Open Forum Infectious Diseases最新文献

Background: Neurocysticercosis (NCC) is the most prevalent helminth infection affecting the human central nervous system. Although neuroimaging is required for definitive diagnosis, serology supports case confirmation and clarifies diagnostic doubts. Serology gold standard is antibody detection using the enzyme-linked immunoelectrotransfer blot assay, which uses 7 antigenic lentil-lectin purified parasite glycoproteins (LLGP-EITB). LLGP-EITB is poorly accessible to low-resource settings due to its technical complexity and costs, and it is inaccessible in many settings in which parasitic material to produce antigens is not readily available. We recently developed a 3-antigen multiantigen print immunoassay (MAPIA) based on recombinant/synthetic antigens (rGP50, rT24H, and sTs14), corresponding to the 3 principal diagnostics antigenic families from LLGP-EITB, that is simpler and does not require parasite-derived materials.

Methods: MAPIA performance was evaluated using a well-defined set of serum samples from NCC patients confirmed by imaging, including 73 samples from subarachnoid NCC, 72 with >5 parenchymal cysts, 59 with 3-5 parenchymal cysts, 95 with 1-2 parenchymal cysts, and 77 healthy negative controls and compared it with the LLGP-EITB performance.

Results: Overall, our MAPIA presented a sensitivity of 97.7% and a specificity of 97.4%. Subgroup analyses by NCC type demonstrated a sensitivity of 100% for subarachnoid and parenchymal NCC with >5 cysts and a slight decrease for the groups with 3-5 cysts (96.6%) and 1-2 cysts (94.7%). Observed agreement with the LLGP-EITB assay was 98.33%.

Conclusions: Our 3-antigen MAPIA obtained comparable results to LLGP-EITB and emerges as a simpler, reproducible, and easy-access alternative tool for antibody diagnosis in NCC.

The limited but rising threat of ceftaroline-resistant MRSA poses a therapeutic challenge. We show that ceftaroline plus carbapenems restores activity against a resistant strain both in vitro and in a murine bacteremia model. These findings support combination therapy as a potential strategy for difficult MRSA infections, warranting further clinical investigation.

Background: Latent Epstein-Barr virus (EBV) infection is asymptomatic in most adults but can be associated with lymphoma, particularly in immunocompromised patients. Options are limited for patients with EBV viremia disease refractory to B-cell depleting antibodies or chemotherapy. Cellular therapies targeting EBV have shown promise in treating EBV-associated malignancies and restoring anti-EBV immunity.

Methods: This is a phase I/II clinical trial in 9 patients, along with 3 additional single-patient trial cases, evaluating patient-specific manufacturing and administration of virus-specific T cells (VSTs) from various sources for the treatment or prevention of EBV-related lymphoma. The VSTs were produced from autologous and allogeneic peripheral blood mononuclear cells (PBMCs) using synthetic viral peptides stimulation.

Results: Three patients were allogeneic hematopoietic stem cell transplant (HCT) recipients, 4 were solid organ transplant (SOT) recipients, and 2 were nontransplant patients with EBV-associated lymphoma. VSTs were successfully manufactured from healthy donors and demonstrated strong and specific reactivity to EBV. Six patients achieved or maintained complete responses (3 SOT and 3 HCT) while 3 did not respond to therapy (1 SOT recipient and 2 nontransplant patients), resulting in an overall response rate of 67% (86% in transplant patients). One patient died of noninfusion related complications during the study follow-up period. Cell infusions were well tolerated with no treatment-related serious adverse events reported.

Conclusions: These results strengthen previously published results using VSTs from healthy donors and further support the development of EBV-specific T cell therapies to treat refractory EBV reactivation and EBV-associated malignancies, particularly in transplant recipients.

Background: Klebsiella pneumoniae (KPn) is a leading cause of invasive bacterial disease in African children, albeit with a scarcity of genotypic characterization.

Methods: We sequenced invasive KPn isolates from infants ≤90 days, collected through observational hospital surveillance (n = 226) between March 4, 2019 and February 27, 2021, and between May 13, 2022 and October 31, 2023, and postmortem sampling (n = 111) between February 15, 2018 and April 18, 2023. Postmortem Kpn isolates were attributed in the causal pathway to death by the determination of the cause of death panel, which consists of local experts.

