HIGHLIGHTS - SUMMER 2017
APUA endorses S-FAR letter to new CDC Director Fitzgerald
APUA and other organizations comprising the U.S. Stakeholder Forum on Antimicrobial Resistance (S-FAR) have written a letter to the newly appointed director of the CDC, Brenda Fitzgerald. The letter notes Fitzgerald’s former work promoting antimicrobial stewardship while serving as Georgia’s Health Commissioner, and urges her to maintain the CDC’s Antibiotic Resistance Solutions Initiative (ARSI), which aims to develop public health infrastructure and laboratory capacity. It likewise urges support for the continued surveillance of antimicrobial resistant organisms and hospital antimicrobial use data collected by NHSN’s Antibiotic Resistance and Use module. Recognizing that hospital reporting of these data remains low, the letter offers S-FAR assistance in improving compliance. While noting concern over the global threat posed by MDR TB, the letter also expresses encouragement gained by the recent commitment to AMR containment issued by the recent G20 Summit in Germany. The letter ends by offering S-FAR’s support towards advancing a multi-faceted solution to AMR.Note: Recently, Director Fitzgerald expressed her belief that preventing infections is a priority for the CDC, including “doing more to prevent antibiotic resistance, tracking emerging infections overseas and helping other countries build their infectious disease-fighting capacities.” Her full interview with the Wall Street Journal on July 16 can be found here.
APUA’s 2014 Leadership Award winner turns spotlight on the search for natural antimicrobials
Public health journalist and author Maryn McKenna is featured in the July/August issue of The Atlantic with an article titled Hunting for Antibiotics in the World’s Dirtiest Places. McKenna chronicles the history of the search for new antimicrobials and details the sleuthing efforts of contemporary scientist Adam Roberts of London. Rather than focusing on extreme or exotic environmental sites, Roberts utilizes a crowd-sourcing campaign called Swab and Send to solicit promising samples from atypical, but common, germ-filled environmental niches; e.g., compost bins, pet bowls, keyboards, railings, public toilets, dirty fridges, etc. Any isolated bacterium that shows signs of inhibiting a stock bacterial or fungal strain undergoes additional testing. From thousands of samples tested to date, 18 bacteria exhibit activity against a strain of E. coli that is resistant to 15 different drugs. Any promising compounds that emerge from the process will still require late-stage clinical trials with considerable commercial support to bring them to market.
EU adopts a One Health Action Plan against Antimicrobial Resistance (AMR)
Evaluations and feedback on AMR undertaken by the European Union since 2011 have now culminated in the adoption of a new European Union One Health Action Plan against AMR. The plan is designed to support innovative, effective and sustainable responses to the AMR problem, and to play a leading role by making the EU a “best practice region” by boosting innovative research and development and shaping the global agenda. The first deliverable is release of the EU Guidelines on the prudent use of antimicrobials in human health, which includes measures to be considered by member states in the development of their national strategies to promote the prudent use of antimicrobials. The 20-page document contains non-binding advice that targets all actors who play a role in antimicrobial use. It concludes with guidelines aimed at international collaboration to control cross-border threats.
G20 summit commits to combating antimicrobial resistance
Recognizing the growing threat of antimicrobial resistance to public health and economic growth, The G20 Leaders’ Declaration out of Hamburg, Germany (July 2017), states :“We aim to have implementation of our National Action Plans, based on a One-Health approach, well under way by the end of 2018.” The statement reiterates its opposition to the use of antibiotics for growth promotion in animals, its support for strengthening public awareness and infection prevention and control, and promoting access to affordable and quality antimicrobials. In addition, the group has issued an invitation to join a new, international R&D Collaboration Hub aimed at maximizing the development of new antimicrobials and examining market incentive options.
