1: Ann Intern Med. 2004 Jan 6;140(1):73-4. Related Articles, Links
Gatifloxacin-induced hepatotoxicity and acute pancreatitis.
Cheung O, Chopra K, Yu T, Nalesnik MA, Amin S, Shakil AO.
Publication Types: Case Reports Letter
PMID: 14706991 [PubMed - indexed for MEDLINE]


Gatifloxacin-Induced Hepatotoxicity and Acute Pancreatitis
TO THE EDITOR: Background: Quinolones may induce transient
abnormalities in serum aminotransferase levels. Severe hepatotoxicity
and acute pancreatitis are rare. Gatifloxacin (Tequin, Bristol-Myers
Squibb, New York, New York) is one of the newest members of the
group (1). Increased serum bilirubin, aminotransferase, or amylase
levels occur in less than 1% of patients exposed; 1 case of acute
hepatitis has been reported (2).
Objective: We describe 2 patients who developed acute cholestatic
liver injury and acute pancreatitis while being treated with gati-
floxacin.
Case Reports: Patient 1, a 41-year-old woman, was treated for an
upper respiratory tract infection with oral ciprofloxacin. After 2
doses, the drug was withdrawn because of nausea and vomiting.
Gatifloxacin was initiated orally at 400 mg/d. Two days later, skin
rash appeared on the patient’s upper trunk, followed by dark urine,
pale stools, and abdominal pain in the right upper quadrant. The
patient was not taking other medications.
Laboratory studies revealed a total bilirubin level of 87.2
_mol/L (5.1 mg/dL) with conjugated fraction of 61.6 _mol/L (3.6
mg/dL), an aspartate aminotransferase level of 139 U/L, an alanine
aminotransferase level of 145 U/L, an albumin level of 30 g/L, an
alkaline phosphatase level of 8.03 _kat/L, a _-glutamyl transpeptidase
level of 8.62 _kat/L, an amylase level of 1.38 _kat/L, a lipase
level of 6.5 _kat/L, and a prothrombin time of 6.1 seconds. Serologic
studies excluded viral and autoimmune hepatitis. Abdominal
imaging (ultrasonography and computed tomography scan) revealed
no evidence of biliary obstruction. Liver biopsy showed portal edema
and cholestasis with moderate macrovesicular steatosis. Two weeks
after withdrawal of gatifloxacin, the patient’s abdominal pain resolved
and prothrombin time returned to normal. The patient began
taking and continues to take ursodeoxycholic acid. Over the next 3
months, the results of her liver tests remained abnormal (Figure).
Results of endoscopic retrograde cholangiopancreatography were
normal. Prednisone was started at 30 mg/d. A follow-up liver biopsy
8 months after her initial presentation showed increased portal fibrosis,
early bridging fibrosis, and bile duct loss. A repeated serum antimitochondrial
antibody measurement 10 months later was negative.
The patient’s jaundice completely resolved 1 year later. However, she
continues to have persistent elevation of alkaline phosphatase and
aminotransferase levels.
Patient 2, a 49-year-old man, presented with jaundice and abdominal
pain. He had received oral gatifloxacin, 400 mg/d, for an
upper respiratory tract infection. Three days later, he developed severe
malaise, jaundice, pale stools, and abdominal discomfort. Laboratory
studies revealed a bilirubin level of 94.05 _mol/L (5.5 mg/
dL), an aspartate aminotransferase level of 216 U/L, an alanine
aminotransferase level of 520 U/L, an alkaline phosphatase level of
4.47 _kat/L, a _-glutamyl transpeptidase level of 9.9 _kat/L, an
amylase level of 5.12 _kat/L, and a lipase level of 60.01 _kat/L.
Results of abdominal ultrasonography and computed tomography
scan and endoscopic retrograde cholangiopancreatography were nor-
mal. Results of serologic studies for viral and autoimmune hepatitis
were negative. Liver biopsy showed portal edema, bile ductular proliferation,
and portal inflammatory infiltrate that included eosinophils
with lobular cholestasis. At 3 months after initial presentation,
serum bilirubin level had normalized but serum aminotransferase
and alkaline phosphatase levels remained mildly elevated.
Discussion: Several characteristics in these 2 patients support
gatifloxacin as the cause of liver injury, including the temporal relationship
between the administration of gatifloxacin and injury onset.
Liver biopsies in both patients showed cholestasis with portal edema,
bile duct injury, and eosinophilic infiltration. These changes are consistent
with drug-induced hepatotoxicity, although it can be argued
that underlying steatohepatitis contributed to the disease process in
patient 1. Following discontinuation of gatifloxacin, patient 2 improved
but patient 1 developed progressive liver disease and ductopenia.
Both patients also had concurrent acute pancreatitis, a complication
that has not been described with gatifloxacin before to our
knowledge. Of interest, only 3 cases of acute pancreatitis have been
reported with other quinolones (3–5). Acute pancreatitis therefore
appears to be a rare complication of quinolone-induced toxicity.
Conclusions: Gatifloxacin is a possible cause of severe hepatic
and pancreatic injury. Although these complications appear to be
infrequent, a heightened awareness is needed because gatifloxacin
and other quinolones are used extensively.
Onki Cheung, MD
Kapil Chopra, MD
Tina Yu, MD
Michael A. Nalesnik, MD
University of Pittsburgh School of Medicine
Pittsburgh, PA 15213
Shirish Amin, MD
A. Obaid Shakil, MD
Indiana Hospital
Indiana, PA 15701
References
1. Fish DN, North DS. Gatifloxacin, an advanced 8-methoxy fluoroquinolone. Pharmacotherapy.
2001;21:35-59. [PMID: 11191737]
2. Henann NE, Zambie MF. Gatifloxacin-associated acute hepatitis. Pharmacotherapy.
2001;21:1579-82. [PMID: 11765309]
3. Drabo YJ, Niakara A, Ouedraogo H. [Acute pancreatitis secondary to administration
or norfloxacin] [Letter]. Ann Fr Anesth Reanim. 2002;21:68-9. [PMID:
11878127]
4. Mann S, Thillainayagam A. Is ciprofloxacin a new cause of acute pancreatitis?
[Letter]. J Clin Gastroenterol. 2000;31:336. [PMID: 11129278]
5. Mennecier D, Thiolet C, Bredin C, Potier V, Vergeau B, Farret O. [Acute pancreatitis
after treatment by levofloxacin and methylprednisolone] [Letter]. Gastroenterol
Clin Biol. 2001;25:921-2. [PMID: 11852403]

