Clinical Development of Therapeutic Agents for Hospitalized Patients With Influenza: Challenges and Innovations.

BACKGROUND: Since 1999, the US Food and Drug Administration approved neuraminidase and endonuclease inhibitors to treat uncomplicated outpatient influenza but not severe hospitalized influenza. After the 2009 pandemic, several influenza hospital-based clinical therapeutic trials were unsuccessful, possibly due to certain study factors. Therefore, in 2014, the US Health and Human Services agencies formed a Working Group (WG) to address related clinical challenges. METHODS: Starting in 2014, the WG obtained retrospective data from failed hospital-based influenza therapeutic trials and nontherapeutic hospital-based influenza studies. These data allowed the WG to identify factors that might improve hospital-based therapeutic trials. These included primary clinical endpoints, increased clinical site enrollment, and appropriate baseline enrollment criteria. RESULTS: During 2018, the WG received retrospective data from a National Institutes of Health hospital-based influenza therapeutic trial that demonstrated time to resolution of respiratory status, which was not a satisfactory primary endpoint. The WG statisticians examined these data and believed that ordinal outcomes might be a more powerful primary endpoint. Johns Hopkins' researchers provided WG data from an emergency-department (ED) triage study to identify patients with confirmed influenza using molecular testing. During the 2013-2014 influenza season, 4 EDs identified 1074 influenza-patients, which suggested that triage testing should increase enrollment by hospital-based clinical trial sites. In 2017, the WG received data from Northwestern Memorial Hospital researchers regarding 703 influenza inpatients over 5 seasons. The WG applied National Early Warning Score (NEWS) at patient baseline to identify appropriate criteria to enroll patients into hospital-based therapeutic trials. CONCLUSIONS: Data received by the WG indicated that hospital-based influenza therapeutic trials could use ordinal outcome analyses, ED triage to identify influenza patients, and NEWS for enrollment criteria.

Case report: Rectal adminstration of ivermectin to a patient with Strongyloides hyperinfection syndrome.

Strongyloides hyperinfection syndrome may be complicated by paralytic ileus that interferes with the absorption of oral anti-helminthics. We report on the administration of ivermectin as a rectal enema preparation to a renal transplant recipient with Strongyloides hyperinfection syndrome and progressive ileus. Attempts at treatment using nasogastric albendazole and ivermectin were unsuccessful despite clamping the nasogastric tube after drug administration. Ivermectin tablets were ground to a powder, resuspended in a commercially available suspending agent, and administered per rectum. The suspending agent was chosen for its near-physiologic osmolality to allow longer retention, in contrast to many enema preparations that have a laxative effect. The patient improved markedly within 72 hours of initiation of the therapy per rectum and recovered fully. Ivermectin administered as an enema may be beneficial in patients with severe strongyloidiasis who are unable to absorb or tolerate oral therapy.

Primary cutaneous fungal infections in solid organ transplantation: a case series.

Cutaneous fungal infections in solid-organ transplant patients present in a variety of nonspecific ways, requiring a high index of suspicion to diagnose correctly. In the present series of four transplant recipients, subsequent primary cutaneous fungal infections presented as papules, plaques, ulcers and subcutaneous nodules. Transplantations included one cardiac, two renal and one renal-pancreatic transplant. Fungal infections were limited to the skin; there was no evidence of disseminated disease in any case. The pathogens isolated were Scedosporium apiospermum (Pseudallescheria boydii), Alternaria species, Aspergillus fumigatus, and a coelomycete in the Coniothyrium-Microsphaeropsis complex of dark molds. Individuals were successfully treated with surgical debridement, antifungal agents, and reduction of immunosuppressive therapy. All patients and allografts survived. Accurate diagnosis, aggressive surgery and appropriate antifungal therapy, combined with close outpatient follow-up, optimize the likelihood of a cure in a transplant population.