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BackgroundInvasive fungal diseases (IFD) caused by Cryptococcus and dimorphic fungi are associated with significant morbidity and mortality. Isavuconazole (ISAV) is a novel, broad-spectrum, triazole antifungal agent (IV and by mouth [PO]) developed for the treatment of IFD. It displays potent activity in vitro against these pathogens and in this report we examine outcomes of patients with cryptococcosis or dimorphic fungal infections treated with ISAV.MethodsThe VITAL study was an open-label nonrandomized phase 3 trial conducted to evaluate the efficacy and safety of ISAV treatment in management of rare IFD. Patients received ISAV 200 mg 3 times daily for 2 days followed by 200 mg once-daily (IV or PO). Proven IFD and overall response at end of treatment (EOT) were determined by an independent, data-review committee. Mortality and safety were also assessed.ResultsThirty-eight patients received ISAV for IFD caused by Cryptococcus spp. (n = 9), Paracoccidioides spp. (n = 10), Coccidioides spp. (n = 9), Histoplasma spp. (n = 7) and Blastomyces spp. (n = 3). The median length of therapy was 180 days (range 2-331 days). At EOT 24/38 (63%) patients exhibited a successful overall response. Furthermore, 8 of 38 (21%) had stable IFD at the end of therapy without progression of disease, and 6 (16%) patients had progressive IFD despite this antifungal therapy. Thirty-three (87%) patients experienced adverse events.ConclusionsISAV was well tolerated and demonstrated clinical activity against these endemic fungi with a safety profile similar to that observed in larger studies, validating its broad-spectrum in vitro activity and suggesting it may be a valuable alternative to currently available agents.Clinical trials registrationNCT00634049.

Background Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc. Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. Methods Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3–6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. Results A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90. Conclusions V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration.  clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11. [ABSTRACT FROM AUTHOR]

Mucormycosis is a life-threatening infection. This is the first report of transdiaphragmatic mucormycosis in a series of 3 patients. We observed this phenomenon in 11% of patients. Clinicians should be aware of this possibly underreported entity, and as a consequence we envision more comprehensive imaging studies in patients with mucormycosis. [ABSTRACT FROM AUTHOR]

In a pooled analysis of data from 2 large, randomized, controlled trials of patients with Clostridium difficile infection, the toxin-binding polymer tolevamer was inferior to both metronidazole and vancomycin with regard to clinical success, and metronidazole was inferior to vancomycin.Background. Clostridium difficile infection (CDI) is a common complication of antibiotic therapy that is treated with antibiotics, contributing to ongoing disruption of the colonic microbiota and CDI recurrence. Two multinational trials were conducted to compare the efficacy of tolevamer, a nonantibiotic, toxin-binding polymer, with vancomycin and metronidazole.Methods. Patients with CDI were randomly assigned in a 2:1:1 ratio to oral tolevamer 9 g (loading dose) followed by 3 g every 8 hours for 14 days, vancomycin 125 mg every 6 hours for 10 days, or metronidazole 375 mg every 6 hours for 10 days. The primary endpoint was clinical success, defined as resolution of diarrhea and absence of severe abdominal discomfort for more than 2 consecutive days including day 10.Results. In a pooled analysis, 563 patients received tolevamer, 289 received metronidazole, and 266 received vancomycin. Clinical success of tolevamer was inferior to both metronidazole and vancomycin (P < .001), and metronidazole was inferior to vancomycin (P = .02; 44.2% [n = 534], 72.7% [n = 278], and 81.1% [n = 259], respectively). Clinical success in patients with severe CDI who received metronidazole was 66.3% compared with vancomycin, which was 78.5%. (P = .059). A post-hoc multivariate analysis that excluded tolevamer found 3 factors that were strongly associated with clinical success: vancomycin treatment, treatment-naive status, and mild or moderate CDI severity. Adverse events were similar among the treatment groups.Conclusions. Tolevamer was inferior to antibiotic treatment of CDI, and metronidazole was inferior to vancomycin.Trial Registration. clinicaltrials.gov NCT00106509 and NCT00196794. [ABSTRACT FROM PUBLISHER]

A response by O.A. Cornely to a letter to the editor about his article about the randomized study of invasive aspergillosis (IA) is presented.

The authors examine a study by S. B. Gupta and colleagues, published within the issue which reported on predictors of recurrence of Clostridium difficile infection (CDI) in the 99 placebo-treated patients. They discuss the risk CDI, the predictors identified by the researchers, and factors that are likely to become part of a future integrated score predicting recurrence. Structural hurdles that may affect the successful improvement of patient care are also mentioned.

A reply by O. A. Cornely and colleagues to a letter to the editor about their article "Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing" in the 2007 issue is presented.