The Immunostimulatory Effects of Gentamicin

Overview

Gentamicin is one of the few aminoglycoside antibiotics which are approved for parenteral use in Singapore. As with other aminoglycosides, gentamicin is primarily bactericidal against Gram-negative organisms. It is well known that viral infection increases susceptibility to bacterial infection; increased rates of Gram-negative bacterial sepsis due to gastrointestinal tract bacterial translocation have been reported in Ebola and dengue patients. Gentamicin use in viral infection could thus improve clinical outcome by inhibiting both viral and opportunistic Gram-negative bacterial infection. Parenteral aminoglycosides do not cause perturbations or dysbiosis within the human gut microbiome. This is of importance as dysbiosis would not only increase the risk of antibiotic-resistant bacteria selection within the intestinal tract, it could also lead to negative downstream effects on the host response to infection by altering activation states of both innate and adaptive immunity. Thus, parenteral gentamicin may offer a unique approach to preventing both viral and downstream secondary Gram-negative bacterial infection, while at the same time minimizing the potential development of antibiotic resistance. The overarching goal of this study is to demonstrate that parenteral aminoglycosides exert broad-spectrum antiviral effects against RNA viruses in humans through their immunostimulatory properties. Using the live attenuated yellow fever (YF17D; stamaril) vaccine as an experimental viral infection model, a placebo controlled clinical trial will be carried out to demonstrate the efficacy of parenteral gentamicin in preventing viremia.

Informed written consent will be sought from subjects who fulfil criteria for enrolment. All consented subjects will undergo screening, which includes physical examination, full blood count, liver function test, serum creatinine, and urinary pregnancy test (for female subjects of child-bearing potential). All eligible subjects will proceed to Day 0, where they will undergo randomization to receive either IV gentamicin at a dose of 5 mg/kg or 0.9% normal saline placebo, followed by YF17D vaccination 30 minutes later i.e. 30 minutes after completion of gentamicin/placebo infusion. Urine pregnancy test (for female subjects of child-bearing potential) will be performed prior to study drug administration. Baseline physical examination and vital signs will be done as well. On Day 0, research blood sampling will be performed prior to gentamicin/placebo administration. Subsequently, study subjects will return for follow-up visits on D1, D4, D6, D14 and D30. Research blood samples will be taken at each visit. Physical examination, vital signs, and review of adverse events will be done at each of the visit as well. At any time post-study drug or YF17D administration, subjects will be trained to observe for systemic AEs. A diary will also be given to the subjects to record such events should they occur during this period. Should they develop systemic symptoms that require intervention, they will report to the study site for medical evaluation and receive the appropriate therapy. Duration of symptoms will be recorded. Any concomitant medication use during this period will also be recorded. During the study, full history taking and physical examination will be performed at both scheduled and unscheduled visits. The Common Terminology Criteria for Adverse Events (CTCAE), routinely employed in clinical trials, will be used to define AE terminology and severity. Management of AEs is at the discretion of the study team PI and co-Is, guided by severity and clinical indication for intervention. All medication prescribed for the management of AEs will be documented in the medication/concomitant medication clinical record form.