Factors Influencing Selection of Infectious Diseases Training for Military Internal Medicine Residents.

Background: Applications to infectious diseases fellowships have declined nationally; however, the military has not experienced this trend. In the past 6 years, 3 US military programs had 58 applicants for 52 positions. This study examines military resident perceptions to identify potential differences in factors influencing career choice, compared with published data from a nationwide cohort. Methods: An existing survey tool was adapted to include questions unique to the training and practice of military medicine. Program directors from 11 military internal medicine residencies were asked to distribute survey links to their graduating residents from December 2016 to January 2017. Data were categorized by ID interest. Result: The response rate was 51% (n = 68). Of respondents, 7% were ID applicants, 40% considered ID but reconsidered, and 53% were uninterested. Of those who considered ID, 73% changed their mind in their second and third postgraduate years and cited salary (22%), lack of procedures (18%), and training length (18%) as primary deterrents to choosing ID. Active learning styles were used more frequently by ID applicants to learn ID concepts than by those who considered or were uninterested in ID (P = .02). Conclusions: Despite differences in the context of training and practice among military trainees compared with civilian colleagues, residents cited similar factors affecting career choice. Interest in global health was higher in this cohort. Salary continues to be identified as a deterrent to choosing ID. Differences between military and civilian residents' desire to pursue ID fellowship are likely explained by additional unmeasured factors deserving further study.

Nocardia-induced granulocyte macrophage colony-stimulating factor is neutralized by autoantibodies in disseminated/extrapulmonary nocardiosis.

BACKGROUND: Nocardia species cause infections in both immunocompromised and otherwise immunocompetent patients, although the mechanisms defining susceptibility in the latter group are elusive. Anticytokine autoantibodies are an emerging cause of pathogen-specific susceptibility in previously healthy human immunodeficiency virus-uninfected adults, including anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies with cryptococcal meningitis. METHODS: Plasma from patients with disseminated/extrapulmonary nocardiosis and healthy controls was screened for anticytokine autoantibodies using a particle-based approach. Autoantibody function was assessed by intranuclear staining for GM-CSF-induced STAT5 phosphorylation in normal cells incubated with either patient or normal plasma. GM-CSF-mediated cellular activation by Nocardia was assessed by staining for intracellular cytokine production and intranuclear STAT5 phosphorylation. RESULTS: We identified neutralizing anti-GM-CSF autoantibodies in 5 of 7 patients studied with central nervous system nocardiosis and in no healthy controls (n = 14). GM-CSF production was induced by Nocardia in vitro, suggesting a causative role for anti-GM-CSF autoantibodies in Nocardia susceptibility and dissemination. CONCLUSIONS: In previously healthy adults with otherwise unexplained disseminated/extrapulmonary Nocardia infections, anti-GM-CSF autoantibodies should be considered. Their presence may suggest that these patients may be at risk for later development of pulmonary alveolar proteinosis or other opportunistic infections, and that patients may benefit from therapeutic GM-CSF administration.

Animal Models in Regulatory Breakpoint Determination: Review of New Drug Applications of Approved Antibiotics from 2014-2022.

We sought to better understand the utility and role of animal models of infection for Food and Drug Administration (FDA)-approved antibiotics for the indications of community-, hospital-acquired-, and ventilator-associated bacterial pneumonia (CABP, HABP, VABP), complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), and acute bacterial skin and structural infections (ABSSSIs). We reviewed relevant documents from new drug applications (NDA) of FDA-approved antibiotics from 2014-2019 for the above indications. Murine neutropenic thigh infection models supported the choice of a pharmacokinetic-pharmacodynamic (PKPD) target in 11/12 NDAs reviewed. PKPD targets associated with at least a 1-log bacterial decrease were commonly considered ideal (10/12 NDAs) to support breakpoints. Plasma PK, as opposed to organ specific PK, was generally considered most reliable for PKPD correlation. Breakpoint determination was multi-disciplinary, accounting at minimum for epidemiologic cutoffs, non-clinical PKPD, clinical exposure-response and clinical efficacy. Non-clinical PKPD targets in combination with probability of target attainment (PTA) analyses generated breakpoints that were consistent with epidemiologic cutoffs and clinically derived breakpoints. In 6/12 NDAs, there was limited data to support clinically derived breakpoints, and hence the non-clinical PKPD targets in combination with PTA analyses played a heightened role in the final breakpoint determination. Sponsor and FDA breakpoint decisions were in general agreement. Disagreement may have arisen from differences in the definition of the optimal PKPD index or the ability to extrapolate protein binding from animals to humans. Overall, murine neutropenic thigh infection models supported the reviewed NDAs by providing evidence of pre-clinical efficacy and PKPD target determination, and played, in combination with PTA analysis, a significant role in breakpoint determination for labeling purposes.

