APUA HIGHLIGHTS: SPRING 2017
Faces of Antimicrobial Resistance (FOAR) releases final report
The Infectious Diseases Society of America (IDSA) has released its final publication, The Faces of Antibiotic Resistance—a project that presents the personal stories of patients or family members who have had first-hand experience with a resistant infection such as MRSA, CRE, and C. diff, among others. As a member of IDSA’s U.S. Stakeholder Forum on Antimicrobial Resistance (S-FAR), APUA participated in the project with financial support, and by serving as a vehicle to solicit the stories that were assembled for publication. Each of the 13 individual stories shared by people from across the U.S. attempts to put a human face on the true costs of resistance and to demonstrate the urgent need for efforts to combat resistance and protect patients. As stated in the forward by IDSA president, William Powderly, “press reports and statistics only tell part of the story. Patients like mine—real people, grandparents, parents, children, neighbors, and friends—are the reason we must address the problem of antimicrobial resistance.”
Letter to President Trump urges farsightedness
APUA has joined over 100 other stakeholders in signing a letter to President Trump that requests maintenance of a strong public health workforce capacity. The letter was issued in response to the current hiring freeze on federal jobs issued in January. The letter expresses appreciation for the retention of jobs that respond to public health and medical emergencies, but urges careful consideration of federal public health and biomedical research workforce while forging its long-range federal hiring policies. The letter outlines the important roles played by the CDC, the Health Resources Services Administration, the NIH and the FDA, and asks for a strong work force to support program objectives. Lastly it expresses a desire to provide input into the crafting of longer term policies.
Letter to WHO calls for continued global action
As a member of S-FAR (the U.S. Stakeholder Forum on Antimicrobial Resistance), which was convened by the Infectious Diseases Society of America, APUA has signed on to a group letter to WHO leaders António Guterres and Margaret Chan. The letter expresses a desire to see continued progress on the antimicrobial resistance (AMR) problem subsequent to the UN high level General Assembly in September 2016. The letter reiterates the need for well-coordinated global action in addition to individual national efforts in order to stem the tide of AMR. It calls for progress reports and the rapid establishment of the inter-agency coordination group that was called for in the UN declaration. Additionally it expresses a desire to work more closely with WHO to advance the goals of the declaration.
Center for Global Development (CGD) proposes global treaty to reduce antibiotic use in livestock
In a recent CGD policy paper, coauthors Keany, Elliott and Madan propose that a global treaty to reduce antibiotic use in animals would help make inroads into the human and economic costs posed by antimicrobial resistance. Based on a comparison of the antimicrobial resistance problem with the challenge posed by ozone-depleting substances, the authors suggest that the proposed treaty could be modeled after the highly successful 1987 Montreal Protocol on Substances that Deplete the Ozone Layer. The concept paper outlines three core components to reduce antibiotic use: 1) setting flexible, country-based targets that accommodate individual knowledge gaps; 2) providing incentives for countries to participate, such as: granting a grace period for lower and middle income countries to decrease the burden for implementing a phase-out, and establishing a fund to provide financial and tech support for developing countries; and 3) utilizing a monitoring plan that calculates “apparent consumption” (antibiotic production plus imports minus exports), as opposed to the very challenging undertaking of “direct monitoring.”
To speed the process, the authors suggest starting with the 20 countries that account for 75% of global antimicrobial use in animals.
Hospitals penalized for preventable injuries
The U.S. Centers for Medicare and Medicaid services has begun penalizing hospitals for certain hospital-acquired conditions. Among these avoidable “injuries” are blood clots, bed sores, falls and certain infections. In 2016, there were an estimated 3.8 million such injuries, of which ~250,000 involved nosocomial infection—estimated at 6,300 for MRSA and 100,000 for C. difficile. To date, 769 U.S. hospitals having the highest rates of injury have been flagged and charged penalties amounting to $430 million. Those hospitals will lose 1 percent of Medicare payments over the federal fiscal year, which runs from October 2016 through September 2017. Kaiser Health News has listed those penalized in its searchable database. Specialized hospitals are exempt from the penalties.
