Open Forum Infectious Diseases最新文献

Given the melanocortin-4 receptor's (MC4R) importance in obesity, we examined associations between MC4R gene variants and weight following a switch to integrase inhibitor-containing antiretroviral therapy among participants in Advancing Clinical Therapeutics Globally studies. Among 529 persons with HIV (median age: 50 years, 29% non-Hispanic Black, 22% female), 62% were overweight or obese at integrase strand transfer inhibitor switch, and 62% switched to raltegravir. In adjusted linear models, three variants were associated (P < .05) with weight change after switch in all participants or in prespecified subgroups. These exploratory findings are consistent with the role of melanocortins in appetite and weight and suggest a neuroendocrine contribution to integrase inhibitor-related weight gain.

Crimean-Congo hemorrhagic fever (CCHF) is currently implicated as a public health threat in Iraq. This perspective study explored the increasing rate of CCHF cases during the COVID-19 pandemic, as well as climate change and human-animal conflict during festivities. CCHF mainly spreads through contact with infected humans/animals and by Hyalomma ticks. One health approach takes into account humans and animals as well as environmental science and economics should be established. Rural health care, vector control, and public awareness must be strengthened. It is important to continue cross-border cooperation and research about diagnosis, treatment, and vaccine development to control CCHF in Iraq and the region.

Background: Pediatric febrile illnesses remain a leading cause of health care visits, morbidity, and mortality in low-resource settings. Their etiological diagnosis and outcome evaluation are challenging as available tools are limited. Herein, we describe the epidemiology, trends, and clinical outcomes of febrile pediatric outpatient clinic visits and inpatients during a 17-year-long period in Southern Mozambique.

Methods: We retrospectively analyzed surveillance morbidity and demographic data from children <15 years old presenting with fever (≥37.5°C) at Manhiça District Hospital and 5 peripheral health posts from 2004 to 2020. We characterized diagnoses and clinical signs, stratified by outpatient clinic visits and hospitalizations, and calculated 7-day mortality odds, case fatality ratios (CFRs), and minimum community-based incidence rates.

Results: A total of 664 223 outpatient visits and 23 166 hospitalizations were included. The median age (interquartile range) was 47.1 (20.0-92.3) months for outpatients and 21.2 (10.1-41.5) months for inpatients. The most frequent first encounter diagnoses included malaria (33.5%), upper (27.8%) and lower (10.1%) respiratory tract infections, and acute gastrointestinal infection (6.0%), whose frequencies showed a marked annual decline from 2004 to 2020, particularly among inpatients. All-cause 7-day mortality was 0.1% and 2.2% among outpatients and inpatients, respectively. Sepsis and meningitis were less common but presented the highest CFRs (9%-16%). Malnutrition and HIV infection were major contributors to inpatient mortality. Seizures, edema, dehydration, and reduced consciousness were strong predictors of death.

Conclusions: Malaria, respiratory tract, and acute gastrointestinal infections represented the predominant causes of fever and mortality, with decreasing trends over time. This analysis underscores the value of epidemiological surveillance and the need for improved early diagnosis and clinical management tools for febrile children.

Background: Appropriate in vitro susceptibility testing interpretive criteria (STIC) are crucial to ensure optimal patient care. Pharmacometric analyses for aminoglycosides were undertaken to provide recommendations for dosing regimens adjusted for renal function and to support the original 2019 and 2023 reassessments of STIC for Enterobacterales and Pseudomonas aeruginosa.

Methods: Using simulation, traditional and extended-interval aminoglycoside dosing regimens adjusted for renal function that match drug exposures for patients with normal renal function were constructed. Using in vitro surveillance, nonclinical pharmacokinetic-pharmacodynamic (PK-PD), population pharmacokinetic (PK) model data, and simulation, PK-PD target attainment analyses were carried out to assess aminoglycoside STIC for Enterobacterales and P. aeruginosa. Susceptible breakpoints identified represented the highest minimum inhibitory concentration (MIC) values at which percent probabilities of PK-PD target attainment approached or were ≥90% based upon area under the concentration-time curve (AUC):MIC ratio targets associated with a 1-log₁₀ colony-forming unit reduction from baseline at 24 hours, and extended-interval dosing regimens. Susceptible breakpoints based on therapeutic drug monitoring (S-TDM) were also considered as such data can be used to adjust dose to achieve targeted AUC values for efficacy, in addition to monitoring for safety.

