Hill's Criteria for Causation and the Worldwide Fusarium Keratitis Epidemic of 2004-2006

OBJECTIVE: To identify the exact cause of the worldwide Fusarium keratitis epidemic of 2004-2006, shown previously to be associated with heat and plastic bottles.

METHODS: The epidemic was analyzed with respect to the nine criteria of causation (Temporality, Strength, Dose-Response, Consistency, Plausibility, Alternate Explanations, Experiment, Specificity, and Coherence) proposed by the British epidemiologist, Austin Bradford Hill.

RESULTS: All nine criteria are consistent with the following causation scenario. Bausch & Lomb, the manufacturer of the suspect solution (ReNu with MoistureLoc [RML], containing the antimicrobial agent, alexidine), was cited by the FDA for failure to regulate storage and transport temperatures. Of the multiple container types tested, only the alexidine solution in the RML bottle incubated at 133oF showed fungistatic failure (P=3.72x10-12). Alexidine's anti-Fusarium capability was not neutralized with a phosphate buffered saline solution that had been heated in RML containers, and no leachates were identified by Raman spectroscopy with or without Creighton silver nanoparticles. The alexidine concentration measured by Liquid Chromatography-Mass Spectroscopy in the unheated (vs. heated) solution in RML bottles was 2.3-3.2 times greater. Alexidine deposited into the RML bottle wall at an amount 3.0-3.6 times greater in the heated (vs. unheated) container, measured by Fourier Transform Infrared Spectroscopy.

CONCLUSIONS: When heated, the antimicrobial agent, alexidine, migrates and deposits into the walls of its specific RML plastic bottle, thereby diminishing its concentration within the solution, allowing Fusarium (and other microbial) growth. This phenomenon appears to be a new mechanism of pharmaceutical failure and is consistent with Hill's nine criteria for causation.