarriage, stillbirth, and newborn death. As bacteria grow resistant to antibiotics, so too do fungi to antifungals. Each year, fungal infections result in 1 million deaths, and strains of both the aspergillus and candida fungi are growing resistant to the azole class of antifungals. While there are more than 20 classes of antibiotics, there are only four classes of antifungals, and thus, resistance to just one class of medicines is a major cause for concern. Scientists believe the leading cause of fungal resistance is the widespread use of fungicides on crops and in certain household paints and coatings. While dissecting mosquitoes in Guaico, Trinidad, researchers at the US Army Medical Research Institute of Infectious Diseases discovered a new and bewildering virus, configured unlike any other virus known to infect animals. Most viruses are comprised of a handful of genes packaged into one particle, however, the five genes of Guaico Culex exist as independent particles, and can only infect a mosquito if at least four of the five are present. Previously, viruses with this structure—known as multicomponent genomes—had only been found in plants and fungi. While humans are not susceptible to Guiaco Culex, a related virus has been found in monkeys, indicating that another multicomponent virus could infect humans.