Cefiderocol for the Treatment of Adult and Pediatric Patients With Cystic Fibrosis and Achromobacter xylosoxidans Infections.

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

Management of infections due to nontuberculous mycobacteria in solid organ transplant recipients-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the epidemiology, diagnosis, prevention, and management of nontuberculous mycobacterial infections in the pre- and post-transplant period. NTM commonly cause one of five different clinical syndromes: pleuropulmonary disease, skin and soft tissue infection, osteoarticular infection, disseminated disease, including that caused by catheter-associated infection, and lymphadenitis. Diagnosis of these infections can be challenging, particularly when they are isolated from nonsterile spaces, owing to their ubiquity in nature. Consequently, diagnosis of pulmonary infections with these pathogens requires fulfillment of microbiologic, radiographic, and clinical criteria to address this concern. A combination of culture and molecular diagnostic techniques is often required to make a species-level identification. Treatment varies depending on the species isolated and is complex, owing to drug toxicities, need for long-term multidrug regimens, and consideration of complex drug-drug interactions between antimicrobials and immunosuppressive agents. Given these treatment challenges, efforts should be made in both the hospital and community settings to limit exposure to these pathogens to the extent feasible.

Active Tuberculosis After Solid Organ Transplantation in Individuals With Negative Pretransplant QuantiFERON-TB Gold Testing: A Case Series.

Active tuberculosis (TB) in solid organ transplant (SOT) recipients most commonly occurs due to reactivation of latent infection and is associated with poor clinical outcomes, including allograft loss and death. National transplant societies, including the American Society of Transplantation, recommend screening for latent TB prior to transplant, with treatment in the peritransplant setting to reduce the subsequent risk of TB reactivation. Though screening is traditionally conducted using laboratory-based assays, such as the QuantiFERON-TB Gold, false negatives may occur in SOT candidates due to anergy from end-stage organ dysfunction, highlighting the need for a multimodal diagnostic approach. In this case series, we describe the clinical characteristics and outcomes of 3 SOT recipients at the University of Pennsylvania with negative pretransplant QuantiFERON-TB Gold testing who subsequently developed active TB in the posttransplant setting, contributing to a growing body of knowledge regarding this challenging population. Each patient experienced a complicated clinical course that arose in part from the lack of diagnosis of TB prior to transplant. Because all had epidemiologic risk factors for TB, the findings of our study highlight the need for more individualized approaches to pretransplant TB screening.

Developing an Assessment Framework for Essential Internal Medicine Subspecialty Topics.

BACKGROUND: Assessing residents by direct observation is the preferred assessment method for infrequently encountered subspecialty topics, but this is logistically challenging. OBJECTIVE: We developed an assessment framework for internal medicine (IM) residents in subspecialty topics, using tuberculosis diagnosis for proof of concept. METHODS: We used a 4-step process at 8 academic medical centers that entailed (1) creating a 10-item knowledge assessment tool; (2) pilot testing on a sample of 129 IM residents and infectious disease fellow volunteers to evaluate validity evidence; (3) implementing the final tool among 886 resident volunteers; and (4) assessing outcomes via retrospective chart review. Outcomes included tool score, item performance, and rates of obtaining recommended diagnostics. RESULTS: Following tool development, 10 infectious disease experts provided content validity. Pilot testing showed higher mean scores for fellows compared with residents (7 [SD = 1.8] versus 3.8 [SD = 1.7], respectively, P < .001) and a satisfactory Kuder-Richardson Formula 20 (0.72). Implementation of the tool revealed a 14-minute (SD = 2.0) mean completion time, 61% (541 of 886) response rate, 4.4 (SD = 1.6) mean score, and ≤ 57% correct response rate for 9 of 10 items. On chart review (n = 343), the rate of obtaining each recommended test was ≤ 43% (113 of 261), except for chest x-rays (96%, 328 of 343). CONCLUSIONS: Our assessment framework revealed knowledge and practice gaps in tuberculosis diagnosis in IM residents. Adopting this approach may help ensure assessment is not limited to frequently encountered topics.

Internal Medicine Residents' Knowledge and Practice of Pulmonary Tuberculosis Diagnosis.