NOTABLE TRENDS in ANTIBIOTIC RESISTANCE
The EU reports escalating resistance trends
In February 2017, the ECDC (European Centre for Disease Prevention and Control) released its 2015 analysis of antimicrobial resistance in zoonotic and indicator bacteria from 28 EU member states. The report reflects high levels of antimicrobial resistance in human, animal and food bacteria. Of particular note and concern was “extremely high” resistance found in human cases of foodborne Salmonella: 29% of isolates were multidrug resistant, and some expressed resistance to 7 antibiotics. Resistance was also elevated among human Campylobacter strains, with some countries reporting fluoroquinolone resistance frequencies of 80-100% in C. coli—a level so high that the authors noted “in some member states…this agent can no longer be considered appropriate for routine empirical treatment.” The full report, including resistance in animals can be accessed here.
WHO releases first list of global superbugs
For the first time, WHO has cited a list of the world’s most worrisome drug-resistant bacteria—those for which new antibiotics are urgently needed. The list will help guide its G20 summit, scheduled for July 7–8, 2017 in Hamburg, Germany, where priorities for new antibiotic development will be spelled out. At the top of the list are the gram-negative enterobacteria: E coli, Acinetobacter and Pseudomonas. Other threats include: Enterococcus and Staphylococcus that resist the last resort drug, vancomycin; the stomach ulcer agent, Helicobacter; the food poisoning agents, Salmonella and Campylobacter; untreatable Neisseria gonorrhea; and finally—drug-resistant Streptococcus, Shigella, and Hemophilus influenza.
Aside from taking a heavy toll in blood and lung infections, E. coli causes an estimated 250 million urinary tract infections per year, some of which are resistant to all antibiotics and could soon become life-threatening without the advent of newer drugs. Intravenous colistin has become a last-resort drug for “extensively drug-resistant” E. coli, but colistin resistance has now begun appearing in India.
WHO’s pathogen list closely mirrors the CDC’s 18 biggest drug-resistant threats, but differs in that the CDC list is headed by C. difficile.
Multidrug resistance rising rapidly among youth
In a retrospective study conducted by Case Western Reserve researchers between 2007 and 2015, data analyses showed a 750% increase in multidrug resistance among Enterobacteriaceae (Salmonella, E. coli and Klebsiella) infections in U.S. children under age 18. At 1.5%, the overall frequency is still low, but the rate of increase is alarming and has prompted the label of “public health crisis.”
The study is the first of its kind to examine multidrug-resistant infections in this age group. In 75% of cases, the antibiotic resistance was present upon admission to the hospital, suggesting that the resistant bacteria are already common within the community. Treatment is complicated by a shortage of approved antibiotics for this age group and the resistant infections have led to a 20% longer than normal hospital stay.
Scientists reveal two-step process to antibiotic resistance
In vitro evolution experiments conducted by a Hebrew University and Broad Institute collaboration have now demonstrated that intermittent exposure of bacteria to antibiotics will result in rapid evolution to a state of "tolerance" without actually developing resistance. The tolerant state is actually a dormant or slow-growing state in which bacteria can persist in the presence of antibiotic. With removal of the antibiotic, growth resumes once again. Such "persister cells" make infections extremely difficult to treat as they will rebound in the absence of the antibiotic.
The mutations leading to tolerance are distinct from those that produce classic resistance and always precede it. The tolerance mutations boost the probability of evolution towards resistance. The discovery was made by tracing fully resistant cells (carrying an ampC mutation) back through their genealogy. "It was very clear," says lead investigator Nathalie Balaban. "Each time we got resistance, the bacteria had become tolerant before." The mutations of tolerant bacteria allowed them to slow their growth and tolerate the ampicillin. Subsequently they developed the ampC mutation which allows classic resistance via export of the drug. While there are multiple options for bacterial mutation totolerance, there are few which result in resistance. The double mutations make it less likely that the bacteria will revert to susceptibility.
Whether this process actually occurs in the patient is a key question that scientists hope to answer While there are antibiotics active against tolerant bacteria, such drugs have undesirable side effects. Currently no diagnostics are capable of identifying tolerant bacteria, but their advent could provide a way to combat, or at least delay, resistance development.
NEW LEADS to NOVEL ANTIMICROBIALS
PPMO molecule may revitalize older, "useless" antibiotics
An international research team headed by Bruce Geller at Oregon State University has developed a molecule that successfully neutralizes a bacterium's ability to evade antibiotics. The new molecule - peptide-conjugated phosphorodiamidate morpholino oligomer, or PPMO for short - is aimed at attacking the enzyme (New Delhi metallo-beta-lactamase) produced by the NDM-1 gene, resulting in resistance to the "last-line" carbapenem antibiotics. The scientists demonstrated the effectiveness of PPMO in vitro against three different genera and also in vivo, using mice infected with E.coli bearing NDM-1 and treatment with the antibiotic meropenem. The strategy improved survival by 92% and markedly reduced systemic bacterial burden. PPMO is potentially broadly effective in counteracting multiple gram-negative species that contain the NDM-1 gene. Once PPMO is approved it is viewed as a means of reviving older antibiotics that have become useless. researchers anticipate testing the PPMO molecule in humans in about three years.
