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DRUG RECORD

 

FLUOROQUINOLONES

OVERVIEW
Fluoroquinolones

 

The fluoroquinolones are a family of broad spectrum, systemic antibacterial agents that have been used widely as therapy of respiratory and urinary tract infections.  Fluoroquinolones are active against a wide range of aerobic gram-positive and gram-negative organisms.  Gram-positive coverage includes penicillinase- and non-penicillinase producing Staphylococci, Streptococcus pneumoniae and viridans, Enterococcus faecalis, Listeria monocytogenes, and Nocardia species.  Gram negative coverage includes Neisseria meningitides and gonorrhoeae, Haemophilus influenzae, and most clinically important Enterobacteriaceae species, Pseudomonas aeruginosa and Vibrio species.  The fluoroquinolones are believed to act by inhibition of type II DNA toposiomerases (gyrases) that are required for synthesis of bacterial mRNAs (transcription) and DNA replication.  They demonstrate little inhibition of human, host enzymes and have had an excellent safety record.  The fluoroquinolones are indicated for treatment of several bacterial infections, including bacterial bronchitis, pneumonia, sinusitis, urinary tract infections, septicemia and intraabdominal infections, joint and bone infections, soft tissue and skin infections, typhoid fever, bacterial gastroenteritis, urethral and gynecological infections, and pelvic inflammatory disease and several other infectious conditions.

The fluoroquinolones currently available in the United States include ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin.  These agents are well absorbed orally and well tolerated with a low rate of adverse effects.  Several quinolones and fluoroquinolones were introduced, but were subsequently withdrawn after spontaneous reports of severe adverse events including hepatotoxicity:  temafloxacin (1992), gatifloxacin (2006), and trovafloxacin (1999).  The currently available fluoroquinolones appear to cause idiosyncratic liver injury rarely, at an estimated rate of 1:100,000 persons-exposed.  Idiosyncratic liver injury due to fluoroquinolones may be a “class” effect; the pattern of injury is similar, marked by acute and often severe hepatocellular pattern of injury arising within 1 to 4 weeks of starting therapy.  The fluoroquinolones most frequently linked to liver injury are ciprofloxacin and levofloxacin, but these two agents also have been most widely used.  Minor elevations in liver enzymes occur in 1% to 3% of patients receiving ciprofloxacin, norfloxacin or ofloxacin.  Rates with levofloxacin and moxifloxacin are less well defined, but probably similar.  The common side effects of the fluoroquinolones are gastrointestinal disturbances, headaches, skin rash and allergic reactions.  Less common but more severe side effects include QT prolongation, seizures, hallucinations, tendon rupture, angioedema and photosensitivity.

Ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin are discussed separately with individual clinical cases and references.  General references and selected publications on fluoroquinolones no longer in use are given below.

 

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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Ciprofloxacin HCl 86393-32-0 C17-H18-F-N3-O3.Cl-H.H2-O Ciprofloxacin hydrochloride  chemical structure
Gemifloxacin 175463-14-6 C18-H20-F-N5-O4 Gemifloxacin Chemical Structure
Levofloxacin 100986-85-4 C18-H20-F-N3-O4 Levofloxacin  chemical structure
Moxifloxacin HCl 186826-86-8 C21-H24-F-N3-O4.Cl-H Moxifloxacin  chemical structure
Norfloxacin 70458-96-7 C16-H18-F-N3-O3 Norfloxacin  chemical structure
Ofloxacin 82419-36-1 C18-H20-F-N3-O4 Ofloxacin  chemical structure

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REFERENCES
Fluoroquinolones

 

References updated:  25 March 2014

  1. Zimmerman HJ. Quinolones. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999. p. 603.  (Expert review of hepatotoxicity published in 1999; mentions that cinoxacin, nalidixic acid, ciprofloxacin, norfloxacin, enoxacin, and ofloxacin are associated with minor serum enzyme elevations during therapy and with rare instances of clinically apparent liver injury).

  2. Moseley RH. Fluoroquinolones.  Antibacterial and Antifungal Agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd Edition. Amsterdam: Elsevier, 2013. p. 468-9.  (Review of hepatotoxicity of fluoroquinolones mentions that hepatocellular and cholestatic forms of injury have been reported due to the quinolones, including cases of ductopenia, acute liver failure and death).

  3. Petri WA Jr. The quinolones.  Sulfonamides, trimethoprim-sulfamethoxazole, quinolones, and agents for urinary tract infections. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1470-76.  (Textbook of pharmacology and therapeutics).