Results: Aminoglycoside dosing regimens adjusted for renal function were successfully identified. For Enterobacterales and P. aeruginosa, recommended susceptible, S-TDM, and resistance breakpoints were ≤2, 4, and ≥8 µg/mL, respectively, for amikacin and ≤0.5, 1, and ≥2 µg/mL, respectively, for gentamicin and tobramycin, based on the evaluation of extended-interval dosing regimens.

Conclusions: Use of dosing recommendations adjusted for renal function and United States Committee on Antimicrobial Susceptibility Testing-recommended STIC will allow clinicians to optimally use aminoglycosides.

The results of pharmacometric analyses for aminoglycosides were used to support recommendations for dosing regimens adjusted for renal function and a reassessment of the United States Committee on Antimicrobial Susceptibility Testing susceptibility test interpretive criteria for Enterobacterales and Pseudomonas aeruginosa. Susceptible and susceptible-based on therapeutic drug monitoring breakpoints are recommended for extended-interval amikacin, gentamicin, and tobramycin dosing regimens, thus representing adaptable treatable approaches.

Background: This study (NCT05972993) evaluated a novel mRNA vaccine construct using the SARS-CoV-2 BA.5 Spike (S) protein as the model antigen (mRNA-CR-04).

Methods: This first-in-human Phase 1, randomized, placebo-controlled trial enrolled 72 participants in Part A (sentinel vaccination and dose escalation) and 42 in Part B (dose exploration). Adult participants 18-49 years of age were randomized in 3 groups to receive one dose of mRNA-CR-04 (either 10, 30, or 100 µg) or placebo (3:1) in Part A, and 3 µg, 10 µg, or placebo (3:3:1) in Part B. Vaccine safety and immunogenicity in terms of neutralizing titers were assessed until 6 months postinvestigational product administration.

Results: Solicited adverse events (AEs) were mostly mild to moderate and transient. In Part A, Grade 3 reactogenicity was only observed in the 100 µg group (n = 3, 16.7%), and Grade 3 nonsolicited AEs only occurred as causally unrelated serious AEs in 2 participants. No safety concerns deemed causally related to mRNA-CR-04 were raised on review of clinical safety data and clinical laboratory test results. All doses elicited notable neutralizing titers against the vaccine-encoded SARS-CoV-2 BA.5 variant and induced cross-neutralizing titers against the wild type (D614G) variant. The magnitude of the immune response tended to increase with dose. Neutralizing titers waned by Month 6 but remained above baseline levels.

Conclusions: The investigational mRNA-CR-04 vaccine was generally well tolerated, and all doses induced a robust immune response against the encoded antigen at doses ranging between 3 and 100 µg. Further investigation of potential vaccine candidates using this novel mRNA platform is warranted.

Linezolid is recommended for the treatment of rifampin-resistant tuberculosis (TB), but its role in rifampin-susceptible TB (RS-TB) is less understood. In 45 RS-TB patients treated with linezolid, 8 stopped due to adverse events, most commonly cytopenias. Further research is needed on linezolid efficacy, dosing, and adverse event management in RS-TB.

Loiasis, a filarial vector-borne disease, is common in rural West and Central Africa. Benzimidazole derivatives albendazole and mebendazole are recommended as alternative treatments due to their perceived safety in hypermicrofilaremic patients. There is growing evidence that benzimidazoles might also lead to Loa loa-associated encephalopathy. In this systematic review we analyzed all available evidence of benzimidazole-associated encephalopathy. Literature was systematically searched in PubMed, Google Scholar, and WHO-VigiBase®, including conference abstracts and consultation of experts. Six potential cases of benzimidazole-associated encephalopathy, including 2 fatalities, were identified among microfilaremic loiasis patients. Due to the limited global use of prolonged benzimidazole regimens for loiasis, the number of encephalopathy cases identified raises significant safety concerns, challenging the rationale of their use. Further research on mechanisms and safer alternative regimens is urgently needed.