New bacterial amyloid could foster novel antibiotics
Amyloids consist of a spider web-like network of protein fibrils that are highly stable and able to withstand extreme conditions. A research team based at Haifa’s Technion-Israel Institute of Technology has now described a completely novel form of bacterial amyloid—the “cross alpha” amyloid—which differs in structure from the “cross B” amyloid found in humans. Externally, the two appear identical, but a closer look with X-ray crystallography revealed the amyloid sheets were made of curly alpha helices, not the typical flat beta strands. The toxic fibrils of the bacterial amyloid structure allows organisms such as Staphylococcus aureus to attack human cells.
In identifying the novel defense system, scientists see the possibility of developing antibiotics with a unique action mechanism that could disable the bacterial armor by inhibiting amyloid formation. Because such drugs would attack the amyloid shield, and not the bacterium itself, the probability of developing antibiotic resistance is greatly reduced.
Common Floridian weed can disrupt bacterial signaling
The Brazilian peppertree plant, a common invasive weed in Florida, has long been used by traditional healers of the Amazon for treatment of skin and soft tissue infections. Its antibiotic properties have now become the focus of research efforts by ethnobotanist Cassandra Quave and her team at Emory University. Using a systematic analysis of the berry’s components, Quave found a compound that represses the gene that controls communication between bacterial cells—also known as quorum sensing. The flavone-rich compound effectively quenches the quorum sensing mechanism that allows collective bacterial action. The peppertree chemical can shut down MRSA toxin production, thereby allowing immune system defenses to initiate healing. In a mouse model, a refined version of the peppertree compound successfully inhibited the formation of skin lesions induced by MRSA infection.
Because the peppertree compound disrupts the signaling capacities of a pathogen, it essentially utilizes an anti-virulence approach, without actually killing the organism. Consequently it lacks the bomb-killing effects of powerful antibiotics that promote resistance and disrupt the balance of the skin ecosystem. According to Quave, we need “to better understand how we can best leverage anti-virulence therapeutics to improve patient outcomes.”
Soil bacteria compound may help TB therapy
In the face of an estimated 1.4 million deaths from TB, coupled with increasing resistance to current therapies, an international research partnership led by University of Warwick scientists has discovered a compound which could ultimately lead to a new drug treatment. Working with soil bacteria that prevent the growth of neighboring bacteria on an agar plate, researchers developed chemical analogs of the antibiotic compounds that could effectively kill off Mycobacterium tuberculosis. The chemicals are active against the MraY enzyme, which is crucial in building the cell wall of M tuberculosis. The synthetic analog, named sansanmycin, is both stable in plasma and selectively active against TB, making it a potential future therapy in the treatment of the estimated 480,000 TB cases that fail first-line drugs annually.
DEVELOPMENTS IN THERAPY and NEW DIAGNOSTICS
Three-drug combo shows promise against metallo-beta-lactamases
Treatment options are diminishing for certain multidrug resistant superbugs, especially for those gram-negatives bearing the metallo-beta-lactamase enzymes that have emerged in Southeast Asia and parts of Europe. In 2015, the U.S. approved the antibiotic combination ceftazidime/avibactam, which works well for extended-spectrum beta lactamases (ESBLs), Klebsiella pneumoniae producing carbapenemases (KPCs), and cephalosporinases, but is not effective at combating the newer metallo-beta-lactamases. Now, Robert Bonomo and his team at the Louis Stokes Cleveland VA Medical Center in Ohio have conceived and tested the idea of adding a third drug to the mix. They hypothesized that adding aztreonam—a metallo-beta-lactamase-resistant agent—could work if it were blocked from attack by the other beta-lactamase enzymes, “like an offensive lineman in football blocking for a running back.” The strategy proved successful in both laboratory experiments and mouse models, as well as in two critical human cases—a 72-year old woman with a carbapenem-resistant, metallo-beta-lactamase–producing Enterobacter cloacae bone infection, and a 19 year old renal transplant patient with bacteremia from a metallo-beta-lactamase-producing Stenotrophomonas maltophilia. The study demonstrates how understanding the fundamental mechanisms of bacterial resistance can help inform treatment strategies. Clinical trials are needed before the approach can be fully endorsed.