DEVELOPMENTS IN THERAPY and NEW DIAGNOSTICS
CRE light up with new fluorescence based assay
Carbapenems are important “antibiotics of last resort” for certain highly resistant Enterobacteriaceae and Klebsiella that cause urinary tract and abdominal infections as well as hospital-acquired pneumonia. The emergence of carbapenem-cleaving enzymes in some strains has spurred the search for better detection methods. Chinese scientists working at East China University of Science and Technology have now reported developing a simple fluorescence-based assay to aid in the identification of carbapenem-resistant pathogens. The novel approach involves attaching a fluorogenic dye to a molecule that mimics carbapenem. When recognized by a carbapenemase-producing bacterium, the imposter molecule (called CVB-1), is cleaved, releasing the dye, which then reacts to a specific wavelength by emitting a bright green light. The new, fast and sensitive assay is aimed at avoiding the overuse of non-effective drugs.
Novel CRISPR innovation increases discrimination of dangerous pathogens
A team of scientists from MIT’s Broad Institute and Harvard have taken the first steps towards refining CRISPR technology that could someday create precise, easy and inexpensive diagnostic tests. The new CRISPR offshoot is called SHERLOCK, for Specific High sensitivity Enzymatic Reporter unlocking. The methodology operates with a simple test tube or glass fiber paper and minimal heat, making it adaptable to low-tech environments. Unlike traditional CRISPR, which targets DNA, the new SHERLOCK “scissors”, called Cas 13a, engage in “collateral cleavage”, i.e., cutting nearby RNA repeatedly--enough to produce a fluorescent signal that is detected with an inexpensive device, or even the naked eye. The technology is versatile and potentially useful for detecting viruses, bacteria, and cancer-inducing mutations, and its sensitivity can detect differences in a single nucleotide (equivalent to detecting 2 molecules in a billion billion [quintillion]). Such discrimination could be highly valuable in tracking epidemic pathogens (for example, detecting Zika virus in urine, rather than in blood) and has already demonstrated the ability to distinguish between two important antibiotic-resistant strains of Klebsiella.
ADVANCES in NOVEL ANTIMICROBIALS
Re-engineering longevity into vancomycin
Vancomycin, which came into use 60 years ago, is a last-line treatment for gram-positive bacteria that cause severe infections. It remained highly active until the 1980s, but concern over recent spread of vancomycin resistance into enterococcus and its potential to spread to MRSA has led to reduced vancomycin use. Researchers at the Scripps Research Institute in California have now succeeded in escalating the potency of vancomycin in a way that is predicted to reduce the problem of resistance to this drug. Two previous reconstructions of the drug in the past decade have boosted the potency of vancomycin by 100-fold, but this most recent modification makes the drug 1,000 times more potent than the original. The new “super vancomycin” (reported in PNAS April 14, 2017) is the first antibiotic to have three independent mechanisms in place, leading its developers to believe it is now immune to inactivation.
However, this viewpoint is questioned by others. In her blog, Tara Smith points out that durability of the new vancomycin is more limited where resistance genes are already present, and also when used under less than ideal conditions—which can be anticipated with any new drug. She claims that the historical precedent set by other “resistant immune” compounds suggests that complete immunity to resistance is very unlikely.
New antibiotics (iclaprim, omadacycline) pass phase III clinical studies
A recent phase 3 clinical trial (REVIVE-1), involving treatment of acute bacterial skin and skin structure infections (ABSSSIs) has succeeded in demonstrating the safety and efficacy of the novel antibiotic iclaprim when compared with vancomycin in 600 hospitalized patients. No dosage adjustment is required for renally impaired or obese patients, which may help to reduce treatment costs. The intravenous antibiotic is the product of the biopharmaceutical developer MotifBio, which hopes to promote iclaprim as the safer option for severely ill patients with comorbidities. The drug, which received Fast Track designation by the U.S. FDA, is now headed for a second phase 3 trial of patients enrolled at different sites.
In another phase 3 clinical trial (OASIS), Paratek Pharmaceuticals, Inc. has announced successful treatment of MRSA skin infections using its once-daily treatment of the IV-to-oral drug, omada- cycline. Safety and efficacy were compared against twice-daily linezolid over 7-14 days in 645 patients with acute ABSSSI. Omadacycline is a broad-spectrum antibiotic and the first in a new class of tetracycline derivatives called the aminomethylcyclines. It is designed for the treatment of serious community–acquired infections.
