Coccidioidomycosis in Oklahoma: A retrospective case series.

BACKGROUND: Coccidioidomycosis is a systemic fungal disease endemic to arid regions of the Western Hemisphere. In the south-western US, Coccidioides spp. may account for up to 20%-25% of all cases of community acquired pneumonia. Clinical manifestations vary widely, from asymptomatic infection to life-threatening disease, especially in immunocompromised hosts. OBJECTIVES: The primary objective of the study was to characterise cases of coccidioidomycosis in an area of the United States not considered traditionally endemic for the disease. METHODS: We performed a single-centre retrospective study of all cases of coccidioidomycosis from 1 January 2000 to 31 December 2020, in the University of Oklahoma Health Sciences Medical Center. RESULTS: A total of 26 patients were included for analysis. The central nervous system (CNS) and the lungs were the sites most frequently involved. Twenty (77%) had travelled to a coccidioidomycosis endemic region. Most were male (81%) with a median age of 42 years (range: 3-78 years). The majority (46%) were Caucasians, 19% were African American, 19% Hispanic, and 12% Native American. The most common comorbidities were diabetes mellitus and acquired immunodeficiency syndrome, identified in 27% and 23% of patients, respectively. Patients on immunosuppressive therapy accounted for 12% of all cases. CONCLUSION: Our study is one of the largest single-centre case series of coccidioidomycosis from a non-endemic area. Diabetes mellitus was the most frequent comorbidity. Compared to other case series of coccidioidomycosis, our patient population had higher rates of immunosuppression and had both a higher rate of disseminated disease and overall mortality.

Antivirals With Activity Against Mpox: A Clinically Oriented Review.

Mpox virus is an emergent human pathogen. While it is less lethal than smallpox, it can still cause significant morbidity and mortality. In this review, we explore 3 antiviral agents with activity against mpox and other orthopoxviruses: cidofovir, brincidofovir, and tecovirimat. Cidofovir, and its prodrug brincidofovir, are inhibitors of DNA replication with a broad spectrum of activity against multiple families of double-stranded DNA viruses. Tecovirimat has more specific activity against orthopoxviruses and inhibits the formation of the extracellular enveloped virus necessary for cell-to-cell transmission. For each agent, we review basic pharmacology, data from animal models, and reported experience in human patients.

The diagnostic dilemma for atypical presentation of progressive human Mpox.

BACKGROUND: Human mpox has increasingly been reported worldwide since May 2022, with higher incidence in men who have sex with men (MSM) and persons living with HIV (PLHIV) with presentation typical for generalized macules and papules. CASE PRESENTATION: We are describing a case of human mpox, which presented as widespread, atypical round verrucous lesions that went undiagnosed in the community for six months and was treated with antibacterials and antifungals given the similarity to skin manifestations associated with endemic mycoses. CONCLUSIONS: Suspicion for human mpox should be high in young MSM and PLHIV who present with rash and mpox should be ruled out earlier.

Population Pharmacokinetics of Intraperitoneal Gentamicin and the Impact of Varying Dwell Times on Pharmacodynamic Target Attainment in Patients with Acute Peritonitis Undergoing Peritoneal Dialysis.

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data were obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio > 10) and toxicity (plasma area under the concentration-time curve [AUC] < 120 mg·h/L) was determined for 0.3- to 1.2-mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 h and for the duration of a 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility breakpoint of 4 mg/L, only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. The probability of achieving exposure below the threshold of 120 mg·h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2-mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical breakpoint of 4 mg/L is likely to produce early toxic levels of exposure that are expected to be detrimental to the renal system.

Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era.

BACKGROUND: Cytomegalovirus (CMV) reactivation is one of the most common infectious complications after allogeneic hematopoietic cell transplant (HCT) and may result in significant morbidity and mortality. Primary prophylaxis with letermovir demonstrated a reduction in clinically significant CMV infections (CS-CMVi) in clinical trials of CMV-seropositive HCT recipients. This study aims at exploring the effect of primary letermovir prophylaxis in this population on the incidence and outcomes of refractory or resistant CMV infections. METHODS: This is a single-center, retrospective cohort study of 537 consecutive CMV-seropositive allogeneic HCT recipients cared for between March 2016 and October 2018. Baseline demographics, HCT characteristics, CMV infections, treatment, and mortality data were collected from the electronic medical record. CMV outcomes were defined according to the recently standardized definitions for clinical trials. Characteristics and outcomes were assessed according to receipt of primary letermovir prophylaxis. RESULTS: Of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days after HCT; 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio [HR] 0.26; 95% confidence interval [CI], 0.16-0.41), CMV end-organ disease (HR 0.23; 95% CI, 0.10-0.52), refractory or resistant CMV infection (HR 0.15; 95% CI, 0.04-0.52), and nonrelapse mortality at week 48 (HR 0.55; 95% CI, 0.32-0.93). There was neither resistant CMV nor CMV-related mortality in the primary letermovir prophylaxis group. CONCLUSIONS: Primary letermovir prophylaxis effectively prevents refractory or resistant CMV infections and decreases nonrelapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT.

Immune reconstitution and severity of COVID-19 among hematopoietic cell transplant recipients.

