Summer 2019 Issue of the Association of Public

FEATURE

A Game-changer in the Fight Against Antibiotic Resistance by Nancy Maddox, MPH, writer

4 LAB MATTERS Summer 2019 PublicHealthLabs @APHL APHL.org FEATURE

Arkansas resident Tamika Capone traveled to Tijuana last October for low-cost bariatric surgery and came home with a superbug—VIM-producing carbapenem- resistant Pseudomonas aeruginosa (VIM-CRPA), an organism the US Centers for Disease Control and Prevention (CDC) considers a serious health threat.

As quoted in The Washington Post, her Little Rock physician said “I’ve not yet had a patient with zero [treatment] options, but this is as close as I’ve had.” Capone started on a course of colistin— a last-resort antibiotic that can trigger kidney and nerve damage—but stopped treatment after her face and tongue went numb. Now, as The Post reports, she has an infected hole at the abdominal incision site, and it won’t heal and “hurts a lot.” If the highly drug-resistant bacterium enters her bloodstream, the infection could well be fatal. Arianna Allgood and Erica Terrell read AST plates. Welcome to a world without antibiotics. Photo: TDH DLS Although VIM-CRPA is uncommon in the United States—86 cases were reported to capabilities and the National Tuberculosis CDC through 2017—Capone’s experience Molecular Surveillance Center overseen by is a preview of what will certainly happen the Michigan Department of Health and if our antibiotic pharmacopoeia becomes Human Services. irrelevant. It was the AR Lab Network that generated Given the global rise of drug-resistant the data linking Capone to a handful pathogens over the past few decades, of other CRPA-infected patients who some physicians and scientists warn received healthcare in Tijuana. According of a possible antibiotic apocalypse—a to The Post, eight of these patients, scary, post-antibiotic era. Marion Kainer, including Capone, had surgery at the MD, MPH, an infectious disease expert same hospital. Thanks to the AR Lab who directs the Healthcare-associated Network’s scientific work, CDC issued Infections and Antimicrobial Resistance a travel alert with recommendations Program at the Tennessee Department of for patients who had invasive medical Health (TDH), said such a fate “is definitely procedures in Tijuana and for clinicians a valid threat.” She said, “We have patients who might treat CRPA-infected who have untreatable organisms right individuals. The agency also contacted now. This is not something that’s in the Mexican health authorities, who pinned future. Fortunately, in the US it is still the outbreak on poor infection control relatively rare.” practices and temporarily closed Tijuana’s A $160 million CDC effort now aims to Grand View Hospital. keep antibiotic resistance rare. And the As of April 20, 2019, the VIM-CRPA keystone of this effort is the Antibiotic outbreak associated with Grand View Resistance Laboratory Network (AR Lab Hospital appears to be over. But without Network). Established in 2016, the AR the AR Lab Network, it might never have Lab Network comprises public health been detected. laboratories in 50 states, five cities and Puerto Rico, including seven regional laboratories with advanced testing

PublicHealthLabs @APHL APHL.org Summer 2019 LAB MATTERS 5 FEATURE

course. And nearly all US dairy cows are given prophylactic, intramammary drug infusions—typically penicillins or other beta-lactam drugs—to prevent mastitis. Antibiotics are also used as pesticides. The US Environmental Protection Agency, for example, is in the process of re-approving the use of streptomycin for wholesale spraying on apple, pear and nectarine trees to control citrus canker and citrus greening disease. Global developments have exacerbated the problem. In 2010, India was the world’s largest consumer of antibiotics for human health, followed by China. According to researchers Ramanan Laxminarayan and Ranjit Roy Chaudhury, a perfect storm of poor public health systems, high rates of infectious disease, inexpensive antibiotics and rising incomes has led to the proliferation Tennessee microbiologists Michelle Therrien “Whenever and wherever you and Justin Simpson process carbapenem-resistant use antibiotics, resistance is of resistant pathogens in many parts Enterobacteriaceae specimens. Photo: TDH DLS going to follow” of the world and especially the BRICS countries—Brazil, Russia, India, China and The problem of antibiotic resistance (AR) South Africa. Increased demand for meat has been decades in the making. James and poultry in places like India has fueled “Albert” Burks, IV, MLS(ASCP), RN, who even greater agricultural antibiotic use. oversees carbapenem-resistance testing Even if we have perfect Michael Craig, MPP, CDC’s senior advisor at the TDH Division of Laboratory Services for AR, said, “Whenever and wherever antibiotic prescribing and use, explained that antibiotic research and you use antibiotics, resistance is going AR would still be a problem, largely development “slacked off” beginning to follow.” He said, “We take for granted in the mid-1980s, when an array of because of the transmission of sometimes that antibiotics are really potent antibacterial agents was readily the scaffolding that makes surgical [existing] resistant pathogens.” available. At the same time, he said, procedures possible, organ transplants physicians began prescribing antibiotics Michael Craig, MPP possible, invasive disease treatments for conditions like sinus infections, possible. All of those are risky, and people now known to be mostly viral and susceptible to infections are vulnerable. unresponsive to antibacterial drugs. When antibiotics start to be ineffective, “Patients were taking [antibiotics] until the risk-benefit profiles of those they felt better when the lifecycle of treatments change; doctors might not the virus was complete; they weren’t taking the full regimen,” said Burks. Consequently, mildly drug-resistant pathogens were able to survive and evolve. Outside the healthcare arena, antibiotics have also been overused in veterinary and agricultural settings. In fact, agricultural usage of antibiotics far exceeds their healthcare usage. Farmers administer the drugs not only to treat acute animal illness, but also to prevent illness and to enhance animal growth. According to Tennessee’s GC AR Lab Network Team (from l to r): Robin one estimate, about 90% of pigs raised Rasnic, Arianna Allgood, Erica Terrell, Brielle Davis and for food in the US get tetracyclines or Henrietta Hardin. Photo: TDH DLS similar drugs in their feed as a matter of

6 LAB MATTERS Summer 2019 PublicHealthLabs @APHL APHL.org FEATURE

recommend doing them if we can’t treat agencies to “accelerate response to any infections that might come up.” antibiotic resistance,” including:

In 2014, the World Health Organization • Improving antibiotic stewardship in called AR “a problem so serious that it healthcare settings, including cutting threatens the achievements of modern antibiotic use by 50% in outpatient medicine.” settings and 20% in inpatient settings by 2020 Indeed, Craig said reservoirs of AR are now so great, it is no longer sufficient • Preventing the spread of AR threats to simply stop misusing and overusing • Eliminating the sub-therapeutic use of antibiotics: “Even if we have perfect medically important antibiotics in food antibiotic prescribing and use, AR would animals still be a problem, largely because of the transmission of [existing] resistant • Expanding surveillance for AR bacteria pathogens.” These pathogens may in people and animals colonize individuals who never become • Creating a regional public health symptomatic. Or they may persist in laboratory network animal hosts, in healthcare facilities or Urgent Threats in the broader environment (for example, • Establishing an AR specimen repository after being discharged in hospital waste). and genetic sequence database • Clostridium difficile to facilitate development of new • Carbapenem-resistant Enterobacteriaceae Bacteria containing the AR gene NDM-1 diagnostic tests and pathogen-specific • Drug-resistant Neisseria gonorrhoeae have been found in water pools in treatments. New Delhi streets and in High Arctic soils in Norway’s Svalbard archipelago, So far, Craig said, one of CDC’s biggest Serious Threats demonstrating just how widely dispersed AR achievements, “if not the biggest the organisms are. achievement,” is the founding of the • Multidrug-resistant Acinetobacter regional AR Lab Network. • Drug-resistant Campylobacter And because AR genes are often found • Fluconazole-resistant Candida on mobile genetic elements called All 56 AR Lab Network members • Extended spectrum ß-lactamase producing plasmids, they can be transferred from perform basic testing, such as antibiotic Enterobacteriaceae one microorganism to another without susceptibility testing and detection of • Vancomycin-resistant Enterococcus any antibiotic exposure. So, for example, carbapenemases (enzymes that hydrolyze • Multidrug-resistant Pseudomonas KPC—the most common AR gene found certain antibiotics) in Enterobacteriaceae aeruginosa in carbapenemase-producing organisms and Pseudomonas aeruginosa isolates. • Drug-resistant non-typhoidal Salmonella (CPOs) in the US—may be transferred In addition, the seven regional AR Lab • Drug-resistant Salmonella Typhi from Klebsiella to Salmonella to CRPA. Network members perform molecular • Drug-resistant Shigella In 2013, CDC released an AR threat testing to detect colonization of CPOs in • Methicillin-resistant Staphylococcus report listing 18 microbes, collectively people potentially exposed by an index aureus responsible for more than two million case; fungal susceptibility testing of • Drug-resistant Streptococcus pneumoniae illnesses and at least 23,000 deaths in the Candida species; colonization screening • Drug-resistant tuberculosis US each year. However, the report was for Candida auris; and detection and written before the launch of the AR Lab characterization of emerging threats, Network, when data were less complete. such as mcr-1, a bacterial gene that Concerning Threats Craig said an updated report due out later confers plasmid-mediated resistance to • Vancomycin-resistant this year will note that, “as we expected, colistin (the drug-of-last-resort prescribed Staphylococcus aureus the burden of AR infections is more for Tamika Capone). AR Lab Network • Erythomycin-resistant Group A than we estimated previously; for some laboratories also provide isolates for Streptococcus pathogens, significantly more.” the new CDC/FDA AR Isolate Bank and • Clindamycin-resistant Group B for federal whole genome sequencing Streptococcus The AR Lab Network— projects. “A Game-changer” Source: CDC. Antibiotic Resistance Threats in the United The TDH Division of Laboratory Services— States, 2013 Two years after the threat report came the state public health laboratory—is out, the Obama Administration released the Southeast Regional AR Lab Network its National Action Plan for Combating Laboratory that provides core AR Lab Antibiotic-Resistant Bacteria. The Network testing for six states plus Puerto so-called “CARB” plan directs federal Rico, expanded drug susceptibility testing

