Clinical StudyLack of doxycycline antimalarial prophylaxis impact on Staphylococcus aureus tetracycline resistance
Introduction
Staphylococcus aureus is a widely prevalent pathogen associated with infections in hospitalized patients, in addition to generally healthy individuals (Boucher et al., 2009, Creech et al., 2010, Ellis et al., 2004, Klevens et al., 2007, Sievert et al., 2013, Tenover et al., 2006). One population that is frequently affected by both healthcare-associated (e.g., strain USA100) and community-associated (CA; e.g., strain USA300) S. aureus infections is the military. Specifically, skin and soft-tissue infections (SSTI) related to methicillin-resistant (MRSA) and methicillin-susceptible S. aureus (MSSA) are commonly reported among military trainees, non-deployed active-duty personnel, and deployed service members (Ellis et al., 2004, Ellis et al., 2009, Landrum et al., 2012, Murray et al., 2009, Murray et al., 2010). An analysis of Army personnel undergoing training in the United States found that 3% and 28% of the soldiers were colonized with CA-MRSA and CA-MSSA, respectively (Ellis et al., 2004). In addition, the rate of CA-MRSA and CA-MSSA SSTIs among TRICARE beneficiaries (2005–2010) was estimated at 82.7 and 59.2 per 100,000 person-years, respectively. Regarding hospital-associated SSTIs and bacteremia, the rate of MRSA and MSSA infections was 0.5 and 0.4 per 100,000 person-years, respectively (Landrum et al., 2012).
Along with being resistant to β-lactams, MRSA isolates may develop resistance to other broad-spectrum antimicrobial agents, such as tetracyclines (i.e., tetracycline, minocycline, and doxycycline) (Ardic et al., 2005, Han et al., 2007, Trzcinski et al., 2000). Two main mechanisms of tetracycline resistance through the acquisition of resistance genes (tet genes) have been described: active efflux due to energy-dependent efflux pumps associated with acquisition of plasmid-mediated tet(K) and tet(L) genes; and ribosomal protection involving elongation factor-like proteins, which are encoded by chromosomal or transposonal tet(M) and tet(O) genes (Leamer et al., 2013). Resistance to tetracycline in S. aureus is usually conferred by tet(K), while tetracycline class resistance is associated with tet(M) (Schwartz et al., 2009, Trzcinski et al., 2000). Among non-deployed military personnel, tetracycline resistance has been reported in up to 6% of CA-MRSA colonizing or pathogenic (i.e., linked to a SSTI) isolates (Ellis et al., 2009, Leamer et al., 2013). Furthermore, 5–18% of MRSA isolates collected from U.S. military personnel at combat support hospitals in Iraq have been tetracycline-resistant (Co et al., 2011, Huang et al., 2011, Murray et al., 2010).
Although tetracycline resistance among S. aureus isolates is presently low, there is the possibility that susceptibility may decrease due to use of doxycycline and minocycline to treat MRSA infections (Han et al., 2007, McDougal et al., 2010, Nurjadi et al., 2015, Ruhe and Menon, 2007, Schwartz et al., 2009). In particular, doxycycline has been shown to induce its own resistance in MRSA isolates carrying tet(K) (Schwartz et al., 2009). Furthermore, use of doxycycline as antimalarial prophylaxis is also a concern (Lesens et al., 2007, Vento et al., 2013). In accordance with U.S. Department of Defense (DoD) guidelines (Department of the Army, 2013, Department of Defense, 2010, Department of Defense, 2013), military personnel serving in Afghanistan are prescribed doxycycline or atovaquone/proquanil (Malarone®) (mefloquine is used if there are contraindications to primary antimalarials), which is initiated prior to entering the country and continued throughout deployment. Studies have indicated that compliance with primary antimalarial prophylaxis among deployed soldiers ranges from 38 to 61% (Brisson and Brisson, 2012, Kotwal et al., 2005, Newton et al., 1994, Whitman et al., 2010). Moreover, 74% of military personnel wounded in Afghanistan and evacuated to Landstuhl Regional Medical Center (LRMC; Germany) were prescribed doxycycline by clinicians in order to comply with antimalarial prophylaxis guidelines (Rini et al., 2014). While prophylaxis is warranted when serving in malaria-endemic regions, there are unavoidable consequences of extensive use of doxycycline, including potential for increased tetracycline resistance among S. aureus.
