Rapid evidence synthesis during emerging infectious and re-emerging disease outbreaks is critical, yet traditional systematic reviews rarely meet urgent timelines. Large language models (LLMs) may accelerate evidence synthesis by extracting data from publications. We compared an LLM-assisted data extraction system with manual extraction. We conducted a 1:1, open-label, 2-period, randomized crossover trial at the National Center for Global Health and Medicine, a national reference center for emerging infectious diseases in Japan (2025). Five experienced reviewers extracted predefined items from mpox-related articles under 2 conditions: (i) LLM-assisted extraction using OpenAI's o3 model to generate structured summaries and (ii) manual review of PDF files. The primary outcome was task completion time; secondary outcomes were extraction accuracy and adverse events. Mixed-effects models included condition as a fixed effect and participant and paper IDs as random effects. The protocol, source code, and data are available at https://github.com/SRWS-PSG/emerging_infection_24K13518_open. Five evaluators (4 physicians and 1 pharmacist; 6-10 years postgraduation) completed 20 task-level evaluations (LLM, n = 9; no LLM, n = 11). Mean completion time was 27.5 minutes with LLM assistance versus 34.5 minutes without. The LLM-assisted condition was 7.9 minutes faster on average (95% CI -1.5 to 17.3; P = .099). Extraction accuracy was 100% in both conditions, and no adverse events were reported. LLM assistance might reduce data extraction time by ∼23% (7.9 minutes per article; 95% CI -1.5 to 17.3 minutes) with no observed loss of accuracy. Although statistical uncertainty remains, LLM integration may offer practical value for rapid evidence synthesis during public health emergencies as tools and prompting strategies mature.
Neurosyphilis, ocular syphilis, and otosyphilis occur more frequently among people with HIV-1 and are associated with higher morbidity and treatment failure. Intravenous penicillin G remains the standard therapy but requires hospitalization or prolonged intravenous access, creating barriers that are amplified in resource-limited settings facing recurrent penicillin shortages. Ceftriaxone is a potential alternative; however, comparative data in people with HIV are limited. We conducted a multicenter retrospective cohort study of adults with HIV at 5 public hospitals and 2 outpatient HIV clinics in Mexico (2015-2024). Participants had confirmed neurosyphilis, ocular syphilis, or otosyphilis. Participants received intravenous penicillin G (18-24 million IU/day) or ceftriaxone (1-2 g/day) for 10-14 days. The primary outcome was early serological response (ESR), defined as a ≥4-fold nontreponemal titer decline or seroreversion at 6 months. We performed 1:1 propensity score matching (39 pairs, n = 78), followed by logistic regression in the matched cohort. Of 143 participants, 104 (73%) received intravenous penicillin G and 39 (27%) ceftriaxone. In the matched cohort, ESR occurred in 74.4% of penicillin-treated participants and 71.8% of ceftriaxone-treated participants (odds ratio 0.88, 95% confidence interval .32-2.40; P = .80). The results were consistent across all prespecified sensitivity analyses. In this multicenter cohort of people with HIV diagnosed with neurosyphilis, ocular syphilis, or otosyphilis, ceftriaxone showed comparable ESR to intravenous penicillin G. These findings support ceftriaxone as a reasonable alternative when standard therapy is limited by penicillin shortages, limited inpatient capacity, or financial constraints.
