Livertox

DRUG RECORD

 

MOXIFLOXACIN

 

Moxifloxacin is a fourth generation fluoroquinolone with expanded activity against gram-positive bacteria as well as atypical pathogens. Moxifloxacin has been linked to mild ALT elevations during therapy and to rare instances of idiosyncratic acute liver injury with symptoms and jaundice.

 

Background

Moxifloxacin is a fourth generation fluoroquinolone with expanded activity against gram-positive bacteria including multi-drug resistant strains of Streptococcus pneumoniae. Like other fluoroquinolones, moxifloxacin is active against a wide range of aerobic gram-positive and gram-negative organisms.  The quinolones are believed to act by inhibition of type II DNA toposiomerases (gyrases) that are required for synthesis of bacterial mRNAs (transcription) and DNA replication.  Moxifloxacin was approved for use in the United States in 1999 and is available under the commercial name of Avelox.   Current indications include mild-to-moderate bacterial infections such as sinusitis, bronchitis, community acquired pneumonia, skin infections, cellulitis, abcesses and complicated intra-abdominal infections due to sensitive organisms. Moxifloxacin is available in formulations of 400 mg tablets; the usual dose being 400 mg daily for 5 to 14 days. Intravenous formulations are available for moderate to severe infections, the usual IV dosages being 400 mg daily. Common side effects include gastrointestinal upset, headaches, skin rash and allergic reactions.  Less common but more severe side effects of the fluoroquinolones include prolongation of the QT interval, seizures, hallucinations, tendon rupture angioedema and photosensitivity.

 

Hepatotoxicity

Moxifloxacin 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.  Moxifloxacin has been linked to rare but occasionally severe and even fatal cases of acute liver injury. The time to onset is typically short (1 day to 3 weeks) and the presentation is often abrupt with nausea, fatigue, abdominal pain 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.   In addition, the onset of illness may occur a few days after the medication is stopped.  Many (but not all) cases have prominent allergic manifestations with fever and rash and the liver injury may occur in the context of a generalized hypersensitivity reaction (Case 1).  Autoantibodies are usually not present.  Cases with a cholestatic pattern of enzymes may run a prolonged course but are usually self-limiting, although at least one case of chronic cholestatis, vanishing bile duct syndrome leading to liver failure has been published.  Most reported cases have been mild with recovery within 4 to 8 weeks of onset.

 

Mechanism of Injury

The cause of hepatic injury is unknown but appears to be hypersensitivity.

 

Outcome and Management

Mild to moderate injury should be followed by full recovery within 4 to 8 weeks. Fulminant cases and chronic cholestatic forms with vanishing bile duct syndrome have been described. Cross reactivity of the hepatic injury between different fluoroquinolones has not been demonstrated but is suspected based upon the similarity of clinical patterns of injury and latency. Thus, patients should be advised to avoid further exposure to the fluoroquinolones.

 

Drug Class: Fluoroquinolones

Other drugs within this class: Ciprofloxacin, Gemifloxacin, Levofloxacin, Norfloxacin, Ofloxacin

 

 

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Case 1. Severe hypersensitivity reaction and hepatitis due to moxifloxacin therapy.

[Modified from case 10 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: 517-523. PubMed Citation]

A previously healthy 45 year old man was treated with moxifloxacin for suspected sinusitis and developed severe rash, facial edema and fever one week later. He was admitted with the diagnosis of Stevens Johnson syndrome and was treated with systemic and topical corticosteroids. He had a past medical history of allergic reactions of amoxicillin and erythromycin, but had not received fluoroquinolone antibiotics in the past. He had no history of liver disease, alcohol abuse or risk factors for viral hepatitis.  He was taking no other medications or herbal preparations.  On admission, serum aminotransferase values were markedly elevated (~18 fold) and the day after he became jaundiced (Table). There was no eosinophilia or lymphocytosis. Tests for hepatitis A, B and C were negative as were autoantibodies. An abdominal ultrasound was normal except for somewhat echogenic texture of the liver suggesting fatty infiltration. He was treated with methylprednisolone and his skin rash and jaundice improved over three weeks. Ultimately, liver tests returned to normal values.

 

Key Points

 

Medication:	Moxifloxacin, 400 mg daily
Pattern:	Hepatocellular (R=11.4)
Severity:	3+ (Jaundice and hospitalization)
Latency:	10 Days
Recovery:	Approximately 3 weeks
Other medications:	Antihistamines, ranitidine

 

Laboratory Values

 

Days After Starting	Days After Stopping	ALT (U/L)	Alk P (U/L)	Bilirubin (mg/dL)	Other
10	0	1226	188	1.1	Generalized rash with desquamation
11	1	1311	305	3.0
12	2	975	326	3.5
13	3	979	349	3.6
14	4	2289	373	3.5
15	5	1220	379	3.3
16	6	1300	378	3.3
17	7	1139	330	2.6
18	8	1167	351	2.9
19	9	729	229	2.0
26	16	223	93	0.8
31	21	53	74	0.7
Normal Values		<41	<115	<1.2

Comment

This patient developed symptoms of generalized hypersensitivity approximately 9 days after starting moxifloxacin. He had an accompanying hepatitis and jaundice that was not severe. Some degree of hepatic involvement is common with severe hypersensitivity reactions to antibiotics but usually the allergic manifestations dominate the clinical picture.   Notice that the liver injury worsens for a week after stopping the implicated medication before beginning to resolve.  The patient should be advised strongly to avoid further exposure to fluoroquinolone antibiotics.

 

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REPRESENTATIVE TRADE NAMES
Avelox®

DRUG CLASS
Anti-Infective Agents

 

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH
Avelox® (moxifloxacin hydrochloride) Product Labeling, Bayer Pharmaceuticals Corp.

 

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Moxifloxacin HCl	186826-86-8	C21-H24-F-N3-O4.Cl-H

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References Last Updated: 1 July 2011

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; moxifloxacin is not discussed).

2. Moseley RH. Antibacterial and Antifungal Agents; Quinolones. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd Edition. New York:  Informa Healthcare USA, Inc, 2007. p. 532-3. (Review of hepatotoxicity of antibiotics published in 2007; 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, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 1119-22.  (Textbook of pharmacology and therapeutics).

4. Soto S, López-Rosés L, Avila S, et al. Moxifloxacin-induced acute liver injury. Am J Gastroenterol 2002; 97: 1853-4. PubMed Citation  (69 year old man developed jaundice 3 weeks after completing a 5 day course of moxifloxacin for bronchitis [bilirubin 28.5 mg/dL, ALT 58 U/L, Alk P 249 U/L] resolving within 2 months of onset).

5. [No authors listed] Moxifloxacin--a new fluoroquinolone antibacterial. Drug Ther Bull 2004; 42: 61-2. PubMed Citation  (Review stating that moxifloxacin has no advantage over other, safer and less expensive antibiotics; ALT elevations mentioned as a potential side effect).

6. Nori S, Bebesio C, Brashear R, Travers JB. Moxifloxacin-associated drug hypersensitivity syndrome with toxic epidermal necrolysis and fulminant hepatitis failure. Arch Dermatol 2004; 140: 1537-8. PubMed Citation  (23 year old woman developed fever, rash and abdominal pain 3 days after starting moxifloxacin[bilirubin 2.7 mg/dL, ALT 3453 U/L, lymphocytosis] with progression to toxic epidermal necrolysis and acute liver failure and death despite liver transplantation within 2 weeks).

7. Iannini PB. The safety profile of moxifloxacin and other fluoroquinolones in special patient populations. Curr Med Res Opin 2007; 23: 1403-13. PubMed Citation  (Systematic review of the literature on the safety of moxifloxacin; serum enzyme elevations reported in 2% to 3% of patients, but usually mild and self-limited even with continuing therapy; clinically apparent liver injury has been reported with trovafloxacin, gatifloxacin, and levofloxacin, but not with moxifloxacin).

8. Van Bambeke F, Tulkens PM. Safety profile of the respiratory fluoroquinolone Moxifloxacin. Comparison with other fluoroquinolones and other antibacterial classes. Drug Safety 2009; 32: 359-78.PubMed Citation  (Review of safety of moxifloxacin in comparison to other antibiotics and other fluoroquinolones: rare instances of acute liver failure have been attributed to moxifloxacin [0.7 per million prescriptions based upon FDA reporting rate]).

9. Franco Hidalgo S, Prieto de Paula JM, García Lorenzo R, Salado Valdivieso I.  [Moxifloxacin and hepatic toxicity]. Gastroenterol Hepatol 2009 Dec; 32(10): 719-20. Spanish. PubMed Citation. (44 year old man developed jaundice following a 4 day course of moxifloxacin for sinusitis [bilirubin 5.8 mg/dL, ALT 862 U/L, Alk P 421 U/L] resolving within one month of stopping).

10. Puerto Alonso JL, Díaz Souza P, Chamorro Mohedano J, Rojas Martín E. [Fatal acute hepatitis and cholestasis associated with liver disease]. Med Clin (Barc)  2010 Mar 20; 134(8): 375-6. Spanish. PubMed Citation.  (58 year old man devloped jaundice 1 week after completing a 5-day course of moxifloxacin [bilirubin 27 mg/dL, ALT 2589 U/L, Alk P 94 U/L, prothrombin index 36%] with progressive liver failure and death one month later).

11. 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 Jun; 9(6): 517-523. PubMed Citation.  (Among 679 cases of drug-induced liver injury presenting between 2004 and 2010 at 8 U.S. 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 to 39), with both hepatocellular and cholestatic enzyme patterns, seven with rash or fever, mortality limited to those with hepatocellular injury and jaundice; hepatic injury was class-specific; moxifloxacin cases included 3 men,1 women, ages 45-71 years, onset after 1-7 days, 1 with fever and 2 with rash [bilirubin 0.9-5.3 mg/dL, ALT 220-1311 U/L, Alk P 253-837 U/L] one developed vanishing bile duct syndrome and underwent liver transplantation: see Case 1).

 

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1. Recent References on Moxifloxacin

2. Trials on Moxifloxacin

 

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