PublicHealthLabs @APHL APHL.org Summer 2019 LAB MATTERS 7 FEATURE

for 14 states plus Puerto Rico and surge (the so-called GC AR Lab Network). The 3,277—a 54% increase. capacity nationwide. In 2017-2018, the bacteriology team tests specimens from “The epidemiology of [MRSA laboratory examined over 9,600 specimens high-prevalence sites across the country transmission] is changing,” said Kainer. for carbapenem resistance and detected that participate in CDC’s Gonococcal “It’s now likely to be driven by the opioid or confirmed over 300 highly resistant Isolates Surveillance Program (GISP), epidemic—users injecting with tainted Acinetobacter isolates, over 1,100 resistant enhanced GISP or Strengthening US needles, syringes or other paraphernalia. Pseudomonas isolates and almost 3,500 Response to Resistant Gonorrhea program. They often get these MRSA infections carbapenem-resistant Enterobacteriaceae Since the laboratory joined the GC AR Lab along with endocarditis. Those are very isolates. Network in spring 2017, it has analyzed serious, very expensive, high-mortality over 5,500 isolates for susceptibility to Among other successes, Burks said his conditions.” In fact, one-year mortality seven antibiotics using agar dilution scientific team employed a new PCR for hospital-onset MRSA bloodstream plates produced in-house. Overall, 7% of method to identify three new AR gene infection in Tennessee runs about 50%. isolates have exhibited drug resistance. groups in Acinetobacter. “The number On the flip side, Kainer said, CPOs carrying of Acinetobacter specimens [we receive] Hardin said her team is now involved in the KPC gene have become notably rarer seems to be holding steady,” he said, “but setting susceptibility “breakpoints” for in Tennessee. She said, “We attribute resistance is surprisingly high—about new drugs, like gentamicin, which will that to improved infection control and 70% positive for one of the three genes hopefully prove effective against some environmental cleaning in healthcare Tennessee identified.” But because drug-resistant gonorrhea strains. settings.” And those improvements she there is no reliable pre-AR Lab Network Within the state of Tennessee itself, attributes directly to CDC’s stepped-up assessment of carbapenem resistance in Kainer said the biggest AR threat is investment in AR control. Acinetobacter, Burks said, “We don’t know “an oldie” that is making a comeback: if the rate is increasing or if it was already Before the CARB plan and associated methicillin-resistant Staphylococcus that high.” state funding, Kainer said, “We didn’t aureus (MRSA). She said, “We have seen have laboratory capacity for rapid [AR] Under the direction of Henrietta Hardin, very significant increases particularly detection and identification, and we didn’t MPA, MT(ASCP), the facility’s general among the younger population and more have the public health infrastructure on bacteriology manager, the Tennessee among females.” the epi and infection control side.” laboratory is also one of four regional Between 2014 and 2018, the number of AR Lab Network laboratories testing Today, a single case of CPO infection in MRSA bloodstream infections reported by for resistance in Neisseria gonorrhoeae a Tennessee hospital triggers laboratory Tennessee hospitals jumped from 2,123 to testing to identify the infectious organism and AR gene, sometimes supplemented by more detailed characterization, such as whole genome sequencing. In addition, Kainer’s staff assesses the facility’s infection control practices—hand hygiene, environmental cleaning, use of personal protective equipment and the like—and collects rectal swabs from potentially exposed patients as part of a point prevalence survey to determine whether transmission has occurred. If laboratory testing shows CPO colonization in other patients, further recommendations are made. “We continue these point prevalence surveys every two weeks until we get two consecutive rounds of negative transmission,” said Kainer. “Having the laboratory capacity to process these colonization swabs is a huge thing. The whole aim here is timely data to allow us to take the appropriate infection control and public health actions. It’s literally a game-changer.”