Our understanding of the epidemiology of and risk factors for postchimeric antigen receptor T-cell therapy (CART) infections is largely based on data from single-center studies with small sample sizes. This is a multicenter, cohort study of adult patients treated with CD19 CART between 1 January 2018 and 31 August 2021. The epidemiology of infectious complications occurring within the first year after CART is described. A Fine-Gray subdistribution hazard model was built to identify risk factors for infection. Logistic regression was used to explore risk factors for early (≤90 days post-CART) versus late (>90 days post-CART) and bacterial versus viral infection. One hundred and thirty-one infections occurred in 97 of 311 patients (31.2%) within 1 year of CART. By infection type, the cumulative incidence of infection was 19.0% (viral), 20.9% (bacterial), and 2.3% (fungal). The majority of infections were mild or moderate in severity (86%). Clostridiodes difficile and bloodstream infections due to Gram-negative bacilli were common bacterial infections. Respiratory viral infections were the most common viral complication and fungal infections were rare. No independent predictors of infection were identified. Infectious complications occur in close to a third of patients post-CART but are generally mild in severity. Though we were not able to identify independent predictors of post-CART infection, a description of their clinical characteristics and epidemiology will help to optimize management of these common complications.
Glycopeptide antibiotics remain the cornerstone of therapy for serious Gram-positive bacteremia, yet comparative real-world effectiveness data between teicoplanin and standard-of-care agents remain limited in Middle Eastern healthcare settings. To compare clinical outcomes, safety profiles, and predictors of treatment failure between teicoplanin and standard-of-care antibiotics in adult patients with microbiologically confirmed Gram-positive bacteremia. We conducted a 7-year retrospective cohort study (January 2018-January 2025) at 2 tertiary care centers in Riyadh, Saudi Arabia. Adult patients receiving ≥72 hours of teicoplanin or standard-of-care antibiotics, including prespecified organism-directed beta-lactam therapy when clinically indicated, for Gram-positive bacteremia were included. Propensity score matching (1:1 ratio, caliper 0.2) was employed to balance baseline characteristics. Primary outcome was clinical cure at end of therapy. Secondary outcomes included 90-day all-cause mortality, nephrotoxicity, 14-day treatment failure, 30-day relapse, and antimicrobial switch due to toxicity. Among 547 screened patients, 312 met inclusion criteria (teicoplanin n = 124; standard-of-care n = 188). Prematch analysis revealed significantly higher baseline illness severity in the teicoplanin cohort (median APACHE II 18 vs 14, P = .02). Propensity score matching yielded 102 well-balanced pairs. Clinical cure rates were comparable between groups (teicoplanin 78.4% vs standard-of-care 72.5%; P = .31). Nephrotoxicity occurred significantly less frequently with teicoplanin (6.8% vs 18.2%; P = .01). Antimicrobial switch due to toxicity was lower in teicoplanin-treated patients (8.8% vs 22.5%; P = .01). Ninety-day mortality did not differ significantly (hazard ratio 0.89, 95% CI .54-1.45; log-rank P = .64). Within the teicoplanin cohort, failure to administer a loading dose (odds ratio 3.5, 95% CI 1.21-10.12; P = .02) and infective endocarditis as the infection source (odds ratio 4.1, 95% CI 1.38-12.18; P = .01) independently predicted treatment failure. Subgroup analysis demonstrated optimal teicoplanin efficacy in catheter-related bloodstream infections (cure rate 85.2%), with attenuated efficacy in pneumonia (65.0%) and endocarditis (55.5%). Teicoplanin was associated with comparable clinical efficacy and lower nephrotoxicity compared with standard-of-care antibiotics. It may represent a reasonable alternative, particularly in patients at increased risk of renal adverse events. Prospective studies are warranted.