Severe acute respiratory syndrome coronavirus 2 can lead to life-threatening coronavirus disease 2019 (COVID-19) infections in patients with hematologic malignancies, particularly among hematopoietic cell transplant (HCT) recipients. We describe two patients with COVID-19 during the pre-engraftment period after HCT and review previous reports of COVID-19 in HCT recipients. Because of significant mortality from COVID-19, primarily after allogeneic HCT, early, preemptive, and optimal directed therapy may improve outcomes and reduce the mortality rate but still needs to be established in clinical trials.

Outcomes associated with the use of a revised risk assessment strategy to predict antibiotic resistance in community-onset pneumonia: a stewardship perspective.

Objectives: There is growing evidence that patients with community-onset pneumonia and recent healthcare exposure are not at equally high risk of infection with MDR organisms. An individualized approach is necessary with regard to risk assessment and choice of antibiotics. Methods: We reviewed the records of 102 patients admitted for community-onset pneumonia, before and after the implementation of a revised risk assessment programme for MDR organisms using the drug resistance in pneumonia (DRIP) score. The primary aim of the study was to identify the effects of this intervention on antibiotic days of therapy (DOT), and secondary outcomes included all-cause readmissions and time to clinical improvement. Statistical analysis was performed using generalized linear regression and Cox hazards models. Results: Implementation of the programme resulted in a decrease in anti-MRSA (-1.44 DOT, P = 0.007) and anti-pseudomonal (-2.03 DOT, P < 0.001) antibiotic utilization, but was not associated with a significant difference in the odds of readmissions (OR 0.64, 95% CI 0.16-2.57) or in time to clinical improvement (HR 1.19, 95% CI 0.62-2.21). Conclusions: An individualized MDR organism risk assessment strategy using a clinical prediction score for community-onset pneumonia can decrease the utilization of broad-spectrum antibiotics without an increase in adverse outcomes.

Ceftaroline in CNS and ocular infections: a case series.

Background: There are limited data describing outcomes of patients treated with ceftaroline for infections with CNS or ocular involvement. Objectives: To describe outcomes of patients treated with ceftaroline for methicillin-resistant staphylococcal infections involving the CNS or eye. Patients and methods: This was a retrospective review of 10 patients at an academic medical centre who received ceftaroline for CNS or ocular infections. Results: All patients were treated with ceftaroline as part of a combination for salvage therapy. Four patients died, whereas six patients experienced clinical cure. Only one experienced microbiological recurrence. Conclusions: These preliminary data suggest that ceftaroline may be an option for salvage therapy of severe staphylococcal infections when used in combination.

Advances and Prospect in Herpesviruses infections after Hematopoietic Cell Transplantation: Closer to the Finish Line?

BACKGROUND: Herpesviruses represent common and significant infectious complications after allogeneic hematopoietic cell transplantation (HCT). In the last decade, major advances in the prevention and treatment of these infections were accomplished. OBJECTIVES: The aim of this paper is to review the recent advances in the prophylaxis and treatment of herpesvirus infections after allogeneic HCT, to assess the persisting challenges, and to offer future directions for prevention and management of these infections. SOURCES: We searched PubMed for relevant literature regarding specific herpesviruses complicating allogeneic HCT through March 2024. CONTENT: The largest advances in this past decade were witnessed for cytomegalovirus (CMV) with the advent of letermovir for primary prophylaxis and the development of maribavir as an option for refractory and/or resistant CMV infections in transplant recipients. For Varicella Zoster Virus, prevention of reactivation with the recombinant zoster vaccine offers an additional prophylactic intervention. Pritelivir is being explored for treatment of drug resistant or refractory Herpes Simplex Virus infections. While rituximab is now an established option for preemptive therapy for Epstein Barr Virus, HHV-6 remains the most elusive virus of the herpesvirus family, with lack of evidence supporting benefit of any agent for prophylaxis or for optimal preemptive therapy. IMPLICATIONS: While considerable advances have been achieved for the treatment and prevention of herpes virus infections, most notably with CMV, the coming years should hold additional opportunities to tame the beast in these herpesviruses post allogeneic HCT, with the advent of new antivirals, cell-mediated immunity testing, and cytotoxic T lymphocytes infusions.

CNS Aspergillosis and Cryptococcosis with Cytomegalovirus Pneumonia in a Patient with Chronic Lymphocytic Leukemia Treated with Acalabrutinib.

Bruton's tyrosine kinase inhibitors (BTKis) are the preferred treatment for chronic lymphocytic leukemia (CLL). Despite their therapeutic benefits, these targeted agents have been associated with an increased risk of invasive infections. We describe a 68-year-old male who developed multiple bacterial, fungal and viral infections while on treatment with acalabrutinib. To our knowledge, this is the first reported case of concomitant CNS infections with Cryptococcus neoformans and Aspergillus fumigatus, along with cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) pneumonia while on acalabrutinib. This case adds to the scarce literature of fungal and bacterial infections associated with acalabrutinib, raising the suspicion that infection risk is a medication class effect for BTKis.

Mortality in recipients of allogeneic haematopoietic cell transplantation in the era of cytomegalovirus primary prophylaxis: a single-centre retrospective experience.

OBJECTIVES: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. METHODS: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D-/R- group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. RESULTS: The analysis included 1071 consecutive allo-HCT recipients: 131 D-/R-, 557 R+/LTV-, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D-/R- group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV- and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV-, R+/LTV+, and D-/R- groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12-2.99, p 0.017) for R+/LTV- compared with D-/R- and 1.05 (95% CI 0.62-1.77, p 0.85) for R+/LTV + compared with D-/R-. DISCUSSION: CMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis.