REVIEW ARTICLE. MILITARY MEDICINE, Vol. 180, February MILITARY MEDICINE, 180, 2:145, 2015

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1 REVIEW ARTICLE MILITARY MEDICINE, 180, 2:145, 2015 The State of Antimicrobial Resistance Surveillance in the Military Health System: A Review of Improvements Made in the Last 10 Years and Remaining Surveillance Gaps Ruvani M. Chandrasekera, MPH*; COL Emil P. Lesho, MC USA ; Uzo Chukwuma, MPH ; COL James F. Cummings, MC USA*; LTC Paige E. Waterman, MC USA* ABSTRACT During a military public health laboratory symposium held in 1999, concerns were raised that the military health system lacked a standardized antimicrobial resistance (AMR) surveillance system that allowed comparison of data across sites, investigation of trends, and understanding of resistance mechanisms. The purpose of this review was to assess if current AMR activities in the military health system have addressed the aforementioned gaps. It was determined that much progress has already been made within the Department of Defense with respect to monitoring and understanding AMR through initiatives such as the Antimicrobial Resistance Monitoring and Research Program a strong Department of Defense-wide surveillance program. These surveillance efforts can be made more robust through harmonization of testing and reporting structures across military treatment facilities, and by encouraging military treatment facility participation. BACKGROUND Since the power of antimicrobial therapy was harnessed in the last 60 years, we have witnessed the ability of organisms to rapidly adapt, survive last-line therapeutics, and threaten effective patient care. 1 3 Recognition that action needed to be taken to control the rising rates of antimicrobial-resistant infections prompted discussions at a Military Public Health Laboratory (MPHL) Symposium and Workshop sponsored by the Department of Defense (DoD) Global Emerging Infections Surveillance (now a division within the Armed Forces Health Surveillance Center, and herein referred to as AFHSC-GEIS) in September of ,5 Symposium participants, consisting of clinicians, laboratorians, and other public health professionals, determined that the Military Health System (MHS) lacked a standardized antimicrobial-resistant organism surveillance system that allowed the following: (1) Uniform interpretation of antimicrobial resistance to compare data across sites/regions (2) MHS-wide reporting of data to investigate trends across sites/regions *Armed Forces Health Surveillance Center, 503 Robert Grant Avenue, Silver Spring, MD Multidrug-resistant organism Repository and Surveillance Network, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD EpiData Center, Navy and Marine Corps Public Health Center, 620 John Paul Jones Circle, Portsmouth, VA doi: /MILMED-D (3) An improved understanding of resistance mechanisms and antimicrobial selection across both the military and civilian sectors 6 9 It was perceived that these weaknesses limited the ability of the MHS to address the threat of antimicrobial-resistant organisms as data were not available to inform appropriate clinical treatment, guide drug discovery, aid in development of infection prevention and control measures, and answer requests for DoD-wide information pertaining to antimicrobialresistant organisms. Nearly 15 years later, antimicrobial resistance (AMR) is considered a global public health crisis, 10,11 and remains a looming threat within the MHS The purpose of this review is to identify current AMR activities in the U.S. military, and assess if the gaps identified in the 1999 MPHL symposium have been addressed. The assessment will help refine and focus AMR surveillance efforts within the DoD. METHODS To determine if the gaps identified in the 1999 symposium have been addressed, the objectives of current activities within the DoD were compared against theoretical end states. These end states were created to reflect what should be in place if the gap has been addressed. Table I lists the end states for each gap. Current AMR activities within the DoD were determined by contacting individuals in the AFHSC partner network, conducting interviews with DoD infectious disease and infection prevention consultants, and reviewing literature in electronic bibliographic databases using the terms military resistance and MILITARY MEDICINE, Vol. 180, February

2 TABLE I. AMR Surveillance Gaps and Their Respective End-States Gap Lack of Uniform Interpretation of AMR Data Lack of a MHS-Wide Reporting System for AMR Data Lack of a MHS-Wide System to Research and Understand Resistance End-State A MHS-Wide System Utilizing the Same Protocols So Data Can Be Uniformly Interpreted A MHS-Wide System for Reporting of AMR Data A MHS-Wide System That Contributes to Greater Understanding of Identification and Spread of Resistant Pathogens military surveillance. Proceedings of the MPHL Symposium and Workshop documented in the July 2000 Supplement to Military Medicine (vol 165, no 7) were also reviewed and discussed with respective article contributors. RESULTS Since 1999, several activities have been undertaken to improve patient care and mitigate the spread of antimicrobialresistant infections by conducting surveillance