Bacteriophage therapy saves U.S. patient with multidrug-resistant bacteria
One promising alternative approach to antibiotic therapy is the use of bacterial viruses (bacteriophages) that attack specific strains of bacteria. While the methodology has a relatively long history of use in Eastern Europe and the former Soviet Union, the approach has only now been successfully implemented for the first time in the U.S.—in a severely ill person who failed all antibiotic therapy. The comatose patient was infected with a multidrug resistant strain of Acinetobacter baumanii that had become resistant to a combination of meropenem, tigecycline and colistin. In an incredible, rapid collaboration that involved three distinct research teams, a cocktail of four bacteriophage strains was assembled and purified for clinical use. An emergency investigational new drug application was sought from the FDA, and the phage cocktail was administered both intravenously and also through abdominal catheters. Within three days, the patient emerged from his coma and was removed from life support. While the treatment was ultimately successful, the recovery was precarious—plagued by bacterial resistance to the phages. Continual tweaking with variant phage strains, along with antibiotic therapy, was required to bring about complete elimination of the A. baumanii.
Because of its individualized nature, many unknowns remain attached to bacteriophage therapy, which is considered the “ultimate personalized medicine.” However the advent of molecular tools, robotics and other developments are making it increasingly more plausible as a viable therapy for patients plagued with severe drug-resistant infections.
Immune system-based peroxidases explored as new antimicrobials
A new study reported in Frontiers in Microbiology describes how Irish investigators have utilized hydrogen peroxide, iodide and thiocyanate to form highly reactive antimicrobial compounds that will kill both suspended bacteria as well as those that are firmly attached within highly impenetrable biofilms.
The team was inspired by the peroxidase enzyme that naturally occurs in the human immune defense system and that affords natural protection against bacterial infections. However, as the cost of enzymes is too prohibitive to make them practical, the researchers sought an enzyme-free system and designed the iodo-thiocyanate complexes, which kill bacteria rapidly in small doses and do not develop resistance. Applications for the new complexes can potentially include pre-surgery skin washes, disinfection of hospital surfaces and medical devices, and treatment of wounds and ulcers.
Bioluminescent bacteria recruited to find antimicrobials in New Zealand fungus
Scientists at the Bioluminescent Superbugs Lab at the University of Auckland are examining a collection of 10,000 fungi unique to New Zealand and the Pacific for possible antimicrobials. One thousand fungi have been selected for testing, and 300 have been screened to date using a unique approach that involves bacteria engineered to glow when alive. If the bacteria die in the presence of the fungus, they cease to glow, and an antimicrobial compound is suspected. To date, several fungi have shown activity against MRSA and Mycobacterium tuberculosis and will undergo more tests. The research project, Fight Against Superbugs is funded by a crowd-based campaign which aims to raise $250,000 to complete the study in the next 12 months.
Synthetic mucus shows promise against antimicrobial resistant organisms
Humans produce approximately one gallon of mucus per day that protects the eyes, lungs and digestive tract—largely by controlling, rather than actually killing, pathogenic invaders. MIT scientists are now exploring the natural ability of this mucus to control pathogenic bacteria by engineering polymers that mimic the sugar-coated mucin molecules found in saliva. They conducted competition studies using the cavity-producing tooth pathogen, Streptococcus mutans, and Streptococcus sanguinis, a normal mouth commensal. When grown in a non-mucin environment, the pathogen outcompeted the commensal, but in the presence of a saliva-based mucin called MUC5B, neither organism predominated. The MUC5B mucin was seen to shift cells from the biofilm condition to the single-cell (planktonic) state. The researchers intend to engineer a synthetic version of mucin molecules that will work similarly to support greater bacterial diversity and keep pathogens in check.
