August 13, 2012 — Moxifloxacin and levofloxacin may increase the risk for acute liver injury for older outpatients, according to results from a case-control study by J. Michael Paterson, MSC, from the Institute for Clinical Evaluative Sciences, in Toronto; the Department of Health Policy, Management, and Evaluation of the University of Toronto, Ontario; and the Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada; and colleagues. The researchers report their findings in a study published online August 13 in the Canadian Medical Association Journal.
Members of the popular fluoroquinolone class have received heightened scrutiny lately because of concerns related to drug safety. "Fluoroquinolones are among the most widely prescribed antibiotic agents in North America," write the researchers, and prescriptions continue to rise for broad-spectrum versions, such as levofloxacin and moxifloxacin.
As the use of these antibiotics has risen, unpredictable adverse effects have emerged including hemolysis, renal failure, hepatotoxicity, QT interval prolongation, and other serious events that have led to the market removal of some of the antibiotics in this class (eg, temafloxacin, grepafloxacin, trovafloxacin, and most recently, gatifloxacin), the authors report. The European Medicines Agency has raised concerns about potential hepatotoxicity for moxifloxacin, and Health Canada has issued a warning about the risk for moxifloxacin-associated liver injury.
Still, few epidemiologic studies have been published about the safety of fluoroquinolones. To that end, Paterson and coauthors conducted a population-based, nested, case-control study to investigate the relationship between taking fluoroquinolones and subsequent hospitalization for acute hepatotoxicity.
Within the administrative records of more than 1.5 million older residents of Ontario, the authors focused on a cohort of patients aged 66 years or older with no history of liver disease who had received broad-spectrum antibiotic agents. The researchers scoured the Ontario Drug Benefit Database, which lists outpatient prescription medicines dispensed to Ontario residents aged 65 years and older. They also relied on the Canadian Institute for Health Information Discharge Abstract Database, which provides diagnostic and procedural information for all admissions to acute care hospitals in Ontario, to identify hospital visits for acute liver injury from April 2002 to March 2011.
The researchers' analysis was limited to patients who had been admitted within 30 days of receiving a prescription for 1 of 5 commonly used antibiotics: clarithromycin, cefuroxime, moxifloxacin, levofloxacin, or ciprofloxacin. They excluded a number of patients, including those in their first year of eligibility for prescription drug insurance, to avoid incomplete medication records, as well as patients with any hospital admission, physician service claim, or procedure related to liver disease in the preceding 5 years, to ensure their analysis was limited to patients with no history of liver disease.
The authors retained 144 patients of the 746 patients they identified during the study, and matched (for age and sex) these 144 patients with 1409 control patients who had received 1 of the 5 antibiotics but were not admitted to the hospital for acute liver injury. The mean age was 77.4 years for patients in the case group and 77.0 for control patients;, 47.2% of case patients and 47.9% of control patients were women. For those in the case group, the median time from dispensing the antibiotic to hospital admission for acute liver injury was 9 days and median hospital length of stay was 8 days. Eighty-eight of the patients with liver injury, or 61.1%, died during their index hospital admission.
"In total, about 2.86 million courses of antibiotic therapy were associated with 172 admissions to hospital for acute liver injury (some of the 144 cases were admitted more than once), or about 6 admissions per 100 000 exposures," Paterson and colleagues write.
"Compared with clarithromycin, moxifloxacin was associated with a more than 2-fold increased risk of admission to hospital for acute liver injury (adjusted [odds ratio (OR)] 2.20, 95% [confidence interval (CI)] 1.21 - 3.98) [P = .009]. Levofloxacin was associated with a statistically significant but lower risk of hepatotoxicity than we saw with moxifloxacin (adjusted OR 1.85, 95% CI 1.01–3.39) [P = .046]," the authors write. Adjustments were made for potential confounding variables including alcohol use, household income, number of prescription drugs received in the preceding year, number of outpatient visits to a physician in the preceding year, diabetes mellitus, and receipt of hepatotoxic drugs in the 90 days before admission.
Patients Who Need Antibiotics May Be Prone to Drug Toxicity
"This is not an unexpected finding from 2 perspectives. Of drugs that cause liver injury, antibiotics are, by far, the most common. That raises a very interesting question as to why," Adrian Reuben MBBS, FRCP, chief of the Liver Service, Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, told Medscape Medical News.
Dr. Reuben said patients who require an antibiotic may, in some way, be more susceptible to drug toxicity, or the finding could be a result of the propensity of the fluoroquinolone family of drugs to cause injury with different family members injuring different organs. "This is all plausible," he noted.
Still, the research team's reliance on correlations between various large databases "does beg the question of this being very much circumstantial evidence," Dr. Reuben said. A study of exposure and toxicity, in contrast, would provide the opportunity "to drill down" and find out more about individual circumstances, he said. "It's a very useful pointer to what we need to look at, but it's far from being definitive."
The authors acknowledge that study limitations included their use of administrative data, which lack information about liver function, actual medication consumption, use of over-the-counter medicines, or cause of death. In addition, hospital admission records would exclude less severe instances of liver injury that were treated in the emergency room or other healthcare settings, potentially understating the clinical implications. Finally, the experiences of patients aged 66 years and older may not reflect those of younger patients.
Are Warnings Warranted?
"Although our results require confirmation in other settings, they suggest that both moxifloxacin and levofloxacin be considered for regulatory warnings regarding acute liver injury," the authors conclude.
An accompanying commentary, however, cautions clinicians against choosing 1 antibiotic over another until the study observations are independently validated, in part because of the very low absolute risk for liver injury for any of the antibiotics studied.
"[T]he choice between these antibiotics remains a matter of clinical need rather than hedging the risk of toxicity. In other words, one should still choose the antibiotic most likely to cover the infection and worry less about the liver," write Paul H. Hayashi, MD, from the Division of Gastroenterology at the University of North Carolina School of Medicine in Chapel Hill, and Naga P. Chalasani, MD, from the Division of Gastroenterology and Hepatology at Indiana University School of Medicine in Indianapolis.
The Canadian Institutes of Health Research supported this study. One of the study authors has served on advisory boards or as a consultant for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Novo Nordisk, and Pfizer. Dr. Chalasani is a consultant for Aegerion, Eli Lilly, GlaxoSmithKline, Merck, Mochida, Salix, Sanofi, and Vertex and has received grants from the National Institutes of Health, Cumberland, Eli Lilly, Genfit, Intercept, and Takeda. Dr. Hayashi and Dr. Reuben have disclosed no relevant financial relationships.
CMAJ. Published online August 13, 2012. Full text
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