Brittany O’Brien and Rokebul Anower review results from the real-time PCR developed for Candida auris. Photo: Wadsworth Center

8 LAB MATTERS Summer 2019 PublicHealthLabs @APHL APHL.org FEATURE

Having the laboratory capacity to process these colonization swabs is a huge thing. The whole aim here is timely data to allow us to take the appropriate infection control and public health actions.” Marion Kainer, MD, MPH

The Candida team from the Wadsworth Center Mycology Laboratory. First row (from l to r): Yan Chun Zhu, Brittany O’Brien, Sudha Chaturvedi. Second row (from l to r): Mitchell Kaplan, Manuel Pazos, Jiali Liang, Rokebul Anower. Photo: Wadsworth Center

One organism so far undetected in almost exclusively limited to people nurses and other stakeholders across Tennessee, but an emerging problem with extensive healthcare needs, such the healthcare system; and working with elsewhere in the US is antibiotic-resistant as nursing home residents with chronic sentinel laboratories that serve high-risk Candida auris. ventilator usage and people with multiple populations, such as ventilated nursing ICU admissions. home patients and “medical tourists” who “When CDC put out the original [AR] have had healthcare abroad. “When you’re threats report in 2013, we didn’t even To speed detection of the organism during doing [AR] surveillance, you want to be mention this, because we didn’t know the outbreak, Wadsworth scientists moved sure you’re looking at the places where about it,” said Craig. “It seems to have from MALDI-TOF mass spectrometry you expect to find it,” she said. emerged independently in multiple places testing—which requires culturing around the world and then spread. We specimens over 4 to 14 days—to a rapid Historically, said Craig, “Even in the US don’t know yet how or why it emerged molecular assay developed in-house. The we haven’t done as good a job as we when it did.” new assay provides results within one day should have to detect and respond to [AR of specimen receipt. pathogens].” He said, “With the AR Lab Antibiotic-resistant Candida auris is Network, now we have an infrastructure known for its extreme hardiness in the To date, the Wadsworth Center has to do that, and I’m thankful and grateful environment; its ability to colonize the screened over 17,000 surveillance for all the hard work laboratorians have human gut, skin and bloodstream—and a specimens from the NYC area and put in to support the network; they are mortality rate as high as 80%, depending detected drug-resistant C. auris on the fundamental to its success.” on the strain and infection site. skin of over 450 healthy individuals, 40 of whom went on to develop illness and are Without laboratory data, Craig said, The organism was first described in also included in the clinical case count. “there’s really not a good understanding a Japanese patient in 2009 and first The Center’s molecular assay has been about what [drug-resistant] strains are identified in New York state at the time adopted by CDC and several other AR Lab developing, how they’re emerging and of a multi-hospital outbreak in New York Network members. what’s likely to be transmitted locally and City (NYC) in 2016. According to the New globally.” He warned, “If we’re not looking York State Department of Health, it can “If we’re not looking for it, it’s going for it, it’s going to disseminate secretly now “probably be considered endemic to disseminate” and quietly around the world.” n within some parts of the healthcare system in Brooklyn and Queens.” Containing the threat posed by drug- resistant pathogens is an ongoing project. As of May 31, 2019, the Wadsworth Kainer said jurisdictions can assist Center—the New York state public health by making drug-resistant conditions laboratory and Northeast Regional AR reportable and requiring isolate Lab Network Laboratory—confirmed 334 submission; conducting tabletop exercises clinical cases of drug-resistant C. auris with laboratorians, hospital and nursing among NYC residents, with infection home risk managers, infection control

PublicHealthLabs @APHL APHL.org Summer 2019 LAB MATTERS 9