Experts rethink failed hygiene strategy
Since 2013, “universal decolonization” has become a common strategy in 65% to 80% of U.S. hospitals, aimed at controlling deadly superbugs such as MRSA. The practice, which began in the University of California Irvine Medical Center in 2013, involves daily disinfectant bathing with chlorhexidine and nasal swabbing with the antibiotic mupirocin. The strategy also included isolation of infected patients and stringent hand-washing. Unexpectedly, the strategy failed at the California Medical Center in late 2016 and a total of 10 infants became infected with MRSA, causing some practitioners to reconsider its efficacy.
The approach has been criticized for creating more bacteria resistant to chlorhexidine and to mupirocin. Some argue against broad antibacterial use and worry about the allergic reactions and other unintended consequences (such as reduction of beneficial bacteria) of using these chemicals on very young infants. Others argue that the failure could be corrected by screening incoming patients for MRSA. Although the practice of MRSA screening and isolation is considerably more costly, it has been used very effectively by the U.S. Department of Veterans Affairs, which recently reported an 80% drop in MRSA infections (and a significant decline in their severity) since instituting its MRSA Prevention Initiative in 2007. The price contrasts sharply with the low cost ($40) for the daily disinfection routine. The controversy has caused an ongoing debate about the safety and efficacy of universal decolonization and which method is really the best for controlling the spread of deadly superbugs in hospitals.
A Reuter’s investigation has found that the controversy is further muddled by the industry’s support of using chlorhexidine wipes in the daily washing of patients—considered to be an “off-label” use by the U.S. FDA, which has approved them only for pre-surgical cleaning.
ANTIBIOTIC RESISTANCE /EPIDEMIOLOGY
Hospital Microbiome Project seeks clues to better hygiene interventions
Microbial studies of brand new hospital rooms show that the bacteria of incoming patients overtake hospital surfaces within 7-24 hours of habitation. The study, led by Jack Gilbert at the University of Chicago’s newly opened hospital, the Center for Care and Discovery, sequenced >6,500 surface samples collected over a one-year period. Prior to opening, there was low bacterial diversity, predominated by Acinetobacter and Pseudomonas, while the skin bacteria Corynebacterium, Staphylococcus and Streptococcus became overwhelmingly abundant following patient entry. With the exception of topical antibiotics, which suppressed skin populations, no significant effects on skin bacteria were observed from oral or intravenously administered antibiotics. In samples from patients who were hospitalized for one or more months, some staph strains acquired genes that could promote host infection and boost antibiotic resistance.
The hospital surface sampling will be repeated every five years in hopes of characterizing and possibly understanding the dynamics of the hospital microbiome. In the meantime, efforts are being directed at tracking the daily movements of microbes to learn if surfaces can be manipulated to harbor favorable microorganisms that will reduce the probability of nosocomial infection.
Overall resistance in Staph aureus declines in U.S. hospitals; serious infections remain constant
In a rarely observed, encouraging trend, preliminary results on surveillance of Staphylococcus aureus infections in 42 U.S.-based medical centers have revealed a drop in resistance to key antibiotics. Between 2009 and 2015, resistance to oxacillin fell 5%—from 47.2% down to 42.2%. Resistance also declined for levofloxacin, clindamycin, and erythromycin, while resistance to ceftaroline, trimethoprim-sulfamethoxazole and tetracycline remained stable. Resistance to daptomycin, linezolid, vancomycin and tigecycline remained very rare.
In a retrospective evaluation conducted between 2010 and 2014, CDDEP researchers report a 29% drop in hospitalization for MRSA skin and soft tissue infections. However, no such decline was found in the rates of the most serious invasive (blood and pneumonia) infections.
“Resistomap” showcases resistance data from global human gut microbiomes
In a recent Bioinformatics article, Russian scientists debuted an interactive, global map theycall ResistoMap. The new tool, available at resistomap.rcpcm.org, is a novel visualization of genetic determinants with resistance to antibiotics, heavy metals and biocides in the human gut microbiome. The databank currently consists of ~1500 gut metagenomes from both healthy and diseased subjects published in 12 studies from 15 different countries. Two main interactive working fields—a geographic map and a heat map—contain data that can be sorted by country, gender, age and diagnosis.