Immune response profiles from humans experimentally exposed to Phlebotomus duboscqi bites.

Introduction: Cutaneous leishmaniasis is a neglected vector-borne parasitic disease prevalent in 92 countries with approximately one million new infections annually. Interactions between vector saliva and the human host alter the response to infection and outcome of disease. Methods: To characterize the human immunological responses developed against saliva of Phlebotomus duboscqi, a Leishmania major (L. major) vector, we repeatedly exposed the arms of 14 healthy U.S volunteers to uninfected P. duboscqi bites. Blood was collected a week after each exposure and used to assess total IgG antibodies against the proteins of P. duboscqi salivary gland homogenate (SGH) and the levels of IFN-gamma and IL-10 from peripheral blood mononuclear cells (PBMCs) stimulated with SGH or recombinant sand fly proteins. We analyzed skin punch biopsies of the human volunteer arms from the insect bite site and control skin site after multiple P. duboscqi exposures (four volunteers) using immunohistochemical staining. Results: A variety of immediate insect bite skin reactions were observed. Late skin reactions to insect bites were characterized by macular hyperpigmentation and/or erythematous papules. Hematoxylin and eosin staining showed moderate mononuclear skin infiltrate with eosinophils in those challenged recently (within 2 months), eosinophils were not seen in biopsies with recall challenge (6 month post bites). An increase in plasma antigen-specific IgG responses to SGH was observed over time. Western Blot results showed strong plasma reactivity to five P. duboscqi salivary proteins. Importantly, volunteers developed a cellular immunity characterized by the secretion of IFN-gamma upon PBMC stimulation with P. duboscqi SGH and recombinant antigens. Discussion: Our results demonstrate that humans mounted a local and systemic immune response against P. duboscqi salivary proteins. Specifically, PduM02/SP15-like and PduM73/adenosine deaminase recombinant salivary proteins triggered a Th1 type immune response that might be considered in future development of a potential Leishmania vaccine.

Making the APPropriate choice: Utilization of a smartphone application to optimize antimicrobial decisions among internal medicine trainees.

Utilization of a smart phone application paired with a time-spaced learning curriculum was investigated to determine its impact on antimicrobial stewardship practice among internal medicine trainees. Stewardship behaviors increased, barriers decreased, and trainees had increased confidence in managing common infectious disease syndromes after the intervention.

Multi-Drug-Resistant Organisms in Burn Infections.

Background: Infection is the most frequent complication after severe burns and remains the predominant cause of death. Burn patients may require multiple courses of antibiotics, lengthy hospitalizations, and invasive procedures that place burn patients at especially high risk for infections with multi-drug-resistant organisms (MDROs). Methods: The published literature on MDROs in burn patients was reviewed to develop a strategy for managing these infections. Results: Within a burn unit meticulous infection prevention and control measures and effective antimicrobial stewardship can limit MDRO propagation and decrease the antibiotic pressure driving the selection of MDROs from less resistant strains. Several new antimicrobial agents have been developed offering potential therapeutic options, but familiarity with their benefits and limitations is required for safe utilization. Successful management of MDRO burn infections is supported by a multifactorial approach. Novel non-antibiotic therapeutics may help combat MDRO infections and outbreaks. Conclusions: Multi-drug-resistant organisms are being identified with increasing frequency in burn patients. Effective sensitivity testing is essential to identify MDROs and to direct appropriate antibiotic choices for patient treatment.

The Struggling Infectious Diseases Fellow: Remediation Challenges and Opportunities.

Remediation of struggling learners is a challenge faced by all educators. In recognition of this reality, and in light of contemporary challenges facing infectious diseases (ID) fellowship program directors, the Infectious Diseases Society of America Training Program Directors' Committee focused the 2018 National Fellowship Program Directors' Meeting at IDWeek on "Remediation of the Struggling Fellow." Small group discussions addressed 7 core topics, including feedback and evaluations, performance management and remediation, knowledge deficits, fellow well-being, efficiency and time management, teaching skills, and career development. This manuscript synthesizes those discussions around a competency-based framework to provide program directors and other educators with a roadmap for addressing common contemporary remediation challenges.

