Clavulanate/ticarcillin Disease Interactions

The administration of amoxicillin-clavulanate has infrequently been associated with hepatotoxicity such as elevations in serum transaminases, bilirubin, and/or alkaline phosphatase. The histologic findings on liver biopsy have consisted of predominantly cholestatic and/or hepatocellular changes. Symptoms may occur during or several weeks after therapy. The hepatotoxicity is generally reversible, although deaths have been reported on rare occasions, mostly in patients with serious underlying diseases or concomitant use of other medications. Liver enzyme abnormalities have also been observed with the use of amoxicillin or ampicillin alone. According to the manufacturer, therapy with amoxicillin-clavulanate should be administered cautiously in patients with evidence of hepatic dysfunction. Periodic monitoring of liver function is recommended during prolonged therapy. The use of amoxicillin-clavulanate is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with the drug.

Clostridioides difficile-associated diarrhea (CDAD), formerly pseudomembranous colitis, has been reported with almost all antibacterial drugs and may range from mild diarrhea to fatal colitis. The most common culprits include clindamycin and lincomycin. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C difficile, whose toxins A and B contribute to CDAD development. Morbidity and mortality are increased with hypertoxin-producing strains of C difficile; these infections can be resistant to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea after antibacterial use. Since CDAD has been reported to occur more than 2 months after antibacterial use, careful medical history is necessary. Therapy with broad-spectrum antibacterials and other agents with significant antibacterial activity should be administered cautiously in patients with history of gastrointestinal disease, particularly colitis; pseudomembranous colitis (generally characterized by severe, persistent diarrhea and severe abdominal cramps, and sometimes associated with the passage of blood and mucus), if it occurs, may be more severe in these patients and may be associated with flares in underlying disease activity. Antibacterial drugs not directed against C difficile may need to be stopped if CDAD is suspected or confirmed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C difficile, and surgical evaluation should be started as clinically indicated.

The use of extended-spectrum penicillin antibiotics has rarely been associated with coagulation abnormalities manifested as prolonged prothrombin and bleeding times, abnormal platelet aggregation, purpura, and clinical bleeding. These reactions have been most severe and most frequently reported in patients with renal impairment given high dosages of the drugs for prolonged periods, although they have also occurred with usual dosages in patients with normal renal function. Therapy with extended-spectrum penicillins should be administered cautiously in patients with significantly impaired renal function, severe active bleeding, or a hemorrhagic diathesis such as hemophilia, vitamin K deficiency, hypoprothrombinemia, thrombocytopenia, or thrombocytopathy. Clinical monitoring of hematopoietic and renal function is recommended during prolonged and/or high-dose therapy. Bleeding manifestations are reversible upon discontinuation of the antibiotic.

Most beta-lactam antibacterial agents are eliminated by the kidney as unchanged drug and, in some cases, also as metabolites. The serum concentrations of beta-lactam antibacterial agents and their metabolites may be increased, and the half-lives prolonged, in patients with impaired renal function. Neurotoxic reactions (e.g., encephalopathy, aphasia, asterixis, myoclonus, seizures, nonconvulsive status epilepticus, coma) have been reported in such patients treated parenterally with these agents. Dosage adjustments may be necessary, and modifications should be based on the degree of renal function as well as severity of infection in accordance with the individual manufacturer product information. Renal function tests should be performed periodically during prolonged and/or high-dose therapy since nephrotoxicity and alterations in renal function have occasionally been associated with the use of these drugs.

Penicillin antibiotics (except for agents in the penicillinase-resistant class) are removed by hemodialysis. Doses should either be scheduled for administration after dialysis or supplemental doses be given after dialysis.

Parenteral ticarcillin disodium contains approximately 120 to 150 mg (5.2 to 6.5 mEq) of sodium per each gram of ticarcillin activity. The combination, ticarcillin-clavulanate, contains approximately 109 mg (4.75 mEq) of sodium per gram of total drug. The sodium content should be considered in patients with conditions that may require sodium restriction, such as congestive heart failure, hypertension, and fluid retention. In addition, hypokalemia has been reported rarely during therapy with ticarcillin and other extended-spectrum penicillin antibiotics, which may be particularly important to bear in mind when treating patients with low potassium reserves or fluid and electrolyte imbalance. Clinical monitoring of electrolytes is recommended if these agents are used for prolonged periods.