Listeriosis is a severe foodborne illness with elevated incidence rates among pregnant women, older adults, individuals with medical comorbidities, and certain racial and ethnic subpopulations. Foodborne Diseases Active Surveillance Network (FoodNet) data allow examination of incidence trends and differences. We analyze sporadic invasive listeriosis cases reported to FoodNet from 2008 to 2023. Incidence rates and rate ratios are calculated overall and by studied period, pregnancy status, age, sex, race, and ethnicity. US Census Bureau demographic projections are used to estimate incidence rate changes expected from changes in the structure of the population with time. The overall incidence rate of domestically acquired sporadic listeriosis has remained stable in the FoodNet catchment area over the 15-year period, with a latest estimate (2020-2023) of 0.25 (95% confidence interval [95% CI, .22-.30) per 100 000 person-years. No significant temporal trend in any studied subpopulation is observed. Pregnant women have a 64-fold (95% CI, 47-87) higher risk when compared to non-pregnant women of reproductive age. Incidence rate in the non-pregnant population rises with age, and Hispanic, non-Hispanic Asian, and non-Hispanic Black populations have higher rates than non-Hispanic White populations. An increased overall incidence rate would have been expected because of demographic shifts; instead, the observed stable incidence rate suggests approximately 16% lower exposure to Listeria monocytogenes in 2023 compared with 2008. Stable listeriosis incidence rates despite demographic shifts suggest reduced population exposure to L monocytogenes. Targeted prevention for disproportionately affected subpopulations, alongside continued efforts to reduce exposure broadly, is needed to further reduce the risk of invasive listeriosis.
Norovirus is a leading cause of acute gastroenteritis (AGE) in the United States and is associated with substantial healthcare utilization, including risk of hospitalization. The extent to which underlying medical conditions contribute to this risk is not well understood. This retrospective cohort study analyzed adults with incident medically attended all-cause AGE or cause-specified norovirus AGE episodes identified via International Classification of Diseases, Tenth Revision, Clinical Modification between July 1, 2022 and June 30, 2024 in Optum's deidentified Clinformatics® Data Mart Database (Optum® CDM). Generalized estimating equations estimated adjusted risk ratios (aRRs) and confidence intervals (CIs) for acute hospitalization within 3 days of AGE diagnoses. Of 1 705 514 all-cause AGE and 5805 norovirus AGE cases, 11.3% and 44.6%, respectively, were hospitalized within 3 days of their episode. Hospitalization risk was higher for patients with cardiovascular disease (CVD) (all-cause AGE aRR: 1.67 [95% CI, 1.64-1.69]; norovirus AGE aRR: 1.37 [1.22-1.54]), blood disorders, chronic respiratory disease, and chronic kidney disease. Relative to individuals without underlying conditions, hospitalization risk was higher for those with ≥2 conditions (all-cause AGE aRR: 2.02 [95% CI, 1.98-2.07]; norovirus AGE aRR: 1.79 [1.50-2.14]), exceeding the risk among those with 1 condition. Relative risk of acute hospitalization associated with presence of underlying conditions was higher among adults aged 18-64 years than among those ≥65 years. Underlying conditions, notably CVD and ≥2 underlying conditions, significantly increased the risk of acute hospitalization, which was elevated among adults aged 18-64 years.
Road injuries are a leading cause of mortality and morbidity worldwide. Years of international efforts have aimed to strengthen policy engagement, including the 2020 UN General Assembly's proclamation of the Second Decade of Action for Road Safety (2021-30), targeting a 50% reduction in road traffic deaths and serious injuries by 2030. The aim of this study is to provide estimates to monitor progress and identify intervention gaps. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2023, we estimated incidence, mortality, and morbidity of road injuries for 204 countries and territories from 1990 to 2023. Four road injury types and 47 nature-of-injury categories were examined. Morbidity and mortality data from clinical records, vital registration, and police reports were harmonised using meta-analytic techniques to ensure consistency and correct for systematic bias. Incidence was modelled with the meta-regression tool Disease Modelling-Meta-Regression version 2.1 and cause-specific mortality with the Cause of Death Ensemble model, both incorporating location-specific covariates to support interpolation. Years of life lived with disability (YLDs) were estimated from the prevalence and severity of the nature of road injury, and years of life lost (YLLs) from the number of cause-specific deaths multiplied by the standard life expectancy at the age of death. Disability-adjusted life-years (DALYs) were the sum of YLLs and YLDs. All metrics were calculated with 95% uncertainty intervals (UIs). In 2023, there were 50·9 million (95% UI 46·1-56·1) road injury incident cases, 1·34 million (1·04-1·58) deaths, and 75·3 million (59·8-89·2) DALYs globally. Road injuries were the leading global cause of death among males aged 10-39 years. Between 1990 and 2023, age-standardised incidence decreased by 38·3% (95% UI 36·9-39·7) and mortality decreased by 32·3% (6·1-49·0), but progress varied widely by World Bank income group. Mortality in low-income countries (43·8 [95% UI 31·7-56·0] deaths per 100 000 population) was approximately six times higher than in high-income countries (7·5 [7·1-7·9] deaths per 100 000), despite the high-income countries showing the highest age-standardised incidence rates (858·1 [95% UI 781·9-947·1] cases per 100 000). In the past decade, many countries achieved notable reductions in road injuries, but others, including Ghana and the USA, saw increases. More severe injuries tended to occur in low-income and middle-income countries. Although global incidence, mortality, and DALY rates from road injuries have declined, progress remains uneven, with pronounced disparities across income groups reflecting systemic inadequacies in infrastructure, vehicle standards, enforcement, and post-crash care. Strengthening emergency response, improving road design, enforcing safety measures, and adapting policies to the evolving demographics remain essential. Gates Foundation.