Antimicrobial susceptibilities of geographically diverse clinical human isolates of Leptospira.

Although antimicrobial therapy of leptospirosis has been studied in a few randomized controlled clinical studies, those studies were limited to specific regions of the world and few have characterized infecting strains. A broth microdilution technique for the assessment of antibiotic susceptibility has been developed at Brooke Army Medical Center. In the present study, we assessed the susceptibilities of 13 Leptospira isolates (including recent clinical isolates) from Egypt, Thailand, Nicaragua, and Hawaii to 13 antimicrobial agents. Ampicillin, cefepime, azithromycin, and clarithromycin were found to have MICs below the lower limit of detection (0.016 microg/ml). Cefotaxime, ceftriaxone, imipenem-cilastatin, penicillin G, moxifloxacin, ciprofloxacin, and levofloxacin had MIC(90)s between 0.030 and 0.125 microg/ml. Doxycycline and tetracycline had the highest MIC(90)s: 2 and 4 microg/ml, respectively. Doxycycline and tetracycline were noted to have slightly higher MICs against isolates from Egypt than against strains from Thailand or Hawaii; otherwise, the susceptibility patterns were similar. There appears to be possible variability in susceptibility to some antimicrobial agents among strains, suggesting that more extensive testing to look for geographic variability should be pursued.

Military Internal Medicine Resident Decision to Apply to Fellowship and Extend Military Commitment.

Introduction: Nationally, the number of internal medicine physicians practicing in primary care has decreased amidst increasing interest in hospitalist medicine. Current priorities in the Military Health System include access to primary care and retention of trained personnel. Recently, we have conducted a study of military internal medicine residents' decision to enter infectious disease. As part of our larger effort, we saw an opportunity to characterize factors impacting decision making of internal medicine residents' desire to apply for subspecialty training and to extend active duty service obligations. Materials and Methods: Questions were developed after discussion with various military graduate medical education and internal medicine leaders, underwent external review, and were added to a larger question set. The survey link was distributed electronically to all U.S. military affiliated residencies' graduating internal medicine residents in December 2016-January 2017. Data were analyzed by decision to apply to fellowship and decision to extend military obligation using Fisher's exact test or Pearon's chi-square test. Results: Sixty-eight residents from 10 of 11 military residency programs responded, for a response rate of 51%. The majority (62%) applied to fellowship to start after residency completion. Reasons cited for applying to fellowship included wanting to become a specialist as soon as possible (74%), wishing to avoid being a general internist (57%), and because they are unable to practice as a hospitalist in the military (52%). Fellowship applicants were more likely to plan to extend their military obligation than non-applicants, as did those with longer duration of military commitments. No other factors, including Uniformed Services University attendance or participation in undergraduate military experiences, were found to impact plan to extend active duty service commitment. Conclusion: The majority of graduating internal medicine residents apply for fellowship and report a desire to avoid being a general internist. Prospective fellows anticipate extending their active duty commitment, as do those with longer commitments.

Isolation of Rapidly Growing Nontuberculous Mycobacteria in Wounds Following Combat-Related Injury.

OBJECTIVES: Rapidly growing nontuberculous mycobacteria (RGNTM) have yet to be described in combat-related injuries. This study investigates the epidemiology, clinical findings, treatment, and outcomes of RGNTM infections among combat casualties wounded in Afghanistan from 2010 to 2012. METHODS: Patients with RGNTM were identified from the Department of Defense Trauma Registry through the Trauma Infectious Disease Outcomes Study. Trauma history, surgical management, and clinical data were collected. Six isolates from patients requiring antimycobacterial therapy were sequenced. RESULTS: Seventeen cases were identified. Six cases, predominantly associated with Mycobacterium abscessus, required aggressive debridement and a median of 180 days of multidrug antimycobacterial therapy that included clofazimine. M. abscessus isolates expressed the erythromycin resistance methylase (erm(41)) gene for inducible macrolide resistance, yet there were no clinical treatment failures when macrolides were utilized in combination therapy. No clonal similarity between M. abscessus isolates was found. Eleven cases had positive wound cultures, but did not require antimycobacterial therapy. The median duration of time of injury to first detection of a RGNTM was 57 days. CONCLUSIONS: This represents the first report of RGNTM infections in war-wounded patients. RGNTM should be recognized as potential pathogens in grossly infected combat wounds. Surgical debridement and multidrug antimycobacterial therapy, when clinically indicated, was associated with satisfactory clinical outcomes.

Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis.

Treatment options for cutaneous leishmaniasis in the United States are problematic because the available products are either investigational, toxic, and/or of questionable effectiveness. A retrospective review of patients receiving liposomal amphotericin B through the Walter Reed Army Medical Center for the treatment of cutaneous leishmaniasis during 2007-2009 was conducted. Twenty patients who acquired disease in five countries and with five different strains of Leishmania were treated, of whom 19 received a full course of treatment. Sixteen (84%) of 19 experienced a cure with the initial treatment regimen. Three patients did not fully heal after an initial treatment course, but were cured with additional dosing. Acute infusion-related reactions occurred in 25% and mild renal toxicity occurred in 45% of patients. Although the optimum dosing regimen is undefined and the cost and toxicity may limit widespread use, liposomal amphotericin B is a viable treatment alternative for cutaneous leishmaniasis.

Activity of the Diaminopyrimidine AR-709 against recently collected multidrug-resistant isolates of invasive Streptococcus pneumoniae from North America.

Broth microdilution was used to determine the MICs of AR-709 and comparator antimicrobial agents for 224 invasive multidrug-resistant isolates of Streptococcus pneumoniae. AR-709 was highly active, with a MIC 50 of 0.25 microg/ml, a MIC 90 of 0.5 microg/ml, and a range of

Outcomes of bacteremia in burn patients involved in combat operations overseas.

BACKGROUND: Burn patients constitute approximately 5% of casualties injured in support of US military operations in Iraq (Operation Iraqi Freedom [OIF]) and Afghanistan (Operation Enduring Freedom [OEF]). Since the onset of these conflicts, there have been numerous casualties infected with multidrug-resistant bacteria. It is currently unclear if bacteremia with these multidrug-resistant organisms in OIF/OEF burn casualties is associated with increased mortality. STUDY DESIGN: We performed a retrospective cohort study of all patients admitted to the US Army Institute of Surgical Research burn center from January 2003 to May 2006 to evaluate bacteremia in our burn-patient population. RESULTS: One hundred twenty-nine of 1,258 patients admitted to the burn center became bacteremic during their hospitalization. Of these, 92 had bacteremia with the top four pathogens in our burn center, ie, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter calcoaceticus-baumannii complex, and Staphylococcus aureus. Presence of any bacteremia was associated with mortality and increased ventilator days. Bacteremia with K pneumoniae was associated with a statistically increased mortality and a prolonged ventilator course relative to all other pathogens. CONCLUSIONS: Casualties of OIF/OEF with burn injuries did not have different outcomes than patients whose burns were not associated with military operations. Bacteremia, especially with a multidrug-resistant organism, causes increased mortality in burn patients. Of all the pathogens causing bacteremia, K pneumonia appears to have the greatest impact on mortality.

Efficacy of caspofungin and posaconazole in a murine model of disseminated Exophiala infection.

Disseminated phaeohyphomycosis is an uncommon infection affecting immunocompetent and immunocompromised individuals in which response to older antifungal agents has been variable. We compared the effect of six days of therapy with caspofungin, posaconazole, and amphotericin B in parallel studies of survival and fungal burden in an immunocompromised mouse model of Exophiala infection. Mice immunocompromised with cyclophosphamide were treated for 6 days starting one day after initiation of infection. Treatment regimens included amphotericin B, caspofungin, and posaconazole. In the survival studies, experimental animals were observed for 14 days. In the fungal burden tests the experimental animals were sacrificed 7 days after infection and brain and kidney burden determined. Treatment with any agent decreased mortality (P < 0.05), with 40%, 30%, and 80% observed survival of the animals treated with amphotericin B, caspofungin, and posaconazole, respectively. Amphotericin B and posaconazole treatment resulted in a decrease in fungal burden compared to untreated controls (P < 0.05). No reduction in fungal burden was noted in the caspofungin group. All three antifungals evaluated improved survival of immunocompromised mice in this otherwise fatal disseminated phaeohyphomycosis. Amphotericin B and posaconazole reduced fungal burden. Posaconazole and caspofungin appear to have potential for use in treatment of this rare infection.