Ciprofloxacin is a second generation fluoroquinolone antibiotic that is widely used in the therapy of mild-to-moderate urinary and respiratory tract infections caused by susceptible organisms. Ciprofloxacin has been linked to rare but convincing instances of liver injury that can be severe and even fatal.
Ciprofloxacin (sip" roe flox' a sin) is an oral fluoroquinolone that is used to treat mild-to-moderate urinary and respiratory tract infections. Ciprofloxacin is also used for infectious diarrhea, typhoid fever, uncomplicated gonorrhea, treatment of Neisseria meningitides nasal carriage and prophylaxis against anthrax. Like other fluoroquinolones, ciprofloxacin is active against a wide range of aerobic gram-positive and gram-negative organisms. 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.Ciprofloxacin was approved for use in the United States in 1990 and, currently, approximately 20 million prescriptions are filled yearly. Ciprofloxacin is available in multiple oral formulations of 100, 250, 500 and 750 mg tablets and extended release formulations of 500 and 1000 mg tablets. Ciprofloxacin is available generically and under several commercial names including Cipro and Proquin. The usual dose is 250 to 500 mg every 12 hours. Oral formulations are recommended for mild-to-moderate infections due to susceptible organisms, including urinary tract infections, sinusitis, bronchitis, skin infections, urethral and cervical infections. Intravenous formulations are available for moderate to severe infections, including pneumonia, sinusitis, septicemia, intraabdominal and bone and joint infections, the usual dosages being 200 to 400 mg IV every 8 hours. Oral therapy is typically continued for 7 to 10 days, but both shorter and longer courses are used. Common side effects include gastrointestinal upset, headaches, skin rash and allergic reactions. Less common, but more severe side effects include prolongation of the QT interval, seizures, hallucinations, tendon rupture, angioedema, Stevens Johnson syndrome and photosensitivity.
Ciprofloxacin like other fluoroquinolones is associated with a low rate (1% to 3%) of serum enzyme elevations during therapy. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. More importantly, ciprofloxacin has been linked to rare, but occasionally severe and even fatal cases of acute liver injury. The time to onset is typically short (2 days to 2 weeks) and the presentation is often abrupt with nausea, fatigue and abdominal pain, followed by dark urine and jaundice. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic; cases with the shorter times to onset usually being more hepatocellular with markedly elevated ALT levels, and occasionally with rapid worsening of prothrombin time and early signs of hepatic failure. The onset of illness also may occur a few days after the medication is stopped. Cases with a cholestatic pattern of enzymes may run a prolonged course, but are usually self-limiting. Nevertheless, chronic cholestasis and vanishing bile duct syndrome have been reported with ciprofloxacin and other fluoroquinolones. Finally, the enzyme pattern can be initially hepatocellular and then evolve during the course of illness from a hepatocellular into a mixed or cholestatic pattern. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present.
Likelihood score: B (likely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of ciprofloxacin hepatotoxicity is suspected to be hypersensitivity. Rechallenge leads to recurrence with a shorter time to onset and more severe course and should be avoided.
Outcome and Management
Severity ranges from mild and transient serum enzyme elevations to a self-limited hepatitis, to prolonged cholestatic hepatitis to a fulminant hepatic failure. If not fatal during the acute phase, complete recovery is expected after stopping the drug and is usually rapid (2 to 4 weeks) depending upon the severity and degree of cholestasis. Some instances of cholestatic liver injury from ciprofloxacin have resulted in vanishing bile duct syndrome. Corticosteroids have been used with variable degrees of success. Cross reactivity of the hepatic injury between different fluoroquinolones has been demonstrated in a small number of cases, but should be assumed based upon the similarity of clinical patterns of injury and latency. Thus, patients should be advised to avoid further exposure to the fluoroquinolones.
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Case 1. Cholestatic hepatitis due to ciprofloxacin therapy.