Letters
www.annals.org 6 January 2004 Annals of Internal Medicine Volume 140 • Number 1 73




1: Ann Fr Anesth Reanim. 2002 Jan;21(1):68-9. Related Articles, Links
[Acute pancreatitis secondary to administration or norfloxacin]
[Article in French]
Drabo YJ, Niakara A, Ouedraogo H.
Publication Types: Case Reports Letter
PMID: 11878127 [PubMed - indexed for MEDLINE]



1: Gastroenterol Clin Biol. 2001 Oct;25(10):921-2. Related Articles, Links
[Acute pancreatitis after treatment by levofloxacin and methylprednisolone]
[Article in French]
Mennecier D, Thiolet C, Bredin C, Potier V, Vergeau B, Farret O.
Publication Types: Case Reports Letter
PMID: 11852403 [PubMed - indexed for MEDLINE]



1: J Clin Gastroenterol. 2000 Dec;31(4):336. Related Articles, Links
Is ciprofloxacin a new cause of acute pancreatitis?
Mann S, Thillainayagam A.
Publication Types: Case Reports Letter
PMID: 11129278 [PubMed - indexed for MEDLINE]

Is Ciprofloxacin a New Cause of Acute Pancreatitis?
Letters to the Editor
Journal of Clinical Gastroenterology. 31(4):336, December 2000.
Mann, Steven M.R.C.P.; Thillainayagam, Andrew M.D., M.R.C.P.

Stingray bite and bilateral Achilles tendonitis due to LEVOFLOXACIN use

Lini S. Bhatia, M.D., PGY2, Department of Internal Medicine, James H. Quillen College of Medicine, ETSU, Johnson City, TN



