American Journal of Therapeutics 0, 000000 (2013)

Levofloxacin-Induced Hepatotoxicity and Death

Muge Gulen, MD,1 Mehmet Oguzhan Ay, MD,2* Akkan Avci, MD,2
Ayca Acikalin, MD,3 and Ferhat Icme, MD4

Drug-induced hepatotoxicity is a major cause of hepatocellular injury in patients admitting to emergency

services with acute liver failure. Hepatic necrosis may be at varying degrees from mild elevations in
transaminases to fulminant hepatitis, and even death. The case of a 53-year-old female patient with toxic
hepatitis due to levofloxacin and multiple organ failure secondary to toxic hepatitis is presented. Patient
suffered itching, redness, and rash after receiving a single dose of 750 mg of levofloxacin tablets for
pulmonary infection 10 days ago. Skin lesions had regressed within 3 days, but desquamation formed all
over the body. After the fifth day of drug intake, complaints of abdominal pain, vomiting, and yellowing
in skin color had started. The patient was referred to our emergency department with these complaints
10 days after drug intake. Patient was thought as a candidate for liver transplant, but cardiopulmonary
arrest occurred, and the patient died before she could be referred to a transplant center. This case is
important because hepatotoxicity and death due to levofloxacin is uncommon in the literature.
Keywords: levofloxacin, hepatotoxicity, multiple organ failure

INTRODUCTION
Acute hepatic failure (AHF) is a clinical syndrome that
may be potentially reversible, but with a high mortality
rate characterized by a sudden complete or near-complete
loss of liver functions without any previous liver disease
and accompanied by hepatic encephalopathy.1
Drug-induced hepatotoxicity is a major cause of
hepatocellular injury in patients admitting to emergency services with acute liver failure. Hepatic necrosis may be at varying degrees from mild elevations in
transaminases to fulminant hepatitis, and even death.2

Emergency Medicine Service, Eskisehir Yunus Emre State Hospital,

Eskisehir, Turkey; 2Department of Emergency Medicine, Adana
Numune Education and Research Hospital, Adana, Turkey; 3Department of Emergency Medicine, School of Medicine, Cukurova
University, Adana, Turkey; and 4Department of Emergency Medicine, Ataturk Education and Research Hospital, Ankara, Turkey.
The authors have no conflicts of interest to declare.
*Address for correspondence: Department of Emergency Medicine, Adana Numune Education and Research Hospital, Ege
Bagatur Boulevard, Yuregir, 01240 Adana, Turkey. E-mail:
droguzhan2006@mynet.com
10752765
2013 Lippincott Williams & Wilkins

In this case, we aimed to examine a 53-year-old

female patient with toxic hepatitis that developed after
intake of a single dose of levofloxacin due to lower
respiratory tract infection and resulted in death in
the light of the recent literature.

CASE REPORT
A 53-year-old female patient was referred to our emergency department with confusion, abdominal pain, jaundice, and impairment of liver function tests. The patient
was confused and her Glasgow Coma Scale was 12 (E3,
V4, M5) at admission. Her vital signs were as follows:
arterial blood pressure was 90/60 mm Hg, heart rate
110/min, body temperature 36.7C, and respiratory rate
35/min. As the patient was confused, her measured bedside blood glucose level was 53 mg/dL. The skin was all
covered with squamous lesions, and the skin and sclera
were icteric. There were generalized edema around the
eyes, widespread ecchymotic areas on arms, and petechiae on the tibia surface. At cardiac examination, the
heart was rhythmic and tachycardic. There were no additional sound and murmur. The patient was dyspneic and
tachypneic. There were basilar crepitant crackles in bilateral lungs. She had abdominal tenderness, but spleen and
liver were not palpable. Traube space was open.
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Neurological examination revealed no evidence of a side