within the U.S. military. These activities can be categorized into independent studies conducted within fixed timeframes, and surveillance activities that are programmatic in nature. The programmatic surveillance activities can be further divided into activities occurring at the individual military treatment facility (MTF) level, and those which are MHS-wide. Each MTF infection prevention and control office monitors antimicrobial resistance at the facility. When the hospital microbiology laboratory identifies an organism of epidemiological significance to the facility, the infection control team and treating physician are notified to ensure appropriate patient care and appropriate infection control strategies are implemented. MTFs with microbiology capability also produce antibiograms for review by the infection prevention team and/or antimicrobial stewardship committees to aid in formulary modification, guide empiric therapy, and meet other needs. Implementing MHS-wide AMR surveillance has proven more challenging due in part to the sheer size of the system (more than 230 MTFs) and the stovepipe approach to data handling. Two strategies have been taken to address the need for AMR surveillance across the MHS: one by the Walter Reed Army Institute of Research with the Multidrug-Resistant Organism Repository and Surveillance Network and the other by the Navy Marine Corps Public Health Centers EpiData Center (NMCPHC-EDC). Together, the Multidrug-Resistant Organism Repository and Surveillance Network (MRSN) and EpiData Center (EDC) form the Antimicrobial Resistance Monitoring and Research Program (ARMoR). 15 The MRSN is a surveillance initiative set up in 2009 to identify and characterize multidrug resistant organisms (MDRO) of importance within the MHS. Although Navy and Air Force MTFs are not mandated to participate in MRSN surveillance activities unlike their Army counterparts, Navy and Air Force participation is highly encouraged. There are approximately 30 MTFs (not all are Army) that participate consistently in MRSN surveillance efforts. The MRSN collects MDROs from MTFs, conducts confirmatory MDRO testing, advanced molecular characterization, and provides results to the submitting MTF in a clinically relevant turnaround time to aid in infection mitigation measures. 16,17 Specifically, confirmatory testing results for pathogen identification and antimicrobial susceptibility (ID/AST) are provided to the MTF within 48 hours along with results from PCR screening for resistance genes. Results which have more epidemiological significance, such as pulsed-field gel electrophoresis, optical mapping, and whole genome sequencing, are made available to the MTF within 7 days. Through the aforementioned activity, the MRSN has been able to describe the first appearance of several drug-resistant genes and isolates in the MHS Reports and executive summaries (e.g., emerging pathogen alerts and outbreak reports) are distributed through electronic mailing lists to the DoD community. The EDC has conducted AMR surveillance activities since 2007 to support congressional inquiries and provide situational awareness of AMR within the Navy and across the DoD utilizing microbiology laboratory data captured by the MHS-wide patient care management system, the Composite Health Care System. The EDC has developed algorithms to mine the complex laboratory data and rapidly identify and monitor emerging antimicrobial resistance in organisms such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and other epidemiologically important pathogens of public health concern. 15 Results from this surveillance are published in reports on the NMCPHC website and distributed to the DoD community through electronic mailing lists. The ARMoR program leverages the strengths of both the MRSN and EDC. There are instances in which MTFs may not identify and notify the MRSN of important MDROs. Collaboration between the EDC, the MRSN, and the MTFs, serves as a quality assurance process to ensure that MDROs are being captured. When the EDC identifies a suspect MDRO of interest, the MRSN and the MTFs can cross-check their records and determine if the isolate should be obtained by the MRSN for characterization (if this has not already been done). Another DoD effort to conduct MHS-wide surveillance that feeds into a national system, the Centers for Disease Control and Prevention s (CDC s) National Healthcare Safety Network (NHSN), has been championed by the Assistant Secretary of Defense for Health Affairs. The NHSN is a voluntary reporting system focused on tracking healthcare associated infections (HAIs) through a number of modules including one developed specifically for tracking MDROs. 25 In May 2012, 146 MILITARY MEDICINE, Vol. 180, February 2015