Results: Three hundred and thirty-seven isolates (226 identified during hospital surveillance and 111 from postmortem sampling) were included in the final analysis. Genomic analysis identified 85 distinct clonotypes. Sequence type (ST) 17 (22.0%) predominated, followed by ST39 (12.7%). The dominant K-locus (KL) were KL25 (24.0%), KL2 (14.5%), and KL149 (13/4%), while the dominant O-antigens included O1αβ,2α(48.4%), and O5 (19.9%). Eighty-five percent (287/337) of the KPn isolates harbored multidrug resistant genes, including 32.9% to carbapenems. Notably, bla_OXA-181, bla_NDM-5, and bla_NDM-1 were detected in 26.4%, 2.1% (7/337), and 0.3% (1/337) of isolates, respectively.

Conclusions: Although a wide diversity of strains were associated with Kpn invasive disease, over 80% of the cases were attributed to 11 K loci. These data provide critical insights into KPn epidemiology and highlight potential antigen targets for vaccine development in young African children.

Background: Respiratory syncytial virus (RSV) frequently causes upper respiratory tract infections, lung disease, and mortality in hematopoietic cell transplant (HCT) recipients. Currently, little is understood about what clinical and immunologic factors increase a patient's risk of infection or are protective against infection in immunocompromised populations.

Methods: This study analyzed clinical and serologic data from a cohort of HCT recipients followed longitudinally with weekly blood draws and PCR surveillance for respiratory viruses to gain insight into clinical and antibody-based risk factors for RSV infection post-transplant. Serum was analyzed by a plaque reduction neutralization assay to determine neutralizing antibody titers to RSV.

Results: Sixteen of 471 HCT recipients tested positive for RSV within the first 100 days post-transplant. A multivariate analysis of clinical factors revealed that prophylaxis with sirolimus for graft-versus-host disease (GVHD) was significantly correlated with increased risk of RSV infection. Moreover, higher levels of neutralizing antibody to RSV were associated with reduced risk for RSV infection, in a time-varying analysis.

Conclusions: GVHD prophylaxis with sirolimus and low serum neutralizing antibody titers were correlated with increased risk of RSV infection in the early post-transplant period. These results support the role of developing and implementing strategies that boost neutralizing antibody levels to prevent RSV infections in HCT recipients.

Background: Physicians prescribing antibiotics for common infections must weigh trade-offs across drug attributes such as efficacy, dosing, side effects, and resistance. Understanding these priorities can help inform drug development, regulatory decisions, and insurance coverage determinations.

Methods: We conducted a discrete choice experiment between June 5 and 9 July 2024, among a national sample of US physicians who prescribed antibiotics for community-acquired pneumonia (CAP) or complicated urinary tract infections (UTIs) in the past year. Respondents evaluated paired hypothetical antibiotics varying by 5 attributes: time to symptom improvement, dosing frequency, risk of nonserious and serious side effects, and risk of future resistance to the patient. Preference weights and relative importance scores were estimated using conditional logistic models. Subgroup analyses were conducted by disease, care setting, and specialty.

Results: Of 880 enrolled physicians, 756 (86%) completed the survey. Respondents had a mean age of 51.5 years; 60% were male, and most practiced general internal medicine (64%) or infectious disease (15%). The most influential attributes overall were symptom improvement (relative importance score: 28%) and dosing convenience (relative importance score: 27%). In inpatient settings, physicians prioritized symptom improvement (relative importance score: 33%), while outpatient physicians prioritized dosing frequency (relative importance score: 31%). Risk of future antibiotic resistance to the patient was consistently the least influential attribute (relative importance score: 7%-13%) across disease-types and clinical settings.

Conclusions: In this national survey study, physicians prioritized rapid symptom relief and dosing convenience over other drug attributes when prescribing antibiotics for CAP and UTIs. Understanding physician priorities can help inform stewardship strategies and clinician-facing decision support, and encourage regulators and sponsors to prioritize clinically meaningful trial endpoints.

Patent foramen ovale (PFO) has a prevalence of approximately 25%. Its association with pyogenic brain abscess (PBA) is unclear. We reviewed adults with PBA and known PFO status from 1 January 2009 through 31 December 2021 at Mayo Clinic. High PFO prevalence (40.5%) was seen. PBA patients with PFO had distinct abscess characteristics but unchanged 1-year, all-cause mortality.