finding and pathological reflexes.
According to the patients medical history told by her
relatives, the patient had no previously known chronic
illness, drug use, or a history of chronic alcohol intake.
They did not describe any blood transfusion, operation,
or suspected contact history. When investigated, it was
learned that the patient had been diagnosed as having
pulmonary infection 10 days ago at primary health center
where she had admitted with complaints of cough and
sputum, and 750 mg of levofloxacin at a dose of 1 3 1
tablet had been started. Itching, redness, and rash had
begun to emerge after taking the first dose of the medicine. Physician of the same primary health center had
stopped the medicine. Steroid and antihistamine injections had been administered for rashes. Skin lesions
had regressed within 3 days but desquamation formed
all over the body. After the fifth day of drug intake,
complaints of abdominal pain, vomiting, and yellowing
in skin color had started. However, the patient was
referred to our emergency department with these complaints 10 days after ingestion of medicine.
The results of complete blood count and biochemical
tests on admission were as follows: white blood cell count
was 16,200/mm3, hemoglobin (HGB) 10.4 g/dL, hematocrit (HCT) 32.3%, platelet (PLT) 23,000/mm3, glucose
54 mg/dL, urea 32 mg/dL, creatinine 2.6 mg/dL, alanine
aminotransferase 1222 IU/L, aspartate transaminase
2629 IU/L, total bilirubin 14.6 mg/dL, direct bilirubin
8.2 mg/dL, lactate dehydrogenase 2479 IU/L, albumin
1.5 g/dL, amylase 246 IU/L, sodium 131.9 mmol/L,
potassium 5.2 mmol/L, chlorine 103.3 mmol/L, and
C-reactive protein 4.56 mg/dL. Full urinary analysis revealed urine density of 1020, pH 6.0, leukocyte (+), bilirubin (++), and increased urobilinogen. Arterial blood gas
examined while patient receiving oxygen revealed pH
of 7.041, PO2 119.7 mm Hg, PCO2 14.0 mm Hg, HCO3
6.1 mmol/L, base excess (BE) 224.9 mmol/L, and SO2
94.7%. Serology for HBsAg, HBeAg, anti-HBe, anti-HBc
IgM, anti-HCV, anti-HAV IgM, and anti-HIV was negative and anti-HBsAg was positive. Coagulation parameters were as follows: prothrombin time .100 seconds and
INR .6.5. Liver and gall bladder were normal sized at
ultrasonography. There was no pathological image in the
lumen of the gallbladder. Gallbladder wall thickness was
4 mm, and the liver was hyperechoic and there were no
focal lesions.
When history, physical examination, and laboratory
findings were evaluated together, toxic hepatitis due
to levofloxacin and multiple organ failure secondary to
toxic hepatitis were considered.
The patient was admitted to the emergency intensive
care unit. With monitoring, oxygen at a dose of 4 L/min
was introduced through nasal cannula. Vascular access
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Gulen et al

was maintained. Dextrose infusion (30%) was administered to the patient as her blood glucose was 53 mg/dL.
The patient was given NaHCO3 due to metabolic
acidosis at blood gas analysis. Intravenous N-acetyl cysteine (NAC) loading and maintenance therapy was
started. Complete blood count and biochemical tests
results after 1 hour of NAC loading treatment were as
follows: white blood cell count was 18,000/mm3, HGB
8.3 g/dL, HCT 26.1%, PLT 31,000/mm3, glucose
361 mg/dL, urea 32 mg/dL, creatinine 2.8 mg/dL, alanine aminotransferase 942 IU/L, aspartate transaminase
1724 IU/L, total bilirubin 11.4 mg/dL, direct bilirubin
7.2 mg/dL, albumin 1.2 g/dL, amylase 204 IU/L,
sodium 127.6 mmol/L, potassium 5.67 mmol/L, and
chlorine 101.0 mmol/L. Coagulation parameters were
still high. Prothrombin time was .100 seconds and
INR was .6.5. Fresh frozen plasma, apheresis platelets,
red blood cells, and albumin replacement was scheduled.
Patient was thought as a candidate for liver transplant
but cardiopulmonary arrest occurred at the third hour of
hospitalization before the patient could be referred to
a transplant center. Patient responded to cardiopulmonary resuscitation at the 10th minute. She was connected
to mechanical ventilation but another cardiopulmonary
arrest occurred at the fourth hour. Patient, unresponsive
to cardiopulmonary resuscitation, died during the fifth
hour of hospitalization.

