Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: A collaborative investigation by scientists and members of a social network

Kamaljeet Kaur, Raja Fayad, Arpit Saxena, Norma Frizzell, Anindya Chanda, Suvarthi Das, Saurabh Chatterjee, Shweta Hegde, Manjeshwar Shrinath Baliga, Venkatesh Ponemone, Matthew Rorro, Jennifer Greene, Yasmine Elraheb, Alan J. Redd, John Bian, John Restaino, Leann B. Norris, Zaina P. Qureshi, Bryan L. Love, Brandon BookstaverPeter Georgantopoulos, Oliver Sartor, Dennis W. Raisch, Gowtham Rao, Kevin Lu, Paul Ray, William Hrusheshky, Richard Schulz, Richard Ablin, Virginia Noxon, Charles L. Bennett

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Background The 3 fuoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identifed through novel collaborations between FQtreated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. Objective To conduct basic science and clinical investigations of a newly identifed adverse drug reaction, termed FQassociated disability. Methods 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDAapproved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. Results Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identifed disability syndrome termed "FQ-associated disability" (FQAD). Limitations Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. Conclusion Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised. Funding This work was funded partly by the National Cancer Institute (1R01CA165609-01A1), the American Cancer Society (IRG-13-043-01), the South Carolina SmartState Program, and an unrestricted from Doris Levkoff Meddin to the South Carolina College of Pharmacy Center for Medication Safety and Effcacy.

Original languageEnglish (US)
Pages (from-to)54-65
Number of pages12
JournalJournal of Community and Supportive Oncology
Volume14
Issue number2
DOIs
StatePublished - Feb 2016

ASJC Scopus subject areas

  • Hematology
  • Oncology

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