Severe hepatitis associated with oxacillin therapy.

ABSTRACT: A 6-year-old girl had fever, abdominal pain, and severe anicteric hepatitis during intravenous oxacillin therapy for staphylococcal osteomyelitis. She had greatly elevated liver enzymes, prolonged prothrombin time, leukopenia, and eosinophilia. Clinical symptoms resolved and laboratory data returned to normal after withdrawing oxacillin and substituting cefazolin. This hepatotoxicity appears to be specific to oxacillin and not to other [beta]-lactams. Monitoring liver function tests during oxacillin therapy, especially in patients receiving prolonged treatment, may be warranted.

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HEPATIC INJURY, manifested as elevation of transaminases or cholestatic jaundice or both, has been associated with many drugs.' Several antibiotics can cause hepatic injury.2 Penicillins commonly cause hypersensitivity reactions but rarely produce hepatic injury. (3,4) High doses of semisynthetic penicillins may cause asymptomatic elevation of liver enzymes.5-7 Toxic hepatitis and elevation of liver enzymes have been described after the use of ampicillin, carbenicillin, and oxacillin. (1,5,8) Oxacillin-induced hepatitis has been reported in adults with underlying medical risk factors. (5,8,9) However, few cases of asymptomatic elevation of liver enzymes in association with oxacillin therapy have been reported in children.'0"' We report an unusually severe but reversible acute hepatitis in a child receiving oxacillin therapy.

CASE REPORT

A 6-year-old, previously healthy girl was admitted with fever associated with swelling, pain, and erythema, and bone tenderness of the left big toe. The white blood cell (WBC) count was 13,000/mm (3) with 62% neutrophils, 28% lymphocytes, 7% monocytes, and 3% eosinophils. The erythrocyte sedimentation rate was 27 mm/hr. Culture of a bullous skin lesion on the toe grew methicillin-susceptible Staphylococcus aureus. A technitium-99 hone scan showed increased uptake in the toe region compatible with osteomyelitis. She was given intravenous oxacillin at 200 mg/kg/day divided every 4 hours. Her clinical condition improved, but on the 14th day of therapy, fever (temperature 39[degree] to 40[degree]C), chills, abdominal pain, and vomiting developed. She had no diarrhea or urinary tract symptoms.

Physical examination on that day revealed a temperature of 39[degree[C, pulse rate 124/min, respiratory rate 28/min, and blood pressure 116/67mm Hg. The skin and mucous membranes were normal, without icterus. Examination of the ears, nose and throat, lungs, and heart showed no abnormality. The abdomen was enlarged and tender, and the liver was palpated 2 cm below the right costal margin. The left big toe was slightly tender, without erythema or drainage. Repeated WBC was 2,800/mm3 with 27% neutrophils, 53% lymphocytes, 7% monocytes, and 13% eosinophils. Serum electrolyte, blood urea nitrogen, and creatinine values were normal. Liver function tests showed elevated alanine aminotransferase (ALT) of 2,257 U/mL and aspartate aminotransferase (AST) of 2,247 U/mL. The alkaline phosphatase level was normal (430 U/mL), total bilirubin value was 0.3 mg/dL, and albumin value was 3.7 g/dL. Prothrombin time (PT) was prolonged at 17.8 seconds (normal, 9.5 to 12.1 seconds), with an international normalization ratio (INR) o f 2.3 (normal, 0.8 to 1.2). Serum glucose, ammonia, amylase, and lipase levels were normal. Because of possible drug-induced hepatic toxicity, oxacillin therapy was discontinued, and intravenous cefazolin therapy was started. Workup for possible acute viral hepatitis revealed negative hepatitis A 1gM antibody and negative hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C antibody. lgM antibody titers for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were also negative. Toxicology screen for acetaminophen, salicylates, tricyclics, barbiturates, benzodiazepines, and alcohol was negative. Antinuclear antibody and liver and kidney microsomal antibodies were negative. Serum levels of copper, ceruloplasmin, and [[alpha].sub.1]-antitrypsin were normal. Abdominal ultrasonography showed no abnormalities. Blood and urine cultures were negative. The patient's condition progressively improved, and she became afebrile after 48 hours without oxacillin. Abdominal pain gradually improved, serial de terminations of transaminase levels showed progressive decline, and PT returned to normal. She remained anicteric and had no skin rash, lymph node enlargement, or joint involvement. Six days after cessation of oxacillin therapy, ALT and AST levels were 479 and 176 U/mL., respectively, and WBC count was 6,800/[mm.sup.3] with 52% neutrophils, 34% lymphocytes, 10% monocytes, and 4% eosinophils. Eighteen days after cessation of oxacillin therapy, transaminase values were normal (ALT 48, AST 48 U/mL).