Current analyses of European data show a low resistome among Danes and highest levels among the French, which broadly corresponds with antibiotic use in their respective countries.
The online visualization tool is expandable to accept newly generated data and is expected to help provide insights into optimizing antibiotic use in both medicine and agriculture.
Crowd funding study approach used to solicit ESBL study data
A novel study has begun collecting global data on predicting the presence of ESBL-producing bacteria at the time of antibiotic onset. Frustrated with the difficulties of using current guidelines for predicting ESBL producers, two Dutch PhD students have teamed up to test two novel prediction rules: one for community-onset blood stream infections (BSI), and one for hospital-onset BSI. To validate the new rules and test whether they could reduce unnecessary carbapenem antibiotic use, the team utilized a crowd-funding study approach and created an electronic case report form (eCRF) to record scores—one on the day of empiric antibiotic treatment, and one five days later, for culture results.
The study began with an initial blog post for recruiting participants in Europe, and has now expanded to acquire data from Japan, Netherlands, Sweden, Spain, Italy, Germany, Switzerland, Serbia, Montenegro and the UK. As of early July, 2,192 data sets have been entered towards the goal total of 20,000. To date, 3.1% of all blood cultures, and 11.8% of all positive blood cultures have yielded 3rd-generation cephalosporin-resistant Enterobacteriaceae; six are carbapenem-resistant
The invitation has been extended to all hospitals globally. Those desiring to join may inquire by emailing email@example.com.
INCREMENT project yields findings on BSI treatment
Infections with carbapenemase-producing enterobacteria (CPE—typically E. coli and Klebsiella) are deadly, often killing up to half of all patients. Contrary to the current recommendations, a new study of patients with bloodstream infections due to CPE has shown for the first time that combination antibiotic therapy can be avoided in a substantial number of cases. While dual therapy is very effective in those with a high risk of dying—i.e., the risk of death is reduced by 50%, it is not better than single antimicrobial therapy in those patients with a low risk of dying. The findings are important because use of fewer antibiotics can help reduce the risk of adverse effects that come with multiple antibiotic use.
A second finding from the INCREMENT project was that carbapenems are not necessarily needed as initial therapy while waiting for antibiotic susceptibility test results. Other drugs can be used empirically without a detrimental outcome, as long as the correct, active drug is used as soon as it is identified. Again, the unnecessary use of “last resort” carbapenems can be avoided, thereby reserving them for critical infections that are resistant to all other antibiotics.
The INCREMENT project is an international, restrospective study involving 37 hospitals in 11 countries. Patients were evaluated using an INCREMENT-CPE score which takes into account age, infection source, type and severity of infection and presence of other co-morbidities.
Stewardship expert shares tips on implementing new required plans
In October 2016, the Centers for Medicare and Medicaid Services final rule establishing an antimicrobial stewardship program in long-term care facilities will go into effect. It is estimated that 75% of the antibiotics administered in nursing homes are prescribed incorrectly. With just a few months remaining, APUA author and infectious disease specialist at PYA (Pershing Yoakley & Associates) James Keegan* has provided some recommendations for the smooth implementation of ASP programs. He stresses the importance of educating staff about the benefits of maintaining protective bacteria which diminish the chances for acquiring C diff and MRSA, the leading causes of hospital readmission. Among the recommendations are:
· Get up front help from an ASP expert
· Avoid empirical prescribing of an antibiotic as a “just in case” solution
· Review your local hospital antibiogram
· Create a “preferred antibiotic” list
· Consider the financial benefits of not prescribing ineffective antibiotics
· Explore rapid diagnostic technology
The recommendations can be found in more detail here.