[Modified from: Sherman O, Beizer JL. Possible ciprofloxacin-induced acute cholestatic jaundice. Ann Pharmacother 1994; 28: 1162-4. PubMed Citation]
An 84 year old female resident of a long term care facility received a course of ciprofloxacin for urinary tract infection. Six days later she was found to have a rash and ciprofloxacin was stopped. Nevertheless, 3 days after stopping she was noted to be jaundiced. Serum bilirubin rose to as high as 8.2 mg/dL, but she recovered within 6 weeks.
|Medication:|| Ciprofloxacin, 500 mg daily for 6 days|
|| Cholestatic (R=0.2)
|| 3+ (jaundice and hospitalization)
|| 6 days
|Recovery:|| Approximately 6 weeks|
|| Cefoperazone IV for 6 days before starting ciprofloxacin; and docusate/casanthranol, lorazepam and acetaminophen chronically as needed.
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Ciprofloxacin stopped because of rash
||Abdominal ultrasound normal
* Converted from µmol/L
This patient received multiple medications, but the timing of onset and pattern of injury was typical of fluoroquinolone induced liver injury with short latency and rapid recovery upon withdrawal. The cholestatic pattern of injury is somewhat atypical, but occurs when the jaundice is severe and prolonged; also, the lack of blood tests at earlier time points precludes a full assessment of the enzyme response. Interestingly, this patient had received two previous courses of ciprofloxacin and was said to be allergic to sulfonamides.
Case 2. Severe acute hepatitis due to ciprofloxacin therapy.
[Modified from Case 12 in: 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: 517-23. PubMed Citation]
An 80 year old female developed nausea, anorexia and increasing forgetfulness followed by jaundice starting the week after completing a 10 day course of ciprofloxacin (500 mg twice daily) and while taking metronidazole (250 mg twice daily). She had a past medical history of hypertension, congestive heart failure, atrial fibrillation, colonic polyps and depression. Her other medications included furosemide, atenolol, valsartan, warfarin, vitamins and ginkgo biloba. She also took occasional acetaminophen with or without oxycodone for pain. She had no history of liver disease or risk factors for viral hepatitis and did not drink alcohol. Two months before onset of jaundice, she had developed diarrhea and abdominal pain which was presumed to be diverticulitis and for which she was given the two antibotics. During the week before admission, she had increasing fatigue and forgetfulness and the day before presentation developed pruritus, dark urine and jaundice. Physical examination was unremarkable except for jaundice. She did not have fever, rash, hepatomegaly, splenomegaly, ascites or asterixis. Laboratory testing showed total bilirubin of 9.6 mg/dL (direct 6.8 mg/dL), ALT 705 U/L and INR 8.2 (Table). There was mild eosinophilia. Serum antinuclear antibody was negative, smooth muscle antibody was weakly positive (1:20). She was admitted and all medications including warfarin were stopped. Because of concern over acute liver failure, she was transferred to a tertiary care hospital for management. Tests for hepatitis A, B and C (including HCV RNA) were negative as were tests for Ebstein Barr virus and cytomegalovirus infection. CT scans showed mild hepatosplenomegaly, mild ascites, absence of a gall bladder and no evidence of biliary obstruction. A liver biopsy showed severe acute hepatitis with giant cells and bridging necrosis. She developed worsening jaundice, ascites, and hepatic encephalopathy and died of multiorgan failure 5 weeks after onset of jaundice.
|| Ciprofloxacin, 500 mg daily for 10 days
|| Hepatocellular (R=11.1)
|| 5+ (death from acute liver failure)
|| 18 days (5 days after stopping medication)
|| Metronidazole for previous 18 days; warfarin, atenolol, valsartan, furosemide chronically
|Days After Starting
||Days After Stopping
||Alk P (U/L)
||INR 8.2. Admitted
||Patient died of multiorgan failure
An example of acute hepatocellular injury attributed to ciprofloxacin. Metronidazole can also cause acute hepatocellular injury and acute liver failure, but such cases are exceedingly rare. In contrast, the precipitious onset and relatively short latency are typical of fluoroquinolone induced acute liver injury. Also, ciprofloxacin induced liver injury tends to be more common and more severe in the elderly.
REPRESENTATIVE TRADE NAMES
Ciprofloxacin – Generic, Cipro®, Proquin®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO
References updated: 10 October 2017
Abbreviations used: SJS, Stevens Johnson syndrome; TEN, toxic epidermal necrolysis.
