Peripheral Neuropathy in a Patient Taking Ciprofloxacin

Case in Point Peripheral Neuropathy in a Patient Taking Ciprofloxacin

Norak P. Chhieng, MD, LCDR, MC, USN, Michael J. Matteucci, MD, CDR, MC, USN, and Richard F. Clark, MD

This case, strengthened by an unintentional rechallenge, adds to a growing body of anectodal evidence that the often prescribed ciprofloxacin may be associated with peripheral neuropathy.

iprofloxacin is a commonly (GABA) receptors, they produce describe evidence of an association prescribed antibiotic that is dose-related central nervous system between the drug and the condi- used to treat a wide range of excitation.2 The drugs can lower the tion that we found through a review bacterial infections and is the seizure threshold and induce psy- of FDA MedWatch data, along with C 2 preferred prophylactic agent against chosis, and they cause such adverse evidence that has been published in anthrax. It is in the drug class known central nervous system effects as diz- previous reports. Finally, we specu- as fluoroquinolones, which act by se- ziness, headache, restlessness, and late on the possible mechanism of lective inhibition of DNA gyrase and seizure in 0.9% to 4.4% of patients.3 ciprofloxacin-associated peripheral topoisomerase IV. Ciprofloxacin is In addition, in July 2008, the FDA neuropathy, and we describe the diag- well absorbed from the gastrointesti- required all manufacturers of fluoro- nosis and treatment of the condition. nal tract; it has 50% to 85% bioavail- quinolones, including ciprofloxacin, ability and minimal loss by first pass to add a boxed warning regarding the Initial Exam and patient metabolism, and about 20% to 40% risk of tendinitis and tendon rupture history of it is protein bound. It is metabo- in patients taking fluoroquinolones.4 A 62-year-old man reported to the lized hepatically by the cytochrome Ciprofloxacin is well tolerated in medical toxicology service of a large P4501A2 enzyme system to active most patients, however, and the ma- medical center. The patient’s pri- metabolites and excreted unchanged jority of its adverse effects are mild mary care physician referred him to through the kidneys (40% to 50%) and self-limiting. The most common this service for evaluation of a sus- and feces (20% to 35%), with a half- of these effects are nausea (2.5%), pected adverse reaction to prescribed life of four hours.1 diarrhea (1.6%), and abnormal liver ciprofloxacin. The patient had been Although there is anecdotal evi- function tests (1.3%).1 In comparison experiencing symptoms of periph- dence of an association between to these more common adverse effects eral neuropathy intermittently for fluoroquinolones, including cipro- of ciprofloxacin and fluoroquinolones approximately two months. He had floxacin, and peripheral neuropa- in general, peripheral neuropathy is been evaluated by a neurologist al- thy, this association has not yet been not as well described.1 ready and the results of electromy- proven. Fluoroquinolones are well In this article, we present evidence ography were consistent with mild known to be neurotoxic—by in- pointing to an association between sensorimotor peripheral neuropathy. hibiting gamma-aminobutyric acid ciprofloxacin and peripheral neurop- About two months earlier, the athy. We describe the case of a patient previously healthy patient was dis- LCDR Chhieng is the chief of emergency medi- who developed symptoms of periph- covered to have an elevated pros- cine at Naval Hospital, Yokosuka, Japan. CDR eral neuropathy after beginning a tate-specific antigen level of about 4 Matteucci and Dr. Clark both are clinical toxi- cologists in the division of medical toxicology at course of ciprofloxacin, experienced ng/mL (normal levels generally are University of California San Diego Medical Cen- a cessation of these symptoms after defined as less than 4 ng/mL, alter, San Diego. In addition, CDR Matteucci is a completing the drug course, and ex- though levels vary with age, gender, staff physician in the department of emergency medicine at Naval Medical Center San Diego, San perienced a return of the symptoms medication use, and inflammatory Diego, CA. after a rechallenge. In addition, we processes) and underwent a digital