Congenital cytomegalovirus (cCMV) is the leading infectious cause of long-term neuro-sensory impairment. Aim of meta-analysis was to evaluate the efficacy of antenatal immunoglobulin therapy-particularly cytomegalovirus-specific hyperimmune globulin (HIG)-in preventing vertical transmission and congenital cytomegalovirus infection (cCMV) in pregnancies complicated by primary maternal CMV infection. A search of PubMed, Cochrane Library, Embase, Scopus, ScienceDirect, Taylor & Francis Online, Wiley Online Library, ClinicalTrials.gov, and Google Scholar identified randomized controlled trials, prospective or retrospective cohort studies including pregnant women with serologically confirmed primary CMV infection. Eligible interventions included antenatal CMV-specific or nonspecific immunoglobulins (vs placebo, usual care, historical controls, or no treatment), although all included studies evaluated CMV-specific HIG. Controlled studies showed no significant reduction in transmission (RR 0.73, 95% CI .54-1.00; P = .051) with moderate heterogeneity. The pooled transmission rate after HIG was 27.2%, with substantial heterogeneity. Current evidence does not support routine antenatal immunoglobulin to prevent cCMV.
Recurrent diarrhea after an episode of Clostridioides difficile infection (CDI) is common although not always secondary to recurrent disease. Bacterial and viral gastroenteritis has been associated with postinfectious functional bowel disorders (FBDs). We aimed to compare characteristics of patients diagnosed with CDI-associated FBD with those of patients diagnosed with initial or recurrent CDI alone. This was a retrospective review of the electronic medical records of patients referred to the Complicated C. difficile Clinic at University of Virginia Health from March 2020 to January 2023. The characteristics of the patients we studied included demographics, risk factors, and outcomes. Of 159 patients seen at the clinic, 44 (27.7%) referred for recurrent CDI had symptoms of FBD; 90 (56.6%) had symptoms of CDI alone. Compared with patients with CDI only, patients with CDI-associated FBD were younger (P = .001), more likely to be female (P = .029), had fewer comorbidities (P < .001), and more frequently had a history of anxiety (P < .001) and depression (P = .003). In a multiple regression model, FBD remained associated with fewer comorbidities (P = .032). At 3 months, patients with FBD were less frequently well (P = .039) and more frequently continued to have gastrointestinal symptoms (P < .001) than patients with CDI alone. CDI-associated FBD is prevalent but may be misdiagnosed as solely CDI recurrence, contributing to incomplete resolution of symptoms despite anti-C. difficile treatments.