3 the Assistant Secretary of Defense for Health Affairs released a policy memorandum mandating that all MTFs meeting NHSN criteria for participation, initiate reporting to the system. DoD facilities were expected to fully implement reporting to NHSN at minimum for the Device Associated Infection Module by August As of May 2014, there are 43 MTFs reporting within the DoD NHSN group, however, the DoD NHSN group does not have visibility on which NHSN modules are being utilized by the participating MTFs (personal communication). To increase MTF participation in the NHSN module pertaining specifically to MDROs, the EDC is piloting an effort that leverages its capability to access, identify and monitor resistant organisms from Composite Health Care System microbiology laboratory data, and report this AMR data on behalf of all MTFs to the NHSN. On a smaller scale, a number of independent studies conducted by research groups within the DoD contribute to the general body of AMR knowledge. Over the last 10 to 15 years, studies have been conducted in recruit and deployed U.S. military personnel to measure incidence, prevalence, understand resistance mechanisms and guide clinical management of pathogens causing wound and skin and soft tissue infections As emerging pathogens are identified, studies are commissioned to learn more. For example, when drugresistant Acinetobacter calcoaceticus-baumannii appeared in wound infections during the initial years of Operations Enduring Freedom and Iraqi Freedom and spread precipitously within the MHS, studies were conducted to better define the problem and track the spread of this species. 12,32 34 In addition, since AMR is a global issue, the AFHSC-GEIS is leading initiatives to develop AMR surveillance capabilities at overseas locations (particularly resource-constrained regions). This development will provide partner countries with data to make more informed policy and treatment decisions, and through collaboration with the MRSN, enhance the U.S. military s visibility of emerging resistant pathogens globally. DISCUSSION Although there are efforts to address the need for antimicrobial resistance data in the military, the question remains if activities within the MHS have closed the three previously identified gaps: (1) lack of data that can be interpreted uniformly, (2) lack of a system that allowed MHS-wide reporting of AMR data, and (3) the need for a system that allowed a better understanding of AMR. Uniform Interpretation of Data There is no mandate or DoD guidance to track resistance at the MTF level across all services in the DoD. There are, however, a number of guidelines for conducting AMR surveillance issued by institutions such the CDC, 35 the Association for Professionals in Infection Control and Epidemiology, the Society for Healthcare Epidemiology of America, and the DoD Joint Theater Trauma System, 36 which can aid infection control and prevention officers devise strong surveillance programs. Nevertheless, although AMR surveillance programs may be functional at some MTFs, the data collection and analyses are not necessarily done in a standardized manner between facilities, and therefore, data are less directly comparable. To be confident in the interpretation of antimicrobial resistance data across different sites, consistent, robust criteria must be applied for specimen collection, testing methods for organism characterization, and data reporting. 37 With regard to laboratory testing, adoption of the nationally recognized Clinical and Laboratory Standards Institute (CLSI) guidelines by U.S. clinical microbiology laboratories, 38,39 increases the comparability of data. In addition, use of commercially available automated ID/AST platforms which incorporate CLSI cut-off values for AST which are widely utilized at MTFs can also add an aspect of standardization. However, consideration should be given to a number of potentially data biasing factors with regard to use of automated ID/AST platforms: (1) the type of automated platform in use at each site can differ; (2) MTF ID/AST machine software updates are conducted on different timelines, which complicates uniform reporting of data; and (3) ID/AST platforms in the United States are required to report antibiotic susceptibility results from minimum inhibitory concentration values using Food and Drug Administration-approved breakpoints, however, there is a delay between timing of CLSI and FDA breakpoint updates. The centralized laboratory services of the ARMoR program can provide standardization for resistant bacteria collected within the MHS and allow uniform interpretation of data and comparison of data across regions For example, isolates containing genes conferring carbapenem resistance such as bla KPC and bla NDM have been compared to analogous isolates across all the facilities in the MHS (manuscript in preparation) by the MRSN. This has revealed that certain strains were being transmitted from one MTF to another. Another example involves a recent fatal outbreak of Acinetobacter infections where whole genome analysis demonstrated that two unrelated AB clades were actually associated with the outbreak. The clone associated with the majority of patient deaths, Clade B, is evolutionarily distinct from the three international clonal complexes, belongs to multilocus sequence type (MLST)-10, and is closely related to strains isolated from the Czech Republic, Germany and California in 1994, 2003, and 2006, respectively. These data can impact treatment and prevention guidelines. In addition to employing centralized molecular characterization, the ARMoR program is in the process of adopting the NHSN case definitions and testing guidelines which will enable data comparisons across the civilian sector as well. Summary: There currently is no MHS-wide requirement for MTFs to track a minimum set of epidemiologically significant resistant organisms, nor is there a requirement to conduct testing utilizing a specific method. This can lead to gaps in data when attempting to compare data collected from one site MILITARY MEDICINE, Vol. 180, February