The objective is to teach proper management of stingray bites and their potential complications. This case also illustrates an important side effect of the nearly ubiquitous fluoroquinolone antibiotics: Achilles tendonitis. A 44-year-old man was walking barefoot on a beach in South Carolina. He suddenly felt a sharp jab in his left foot and realized he had stepped on a stingray and was stung. He noticed a puncture wound with active bleeding. He developed ascending cellulitis and tissue necrosis. Cultures grew Staphylococcus aureus sensitive to levofloxacin. Due to concern for early osteomyelitis and to cover seaborne bacteria, levofloxacin 750mg/day was started and continued for 6 weeks. The wound ultimately healed in 3 months after 2 surgical debridements. The patient developed bilateral Achilles tendonitis within 14 days of starting levofloxacin. The tendonitis gradually improved after stopping the antibiotic. Atlantic Stingrays are the most common venomous fish found in the shallow waters of US beaches and are responsible for over 1,500 injuries per year. Stingrays attack people with its tail spine only as a form of defense if stepped on or threatened. Stingray bites may produce severe penetrating injuries and subsequent infections including tetanus. The venom has serotonin, 5’-nucleotidase, and phosphodiesterase, which cause both local and systemic effects. Treatment of stingray bites includes immersion of wound in hot water to inactivate heat-labile venom, thorough debridement and irrigation, pain control, prophylactic antibiotics, and to tetanus immunization. Achilles tendonitis is a well recognized but rare adverse effect of levofloxacin and other fluoroquinolones. The incidence of achilles tendonitis is between 0.01–0.1% and of tendon rupture is less than 0.01%. Pefloxacin and ofloxacin have the highest incidence of this side effect. Tendon disorders usually occur during the first month of treatment, but have been described to occur 2 to 42 days after starting the fluoroquinolone. Risk factors for tendinopathy is old age, chronic lung disease, steroid treatment and impaired renal function, and exceeding the therapeutic range of fluoroquinolone levels. The exact pathological mechanism of tendinitis due to fluoroquinolones is unknown. Animal studies suggest chelation of magnesium and free radical formation result in oxidative stress leading to a direct toxic effect on collagen. Arthropathy is seen in immature animals of various species when fluoroquinolones are administered at doses close to the therapeutic dose in humans, therefore is best avoided in children, adolescents, and pregnant or lactating women. The medication should be discontinued immediately at first sign of tendinopathy. Patients may need to be hospitalized and have surgical repairs. They may become disabled for prolonged periods. Stingray bites require special attention and treatment to prevent serious complications. Treatment requires debridement, irrigation, pain control (including immersion of wound in hot water (45o) for 30-90 minutes which can inactivate heat-labile venom), and prophylactic antibiotics. Antibiotics should cover Staphylococcus, Streptococcus, Vibrio, and Aeromonas species. Update the patient’s tetanus immunization. Cryotherapy is contraindicated. Wounds should be allowed to heal by secondary intention or delayed closure. While fluoroquinolones may be used for such infections, Achilles tendonitis and tendon rupture are potential side effects.


MINUTES OF THE 114TH MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
THE VISCOUNT ROOM, WELLINGTON AIRPORT CONFERENCE CENTRE
26 JUNE 2003, COMMENCING AT 9.00AM

NZPhVC review of March 2003 issue of 'Signal - Analyses of adverse reaction reports in the WHO database.'
Note: Signal is produced by the UMC and presents observations derived from reports submitted to the WHO International Drug Monitoring database by contributing national centres worldwide. This document is published regularly throughout the year, identifying signals of possible causal relationships between adverse events medicines that were previously unknown, or incompletely documented. The topics are researched and authored by the UMC Review Panel comprising international experts.
Signals Rosiglitazone and pancreatitis

This medicine is now available, but not funded, in New Zealand. The UMC reviewer has concluded that there is a strong signal, despite the fact that many of the patients would have received other medicines or had other disorders that could cause pancreatitis. Rosiglitazone improves insulin sensitivity at sites where resistance occurs most often, and is therefore used as an adjunctive treatment in type-2 diabetes.

Alendronate and synovitis

The sponsor company for alendronate does not believe this is a signal, however, there is one positive rechallenge and CARM holds a further report (not yet in the WHO ADR database, Vigibase), which described synovitis, an elevated C-reactive protein, and a positive rechallenge. Alendronate is widely used in New Zealand for severe osteoporosis with fractures.

Sirolimus and GI haemorrhage

There is one further report in the CARM database of diarrhoea and haematemesis (Mallory-Weiss tear found on endoscopy).

Moxifloxacin and respiratory insufficiency

This may be part of an anaphylactic reaction. The data sheet for moxifloxacin states that severe hypersensitivity reactions can occur, although it does not specifically mention respiratory effects.

Gatifloxacin and rhabdomyolysis

There is one report for gatifloxicin in the CARM database (fasciitis). The UMC reviewer commented, "Myalgia and rhabdomyolysis can occur with fluoroquinolones but are not well documented".

Discussion Members noted the above summary by CARM. It was agreed that the most noteworthy signal is rosiglitazone and pancreatitis. It was proposed that CARM and Medsafe keep a watching brief on this signal.
Recommendation The Committee recommended that CARM and Medsafe keep a watching brief on the signal of pancreatitis with rosiglitazone