People with human immunodeficiency virus (HIV) are at increased risk of severe COVID-19 and are recommended for priority vaccination. We investigated the safety and immunogenicity of a 2-dose regimen of the mRNA vaccine BNT162b2 in people with HIV (PWH) on antiretroviral therapy (ART). Safety, reactogenicity, and immunogenicity data were obtained from PWH on ART ≥16 years enrolled in the phase 1/2/3 BNT162-02 trial/C4591001 (NCT04368728) between September and November 2020, which randomized participants (1:1) to receive BNT162b2 or placebo. Immunogenicity was also investigated in a substudy of the open-label phase 1/2 BNT162-01 trial (NCT04380701) in PWH aged 18-85 years and age- and sex- matched HIV-negative controls enrolled February to March 2021. In total, 201 PWH were included from the BNT162-02 trial. Higher rates of local and systemic reactions were reported during the 7 days following both doses by participants administered BNT162b2 versus participants administered placebo, most notably pain at injection site, fatigue, headache, and chills. Most reactions were mild to moderate in severity. No serious adverse events occurred up to 1 month post-dose 2. Spike protein-binding and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody responses were elicited in participants who received BNT162b2 and remained above prevaccination baseline levels through 6 months post-dose 2. In the BNT162-01 trial, all PWH (N = 15) seroconverted, with BNT162b2-induced SARS-CoV-2 neutralization titers and longitudinal T-cell responses similar to those observed in the HIV-negative cohort. Primary 2-dose vaccination with BNT162b2 in PWH was well tolerated and immunogenic with sustained responses up to 6 months, supporting vaccination in this priority population.
Campylobacter spp bloodstream infections (BSIs) are an emerging clinical challenge, yet information on their clinical features remains limited. We aimed to evaluate their differential clinical characteristics and outcomes in immunocompetent (IC) and immunodeficient (ID) patients. A multicenter, multinational, retrospective cohort study of consecutive Campylobacter spp BSIs between 2009 and 2024 was carried out. Demographics, Charlson comorbidity index, types of immunodeficiencies, clinical characteristics, and antimicrobial susceptibility were analyzed. The primary outcomes were relapse or reinfection and death (all-cause mortality outcome). A total of 261 episodes were included, 89 (34.1%) in IC and 172 (65.9%) in ID patients. Among the 172 ID patients, 104 (60.5%) and 68 (39.5%) had humoral or nonhumoral immunodeficiency (primary or secondary), and 42 (24.4%) had primary immunodeficiencies (PIDs). Patients with humoral immunodeficiency (humoral-ID patients) were younger (median age, 40 years [interquartile range, 23-66 years]), had lower Charlson comorbidity indexes (2 [1-5]), and had a higher frequency of previous Campylobacter spp infection. Resistance rates to fluoroquinolones (75%) and macrolides (14.5%) were high. BSI relapse or reinfection occurred in 21 (8.0%) patients, mostly humoral-ID patients (n = 19 [18.3%]), 11 (57.9%) of whom had PID. Death occurred with 30 days (all-cause mortality outcome) in 26 patients (9.9%) across the entire cohort; the 30-day mortality rate was lower in humoral-ID (n = 5 [4.8%]) than in IC (n = 12 [13.5%]; P = .05) patients. Humoral-ID patients and those with Campylobacter spp BSI were younger and had fewer comorbid conditions, and Campylobacter coli was the most frequent species. Relapse or reinfection was common in humoral-ID patients, particularly those with PID. The antimicrobial resistance in C coli and Campylobacter jejuni represents a clinical concern.
Dengue-associated liver injury is common, prognostically significant, and associated with high mortality at severe thresholds. Oxidative stress is a key, potentially modifiable mechanism. N-acetylcysteine has strong biological plausibility and supportive preclinical data, but clinical evidence remains limited, underscoring the need for well-designed randomized trials to inform practice and policy.
A central Texas resident found an engorged Ornithodoros turicata tick attached to their ankle while at home. The tick tested positive for Borrelia turicatae, an agent for soft tick-borne relapsing fever. Three weeks earlier, the patient started experiencing febrile episodes, rash, and nausea, yet the etiological agent went undiagnosed.