4 to another. However, it is feasible to harmonize across labs, as a number of key pathogens are already tracked by all facilities (e.g., methicillin-resistant Staphylococcus aureus, Klebsiella spp, etc.), and although antibiograms may differ by MTF, standardizing minimum data elements for inclusion on an antibiogram is possible. Additionally, if the same standards are being held (CLSI) by all microbiology laboratories, this would be a step closer to being able to compare data across MTFs. At a DoD-wide level, the ARMoR Program is a significant achievement and resource for the military and has generated substantial MDRO surveillance data in the last 4 years that allows uniform interpretation of data. With continued support, MTFs can provide data of higher quality to the ARMoR program while the program continues to provide central reference hub capabilities. MHS-Wide Reporting System There are several benefits to having an antimicrobial resistance surveillance system that is MHS-wide, and there are two efforts to address MHS-wide reporting of AMR data: the ARMoR program, and DoD (MTF) participation in CDC s NHSN. Having such systems allow patients and their treatment to be tracked as they receive services across the continuum of care. For example, through the ARMoR program, the EDC identified a patient as a potential carrier for bla NDM at Landstuhl Regional Medical Center. Both Landstuhl and the MRSN were notified and MRSN confirmed the case. The infection control team at the MTF to which the patient was transferred was notified so the team was better prepared to care for the patient and take appropriate infection prevention and control measures. Another reason to have MHS-wide reporting is to compare data across all participating sites, provided the data are collected and interpreted in a standardized manner. A major limitation of current DoD efforts is that MTF participation is relatively low. MTF participation needs to increase in the ARMoR program and the DoD NHSN group so that visibility of MDROs in the MHS will improve. This can be done through policy that mandates participation in AMR surveillance programs, and education among infection prevention and control teams at MTFs to increase their awareness of MHS-wide surveillance efforts. The EDC is also piloting an effort to report AMR data on behalf of all MTFs to the NHSN. If successful, a great stride will be made toward comparing data across MTFs and between DoD and civilian populations. There are other factors that could substantially enhance MHS wide reporting. Currently, there are no main International Classification of Disease (ICD) codes for patients with MDRO infections. Health events pertaining to AMR are sometimes captured under V or Z codes which supplement main ICD code categories and, therefore, are not utilized routinely in health care settings. This coding limits the ability of agencies such as the AFHSC and NMCPHC, which employ patient medical and billing records as sources of data for surveillance, to provide pertinent AMR data. 43 Countries such as the Netherlands and Israel have made certain MDRO, reportable events (much the same as syphilis or plague in the United States). 44 There are also efforts in a number of states to institute mandated reporting of MDRO like carbapenem resistant Enterobacteriaceae. 45 It behooves the MHS to explore alternative data reporting sources such as implementation of mandated reporting of specific MDRO or improving ICD coding practices at MTFs. Summary: There are MHS-wide reporting systems in place, however, more needs to be done to encourage MTF participation in current reporting systems. Alternative AMR reporting solutions should also be explored, bearing in mind that for the system to be truly useful, data must be collected and tested in a consistent manner. MHS-Wide System to Research and Understand Resistance By understanding the mechanisms that drive dissemination of resistance genes and trends of direct transmission of antimicrobial-resistant organisms, guidance may be provided to help reduce infection-related mortality and morbidity rates, the cost of treating antibiotic-resistant infections, and limit inappropriate antibiotic use. To determine which genes are responsible for conferring resistance and the diversity of such genes, appropriate assays or screening tools can be developed which target resistant pathogens in a timely manner. Timely detection can lead to improved infection prevention practices and appropriate treatment. 36 In addition, genomics sequencing and bioinformatics have opened up opportunities in basic antimicrobial research to better understand resistance. 5 The ARMoR program is playing a lead research role in the DoD by conducting timely, molecular characterization and sequencing studies to understand how resistance is spreading. 