DISCUSSION
Levofloxacin, activated from l-isomer of ofloxacin, is
a commonly used fluoroquinolone used for respiratory,
skin, soft tissue, and genitourinary tract infections.3 It is
a generally well-tolerated drug with a safety profile.4 In
a study conducted in Europe and America, levofloxacin
was found to be the safest drugs of fluoroquinolones
and have 2.4% total side effects.5 The most common
side effects are 0.8% nausea, 0.5% rash, 0.4% abdominal
pain, 0.3% diarrhea, dizziness, and vomiting.4 Phototoxicity, cardiotoxicity, central nervous system side effects, and hepatotoxicity are less frequent.6 According
to surveillance data from all over the world, it can cause
increase in liver function tests at a rate of 0.3% and liver
failure rate of less than one in a million.4 In a study
conducted in Japan, 87 serious hepatic problems were
seen among 88 million patients who used levofloxacin.
This is lower than 1/100,000.6
Toxic hepatitis is a pathology commonly causing liver
dysfunction. It has a wide clinical spectrum, ranging
from mild biochemical abnormality to acute liver failure. Drug-induced toxic events are described as one of
the most common causes of liver damage. The reason
for this is that liver is the major organ for the metabolism of many drugs or chemical agents. It is one of the
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Levofloxacin-Induced Hepatotoxicity

most common reasons for withdrawal of drugs from the

market.7 For example, trovafloxacin, a fourth-generation
quinolone, was withdrawn from the market because of
severe hepatic deficiencies.3
The first of the major mechanisms that can lead to toxic
effects on the liver is intrinsic mechanism. This mechanism can be predicted and dose dependent. Some of the
drugs acting by this way are valproate, acetaminophen,
methotrexate, contraceptive steroids, vinyl chloride,
cocaine, cyclophosphamide, and niacin. The second
mechanism is defined as idiosyncratic type and it is the
most common form of hepatotoxicity.7 Cytopathic damage of hepatocytes occurs indirectly with immunological
mechanism.8 It is characterized by unpredictable reactions depending on the person. Genetic differences varying according to the individual are also important as well
as environmental factors in drug metabolism. This type of
toxic reaction is not dose dependent. Examples of drugs
acting in this way are isoniazid, chlorpromazine, phenylbutazone, diclofenac, halothane, phenytoin, acetylsalicylic
acid, tetracycline, erythromycin, oral contraceptives,
methotrexate, and amoxicillin clavulanate.7 The reaction
was an idiosyncratic reaction in our case. Symptoms
starting with skin rash continued with nausea, vomiting,
and abdominal pain and proceeded up to toxic hepatitis.
Determining the etiology mostly depends on patients history and serological investigations in AHF.
Etiological factor can be identified in 60%80% of the
cases. Rapidly identifying etiological factor is vital in
terms of the implementation of a specific antidote
treatment and supportive treatment.9 Cause of 70%
of all AHF is hepatitis viruses and 10%20% are toxins
and drugs (ecstasy, cocaine, mushrooms, acetaminophen, halothane, anti-tuberculosis drugs, and drugs
causing toxic hepatitis due to idiosyncratic reaction).10
According to the medical history provided by relatives, a chronic disease (autoimmune, cardiovascular,
malignancy, chronic liver disease), use of drugs or
chronic alcohol intake history leading to deterioration
of liver tests were not present in our case. They did not
describe any blood transfusion, operation history, and
suspected contact. The serology test results were not in
favor of viral hepatitis.
Size of the liver and gallbladder, intrahepatic and
extrahepatic bile ducts were normal on ultrasonography.
There was no pathological image in the lumen of the
gallbladder. Gallbladder wall thickness was 4 mm, and
the liver was hyperechoic and there were no focal lesions.
As there is no other drug use except levofloxacin, we
thought that levofloxacin might be responsible. Drugassociated hepatitis hypothesis may be strengthened by
possible transaminase elevations if measurement of drug
levels, liver biopsy, or re-use of the drug occurred. Measurements of liverkidney microsome antibody (antiwww.americantherapeutics.com