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rectal examination. He was diagnosed right forearm and an occasional ache low. After we ruled out these common with prostatitis and was prescribed in his right arm and shoulder. His causes of the problem, and since sig- oral ciprofloxacin 250 mg twice daily blood pressure was 152/102 mm Hg nificant improvement after discontin- for 10 days. Several days into the and he had a pulse of 65 beats/min uation of the ciprofloxacin was seen, course of his therapy, he began expe- and a respiratory rate of 18 breaths/ we concluded it was highly probable, riencing a “pins and needles” sensa- min. He was afebrile. Physical exami- by the Naranjo criteria (score = 7),5 tion in his lower legs and feet. After nation revealed no distress, and his that the patient’s neuropathy resulted finishing this course of antibiotics, his skin examination was unremarkable. from ciprofloxacin exposure. paresthesias had improved. On return Neurologic examination revealed no to his primary care physician, he was focal deficits, and cranial nerve test- Treatment Course prescribed an additional five days of ing was normal. His deep tendon Since the patient no longer was tak- ciprofloxacin for continued prostate reflexes were 2+/4+ bilaterally. No ing ciprofloxacin and his peripheral pain. His paresthesias returned, and tremors, akasthesias, or rigidity were neuropathy was resolving, no treat- now included a stocking-glove dis- detected. The patient’s sensation to ment was required. About one month tribution to all his extremities and light touch was grossly intact and his after his toxicology evaluation, the involvement of the perioral and peri- motor examination was equal, sym- patient was essentially recovered from orbital areas. metric, and 5/5 in all extremities. No the neuropathy. At the time of toxicology evalu- clonus, pronator drift, or ataxia were ation, approximately 30 days had noted. Finger-to-nose and Romberg About the Condition elapsed since the patient’s last dose of testing were normal and the Babinski To investigate further the possibility ciprofloxacin. His prostate pain had reflex was down-going bilaterally. of an association between ciproflox- resolved completely, and he reported Screening laboratory testing was acin and peripheral neuropathy, we an 80% improvement of his paresthe- completed about three weeks after the reviewed FDA MedWatch data from sias. A review of the patient’s medical patients’ evaluation by the toxicology November 1997 through March 2006 history was significant for paroxysmal service. Liver function studies, chem- for adverse events associated with atrial fibrillation (which was well con- istry studies, and a thyroid panel all ciprofloxacin use.6 We found a total trolled without medication) and mild were normal. of 7,282 reports, 338 (4%) of which cervical and lumbar spinal stenosis. The normal laboratory findings documented peripheral paresthesia He reported being active and taking essentially ruled out thyroid disease, or polyneuropathies. Of these 338 re- supplemental magnesium daily but no diabetes, and electrolyte abnormali- ports, 281 (83%) listed ciprofloxacin herbal supplements and no prescrip- ties as potential causes of the patient’s as the primary suspect (Table). tion medication prior to his ciproflox- neuropathy. Since tests of his renal A possible association between acin course. The patient also reported and liver function also were normal, the drug and the condition was first no exposure to chemicals (although these functions would not affect the reported in 1992,7 and scattered re- he was employed as an executive of a metabolism or excretion of cipro- ports have been published since then. large consumer products company) or floxacin. In addition, his history and A recent report discussed acute pe- history of smoking or illicit drug use. physical examination did not raise ripheral neuropathy in a patient with His reported last alcoholic ingestion any suspicion for alcoholism, drug lupus whose symptoms resolved after had been about two years ago. The abuse, autoimmune disorder, occult discontinuation of ciprofloxacin. The patient’s family history was negative paraneoplastic process, or exposures patient did not have a lupus flare at for any neurologic diseases. to toxins in the workplace that might the time of her peripheral neuropa- A comprehensive review of sys- produce neuropathies. The patient thy, and, although the temporal re- tems revealed no unintentional appeared reliable and adherent to lationship suggested an association, weight loss, fevers, night sweats, or his medication instructions, and it is a rechallenge was not undertaken.8 other constitutional symptoms. The doubtful that he ingested more than Another report described 37 cases of patient reported no cranial nerve the prescribed dose of ciprofloxacin. fluoroquinolone-associated peripheral symptoms, including visual symp- As his only other medication was neuropathy—five of them involving toms, dysarthria, or vertigo. His supplemental magnesium, the likeli- ciprofloxacin—that were reported to only other reported symptoms were hood that his peripheral neuropathy the Swedish Adverse Drug Reactions a vague, nonspecific pruritus on his resulted from a drug interaction was Advisory Committee over a seven-

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Continued from page 26 year period. Most of these cases were Table. All cases of adverse peripheral neurologic effects with mild and resolved after discontinua- ciprofloxacin listed as a suspected agent, according to FDA tion of the fluoroquinolones.9 In addition, a survey conducted through MedWatch data, November 1997–March 2006 the internet in 2001 found 45 cases Ciprofloxacin of peripheral neuropathies associated Ciprofloxacin listed listed as secondary with fluoroquinolones. Eleven of the Reported symptom as primary suspect, no. suspect, no. cases involved courses of ciprofloxa- Paresthesia 97 17 cin, and 36 reported severe events.10 Peripheral 79 11 Schering-Plough (Kenilworth, NJ), neuropathy the distributor of ciprofloxacin, re- sponded to concerns about the Hypoesthesia 70 17 possible association by including pe- Polyneuropathy 16 9 ripheral neuropathy in the product Guillain-Barre 10 2 labeling as a postmarketing adverse syndrome event in 2004.11,12 Hyperesthesia 6 1 The anthrax bioterrorism incident of 2001 also led to some possible evi- Mononeuritis 2 0 dence of an association between the Neuritis/sciatica 1 0 drug and the condition. The incident Total 281 57 created an unprecedented, nation- wide increase in prescriptions filled association is unclear.14 Due to their tion studies. This finding is consistent for postexposure prophylaxis in gen- excellent tissue penetration, low pro- with the pathologic changes—primary eral and ciprofloxacin in particular.13 tein binding, and long elimination axonal degeneration with secondary Bayer HealthCare (Wayne, NJ), the half-life, fluoroquinolones frequently breakdown of myelin sheath—that manufacturer of the ciprofloxacin are used selectively in pediatric pa- previously have been seen in most brand Cipro, disclosed a dispropor- tients.14–16 The only approved pediatric drug-induced peripheral neuropa- tionate increase in peripheral neurop- indications for ciprofloxacin, how- thies.17 In vitro studies using hepatic athy and other neurologic symptoms, ever, are in complicated urinary tract microsomes have demonstrated the along with gastrointestinal and mus- infections (in which case the drug is production of free radicals in a dose- culoskeletal symptoms, during the not used as a first-line agent) and in and time-dependent fashion. This incident as compared to previously postinhalational anthrax exposure. finding of oxidative stress at the mo- reported clinical trials. The manufac- Overall, while we lack the stan- lecular level has been cited in medical turer warned against any premature dardized clinical trials needed to prove literature as a suspected mediator of conclusions relating to any drug- an association between ciprofloxacin tissue destruction.18 Because the cy- related event, however, because its and peripheral neuropathy, we believe tochrome P4501A2 system exhibits findings lacked a control group and that our case, together with the other genetic polymorphism and its expres- were laden with multiple confounding cases described here, offers convinc- sion is highly variable, the likelihood factors.1 ing evidence for such an association. of an adverse event would be expected It is worth noting that there have to be higher in patients who have a di- been no reported cases of peripheral Possible mechanism of minished capacity for biotransforma- neuropathy in the pediatric popula- association tion of the parent drug. This genetic tion—which likely is due to the low The exact mechanism of action that polymorphism has not been linked prevalence of fluoroquinolone use could lead to the development of pe- directly to the development of periph- in children. Data on the drug’s long- ripheral neuropathy in certain patients eral neuropathy, however.19 term safety in the pediatric popula- using ciprofloxacin is unclear. The tion is limited.1 There are concerns patient in our case and many of the Diagnosis and treatment about joint and cartilage toxicity, but patients in previous studies revealed The diagnosis of ciprofloxacin-associ- this toxicity was discovered through similar axonal disease, as evidenced ated peripheral neuropathy is based juvenile animal studies, and a direct by biopsy reports or nerve conduc- on a history of exposure and subse-

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quent neuropathic symptoms—usu- educate their patients properly when formation for specific drugs or drug ally within the first week of therapy, prescribing ciprofloxacin and that combinations—including indications, although reports of symptom onset they have a high index of suspicion contraindications, warnings, and ad- after several weeks or even months when a patient taking the drug pres- verse effects—before administering of therapy exist.7,9,10 If the findings ents with symptoms consistent with pharmacologic therapy to patients. are early and the diagnosis is still in peripheral neuropathy. These sim- doubt, nerve conduction studies and ple measures may prevent long-term References 1. Cipro [package insert]. Wayne, NJ: Bayer Health- a biopsy may be beneficial. sequelae and, possibly, irreversible Care Pharmaceuticals Inc; September 2008. The optimal treatment for the nerve damage. 2. Lietman PS. Fluoroquinolone toxicities. An update. Drugs. 1995;49(suppl 2):159–163. problem is cessation of ciprofloxacin. The index of suspicion should be 3. Wolfson JS, Hooper DC. Fluoroquinolone antimi- Although certain medications—in- heightened if peripheral neuropathy crobial agents. Clin Microbiol Rev. 1989;2(4):378– 424. 4. Information for healthcare professionals: Fluoro- quinolone antimicrobial drugs. US Food and Drug Administration web site. http://www.fda.gov/cder /drug/InfoSheets/HCP/fluoroquinolonesHCP.htm. Issued July 8, 2008. Accessed November 20, 2008. The index of suspicion should be 5. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reac- heightened if peripheral neuropathy tions. Clin Pharmacol Ther. 1981;30(2):239–245. 6. The Adverse Event Reporting System (AERS) older cannot be explained by reasons other quarterly data files. US Food and Drug Administra- tion web site. http://www.fda.gov/cder/aers/aers- than ciprofloxacin use. prev-data.htm. Posted July 29, 2005. Updated October 16, 2008. Accessed October 22, 2008. 7. Aoun M, Jacquy C, Debusscher L, et al. Peripheral neuropathy associated with fluoroquinolones. Lan- cet. 1992;340(8811):127. 8. Singh J. Ciprofloxacin-related acute peripheral neuropathy in a patient with lupus nephritis. J Clin cluding gabapentin, lidocaine, imip- cannot be explained by reasons other Rheumatol. 2002;8(3):143–146. ramine, carbamazepine, and even than ciprofloxacin use or if there is a 9. Hedenmalm K, Spigset O. Peripheral sensory distur- bances related to treatment with fluoroquinolones. J vitamins—have been used to treat climate of increased terrorist threat. Antimicrob Chemother. 1996;37(4):831–837. peripheral neuropathy, there is no With regard to the later scenario, it 10. Cohen JS. Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother. antidote for ciprofloxacin-associated is worth noting that a significant an- 2001;35(12):1540–1547. peripheral neuropathy. Furthermore, thrax exposure would increase the 11. Cipro (tablets and oral suspension) [package insert]. West Haven, CT: Bayer Pharmaceuticals Cor- it is possible that these remedies do number of prescriptions filled for cip- poration; April 2004. nothing to alter the course of the rofloxacin, the number of erroneous 12. Albrecht R. Cipro labeling revision letter. US Food and Drug Administration web site. underlying condition and may, in uses of the drug, and, consequently, http://www.fda.gov/cder/foi/appletter/2004/ fact, be harmful. There have been re- the incidence of ciprofloxacin-associ- 19537s053,054,20780s017,018ltr.pdf. Issued July ● 14, 2004. Accessed November 20, 2008. ported cases of ciprofloxacin-associated adverse events. 13. Sikka R, Khalid M, Chae E, Alemayehu B. Impact of ated peripheral neuropathy that have the anthrax bioterrorism incidents of 2001 on antibiotic utilization. Ann Emerg Med. 2004;44(suppl persisted or resulted in long-term Author disclosures 4):S92–S93. disability, but it remains to be seen if The authors report no actual or poten- 14. Gendrel D, Moulin F. Fluoroquinolones in paediat- rics. Paediatr Drugs. 2001;3(5):365–377. this truly is due to a cause-effect re- tial conflicts of interest with regard to 15. Leibovitz E. The use of fluoroquinolones in chil- lationship or if other factors may be this article. dren. Curr Opin Pediatr. 2006;18(1):64–70. 10 16. Alghasham AA, Nahata MC. Clinical use of fluo- involved. Further well controlled roquinolones in children. Ann Pharmacother. studies in this area are warranted. Disclaimer 2000;34(3):347–359. 17. Blaine PG, Lane RJM. Neurological disorders. In: The opinions expressed herein are those Davies DM, ed. Textbook of Adverse Drug Reactions. in summary of the authors and do not necessarily 4th ed. Oxford, England: Oxford University Press; 1991:535–566. The prognosis for ciprofloxacin-asso- reflect those of Federal Practitioner, 18. Gürbay A, Gonthier B, Daveloose D, Favier A, ciated peripheral neuropathy appears Quadrant HealthCom Inc., the U.S. Hincal F. Microsomal metabolism of ciprofloxacin generates free radicals. Free Radic Biol Med. to be good if the potential drug- government, or any of its agencies. 2001;30(10):1118–1121. effect relationship is recognized early This article may discuss unlabeled or 19. Van der Weide J, Steijns L. Cytochrome P450 enzyme system: Genetic polymorphisms and im- and the ciprofloxacin is discontin- investigational use of certain drugs. pact on clinical pharmacology. Ann Clin Biochem. ued. It is imperative that physicians Please review complete prescribing in- 1999;36(pt 6):722–729.

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