Journal of Infectious Diseases最新文献

Background: The frequent temporal recurrence of Clostridioides difficile infection (CDI) may be the result of relapse with the same strain or reinfection with a different strain. We used whole-genome sequencing (WGS) to assess the genetic diversity and molecular evolution of strains that caused recurrent or sequential CDI.

Methods: We analyzed data from active population- and laboratory-based surveillance of CDI in Minnesota, USA. We performed WGS on isolates collected from 306 patients with multiple CDI events during 2019-2021. We identified multi-locus sequence types (MLSTs), nucleotide variants, and putative mobile genetic elements (MGEs) from WGS data to study the genetic similarity and evolution of those C. difficile genomes.

Results: Among patients with multiple CDI events in the surveillance period, 198 (64.7%) had multiple infections of the same MLST, including 49.6% of patients with subsequent infections beyond the 8-week limit of the case definition for recurrent CDI Among 232 temporally defined events of recurrent CDI, 155 (66.8%) involved isolates of the same MLST. There were no statistically significant correlations between accumulated mutations and elapsed time between same-MLST CDI events. Analysis of sequential same-MLST C. difficile genomes showed evidence of gain or loss of putative mobile genetic elements (MGEs) in 45.6% of genome pairs.

Conclusions: Leveraging the largest CDI genomic dataset to date, our results confirm prior findings that recurrent CDI is a combination of reinfection and/or change in the ascendant strain in mixed infection, and relapse, while expanding knowledge on the evolution of pathogenic C. difficile strains in the human gastrointestinal tract.

Lyme disease spirochetes are maintained in natural reservoirs before spilling over into human populations. Targeting these reservoirs with vaccinations or antibiotics could impact the Borrelia burgdorferi enzootic cycle and reduce the risk of human Lyme disease. In this work we report that the narrow-spectrum antibiotic hygromycin A is sufficient to disrupt B burgdorferi transmission from the main eastern US reservoir, Peromyscus leucopus, to ticks. Additionally, hygromycin A-containing baits can clear B burgdorferi from P leucopus. These studies lay the foundation for the use of hygromycin A as a reservoir-targeted antibiotic to eradicate B burgdorferi in the wild.

Background: Extraintestinal pathogenic Escherichia coli (ExPEC) are a leading cause of human bloodstream infections (BSIs) in sub-Saharan Africa, yet few studies have characterized African strains implicated in BSI or explored their potential reservoirs.

Methods: We enrolled febrile patients at 2 hospitals in Moshi, Tanzania, 2007-2019, and performed blood cultures. Whole-genome sequencing was conducted on E. coli originating from the bloodstream to characterize sequence types (STs), serotypes, and theoretical coverage of a 9-valent ExPEC polysaccharide conjugate vaccine (ExPEC9V). Separately, we evaluated 601 E. coli whole-genome sequences from humans, animals, and environmental sources in nearby communities. We assessed genetic relatedness between bloodstream and community isolates based on single-nucleotide polymorphisms and allele differences.

Findings: Of 3046 participants receiving blood culture, 48 (0.2%) had BSI yielding 48 E. coli isolates. The median (range) age of participants with E. coli BSI was 40.7 (0.3-89.0) years, and 32 (68.1%) were female. We identified 16 STs including ST131 (n = 16, 33.3%), ST73 (n = 10, 20.8%), and ST69 (n = 6, 12.5%) and 19 O groups including O25 (n = 13, 27.1%), O6 (n = 10, 20.3%), O17 (n = 4, 8.3%), and O18 (n = 4, 8.3%). Theoretical coverage for an ExPEC9V was 72.9%. None of the bloodstream and community E. coli pairs were closely related.

Conclusions: We found a high diversity of STs among E. coli human bloodstream isolates in Tanzania. Despite this diversity, we observed that an EXPEC9V in development would provide good coverage. Reservoir-attribution studies at finer spatial and temporal scales may better identify transmission networks and reservoirs of ExPECs.

Background: There are no published data on clofazimine pharmacokinetics during pregnancy, and safety data are limited. We present data from pregnant and postpartum women receiving clofazimine for treatment of rifampicin-resistant tuberculosis (RR-TB).

Methods: IMPAACT P1026s was an observational study to assess the pharmacokinetics of tuberculosis and/or antiretroviral drugs during pregnancy. Between 2017 and 2019, pregnant women receiving ≥2 second-line antituberculosis drugs in routine care were enrolled in the second or third trimester and had intensive pharmacokinetic sampling at least once during pregnancy, and 2-8 weeks postpartum. Pharmacokinetic parameters were estimated using noncompartmental methods and compared between the antepartum and postpartum periods using geometric mean ratios (GMR) with 90% confidence intervals (CIs) and the Wilcoxon signed rank test for paired data.

