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Prior studies have demonstrated high rates of colonization and infection with multidrug-resistant Gram-negative bacilli (MDR-GNB) in injured military personnel. Our analysis shows that injuries inflicted during peak combat periods, massive blood transfusion requirement, and post-trauma cefazolin prophylaxis (additive effect with fluoroquinolones) were risk factors for MDR-GNB colonization.
Infections with multidrug-resistant Gram-negative bacilli (MDR-GNB), such as extended-spectrum β-lactamase (ESBL)-producing Escherichia coli, pose a dangerous threat to individuals worldwide, and in particular to those with battlefield injuries (Murray, 2008). One prospective longitudinal study showed that individuals deployed in Afghanistan and Iraq were almost three times more likely to be colonized with MDR-GNB than those who were not deployed, and personnel with recent injuries possessed a greater risk (Weintrob et al., 2013). Prior research demonstrates colonization occurs primarily through hospital-associated transmission, and rates increase as patients transit through the medevac chain, which involves multiple facilities. Given these findings, our objective was to further ascertain risk factors for MDR-GNB colonization by examining data from wounded military personnel.
Injured service members evacuated through Landstuhl Regional Medical Center (LRMC; Germany) and admitted to a participating US hospital (National Capital Region or San Antonio Military Medical Center) between June 2009 and May 2012 were included. Patient characteristics were captured through the DoD Trauma Registry, while antimicrobial administration, infections, and active surveillance cultures (ASC) were obtained through the supplemental Trauma Infectious Disease Outcomes Study infectious disease module (Tribble et al., 2011). An ASC specimen was obtained from groin or axilla swabs performed within two days of US hospital admission. Gram-negative bacilli were determined to be multidrug-resistant if they showed resistance to at least three of four antibiotic classes or were producers of ESBL or carbapenemases (Division of Healthcare Quality Promotion, 2008.). Antimicrobial susceptibility tests were performed using automated systems (BD Phoenix [BD Biosciences, Sparks, MD] or Vitek 2 [bioMerieux Inc., Hazelwood, MO]) along with disc diffusion and E-test methods (Clinical and Laboratory Standards Institute, 2009). Characteristics were compared using Chi-square or Fisher’s exact test (SAS version 9.4, SAS, Cary, NC). Logistic regression models were performed to evaluate risk factors associated with MDR-GNB colonization.
Among the 2079 trauma patients, 289 (14%) were colonized with MDR-GNB (Table 1). E. coli was the most common MDR (or ESBL-producing) organism isolated (74% out of 301 bacterial isolates), followed by Acinetobacter baumannii complex (15%), Klebsiella pneumoniae (10%), Enterobacter cloacae (1%), and Citrobacter spp. (<1%). Two hundred and twenty-two (77%) colonized patients were classified as having ESBL-producing E. coli.
Overall, 284 (98%) colonized patients received antibiotics (for prophylaxis or empiric therapy) prior to ASC with most being prescribed more than one. Cefazolin, with/without fluoroquinolones, was most commonly prescribed and was received by 823 (40%) and 839 (40%) trauma patients, respectively. Among MDR-GNB colonized patients, 57% and 35% received cefazolin with/without fluoroquinolones, respectively. Administration of antibiotics was so common that 93% of colonized patients who were given fluoroquinolones also received cefazolin. Few patients received only cefazolin or fluoroquinolones alone (111 and 5 patients, respectively). A total of 101 patients received only doxycycline (for malaria prophylaxis and not active infection) and 136 did not receive any antibiotics, of which 2% and 4% were colonized, respectively.
Since the population of patients receiving only one antibiotic was small, and because colonization rates among those who received either doxycycline alone or no antibiotics were similar, both were considered as a reference group. Statistically significant variables in the univariate analysis were assessed using stepwise selection for inclusion in the multivariate logistic regression analysis (Table 1). Peak combat period, blood transfusion requirement, and cefazolin administration with/without fluoroquinolones were independently associated with MDR-GNB colonization. It is noteworthy that cefazolin plus fluoroquinolones had a higher risk than cefazolin without fluoroquinolones. When the model was restricted to ESBL-producing E. coli, similar statistically significant results were observed (data not shown). A restricted model directly compared cefazolin with/without fluoroquinolones, excluding all other patients. In this model, cefazolin with fluoroquinolones was an independent predictor of MDR-GNB colonization (odds ratio: 1.57; 95th confidence interval: 1.12–2.19).
Our study demonstrates that wounded military personnel are often colonized with MDR-GNBs, predominantly ESBL-producing E. coli, which corresponds with previous data showing a 5.5-fold increase of ESBL-producing E. coli colonization among personnel in Afghanistan compared with those in the US (Vento et al., 2013). Being injured during peak combat periods was associated with increased risk for colonization and may be reflective of the large number of patients transitioning through combat support hospitals during this time or possibly represents a seasonal pattern among these healthcare-associated infections. Blood transfusions were also associated with MDR-GNB colonization, which is not unexpected as large-volume transfusions are a marker of injury severity and likely related to patients’ increased exposure to antibiotics and location in a critical care setting.
One important finding was an additive risk for MDR-GNB colonization when cefazolin was combined with fluoroquinolone administration. A possible explanation for the synergistic effect seen for increased MDR-GNB colonization with multiple antibiotics is the high prevalence of antibiotic-resistance gene transfer and acquisition between bacteria. Our results show that MDR-GNB colonization risk remains high with antibiotic exposure regardless of intensive care unit admission, suggesting a major role for resistance emergence in addition to endogenous bacteria flora within high-risk critical care environment. While we recognize the limitation of using doxycycline as a reference group, and would have preferred instead to analyze colonization rates of individual antibiotics and their combinations against cefazolin exposure alone, there is value in understanding this complicated, but likely important, relationship. It also reflects the reality that the majority of patients receive several antibiotics concurrently.
Antibiotics, such as fluoroquinolones and cephalosporins, are routinely prescribed for surgical prophylaxis and treatment of infectious complications. Cefazolin forms the backbone of most post-trauma prophylactic guidelines (Hospenthal et al., 2011) and research shows that fluoroquinolones offer no advantage over cefazolin and may even deter wound healing. Current civilian and military guidelines do not recommend coverage for Gram-negative organisms except in wounds with extensive damage (Hoff et al., 2011). Thus, with the results of our study demonstrating an increased risk for MDR-GNB colonization with administration of multiple antibiotics, adherence to current practice guidelines and evidence-based infection control measures is a critical component of antibiotic stewardship required to halt the precipitous rise of colonization in MDR-GNB infections.
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.
Financial Support: Support for this work (IDCRP-024) was provided by the Infectious Disease Clinical Research Program, 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 National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072, and the Department of the Navy under the Wounded, Ill, and Injured Program.
Presented in part: Infectious Disease Society of America, ID Week, October 8–12, 2014, Philadelphia, PA
The authors have no conflict of interest.
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, Henry M. Jackson Foundation for the Advancement of Military Medicine, the National Institutes of Health or the Department of Health and Human Services, Brooke Army Medical Center, Walter Reed National Military 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 Force. Mention of trade names, commercial products, or organization does not imply endorsement by the US Government.
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