  4. Halkin H. Adverse effects of the fluoroquinolones. Rev Infect Dis 1988; 10 (Suppl 1): S258-61. PubMed Citation

  5. Wolfson JS, Hooper DC. Overview of fluoroquinolone safety. Am J Med 1991; 91 (Suppl 6A): 153S-61S. PubMed Citation  (Review of side effects reported in 22 clinical trials of fluoroquinolones; elevations in ALT and/or Alk P levels occurred in 1.8-2.7% of patients on cipro-, nor-, or ofloxacin).

  6. Blum MD, Graham DJ, McCloskey CA. Temafloxacin syndrome: review of 95 cases. Clin Infect Dis 1994; 18: 946-50. PubMed Citation  (FDA analysis of 95 cases showing hemolysis occurring within 1-2 weeks of starting temafloxacin, most with LDH elevations, half with AST elevations, many with multisystem disease).

  7. Ball P, Tillotson G. Tolerability of fluoroquinolone antibiotics. Past, present and future. Drug Saf 1995; 13: 343-58. PubMed Citation

  8. http://www.fda.gov/cder/news/trovan/default.htm  (FDA advisory concerning trovafloxacin; despite no hepatic adverse event reports during prelicensure studies, spontaneous reports after licensure were common and included 140 cases of hepatotoxicity which led to its withdrawal in 1999).

  9. Bertino J Jr, Fish D. The safety profile of the fluoroquinolones. Clin Ther 2000; 22: 798-817; discussion 797. PubMed Citation  (Systematic review of side effects of fluoroquinolones; common side effects being gastrointestinal intolerance [1-5%], headaches and dizziness [1-2%], and skin rashes [~2%]; trovafloxacin was associated with hepatotoxicity, which was not seen in clinical trials in 7000 patients before approval in 1997, but since then 150 cases of clinically apparent liver toxicity and at least 14 fatalities have been reported).

  10. Chen HJ, Bloch KJ, Maclean JA. Acute eosinophilic hepatitis from trovafloxacin. N Engl J Med. 2000; 342: 359-60. PubMed Citation  (66 year old man developed fever and eosinophilia with ALT elevations [841 U/L] without jaundice [bilirubin 1.6 mg/dL] after 4 weeks of trovafloxacin therapy, that rapidly resolved with steroid therapy).

  11. Lucena MI, Andrade RJ, Rodrigo L, Salmeron J, Alvarez A, Lopez-Garrdio MJ, Camargo R, et al. Trovafloxacin-induced acute hepatitis. Clin Infect Dis 2000; 30: 400-1. PubMed Citation  (3 men, ages 33 to 68 years, developed liver injury 7 to 14 days after starting trovafloxacin [bilirubin 1.2, 5.1 and 29.5 mg/dL, ALT 1990, 716 and 731 U/L, Alk P 1-2.5 times ULN, eosinophils 6-14%], self-limited in all, resolving within 6-8 weeks of stopping).

  12. Henann NE, Zambie MF. Gatifloxacin-associated acute hepatitis. Pharmacotherapy 2001; 21: 1579-82. PubMed Citation  (44 year old woman developed jaundice after 5 days of gatifloxacin therapy [bilirubin 4.1 rising to 9.4 mg/dL, ALT 669 U/L, Alk P 243 U/L], resolving within 6 weeks of stopping).

  13. Lazarczyk DA, Goldstein NS, Gordon SC. Trovafloxacin hepatotoxicity. Dig Dis Sci 2001; 46: 925-6. PubMed Citation  (19 year old woman developed rash and fever 5 days after starting trovafloxacin followed one week later by ascites and jaundice [bilirubin 1.3 mg/dL, ALT 901 U/L, Alk P 233 U/L], liver biopsy showing centrolobular necrosis, treated with corticosteroids and recovered).

  14. Rubinstein E. History of quinolones and their side effects. Chemotherapy 2001; 47 (Suppl 3): 3-8; discussion 44-8. PubMed Citation  (Between 1985 and 1999, 11 fluoroquinones in clinical development or already in clinical use were withdrawn because of serious side effects, including trovafloxacin which was implicated in at least 140 cases of clinically apparent liver injury).

  15. Coleman CI, Spencer JV, Chung JO, Reddy P. Possible gatifloxacin-induced fulminant hepatic failure. Ann Pharmacother 2002; 36: 1162-7. PubMed Citation  (76 year old man developed jaundice at the end 10 day course of gatifloxacin [bilirubin 5.4 rising to 34.2 mg/dL, ALT 545 U/L, Alk P 110 U/L, INR 1.3 rising to 7], with progressive liver failure and death 25 days later).