DISCUSSION

Elevation of transaminase levels in our patient was directly attributable to oxacillin. Infectious hepatitis was excluded by negative serologic tests for hepatitis A, B, and C as well as negative serologic tests for EBV and CMV infections. Negative tests for antinuclear antibodies, as well as liver and kidney microsomal antibody tests excluded autoimmune hepatitis. Toxic causes and Wilson's disease were also excluded. In addition, the hepatic dysfunction gradually resolved after discontinuance of oxacillin therapy. Substitution with cefazolin was not associated with any deterioration in liver enzyme profile or clinical symptoms.

Pollock et a1 (5) reported a series of 41 adults with oxacillin-induced hepatitis, all of whom had elevated AST/ALT levels ranging between 210/125 and 800/700 units. Olans and Weiner (10) described a 4-year-old girl with serum AST/ALT levels of 1,110/1,359 associated with oxacillin therapy. Bruckstein and Attia (12) described a 38-year-old heroin abuser who had AST/ALT of 1,380/1,164 on the 28th day of oxacillin therapy. In contrast to our patient, both subjects in the last two reports were asymptomatic. We believe our patient had the highest elevation of liver enzymes and the most prolonged prothrombin time associated with oxacillin therapy. Our case differs in that most of the previously described patients were adults with underlying conditions such as drug abuse, endocarditis, and human immunodeficiency virus (H1V) infection. (5,6,9) Cholestatic hepatitis in association with cloxacillin and oxacillin has also been reported in some patients. (13-15)

It is not clear whether oxacillin-induced hepatotoxicity is chemically or immunologically mediated. However, it is known that the isoxazole ring of oxacillin is degraded to 2-butanone and hydroxylamine. It is postulated that scavenging of hydroxylamine derivatives by glutathione is necesssary to prevent cytotoxicity. Patients with HIV infection have been reported to be unusually sensitive to chemical hepatitis caused by oxacillin. Deficiency of systemic glutathione in HIV-infected patients has been suggested as a predisposing factor for the increased oxacillin hepatotoxicity in this patient population. (9, 16)

Elevated liver enzymes have been detected as early as 5 days and as late as 35 days after starting oxacillin therapy. The serum alkaline phosphatase and bilirubin levels are usually normal. (5,6,10,15,17) The total amount of oxacillin sodium given before abnormal transaminase levels are first detected also varies widely. It has been suggested that patients receiving a high daily dose of oxacillin are more likely to have hepatitis regardless of a short or long treatment duration. (5) Our patient's hepatitis was diagnosed after 14 days of oxacillin therapy at 200 mg/kg/day. However, liver enzymes were not measured before the onset of symptoms, and it is possible that she had earlier asymptomatic elevation of liver enzymes.

Several hours after cessation of oxacillin therapy, the patient's liver enzymes started to decrease, and on the seventh day the AST level was 107 U/mL. This is similar to other case reports of oxacillin-induced hepatitis in which liver enzyme elevation reversed upon cessation of oxacillin therapy. No cases of persistent hepatic damage due to oxacillin toxicity have been reported after discontinuance of therapy. (5-7,10,11,15,17) Pathologic findings associated with oxacillin-induced hepatitis include areas of liver cell necrosis and a marked mononuclear infiltration in a few portal triads. (15) Liver biopsy was not done in our patient.

Toxic hepatic reactions to penicillin or oxacillin may also occur on a hypersensitivity basis, in association with urticaria, eosinophilia, or serum sickness. (3,5,10) However, not all patients have all of these allergic manifestations.5"0"8 Our patient had leukopenia and eosinophilia, but no skin rash, joint symptoms, or angioedema. In contrast to a hepatotoxin toxicity, which is dose-related, predictable, and can be elicited in all subjects, (15,18) oxacillin toxicity appears to be unpredictable and may or may not be doserelated. Systemic glutathione deficiency may be a predisposing condition for oxacillin-associated hepatitis and needs further evaluation.