BACKGROUND: Internal medicine physicians are often the first providers to encounter patients with a new diagnosis of tuberculosis. Given the public health risks of missed tuberculosis cases, assessing internal medicine residents' ability to diagnose tuberculosis is important. METHODS: Internal medicine resident knowledge and practice patterns in pulmonary tuberculosis diagnosis at 7 academic hospitals were assessed utilizing (a) a 10-item validated pulmonary tuberculosis diagnosis assessment tool and (b) a retrospective chart review of 343 patients who underwent a pulmonary tuberculosis evaluation while admitted to a resident-staffed internal medicine or infectious disease service. Our primary outcomes were the mean score and percentage of correct responses per assessment tool question, and the percentage of patients who had Centers for Disease Control and Prevention-recommended tuberculosis diagnostic tests obtained. RESULTS: Of the 886 residents who received the assessment, 541 responded, yielding a response rate of 61%. The mean score on the assessment tool (SD) was 4.4 (1.6), and the correct response rate was 57% (311/541) or less on 9 of 10 questions. On chart review, each recommended test was obtained for ≤43% (148/343) of patients, other than chest x-ray (328/343; 96%). A nucleic acid amplification test was obtained for 18% (62/343) of patients, whereas 24% (83/343) had only 1 respiratory sample obtained. Twenty patients were diagnosed with tuberculosis. CONCLUSIONS: Significant knowledge and practice gaps exist in internal medicine residents' abilities to diagnose tuberculosis. As residents represent the future providers who will be evaluating patients with possible tuberculosis, such deficiencies must be addressed.

Deaths Related to Nontuberculous Mycobacterial Infections in the United States, 1999-2014.

RATIONALE: Unlike tuberculosis, nontuberculous mycobacterial disease is not reportable to public health authorities in the United States, and the total burden of disease is uncertain. OBJECTIVES: To estimate the mortality of nontuberculous mycobacterial disease in the United States over a 15-year period and to identify temporal trends. METHODS: The U.S. Multiple Cause of Death Files from 1999 through 2014 were searched for a listing of nontuberculous mycobacterial disease by International Classification of Diseases, Tenth Revision code as either the underlying or a contributing cause of death. Characteristics of individuals with nontuberculous mycobacteria-related deaths in the United States were summarized according to demographic characteristics. Age-adjusted mortality rates and rate ratios were calculated using bridged-race population estimates of U.S. census population data. Time trends were evaluated with negative binomial regression. MEASUREMENTS AND MAIN RESULTS: There was a significant increase in nontuberculous mycobacteria-related deaths among individuals without a diagnosis of HIV infection (P = 0.004). Mortality rates increased with advancing age. Age-adjusted mortality rate ratios were lower for men (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.80-0.87) compared with women, and were lower for Hispanic individuals (RR, 0.53; 95% CI, 0.49-0.56) and black, non-Hispanic persons (RR, 0.83; 95% CI, 0.77-0.88) compared with white, non-Hispanic individuals. CONCLUSIONS: The mortality rate of nontuberculous mycobacterial disease among HIV-uninfected individuals has increased in the United States between 1999 and 2014. These deaths occurred disproportionately in older white women. Considering the concurrent decline in tuberculosis-related deaths, these findings demonstrate a shift in the epidemiology of fatal mycobacterial infections in the United States.

Asymmetric T lymphocyte division in the initiation of adaptive immune responses.

A hallmark of mammalian immunity is the heterogeneity of cell fate that exists among pathogen-experienced lymphocytes. We show that a dividing T lymphocyte initially responding to a microbe exhibits unequal partitioning of proteins that mediate signaling, cell fate specification, and asymmetric cell division. Asymmetric segregation of determinants appears to be coordinated by prolonged interaction between the T cell and its antigen-presenting cell before division. Additionally, the first two daughter T cells displayed phenotypic and functional indicators of being differentially fated toward effector and memory lineages. These results suggest a mechanism by which a single lymphocyte can apportion diverse cell fates necessary for adaptive immunity.

Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin.

Two seemingly unrelated hallmarks of memory CD8(+) T cells are cytokine-driven proliferative renewal after pathogen clearance and a latent effector program in anticipation of rechallenge. Memory CD8(+) T cells and natural killer cells share cytotoxic potential and dependence on the growth factor interleukin 15. We now show that mice with compound mutations of the genes encoding the transcription factors T-bet and eomesodermin were nearly devoid of several lineages dependent on interleukin 15, including memory CD8(+) T cells and mature natural killer cells, and that their cells had defective cytotoxic effector programming. Moreover, T-bet and eomesodermin were responsible for inducing enhanced expression of CD122, the receptor specifying interleukin 15 responsiveness. Therefore, these key transcription factors link the long-term renewal of memory CD8(+) T cells to their characteristic effector potency.