Open Forum Infectious Diseases最新文献

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: 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.

Background: Bone and joint infections (BJIs) are increasingly reported worldwide, but data on their epidemiology remain limited in tropical settings. We aimed to characterize the causative agents of BJIs and their resistance patterns, in order to inform empirical antibiotic in our tropical setting.

Methods: This 6-year retrospective study included all adults with a first microbiologically confirmed episode of BJI between January 2019 and December 2024 at the Guadeloupe University Hospital, a tertiary care center in the Caribbean.

Results: A total of 312 patients with BJI were included. Among the 449 isolates recovered, Gram-negative bacilli (GNB) were predominant (41%), including AmpC β-lactamase-producing Enterobacterales (13%, 59/449) and Pseudomonas aeruginosa (9%, 39/449). Methicillin-resistant Staphylococcus aureus accounted for 3% (13/449). At least one GNB was identified in 31% of native septic arthritis (27/88), 33% of spondylodiscitis (9/27), 38% of prosthetic joint infections (27/71), 47% of osteosynthesis-associated infections (48/103), and 52% of osteomyelitis (12/23). Factors independently associated with GNB infection were a history of bite/scratch wound, contact with soil/vegetation and lower limb infection. Cefazolin provided limited likelihood of in vitro adequacy against causal pathogens in native septic arthritis episodes (74%, as compared to 92% for both cefepime and piperacillin-tazobactam). Lower rates were observed in cases of osteosynthesis-associated and prosthetic joint infections (48%-68%, as compared to 62%-75% for third-generation cephalosporins, 79%-80% for cefepime and 80%-86% for piperacillin-tazobactam).

Conclusions: Our findings highlight the prominent role of GNBs in tropical BJI and support the implementation of local surveillance systems to guide empirical treatment strategies.

Background: Although failure of rabies postexposure prophylaxis is rare, several factors, including improper vaccine or rabies immunoglobulin administration, may increase the risk. Where there is the potential for postexposure prophylaxis failure, public health units may recommend serology to confirm a therapeutic immune response. This study evaluates which factors increase the risk of failed seroconversion in cases where serology was indicated after rabies postexposure prophylaxis.

Methods: Potential lyssavirus exposure notifications where serology was collected were identified from 5 Southeast Queensland public health units from June 2015 to December 2022. Data on the indication and outcome of serology were extracted from public health case notes. Descriptive analysis was performed comparing serology outcomes by demographic and PEP course characteristics. Modeling for identified risk factors was conducted using hierarchical selection logistic regression analysis.

Results: One hundred eighty-one potential exposures were included in the study. Giving a rabies vaccine in the wrong site (relative risk [RR], 10.8; 95% CI, 2.6-36.4) or a vaccine into the same arm within 72 hours of rabies immunoglobulin (RR, 5.6; 95% CI, 1.9-16.9) increased the risk of nontherapeutic serology after adjusting for age and serology indication. Age ≥65 also increased the risk of nontherapeutic serology after controlling for administration errors (RR, 4.0; 95% CI, 1.3-11.7).

Conclusions: Administering rabies vaccine into an incorrect site or into the same arm within 72 hours of rabies immunoglobulin increases the risk of failed seroconversion. In such cases, we recommend that the risk is sufficient to invalidate the dose and immediately repeat it without serology. Older age may be an independent risk factor for failed seroconversion.