CONCLUSION

Hepatitis, ranging from asymptomatic to severe, may develop during oxacillin therapy. This appears to be specific to oxacillin and not to other [beta]-lactams and is reversible on discontinuance of oxacillin therapy. Monitoring liver function during oxacillin therapy, especially in patients receiving prolonged treatment, may be warranted.

References

(1.) Farrell GC: Drug-induced hepatic injury. J Gastroenterol Hepatol 1997; 12(suppl):S242-5250

(2.) Hautekeete ML: Hepatotoxicity of antibiotics. Acta Gastroenterol Belg 1995; 58:290-296

(3.) Sher TH: Penicillin hypersensitivity--a review. Pediatr Clin North Am 1983; 30:161-176

(4.) Moller NE, von Wurden K: Hypersensitivity to semisynthetic penicillins and cross-reactivity with penicillin. Contact Derm 1992; 26:351-352

(5.) Pollock AA, Berger SA, Simberkoff MS, et al: Hepatitis associated with high-dose oxacillin therapy. Arch Intern Med 1978; 138:915-917

(6.) Onorato IM, Axelrod JL: Hepatitis from intravenous high-dose oxacillin therapy: findings in an adult inpatient population. Ann Intern Med 1978; 89:497-500

(7.) Halloran TJ, Clague MD: Hepatitis associated with high-dose oxacillin therapy. Arch Intern Med 1979; 139:376-377

(8.) Knirsch AX, Gralla EJ: Abnormal serum transaminase levels after parenteral ampicillin and carbenicillin administration. N Engl J Med 1970; 282:1081-1082

(9.) Saliba B, Herbert PN: Oxacillin hepatotoxicity in HIV-infected patients. Ann Intern Med 1994; 120:1048

(10.) Olans RN, Weiner LB: Reversible oxacillin hepatotoxicity. J Pediatr 1976; 89:835-838

(11.) Nahata MC, DeBolt SL, Powell DA: Adverse effects of methicillin, nafcillin and oxacillin in pediatric patients. Dev Pharmacol Ther 1982; 4:117-123

(12.) Bruckstein AH, Attia AA: Oxacillin hepatitis. two patients with liver biopsy, and review of the literature. Am J Med 1978; 64:519-522

(13.) Ten Pas A, Quinn EL: Cholestatic hepatitis following the administration of sodium oxacillin. JAMA 1965; 19:138-139

(14.) Tauris, P, Jorgensen NF, Petersen CM, et al: Prolonged severe cholestasis induced by oxacillin derivatives a report on two cases. Acta Med Scand 1985; 217:567-569

(15.) Konikoff F, Alcalay J, Halevy J: Cloxacillin-induced cholestatic jaundice. Am J Gastroenterol 1986; 81:1082-1083

(16.) Buhl R, Jaffe HA, Holroyd KJ, et al: Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet 1989; 2:1294-1298

(17.) Taylor C, Corrigan K, Steen S, et al: Oxacillin and hepatitis. Ann Intern Med 1979; 90:857-858

(18.) Dismukes WE: Oxacillin-induced hepatic dysfunction. JAMA 1973; 226:861-863

RELATED ARTICLE: KEY POINTS

* Oxacillin can induce hepatitis that is specific to Oxcaillin and' not to other [alpha]-lactams.

* Oxacillin-induced hepatitis is usually anicteric, with variable elevation of transaminases, and normal or slightly elevated alkaline phosphatase level.

* Oxacillin-induced hepatitis is reversible and has no apparent long-term injurious effects.

* The predisposing factors and mechanism of oxacillin-induced hepatitis are not known.

From the Department of Pediatrics, Wayne State University School of Medicine, and the Divisions of Gastroenterology and Infectious Diseases, Children's Hospital of Michigan, Detroit.

Reprint requests to Basim I. Asmar, MD, children's Hospital of Michigan, Division of Infectious Diseases, 3901 Beaubien Blvd, Detroit, MI 48201.