Avian influenza viruses (AIVs) have been reported to cause infections in humans following avian-to-human transmission, resulting in a range of clinical outcomes. A(H5N1) and A(H7N9) infections, which constitute the majority of human AIV cases, are responsible for severe infections leading to high mortality. The neuraminidase inhibitor oseltamivir is expected to play a major role for the control of AIV infections in humans. However, the emergence of resistance may compromise the impact of antiviral therapy. The objective of this article is to review human cases of A(H5N1) and A(H7N9) infections for which mutations of oseltamivir resistance were detected. Neuraminidase mutations rapidly occurred in a subtype-specific manner, with H274Y and N294S substitutions predominating in A(H5N1) cases and the R292K substitution in A(H7N9) cases. Serious clinical outcomes and mortality were seen in most A(H5N1) and A(H7N9) cases despite oseltamivir therapy, thus highlighting the need for improving antiviral strategies against these AIVs.
Guidelines now support anal squamous cell carcinoma (ASCC) screening in men who have sex with men (MSM) living with HIV (LWH) aged ≥35 years. There is limited data on screening in MSM LWH <35 years. Two academic HIV clinics in the Northeastern US. We retrospectively evaluated all anal cytology and high-resolution anoscopy (HRA; referral criteria: atypical cells of undetermined significance [ASC-US] or worse cytology) performed for MSM LWH between ages 18-34 from 2013 to 2023. We evaluated risk factors for abnormal cytology or histology, and prevalence of high-grade dysplasia (HSIL) and ASCC. Of 216 eligible MSM LWH, 111 (51%) were screened for ASCC at least once. Screened individuals had longer follow-up (median 4.0 vs 1.6 years) but were otherwise similar to unscreened individuals. Among 246 cytology tests, 19% were unsatisfactory and 31% abnormal, of which 1.2% reported HSIL. Of 23 HRAs following abnormal cytology, 10 (43%) revealed HSIL. Testing in response to symptoms was associated with abnormal results (OR 8.54; 95% CI 2.55-28.67). Human papillomavirus vaccination trended toward protection against abnormal results. We identified two cases of local ASCC, both in individuals with symptomatic condyloma and severe immunosuppression. Over 10 years, ASCC screening in MSM LWH <35 years was variable. Anal cytology had high unsatisfactory rates and poor correlation with histology. Despite high dysplasia prevalence among those undergoing HRA, ASCC was rare and diagnosed early from symptoms. Findings support excluding younger (≤34 years) MSM LWH from asymptomatic screening, and support symptom-driven testing to diagnose anal cancer early.
Ebola virus disease (EVD) is often regarded as severe and highly fatal, but growing evidence suggests that subclinical or minimally symptomatic infections occur and frequently go undetected. During the 2017 outbreak in Likati Health Zone, only 8 cases were confirmed despite many reported exposures. We evaluated the extent of asymptomatic or unrecognized Ebola virus infection and associated factors among contacts of reported cases. In November 2017, we conducted a cross-sectional community-based serosurvey among contacts originally identified through Ministry of Health records and newly identified through additional post-outbreak investigations. Participants provided blood samples and completed questionnaires on demographics, exposures, and symptoms within 4 weeks of symptom onset of the EVD case with whom contact was reported. Sera were tested for anti-EBOV nucleoprotein IgG by ELISA. Seropositive individuals were classified as asymptomatic (no symptoms) or unrecognized (≥1 symptom). Secondary attack rate (SAR) was estimated, and logistic regression assessed associations with sociodemographic factors, exposure level, and symptoms. Among 180 participants (79 originally identified; 101 newly identified), 33 (18.3%) were seropositive. Of these, 19 (58%) reported symptoms, and 14 (42%) were asymptomatic. Any EVD-related symptom was associated with higher odds of seropositivity (OR 2.48, P = .021), though no specific symptom was significant. Asymptomatic individuals had higher antibody titers than symptomatic seropositive contacts (P = .009). The overall SAR was 19.1% (95% CI: 15.9-23.0). High exposure level strongly predicted seropositivity (OR 11.2, 95% CI: 3.8-33.3). Asymptomatic infections occurred, including among contacts missed during the response, highlighting the need for exposure-based serologic assessments in EVD investigations and raising questions about immune responses and the true disease burden in outbreak-affected settings.