A recent analysis compared data related to S. aureus colonization between active-duty military personnel who were stationed in the United States (non-deployed) and Afghanistan (deployed). The deployed personnel received doxycycline antimalarial prophylaxis, while non-deployed personnel were not administered any antibiotics within 30 days of S. aureus isolate collection. Although there was no significant difference in doxycycline susceptibility between the populations, a significantly higher proportion of S. aureus isolates collected from deployed personnel were resistant to tetracycline (Vento et al., 2013).
Among clinicians caring for combat wounded personnel, the occurrence of multidrug-resistant organisms presents challenges. Thus, the possibility of MRSA isolates acquiring resistance to tetracyclines is a concern. We examined characteristics related to tetracycline resistance in S. aureus isolates collected from military personnel wounded during the recent conflicts, including doxycycline antimalarial prophylaxis.
Section snippets
Study population and demographics
The overarching project for this analysis is the Trauma Infectious Disease Outcomes Study (TIDOS), which is an ongoing observational cohort study of short- and long-term infectious complications among military personnel injured during deployment in Iraq and Afghanistan (Tribble et al., 2011). Trauma patients were eligible for inclusion in TIDOS if they were active-duty personnel or DoD beneficiaries, at least 18 years of age, and sustained deployment-related injuries requiring medical evacuation
Study population
Between June 2009 and January 2012, 4051 U.S. wounded personnel were admitted to LRMC, of which half transferred to one of the participating clinical facilities in the United States. S. aureus isolates were collected from 168 patients who were utilized as the study population. In general, patients in the study population were young (median age: 24.5 years) men (99%) serving in the U.S. Army and Marines (66% and 27%, respectively) and wounded in military operations in Afghanistan (83%). The
Discussion
Increasing multidrug resistance among bacterial pathogens presents a continuing challenge for clinicians. During the recent wars, there was concern that use of doxycycline antimalarial prophylaxis among military personnel deployed to Afghanistan would have the unintended consequence of increased S. aureus tetracycline resistance (Lesens et al., 2007, Vento et al., 2013). We examined 168 S. aureus isolates collected from wounded military personnel with regards to tetracycline resistance, MRSA,
Conclusion
Overall, our findings highlight a low proportion of MRSA collected from wounded military personnel during the recent wars; however, over half of the MRSA isolates were classified as infecting. There was also a low level of resistance to tetracycline among S. aureus isolates (MSSA and MRSA). Although there was no association between the utilization of doxycycline and resistance to tetracyclines, including doxycycline, further analysis is needed before a definite conclusion can be reached.
Financial Support
Support for this work (IDCRP-024) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences, Department of Preventive Medicine and Biostatistics. This project has been funded by the Department of Defense Global Emerging Infections Surveillance and Response System (GEIS) [HT9404-12-1-0011], a division of the Armed Forces Health Surveillance Center, National Institute of
Conflict of interest
None.
Ethical standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
Disclaimer
The views expressed are those of the authors and do not necessarily reflect the official views of the Uniformed Services University of the Health Sciences, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the National Institutes of Health or the Department of Health and Human Services, Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of Defense or the Departments of the Army, Navy, or Air
Acknowledgments
We are indebted to the Infectious Disease Clinical Research Program Trauma Infectious Disease Outcomes Study team of clinical coordinators, microbiology technicians, data managers, clinical site managers, and administrative support personnel for their tireless hours to ensure the success of this project. We also wish to thank M. Leigh Carson for her assistance in writing and preparing the manuscript.
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