“C-dots” poised to treat MRSA
A technique known as photothermal therapy, and currently used in cancer treatment, has become the basis of a promising approach to treat MRSA. The method utilizes a nanomaterial composed of carbon ‘dots’, or C-dots, which, when exposed to a specified wavelength, begin to vibrate and generate heat. Scientists at two Iranian universities have found that MRSA can be inhibited in vitroby a range of C-dot concentrations, which by themselves, cause cellular stress, resulting in the production of reactive oxygen species (ROS). ROS, in turn, induces protein leakage and ultimately, cell death. But the entire killing process appears to be significantly enhanced when MRSA and c-dots are irradiated with near-infrared light from an 808 nm diode. The precise mechanism of laser light enhancement is still unclear, but exposure markedly altered the classic smooth, round cluster-like appearance of the Staph cells.
C-dots hold numerous advantages in being chemically stable, water soluble, eco-friendly, and of low toxicity. In addition, they do not target a specific bacterial chemical process. If they can be adapted to in vivo applications, C-dot therapy could potentially circumvent one of the thorniest downsides of new drugs—antimicrobial resistance.
On-line risk assessment tool could reduce antibiotic use in newborns
A collaboration between Kaiser Permanente, the University of California SF and the University of Pennsylvania has resulted in the development of an online calculator that evaluates the risk of early onset sepsis in newborns. Of the 15% of newborns that receive evaluation for sepsis, 5-8% will be treated empirically with antibiotics while awaiting diagnostic blood culture results. The new tool will help reduce this antibiotic use by calculating the probability of sepsis—factoring in gestational age, time from membrane rupture, maternal temperature, group B Streptococcus (GBS) carriage status, intrapartum antibiotic use, and clinical presentation. When applied to an analysis of over 200,000 newborns, use of the risk calculator reduced empirical antibiotic use by half—from 5% down to 2.6%—without changing the rate of adverse outcomes. In addition, blood culture testing dropped from 14.5% to 4.9%.
Smartphone device could expand susceptibility testing
A simple and inexpensive smartphone attachment developed by researchers at UCLA can perform routine antimicrobial susceptibility testing. The device contains a plate that can hold up to 96 wells that contain an array of dilutions from a panel of antibiotics. The phone’s camera records LED transmission through the samples, and images are then sent to a server that calculates the antibiotic susceptibility profile (MIC). With a detection accuracy of 98.2%, the results are returned to the phone in ~1 minute. The new technology could potentially speed turn-around time, eliminate the need for trained diagnosticians in remote areas, reduce costs, and assist with global resistance tracking. View a schematic of the novel diagnostic here.
Horizon Prize awards £1million for game-changing diagnostic
The Horizon Prize – Better Use of Antibiotics is an EU-based challenge that sought development of a rapid, point-of-care diagnostic that would distinguish between upper respiratory tract infections that required an antibiotic and those that could be treated safely otherwise. In February 2017, the award was bestowed upon Minicare HNL for its hand-held, finger prick device—an inexpensive, easy-to-use and minimally invasive test that can identify a bacterial infection within 10 minutes. The test is based on the level of human neutrophil lipocalin (HNL), which has been shown to be an effective biomarker due to its increased levels during a bacterial infection. Pending further validation, the test is expected to become available in 2018, and holds promise for markedly reducing the unnecessary use of antibiotics in upper respiratory tract infections.
The Longitude Prize releases Discovery Awards
The £10 million Longitude Prize has been offered for the development of a diagnostic test that helps solve the problem of global antibiotic resistance. As an incentive to help teams facing financial barriers in their application process, the LP has launched the Discovery Awards—small seed grants of up to £25,000 to help pay for critical inputs for advancing applicants’ ideas into products and also to encourage new teams to enter the race. The initial round of Discovery Awards was granted to 12 teams from the US, UK and India. Winners of the second round will be announced in July 2017. The final Longitude Prize will be awarded to the first team that successfully meets the contest criteria.