Results: Eleven pregnant women from South Africa, 7 (64%) with HIV, were receiving clofazimine (100 mg daily) at enrollment, of which 82% received clofazimine for more than 8 weeks prior to pharmacokinetic evaluation. Nine (82%) women continued treatment postpartum. Peak plasma concentrations and area-under-the-concentration-time-curve over 12 hours were comparable to historical clofazimine pharmacokinetic data in nonpregnant women with RR-TB but were approximately 30% higher in the third trimester of pregnancy compared to the postpartum period. Eight women and 8 infants experienced at least one severe adverse event while on study but direct relatedness to clofazimine was considered unlikely.

Conclusions: Overall, antepartum and postpartum clofazimine exposures were comparable to those reported in nonpregnant women with RR-TB. Exposures were lower than expected in the postpartum period, particularly compared with the third trimester of pregnancy.

Background: Antimicrobial resistance (AMR) is an urgent threat to public health, but gaps in surveillance limit the detection of emergent novel threats and knowledge about the global distribution of AMR genes. International travelers frequently acquire AMR organisms (AMROs) and thus may provide a window into AMR dynamics in otherwise poorly monitored regions and environments.

Methods: To assess the utility of travelers as global AMR sentinels, we collected pre- and post-travel stool samples from 608 travelers between 2017 and 2019, which were screened for the presence of extended-spectrum beta-lactamase producing Enterobacterales, carbapenem-resistant Enterobacterales, and mcr-mediated colistin-resistant Enterobacterales. A total of 307 distinct AMROs were sequenced and analyzed in order to determine genotypic patterns and their association with geography and traveler behavior.

Results: Travel-associated AMROs were overwhelmingly Escherichia coli, which exhibited considerable phylogenetic diversity regardless of travel region. However, the prevalence of resistance genes varied by region, with blaCTX-M-55 and blaCTX-M-27 significantly more common in isolates associated with South America and South-Eastern Asia, respectively. Plasmid reconstruction revealed the genomic neighborhood of blaCTX-M-55 frequently matched a motif previously linked to animal populations. The ColV plasmid, a driver of avian pathogenic E. coli, was found to be elevated in frequency in isolates acquired by travelers reporting animal contact. We identified novel variants of the mcr-1 gene in strains acquired from Western Africa.

Conclusions: Traveler pathogen genomic surveillance can provide insight on global AMR dynamics and emerging clinical threats. Ongoing efforts to track travel-acquired organisms could complement existing global AMR surveillance frameworks.

Background: Outcomes in tuberculous meningitis (TBM) are closely linked to host inflammation. Anti-inflammatory corticosteroid therapy improves survival in HIV-negative TBM, but not in people with HIV. In people with HIV, TBM is fatal in 40-50% of cases. Therefore, we investigated how mortality is associated with the local immune response in people with HIV-associated TBM.

Methods: We measured baseline concentrations of immune signalling mediators in cerebrospinal fluid (CSF) of 149 adults with HIV in Uganda, who presented with definite or probable TBM. Participants received both antimycobacterial and corticosteroid therapy.

Results: At baseline, non-survivors had more severe TBM disease and lower blood CD4 T cells than survivors. Mortality at 90 days was strongly associated with CSF hypo-inflammation. CSF interferon gamma (IFN-γ) was most differentially expressed by survivors (2.2 log2-fold change higher, p=.003), and 90-day mortality was lower with increasing concentrations (Tertile-1=50%, Tertile-2=41%, Tertile-3=18%; p=.006). Even among people who successfully mounted a CSF cellular immune response (>5 white cells/μL CSF), those with low CSF IFN-γ had higher risk of death (Hazard Ratio =3.10 (1.44-6.68). Interleukin-13 had a more complex relationship, with lower mortality among people with intermediate CSF interleukin-13 concentrations but higher at the two extremes (Tertile-1=45%, Tertile-2=22%, Tertile-3=40%; p=.017). Of all sub-groups, those with both peripheral CD4 depletion and low CSF IFN-γ had the highest mortality (63%).

Conclusions: In adults with HIV-associated TBM receiving dexamethasone, mortality was strongly associated with CSF hypo-inflammation. Although steroids may be appropriate in those with high inflammation, personalized approaches to immunotherapy are likely necessary to improve outcomes.