Fluoroquinolone antibiotics have been known to cause severe, multisystem adverse side effects, termed fluoroquinolone toxicity (FQT). This toxicity syndrome can present with adverse effects that vary from individual to individual, including effects on the musculoskeletal and nervous systems, among others. The mechanism behind FQT in mammals is not known, although various possibilities have been investigated. Among the hypothesized FQT mechanisms, those that could potentially explain multisystem toxicity include off-target mammalian topoisomerase interactions, increased production of reactive oxygen species, oxidative stress, and oxidative damage, as well as metal chelating properties of FQs. This review presents relevant information on fluoroquinolone antibiotics and FQT and explores the mechanisms that have been proposed. A fluoroquinolone-induced increase in reactive oxygen species and subsequent oxidative stress and damage presents the strongest evidence to explain this multisystem toxicity syndrome. Understanding the mechanism of FQT in mammals is important to aid in the prevention and treatment of this condition.
Methods: Using archival death certificates from 1954 to 1961, this study quantified the age-specific seasonal patterns, excess-mortality rates, and transmissibility patterns of the 1957 pandemic in Maricopa County, Arizona. By applying cyclical Serfling linear regression models to weekly mortality rates, the excess-mortality rates due to respiratory and all-causes were estimated for each age group during the pandemic period. The reproduction number was quantified from weekly data using a simple growth rate method and generation intervals of 3 and 4 days. Local newspaper articles from The Arizona Republic were analyzed from 1957-1958.
Results: Excess-mortality rates varied between waves, age groups, and causes of death, but overall remained low. From October 1959-June 1960, the most severe wave of the pandemic, the absolute excess-mortality rate based on respiratory deaths per 10,000 population was 17.85 in the elderly (≥65 years). All other age groups had extremely low excess-mortality and the typical U-shaped age-pattern was absent. However, relative risk was greatest (3.61) among children and young adolescents (5-14 years) from October 1957-March 1958, based on incidence rates of respiratory deaths. Transmissibility was greatest during the same 1957-1958 period, when the mean reproduction number was 1.08-1.11, assuming 3 or 4 day generation intervals and exponential or fixed distributions.
Conclusions: Maricopa County largely avoided pandemic influenza from 1957-1961. Understanding this historical pandemic and the absence of high excess-mortality rates and transmissibility in Maricopa County may help public health officials prepare for and mitigate future outbreaks of influenza.