*see APUA Newsletter article: Achieving Results by Implementing an Antibiotic Stewardship Collaborative Spring 2016, 34(1):9-11
PUBLICATIONS and WEBINARS of NOTE
Empirical MRSA coverage for nonpurulent cellulitis_ swinging the pendulum away from routine use by EK Shuman and PN Malani. May 2017. JAMA 317(20):2070-2071
Diagnosis and management of skin and soft-tissue infections(SSTI), A literature review and consensus statement: an update by S Esposito et al. Aug 2017. J Chemother. 29(4):197-214
Effect of antibiotic stewardship on the incidence of infection and colonization with antibiotic-resistant bactgeria and Clostridium difficile infection: a systematic review and meta-analysis by D. Bauer et al. 2017 Lancet Infect Dis June 2017
Life after USA300: the rise and fall of a superbug by PJ Planet in J Infect Dis, Feb 2017. 215(supp1) S71-S77
Deadliest Enemy: Our War Against Killer Germs a new book by Dr. Michael Osterholm and Mark Olshaker 2017, Little, Brown and Company, NY
Attributable mortality of healthcare-associated infections due to multidrug-resistant gram-negative bacteria and methicillin-resistant Staphylococcus aureus, by RE Nelson et alJuly 2017, Infect Cont Hosp Epidemiol 38 (7):848-856
Increasing incidence of multiply recurrent Clostridium difficile infection in the United States: a cohort study by GK Ma et al, July 2017. Ann Intern Med 167:152-158
Explaining differences in resistance rates: an online ECCMIDsymposium (SY152, April 24, 2017) with David Fisman, Ramanan Laxminaryan, Evelina Tacconelli and Peter Collignon, co-organized by ASM
Emergence of livestock-associated methicillin-resistant Staphylococcus aureus bloodstream infections in Denmark by J Larsen et al. May 2017. Clin Infect Dis. Cites evidence that Danish pigs are the most likely source of human LA-MRSA CC398 infections.
Impact on morbidity, mortality and length of stay of hospital acquired infections by resistant microorganisms. By JI Barrasa-Villar et alClin Infect Dis. May 2, 2017
MRSA, C. diff and other health-care associated infections. An interview with Dr. Rodney Rohde discussing a variety of HAI topics. on Outbreak News this Week Radio Showhttp://1380thebiz.com
Recommendations for methicillin-resistant Staphylococcus aureus prevention in adult ICUs: a cost-effective analysis by MD Whittington et al. 2017, Crit Care Med 45(8) 1304-1310
Antibiotics and novel therapies
Old drug, new wrapping – A possible comeback for chloramphenicol? By SG Ingebrigtsen et al. 2017. Int J Pharm. Describes a new liposome-in-hydrogel formulation for dermal delivery.526(1-2):538-546
New and improved? A review of novel antibiotics for Gram-positive bacteria by M Abbas et al. June 2017, Clin Microbiol Infect
The whole price of vancomycin: toxicities troughs and time by MN Jeffres. Jul 2017 Drugs 77(11):1143-1154.
Surveillance and tracking
In vitro activity of imipenem against carbapenemase-positive Enterobacteriaceae isolates collected by the SMART Global Surveillance Program from 2008-2014 edited by E Munson in J Clin Microbiol June 2017 55:1638-1649.
The incidence of MRSA infections in the United States: is a more comprehensive tracking system needed? By KT Kavanaugh et al. Antimicrob Resist Infect Contr 2017.6:34
Hygiene and disinfection
Challenges and strategies for prevention of multidrug resistant organism transmission in nursing homes by G Dumyati et al in Curr Infect Dis Rep Apr 19(4):18
Infection prevention strategy in hospitals in the era of community-associated methicillin-resistant Staphylococcus aureus in the Asia-Pacific Region: a review by SY Cho and DR Chung 2017 Clin Infect Dis. May 64(S2):S82-90
Identification of low, high, and super gelers and barriers to hand hygiene among intensive care unit nurses by SL Kurtz, May 2017. Amer J Infect Cont
Patients’ hand washing and reducing hospital-acquired infection by S Haverstick 2017 in Crit Care Nurs June 37(3):e1-e8
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