Older adults evaluated in emergency departments (EDs) frequently receive antibiotics, but the relationships among neighborhood deprivation, antibiotic decision concordance, and downstream outcomes remain incompletely defined. We conducted a retrospective cohort study of 1 365 957 ED encounters among adults aged ≥65 years at 119 CommonSpirit Health facilities across 15 US states (2015-2024). Census-tract Social Deprivation Index (SDI) was standardized for modeling. Indication-level concordance, overuse, and underuse were based on antibiotics administered during the index ED encounter and an encounter-level diagnosis-tier framework. Outcomes were length of stay (LOS), 30-day ED revisit, mortality, Clostridioides difficile infection (CDI), and desirability of outcome ranking (DOOR). Associations between higher SDI and outcomes were statistically detectable but small in absolute magnitude. Guideline-concordant management was associated with shorter LOS, better DOOR, and lower revisit, mortality, and CDI risks; overuse was consistently associated with worse outcomes, whereas underuse showed mixed associations. Concordance mediated only a small share of SDI-associated outcome differences. Sensitivity analyses using a 4-level DOOR outcome, modified Poisson relative risks, and study-period stratification supported the principal interpretation. Neighborhood deprivation had small absolute associations with short-term outcomes. Indication-level concordance and avoidance of overuse were associated with more substantial outcome differences but explained little of the deprivation-associated variation.
Bedaquiline, pretomanid, and linezolid (BPaL) is a 6-month regimen that has revolutionized treatment of multidrug-resistant (MDR) tuberculosis (TB). However, there is limited evidence of using BPaL to treat MDR tuberculous meningitis (TBM), a devastating illness that has high risk of mortality and permanent disability. A patient with fluoroquinolone-resistant pre-extensively drug-resistant (pre-XDR) TBM was cured with a 10-month regimen based on BPaL with clofazimine and cycloserine. Total concentrations of bedaquiline, pretomanid, and linezolid were measured in plasma and cerebrospinal fluid (CSF) via ultraperformance liquid chromatography. Unbound concentrations were estimated from plasma concentrations and CSF concentrations normalized to plasma protein concentrations using the Winter-Tozer formula. AUC24 (24-hour area under the curve) was calculated using the trapezoidal method. The CSF:plasma unbound AUC24 was 1.48 and 0.99 for pretomanid and linezolid, respectively. Pharmacokinetic/pharmacodynamic targets were achieved for pretomanid with CSF concentration above the critical concentration of 0.5 mg/L throughout most of the dosing interval and linezolid AUC24/minimum inhibitory concentration (MIC) of 171 for an MIC of 0.5 mg/L. However, CSF concentrations of pretomanid and linezolid may be below target for strains with MICs >0.5 mg/L. Estimated unbound peak concentrations in CSF in week 21 were comparable to plasma (0.0034 mg/L and 0.0032 mg/L, respectively), suggesting that therapeutic central nervous system concentrations of bedaquiline were achieved. Fluoroquinolone-resistant pre-XDR TBM was cured with 10 months of treatment based on BPaL with clofazimine and cycloserine. BPaL achieved therapeutic concentrations in CSF for most TB strains. Further research is required into optimal treatment and dosing of drug-resistant TBM.