LKM2) and antibodies against cytochrome P450 can be

useful in demonstrating drug hepatotoxicity.11 In our
patient, there was no reuse of the drug, and levofloxacin
blood levels and anti-LKM measurement were not possible. However, a postmortem liver biopsy was performed
after informed consent had been taken. Extensive necrosis
of hepatocytes and deterioration and degeneration of
nucleus and cytoplasm integrity in some of the hepatocytes were observed as a result of the biopsy. Accumulation of polymorphonuclear leukocytes in the portal area
and bile pigment accumulation in some of the hepatocytes were detected. This pathological image had been
reported in accordance with toxic hepatitis (Figure 1).
AHF patients often present to emergency service with
complaints of fatigue, jaundice, abdominal pain, nausea,
vomiting, confusion, and/or drowsiness. After obtaining patients medical history, emergency physician
should do initial assessment, vascular access should be
provided, and respiration, circulation, blood sugar, and
blood gases should be checked. Due to impaired glycogenolysis and gluconeogenesis, hypoglycemia often
develops; severe hypoglycemia (,40 mg/dL) is seen
in 40% of cases and can cause sudden death.9 Bedside
blood glucose of our patient was 53 mg/dL. Metabolic
acidosis is seen in acetaminophen and mushrooms
intoxications and metabolic alkalosis often occur in
AHF due to other causes.12 In our case, there was metabolic acidosis. Patient was given NAC and supportive
treatment. Improvement in some liver function tests was
observed after 1 hour of loading treatment.

FIGURE 1. The microscopic image of postmortem liver

biopsy of the patient. According to the pathology report,
there is extensive necrosis of hepatocytes, deterioration
and degeneration of the nucleus and cytoplasm of some
hepatocytes integrity, polymorphonuclear leukocytes
accumulation in the portal area, and bile pigment accumulation in some of the hepatocytes.
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Jaundice is seen in almost all cases. However, hepatic

encephalopathy may occur before jaundice become clinically recognizable in very young patients.9 Hepatic
damage of drugs is responsible for 2%5% of patients
to be admitted to the hospital due to icteric appearance.
Medicines are also causes of 10% of all hepatitis in adults
and more than 40% in patients older than 50 years.13
Hepatic encephalopathy is the most important finding of AHF of prognostic value. Initially, it is manifested in the form of simple changes in personality,
antisocial behavior, restlessness, and headache; intracranial hypertension develops when rapidly progresses to
stage 4 coma.14 Prognosis is worse in patients with
stage 34. Intracranial hypertension causes cerebral
hypoxemia by decreasing cerebral perfusion pressure
to a permanent basis. Cerebral herniation and hypoxic
brain damage associated with cerebral edema are leading causes of mortality in AHF.15 Our patient had jaundice and stage 3 encephalopathy.
Coagulopathy depending on the impairment of synthesis of clotting factors and thrombocytopenia is an
important complication. Prothrombin time (PT) is a sensitive indicator of hepatocellular injury. Due to the short
half-life of clotting factors, PT begins to increase in parallel with an increase in hepatocyte injury. It is one of the
earliest and most important precursors of acute fulminant hepatitis in a patient. Patients are with increased
risk of gastrointestinal bleeding. Prophylaxis with proton
pump inhibitors should be started. Enteral and parenteral nutrition also reduce the risk of bleeding. For this
purpose, patient in accelerated catabolic process should
be supported with enteral feeding containing 60 g/d protein.12 In our case, widespread ecchymotic areas on arms
and petechiae on the tibia surface were present. Platelet
value was 23,000/mm3 and prothrombin time was .100
seconds and INR was .6.5, respectively.
Toxins that cannot be cleaned from circulation by liver
and active macrophage-derived cytokines, such as tumor
necrosis factora, interleukin-1, and interleukin-6, cause
endotoxemia. There is an increased risk of infection due
to reduction in the synthesis of complement, Kupffer cells
dysfunction, neutrophil adhesion defect, and impaired
opsonic activity. Endotoxemia also leads to a decrease
in peripheral vascular resistance and cardiac output
and cause hypotension.16 Arterial blood pressure of our
patient on admission was 90/60 mm Hg. Dopamine
infusion as a positive inotropic agent was started to the
patient due to decrease in arterial blood pressure despite
fluid treatment. No prophylactic antibiotics were given.
Besides sepsis and endotoxemia, increased nitric oxide
and prostaglandins also cause hemodynamic impairment
by vasodilation and constitute basis for noncardiogenic
pulmonary edema and renal failure.17 In our case, crepitant crackles in middle and lower zones of lungs, increase
American Journal of Therapeutics (2013) 0(0)

Gulen et al

in urine density, and decrease in amount of urine, and

impairment in renal function tests were present.
As a result, toxic hepatitis is a multi-organ failure. Medical history obtained from patient or relatives is very
important in diagnosis. Determining the etiological agent
is vital because it can change both supportive and specific
treatment. The emergency physician should diagnose the
patient early and start the treatment and should refer the
patient to an intensive care unit with a transplant unit.

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