Background. Histoplasmosis may complicate tumor necrosis factor (TNF)–α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for ...long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. Methods. We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. Results. The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio OR, 3.94 95% confidence interval {CI}, 1.06–14.60) and higher urine Histoplasma antigen levels (OR, 1.14 95% CI, 1.03–1.25) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1–69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. Conclusions. In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months.
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention and management of blastomycosis, ...histoplasmosis, and coccidioidomycosis in the pre‐ and post‐transplant period. Though each of these endemic fungal infections has unique epidemiology and clinical manifestations, they all share a predilection for primary pulmonary infection and may cause disseminated infection, particularly in immunocompromised hosts. Culture remains the gold standard for definitive diagnosis, but more rapid diagnosis may be achieved with direct visualization of organisms from clinical specimens and antigen‐based enzyme immunoassay assays. Serology is of limited utility in transplant recipients. The mainstay of treatment for severe infections remains liposomal amphotericin followed by a step‐down azole therapy. Cases of mild to moderate severity with no CNS involvement may be treated with azole therapy alone. The newer generation azoles provide additional treatment options, but supported currently with limited clinical efficacy data. Azole therapy in transplant recipients presents a unique challenge owing to the drug‐drug interactions with immunosuppressant agents. Therapeutic drug monitoring of azole levels is an essential component of effective and safe therapy. Infection prevention centers around minimizing epidemiological exposures, early clinical recognition, and azole prophylaxis in selected individuals.
We report a case of human herpesvirus‐6 (HHV‐6) encephalitis in a neutropenic patient who had undergone chemotherapy induction for acute myelogenous leukemia while on broad‐spectrum antimicrobial ...therapy. The patient displayed symptoms of confusion, amnesia, and lethargy. Diagnosis was made via polymerase chain reaction analysis of cerebrospinal fluid. Electroencephalogram and magnetic resonance imaging of the brain were unremarkable. Following diagnosis, the patient was successfully treated with ganciclovir. HHV‐6 encephalitis should be considered in immunocompromised patients who become encephalopathic.
To our knowledge, an institutional review of systemic histoplasmosis has not been conducted in the United States since the major outbreaks in Indianapolis in 1978-4982. We conducted a retrospective ...review of all patients with systemic histoplasmosis diagnosed at Mayo Clinic over a 15-year period. The case definitions employed were based on an international consensus statement by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG). One hundred eleven patients with systemic histoplasmosis were identified between January 1, 1991, and December 31, 2005. Of these, 78 patients had disseminated histoplasmosis and 55 patients had Histoplasma capsulatum fungemia. The mean age of patients was 55 years, 66% were male, and 98% were white. Fifty-nine percent of patients were immunocompromised. Fever was the most frequently reported symptom (63%), followed by respiratory complaints (43%) and weight loss (37%). The peripheral white blood cell count was <3000 cells/mm in 28%, hemoglobin was <10 g/dL in 29%, and platelet count was <150,000 cells/mm in 41% of patients. Liver enzymes were elevated (alanine aminotransferase >60 U/L in 39%, aspartate aminotransferase >60 U/L in 27%), alkaline phosphatase was >200 U/L in 55%, and albumin was <3.5 g/dL in 70%. Serologic and histopathologic examinations were each positive in 75% of cases, Histoplasma urine antigen screening was positive in 80%, and H. capsulatum was culture positive in 84%. Forty-seven percent of patients were sequentially treated with an amphotericin B-containing product followed by itraconazole, 31% received itraconazole alone, and 7% received an amphotericin B-containing product only. Another 13% of patients did not receive antifungal treatment, and the remaining 2% did not have treatment data available. Sixty percent of patients required hospitalization, and in hospital mortality was 6% with a median survival time of 61 days. The relapse rate was 9%, with a median relapse-free survival of 857 days. Systemic histoplasmosis should be suspected in patients who have lived in endemic areas with fever, bone marrow suppression, and elevated hepatic enzymes, particularly if they are immunocompromised. Evaluation including a combination of Histoplasma serologic screening, urine antigen assay, and fungal culture will secure the diagnosis in most cases.
Gastrointestinal histoplasmosis is common in patients with disseminated disease affecting both immunocompetent and immunocompromised patients. However, it is often unrecognized due to a lack of ...specific signs and symptoms. It has only rarely been reported to cause small bowel obstruction, during which surgical treatment was nearly always necessary. Little is known about the usefulness of endoscopic therapy in gastrointestinal histoplasmosis associated strictures. We report the case of a 32-year-old man with a history of hyperimmunoglobulin M syndrome who presented with small bowel obstruction secondary to disseminated gastrointestinal histoplasmosis. Treatment was successful with a through-the-scope balloon dilator in combination with medical therapy. This report adds to the limited data available on the benefit of endoscopic therapy in infectious strictures, particularly gastrointestinal histoplasmosis.
Background
Recurrent
Clostridioides difficile
infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of ...a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent
C. difficile
infection.
Methods
A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more
C. difficile
infection recurrences with a positive stool assay for
C. difficile
and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of
C. difficile
infection diarrhea within 8 weeks of study treatment.
Results
Of the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment (
n
= 180, RBX2660;
n
= 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events.
Conclusions
RBX2660 is a safe and effective treatment to reduce recurrent
C. difficile
infection following standard-of-care antibiotics with a sustained response through 6 months.
Clinical Trial Registration
NCT03244644; 9 August, 2017.
Infographic
AKN5i_vZYNJMF_jRRaL_sV
Video abstract:
(MP4 62,291 KB)
Plain Language Summary
Clostridioides difficile
is a diarrhea-causing bacterium that is associated with potentially serious and fatal consequences. Antibiotics used to treat or prevent infections have a side effect of damaging the healthy protective gut bacteria (microbiota). Damage to the gut microbiota can allow
C. difficile
to over-grow and produce toxins that injure the colon. Paradoxically, the standard of care treatment of
C. difficile
infection (CDI) is antibiotics. Although initially effective for the control of diarrhea, antibiotics can leave a patient at risk for CDI recurrence after antibiotic treatment is stopped. Live biotherapeutic products are microbiota-based treatments used to repair the gut microbiota. These products have been shown to reduce the recurrence of CDI. RBX2660 is an investigational microbiota-based live biotherapeutic. RBX2660 contains a diverse set of microorganisms. RBX2660 has been developed to reduce CDI recurrence in adults following antibiotic treatment for recurrent CDI. This study was conducted to demonstrate that RBX2660 is effective and safe in treating patients with recurrent CDI. Treatment was considered successful in participants who did not experience CDI recurrence within 8 weeks after administration. Overall, statistical modeling demonstrated that 70.6% of participants treated with RBX2660 and 57.5% of participants treated with placebo remained free of CDI recurrence through 8 weeks. A 13.1 percentage point increase in treatment success was observed with RBX2660 treatment compared with placebo. In participants who achieved treatment success at 8 weeks, more than 90% remained free of CDI recurrence through 6 months. The most common side effects with RBX2660 treatment were abdominal pain and diarrhea. No serious treatment-related side effects were reported. The current data from the comprehensive clinical development program support a positive benefit-risk profile for RBX2660 in the reduction of CDI recurrence in adults following antibiotic therapy for recurrent CDI.
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