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Jones SF, Smith RH. Quinolones may induce hepatitis. BMJ 1997; 314 (7084): 869. PubMed Citation (21 year old man developed jaundice following a 5 day course of ofloxacin and two doses of ciprofloxacin [bilirubin 5.7 rising to 8.2 mg/dL, AST 348 U/L, Alk P 321 U/L], worsening for 7 days and then resolving within 5 weeks of stopping).
Contreras MA, Luna R, Mulero J, Andreu JL. Severe ciprofloxacin-induced acute hepatitis. Eur J Clin Microbiol Infect Dis 2001; 20: 434-5. PubMed Citation (32 year old man developed abdominal pain, fever and rash within 2 days of starting ciprofloxacin [bilirubin not given, ALT 147 rising to 2144 U/L, GGT 98 U/L], with subsequent signs of liver failure, but ultimate recovery after methylprednisolone therapy).
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Dig Dis Sci 2001; 46: 2385-8. PubMed Citation (19 year old woman developed fever followed by rash and jaundice 4 days after starting ibuprofen and 2 days after starting metoclopramide and ketorolac [bilirubin 3.3 rising to 9.2 mg/dL, ALT 300 U/L, Alk P 409 U/L], with worsening fever and rash disgnosed as Stevens Johnson syndrome [SJS], resolving without corticosteroid therapy).
Bataille L, Rahier J, Geubel A. Delayed and prolonged cholestatic hepatitis with ductopenia after long-term ciprofloxacin therapy for Crohn's disease. J Hepatol 2002; 37: 696-9. PubMed Citation (63 year old woman with Crohn disease developed jaundice while being treated with ciprofloxacin and ornidazole [a nitroimidazole derivative also linked to cases of cholestatic jaundice] for 6 months [bilirubin 3.4 rising to 8.1 mg/dL, ALT 740 U/L, Alk P 662 U/L], liver biopsy showing paucity of bile ducts, slowly resolving over the 8 months after discontinuation of both drugs).
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reported in Sweden as associated with this drug. J Am Acad Dermatol 2003; 49 (5 Suppl): S267-9. PubMed Citation (31 and 33 year old women developed rash and oral ulcers diagnosed as SJS 2 and 8 days after starting ciprofloxacin [one with serum enzyme elevations without jaundice], and review of Swedish Drug Information System found 8 other cases of serious cutaneous reactions due to ciprofloxacin).
Goetz M, Galle PR, Schwarting A. Non-fatal acute liver injury possibly related to high-dose ciprofloxacin. Eur J Clin Microbiol Infect Dis 2003; 22: 294-6. PubMed Citation (79 year old woman developed confusion and lactic acidosis within 2 days of starting iv ciprofloxacin [peak bilirubin 1.6 mg/dL, ALT 4878 U/L, Alk P 581 U/L, LDH 6111 U/L], resolving within 2 weeks).
Zaidi SA. Hepatitis associated with amoxicillin/clavulanic acid and/or ciprofloxacin. Am J Med Sci 2003; 325: 31-3. PubMed Citation (80 year old man received both ciprofloxacin and amoxicillin/clavulanate, developing rash and eosinophilia within 1 week followed by self-limiting serum enzyme elevations without jaundice [bilirubin 1.9 mg/dL, ALT 972 U/L, Alk P 358 U/L]).
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Thakur BS, Jain AK, Sirkar S, Joshi G, Joshi R. Ciprofloxacin-induced cholestatic jaundice. Indian J Gastroenterol 2007; 26 (1): 51-2. PubMed Citation (26 year old man developed rash and then jaundice within 5 days of starting ciprofloxacin [ALT 1700 U/L], with slow recovery by 6 months after onset).
Bhagirath KM. A case report of highly suspected ciprofloxacin-induced hepatotoxicity. Turk J Gastroenterol 2008; 19: 204-6. PubMed Citation (39 year old woman developed jaundice 1 month after a 14 day course of ciprofloxacin and metronidazole [bilirubin 16.3 mg/dL, ALT 1406 U/L, Alk P 160 U/L, IRN 1.6], resolving within the next 3 months with prednisone therapy).
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