PUBLICATIONS and WEBINARS of NOTE
A Report of the Efforts of the Veterans Health Administration National Antimicrobial Stewardship Initiative by AA Kelly et al. Infect Control Hosp Epidemiol 2017: Jan 25, 1-8. The VHA has shown that improving antimicrobial usage in a large healthcare system may be achieved through national guidance and resources with local implementation of antimicrobial stewardship program
Global Antimicrobial Stewardship: Barriers and Solutions. A YouTube webinar on global antimicrobial stewardship with infectious disease experts Dr. Debra Goff (USA), Dr. Dilip Nathwani, OBE (UK) and Dr. Marc Mendelson (South Africa). Recorded 2/7/2017 and hosted by The Center for Infectious Disease Research and Policy (CIDRAP)
Eight Habits of Highly Effective Antimicrobial Stewardship Programs to Meet the Joint Commission Standards for Hospitals by DA Goff et al. The Joint Commission (TJC) recently issued New Antimicrobial Stewardship Standards, consisting of eight elements of performance, applicable to hospitals effective January 1, 2017. This paper reviews the eight standards and provides real-world experience from established Antimicrobial Stewardship Programs (ASPs) on how institutions can comply with these guidelines to reduce inappropriate antibiotic usage, decrease antimicrobial resistance, and optimize patient outcomes.
Webinar: Building Cross-Sector Collaborations to Promote Effective Antibiotic Use in Inpatient, Outpatient, and Long-Term Care Settings. A Public Health Foundation (PHF) archived webinar (Feb 7) with a focus on building collaborations between public health and healthcare to develop antibiotic stewardship programs and promote effective antibiotic use.
Linezolid: a promising option in the treatment of Gram-positives by AZ Bialvaei et al in J Antimicrob Chemother (2017) 72 (2): 354-364. A review undertaken to optimize the clinical use of linezolid. Due to the emergence of linezolid resistance, the authors support routine linezolid susceptibility testing before considering its therapeutic use.
What is new in the management of skin and soft tissue infections in 2016? by G Poulakou et al. Curr Opin Infect Dis. 2017 Jan 27. Reviews recent literature covering epidemiology and management of SSTIs; recommends the establishment of precise indications for new antimicrobials and their integration into clinical practice algorithms to help reduce unnecessary admissions, overtreatment and total costs.
Antimicrobial Resistance, edited by H Venter in Essays in Biochemistry, March 2017; 61(1)— a special issue featuring 15 articles on addressing environmental aspects of resistance and innovations in treatment and diagnostics.
Screening test recommendations for methicillin-resistant Staphylococcus aureus surveillance practices: A cost-minimization analysis by MD. Whittington et al, in Amer J Infect Cont, Jan 2017. The total cost of universal preemptive isolation surveillance practice was minimized when a polymerase chain reaction screening test was used. Targeted isolation surveillance (MRSA-pos) was minimized when chromogenic agar 24-hour testing was used.
Infection control in the new age of genomic epidemiology by PT Tang et al. Amer J Infect Cont 45, (2)2017: 170–179 Reviews the advantages of genome sequencing in attaining higher resolution and better tracking and management of outbreaks
Disk Carbapenemase Test for the Rapid Detection of KPC-, NDM-, and Other Metallo-β-Lactamase-Producing Gram-Negative Bacilli by H Kim H et al in Ann Lab Med. 2016 Sep; 36(5):434-40. Describes a new disk carbapenemase test that is simple and can be easily performed, even in small laboratories, for the rapid detection of GNB with KPC, NDM and the majority of IMP, VIM, and SIM carbapenemases.
Double-carbapenem combination as salvage therapy for untreatable infections by KPC-2-producing Klebsiella pneumoniae by M Souli M et al in Eur J Clin Microbiol Infect Dis 2017 Feb 16 Describes adouble-carbapenem combination (ertapenem and high-dose prolonged infusion meropenem) as a safe and valid salvage therapy for untreatable infections by extensively- or pandrug-resistant KPC-producing K. pneumoniae
How hospitals, nursing homes keep lethal ‘superbug’ outbreaks secret by DJ Nelson et al in Scientific American, December 23, 2016. A Reuters investigation of the deadly epidemic America is ignoring.
Comprehensive resistome analysis reveals the prevalence of NDM and MCR-1 in Chinese poultry production by Y Wang et al in Nat Microbiol 2017 Feb 6;2:16260. Describes a phenomenon labeled the “phantom resistome.” Whole-genome sequencing identified common blaNDM-positive E. coli shared among farms, flies, dogs and farmers, providing direct evidence of carbapenem-resistant E. coli transmission and environmental contamination.See comment in PubMed Commons below
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