This study was conducted to investigate the diagnostic value of fungal biomarker differentials and T2Candida polymerase chain reaction (PCR) from catheter and peripheral blood samples and to re-evaluate classical conservative methods, such as differential time to positivity of blood cultures (BCs), for the early identification of catheter-related candidemia (CRC) before catheter removal. This prospective study was conducted (March 2023-April 2025) in 2 tertiary hospitals in Spain and Italy. Adults (aged ≥18 years) with candidemia and a central venous catheter in place at diagnosis were included, provided catheter removal occurred within 48 hours of index BC positivity. CRC was defined in patients with candidemia who showed 1 or 2 of the following criteria in the catheter tip: (1) ≥ 15 CFU/plate (Maki technique) or ≥ 1000 CFU/mL (sonication) and (2) any Candida growth on the catheter tip. Blood samples were collected from peripheral veins and catheter lumens to compare the differentials of 1,3-β-D-glucan (BDG), Candida albicans germ tube antibodies, mannan antigen, antimannan antibody, and T2Candida PCR results. Diagnostic metrics were calculated for each test. Of 179 episodes of candidemia reviewed, 28 (15.6%) met the inclusion criteria (13 in Spain, 15 in Italy). CRC was confirmed in 11 patients (39.3%) using criterion 1 and in 15 patients (53.6%) using criterion 2. BDG differentials (any difference) demonstrated the highest diagnostic accuracy as follows: sensitivity 81.82%, specificity 82.35%, positive predictive value 75.00%, negative predictive value 87.50%, and overall accuracy 82.14% (criterion 1). However, stricter BDG thresholds (≥20 or ≥30 pg/mL) and the application of criterion 2 reduced the sensitivity. Other biomarkers and T2Candida PCR demonstrated low sensitivity (0%-40%) and variable specificity (25%-100%), with overall accuracies of <64%. Differential time to positivity of BCs yielded a sensitivity of 72.73% and a specificity of 52.94%, with limited accuracy. None of the investigated methods achieved sufficient accuracy to diagnose CRC without catheter removal. Despite the limited sample size, this study emphasizes the limitations of current diagnostic approaches and the need for novel tools for reliable noninvasive identification of CRC.
Randomized controlled trials (RCTs) of oral antivirals for COVID-19 conducted early in the pandemic had favorable results in unvaccinated populations. We conducted a systematic review and meta-analysis of the effectiveness of nirmatrelvir-ritonavir and molnupiravir against hospitalization and death in vaccinated populations in the post-Omicron era. We systematically searched PubMed, Embase and the Cochrane library for RCTs conducted from January 2020, and observational studies in adults who were vaccinated conducted from January 2022. We performed a random effects meta-analysis using the inverse variance method with subgroup analysis by age (<65 vs ≥65 years) and study quality (excluding vs including studies at serious risk of bias). We identified 43 studies (8 RCTs, 35 observational). Two RCTs were in vaccinated populations in which no association between treatment with nirmatrelvir-ritonavir and a reduction in death, or treatment with molnupiravir and a reduction in hospitalization or death, was observed. In the meta-analysis of observational studies, nirmatrelvir-ritonavir was associated with a reduction in hospitalization (n = 11; odds ratio (OR): 0.60; 95% CI .54-.67, hazard ratio (HR): 0.69; 95% CI .62-.76) and mortality (n = 9; OR: 0.33, 95% CI .22-.48; HR: 0.56, 95% CI .36-.87). Molnupiravir was not associated with a significant reduction in hospitalization (n = 5; OR = 0.83; 95% CI .65-1.07) with mixed results for mortality (n = 9; OR = 0.61; 95% CI .41-.91; HR = 0.65; 95% CI .42-1.01). In vaccinated populations, RCTs have not demonstrated a reduction in hospitalization or death among populations treated with nirmatrelvir-ritonavir or with molnupiravir. However, RCTs of nirmatrelvir-ritonavir had limited statistical power to detect clinically important differences. Observational studies of nirmatrelvir-ritonavir, but not molnupiravir, consistently suggested a benefit against these outcomes. PROSPERO (CRD420251266532).