  16. Stahlmann R. Clinical toxicological aspects of fluoroquinolones. Toxicol Lett 2002; 127: 269-77. PubMed Citation  (Review of the serious toxicities of the fluoroquinolones, their frequency and possible mechanisms; the hepatotoxicity of trovafloxacin became evident only after appproval and approximately 2.5 milllion prescriptions worldwide, with 140 reported cases of "severe hepatic reactions" despite no serious hepatotoxicity in clinical trials in several thousand patients).

  17. Leone R, Venegoni M, Motola D, et al. Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three Italian regions. Drug Saf 2003; 26: 109-20. PubMed Citation  (Analysis of 432 spontaneous adverse event reports on fluoroquinolones from Italy, 1/3 were serious none of which were liver related).

  18. Cheung O, Chopra K, Yu T, Nalesnik MA, Amin S, Shakil AO. Gatifloxacin-induced hepatotoxicity and acute pancreatitis. Ann Intern Med 2004; 140: 73-4. PubMed Citation  (Two cases of liver injury and mild pancreatitis due to gatifloxacin; 41 year  old woman and 19 year old man developed jaundice and abdominal within 1 week of starting therapy [bilirubin 5.1 and 5.5 mg/dL, ALT 145 and 520 U/L, Alk P 482 and 268 U/L], with elevations in amylase and lipase, resolving slowly and incompletely in the first, and rapidly and completely in the second).

  19. Galan MV, Potts JA, Silverman AL, Gordon SC. The burden of acute nonfulminant drug-induced hepatitis in a United States tertiary referral center [corrected]. J Clin Gastroenterol 2005; 39: 64-7. PubMed Citation  (Ten year experience of 96 patients with acute liver injury, 64 due to viral hepatitis and 32 to drugs; major agents identified being amiodarone, augmentin, minocycline and nitrofurantoin. Trovafloxacin accounted for 1 case which was symptomatic but anicteric, resolving within 6 weeks of stopping).

  20. Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis 2005; 41 (Suppl 2): S144-57. PubMed Citation  (Review of common and rare complications of fluoroquinolones focusing upon QT prolongation, tendon rupture, diabetes, renal injury, and seizures; liver injury discussed in concept of immune related idiosyncratic reactions such as hemolytic anemia, thrombocytopenia, acute interstitial nephritis, Stevens Johnson syndrome, pancreatitis, serum sickness-like syndrome, and eosinophilic meningitis).

  21. Iannini PB. The safety profile of moxifloxacin and other fluoroquinolones in special patient populations. Curr Med Res Opin 2007; 23: 1403-13. Erratum in: Curr Med Res Opin 2007; 23: 2303. Dosage error in text. PubMed Citation  (Review of safety of moxifloxacin and fluoroquinolones in the elderly and patients with liver, kidney, endocrine and cardiovascular disease; no discussion of hepatotoxicity).

  22. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, of which only 1 was attributed to a fluoroquinolone, ciprofloxacin).

  23. Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. PubMed Citation  (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, but no fluoroquinolone was among the top 41 specific causes).

  24. Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. PubMed Citation  (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India, none of which were attributed to a fluoroquinolone).

  25. Orman ES, Conjeevaram HS, Vuppalanchi R, Freston JW, Rochon J, Kleiner DE, Hayashi PH; DILIN Research Group. Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol 2011; 9: 517-523. PubMed Citation  (Among 679 cases of drug induced liver injury presenting between 2004 and 2010 at 8 US medical centers, 12 [1.8%] were attributed to fluoroquinolones including 6 cipro-, 4 moxi-, 1 levo-, and 1 gati-floxacin; average time to onset 4 days [range 1-39], with both hepatocellular and cholestatic enzyme patterns, seven with rash or fever, mortality limited to those with hepatocellular injury and jaundice; hepatic injury appeared to be class specific).

  26. Paterson JM, Mamdani MM, Manno M, Juurlink DN; Canadian Drug Safety and Effectiveness Research Network. Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study. CMAJ 2012; 184: 1565-70. PubMed Citation  (In a population based study using Canadian health care databases, the risk of admission to hospital for acute liver injury was increased for persons who received a prescription for moxifloxacin or levofloxacin relative to clarithromycin, but not for ciprofloxacin).

  27. Hayashi PH, Chalasani NP. Liver injury in the elderly due to fluoroquinolones: should these drugs be avoided? CMAJ 2012; 184: 1555-6. PubMed Citation  (Editorial in response to Paterson [2013] stressing the low absolute risk of liver injury from the fluoroquinolones [4-9 per 100,000 exposures]).

  28. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 114: 1419-25. PubMed Citation  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to a fluoroquinolone).

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OTHER REFERENCE LINKS
Fluoroquinolones
  1. PubMed logoRecent References on Fluoroquinolones

  2. Clinical Trials logoTrials on Fluoroquinolones

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