32 An example of some of these translational research efforts conducted by the MRSN include the identification a novel operon conferring colistin resistance in extremely drug-resistant Acinetobacter isolates which unlike previous reports, was not associated with increased susceptibility to other antibiotics. 21 These types of data can significantly impact treatment guidelines. There are also a number of other groups in the DoD, which have been proactive with regard to studying and tracking the emergence of resistant pathogens in the MHS. Examples of work done by these various groups include the examination of the relationship between colonization and infection by the Infectious Disease Clinical Research Program Trauma Infectious Disease Outcomes Study Group, 31 and studies to understand biofilm formation a potential virulence factor of clinical wound isolates by a research group at the San Antonio Military Medical Center. 46 Again, results from these studies can impact our understanding of virulence and resistance of various pathogens encountered in the MHS. Summary: There are well equipped groups in the DoD that are able to conduct research on antimicrobial resistance. The MRSN 148 MILITARY MEDICINE, Vol. 180, February 2015

5 serves as a resource to the DoD with its molecular characterization, sequencing and bioinformatics capabilities. Collaboration between all these groups can lead to extensive contributions from the DoD to the field of antimicrobial resistance. CONCLUSION The gaps identified from the 1999 symposium are all related to how the data would be utilized to inform treatment for and prevention of infections, as well as guide development of infection control policies. From a clinician s perspective, AST results are needed in a timely fashion to select the appropriate antimicrobial for treatment of an infection. The surveillance component of AST is necessary to generate AMR trend data for a pathogen (or group of pathogens), locally, nationally, and globally, to predict the effectiveness of empiric treatment when necessary. 9 From an infection prevention perspective, AST results can inform the necessary steps to prevent nosocomial infection transmission. 9 From a research standpoint, a clear understanding of selection pressure because of antimicrobial use can also be used to implement infection prevention and treatment control measures. 6 Characterization of pathogens expressing unusual phenotypes will allow a better understanding of resistance mechanisms which in turn can lead to the selection and/or development of appropriate therapeutics to control infections. In the absence of established standards within the MHS for describing the trends and burden of resistant organisms, MTFs have developed their own methods for resistant organism monitoring following national and international guidelines to inform local clinical practices and infection prevention. Although these methods may be appropriate, the inconsistent methods used at MTFs do not facilitate a broad epidemiological understanding of antimicrobial resistance trends within the MHS. There are programs and infrastructure in place that can be leveraged to get more standardized, coordinated AMR data across the MHS. Of note: (1) MTF participation in the MHS-wide ARMoR program means that MDROs collected in the MHS are being validated and characterized in a consistent, standardized manner. If the ARMoR program is able to encourage increased MTF participation, understanding of organism movement throughout the health system will be better elucidated. (2) MTF participation in the CDC s NHSN entails the use of standardized methods. Theoretically, as MTF participation in NHSN expands, data will be collected in a consistent manner that can be interpreted the same way across all participating sites. (3) The ubiquitous use of nationally and internationally recognized guidelines such as CLSI, means that the investment to standardize all facilities can be achievable. Much progress has already been made within the DoD that addresses the AMR concerns raised in the 1999 symposium; however, the DoD can have a much stronger system for monitoring AMR if participation among MTFs is optimized. The impetus to curb the spread of resistance has stimulated discussion and collaboration among multiple global, national and regional institutions. The DoD should harness this energy and encourage more MTF participation in standardized surveillance/monitoring programs. Efforts should also be made to expand the DoD s global AMR surveillance footprint to develop tools enabling rapid identification of resistant organisms within the MHS, and make a significant contribution to the Global Health Security Agenda. ACKNOWLEDGMENTS We thank the following individuals for their technical support: Dr. Helen Crouch, COL Lanette Hamilton, and Dr. Judith English. REFERENCES 1. Gandhi NR, Nunn P, Dheda K, et al: Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet 2010; 375(9728): Kumarasamy KK, Toleman MA, Walsh TR, et al: Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10(9): Gauthier TP. Editorial commentary: rifampicin plus colistin in the era of extensively drug-resistant Acinetobacter baumannii infections. 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