Long-acting injectable (LAI) antiretroviral therapy (ART) is a promising option for people with HIV who face persistent adherence challenges, though literature to support its use in cases of integrase strand transfer inhibitor (INSTI) resistance remains limited. We describe a 36-year-old man with advanced HIV-1, long-standing nonadherence to oral medications, and virologic failure who harbored both an INSTI major mutation (E92Q) and accessory mutation (E157Q). Given persistent nonadherence and viremia, he was started on dual LAI lenacapavir plus cabotegravir/rilpivirine. His viral load declined to 143 copies/mL within 6 weeks after initiation of injectable ART and has remained undetectable thereafter. This case suggests that dual LAI ART may be effective in certain cases of underlying INSTI resistance and highlights the need for further study of this novel regimen in treatment-experienced individuals.

Background: Cystic fibrosis (CF) pulmonary exacerbations shorten survival. Treatment guidelines omit minimal inhibitory concentration (MIC)-based antibiotic dose selection. We tested whether MIC-guided intravenous antibiotic strategies prolong time between exacerbations.

Methods: We retrospectively studied randomly chosen intravenous antibiotic-treated pulmonary exacerbations from 2015 to 2018, followed through 2021. Using pre-admission sputum culture-derived MICs to select dosing targets, we estimated measured:target ratios for β-lactam steady-state and aminoglycoside area under the curve pharmacokinetics. We used Kaplan-Meier and Cox proportional hazards methods to test whether measured:target ratios were associated with time to next exacerbation. We evaluated serial laboratory measurements with linear mixed-effects models for adverse events. We tested model sensitivities to concurrent treatments and severe acute respiratory syndrome coronavirus 2 pandemic-related events.

Results: Compared with measured:target ratios ≤1, β-lactam ratios >1 were associated with a median of 19 more (from 204 to 223) exacerbation-free days (91 exacerbations; hazard ratio [HR], 0.60; 95% CI, 0.37-0.99; P = .045); aminoglycoside ratios >1 were associated with a median of 83 more (from 153 to 236) exacerbation-free days (65 exacerbations; HR, 0.54; 95% CI, 0.31-0.93; P = .026); both antibiotic ratios >1 simultaneously were associated with a median of 210 more (from 185 to 396) exacerbation-free days (60 exacerbations; HR, 0.33; 95% CI, 0.15-0.71; P = .004). No toxic antibiotic levels and few adverse laboratory or clinical events occurred. Models were insensitive to other treatments and pandemic events.

Conclusions: MIC-guided antibiotic dosing prolongs time between pulmonary exacerbations with few adverse events. Reduced exacerbation frequency predicts better survival and may improve quality of life for people with CF.

Background: The success of malaria elimination in sub-Saharan Africa rests largely on the sustained efficacies of the chemointerventions used in malaria treatment and chemoprophylaxis in the highest-burden countries such as Nigeria. Data on the impact of these interventions can guide policy for sustained malaria control toward elimination. We report the complexity of infection (number of genetically distinct same-species parasite strains observed in an infection) and genetic diversity of Plasmodium falciparum in Nigeria and their antimalarial resistance profiles.

Methods: We used targeted amplicon sequencing techniques to analyze 895 P falciparum clinical isolates collected from the 6 geopolitical zones of Nigeria, mostly between 2017 and 2021. Genotypes from 101 single-nucleotide polymorphisms and 36 nonsynonymous amino acid mutations associated with antimalarial drug resistance were used to determine the complexity of infection, the haplotypes of drug resistance genetic markers, genetic diversity, and pairwise relatedness of infections, according to R packages.

Results: Overall, infections were highly complex, with approximately 30% of these having more than a single genetically distinct parasite clone. Furthermore, 55.1% of the parasite isolates carried wild type alleles of the chloroquine transporter gene Pfcrt at codons 74 to 76. Highly related chloroquine-sensitive infections were observed in recent infections in several sites, especially Bauchi. However, the chloroquine-resistant haplotype CVIET persisted in 40.9% of infections, 26.5% of which were monoclonal and 14.4% were mixed. Sulfadoxine-pyrimethamine resistance alleles (codons 51, 59, and 108) at Pfdhfr loci were observed in >50% of infections, while the Pfdhps A437G mutation was detected in 87.3%. Most infections were wild type at Pfkelch13, although 12 nonsynonymous propeller domain mutations were observed.

Conclusions: Chloroquine sensitivity at the molecular level is now dominant in Nigeria, while antifolate resistance persists. Enhanced molecular surveillance of drug resistance-associated loci will serve as an early warning to safeguard the efficacy of chemointerventions in Nigeria.