Avibactam/ceftazidime Disease Interactions

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.

Beta-lactamase inhibitors are available in combination with beta-lactam antibacterial agents. Beta-lactamase inhibitors are primarily eliminated by the kidneys, with 75% to over 95% of the administered dose excreted as unchanged drug. The plasma exposures (AUC) of beta-lactamase inhibitors (and the associated beta-lactam antibacterial agents) are increased with decreasing renal function. Dosage adjustments are generally necessary for products containing beta-lactamase inhibitors, and modifications should be based on the degree of renal dysfunction in accordance with the individual manufacturer product information. Because it may change during the course of therapy, renal function should be monitored regularly and the dosage should be adjusted accordingly, as appropriate.

Beta-lactamase inhibitors and beta-lactam antibacterial agents can be removed by hemodialysis. The dose should be administered after hemodialysis on hemodialysis days.

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.

Decreased clinical response has been observed in adult patients treated with the combination product, ceftazidime and avibactam for complicated intra-abdominal infections (cIAI) with baseline creatinine clearance (CrCl) of 30 to less than or equal to 50 mL/min. The decreased clinical response is not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min). It is recommended to monitor CrCl at least daily in adult and pediatric patients with changing renal function and adjust the dosage of treatment according to manufacturer recommendations.

Fortaz, Tazicef, and Tazidime (brands of parenteral ceftazidime pentahydrate) are formulated with sodium carbonate and contain approximately 53 mg (2.3 mEq) of sodium per each gram of ceftazidime activity. The sodium content should be considered in patients with conditions that may require sodium restriction, such as congestive heart failure, hypertension, and fluid retention. Ceptaz, another brand of ceftazidime, is formulated with l-arginine and contains no sodium.

Most cephalosporin antibiotics are removed by hemodialysis. Doses should either be scheduled for administration after dialysis or supplemental doses be given after dialysis. Cefonicid, cefixime, and ceftriaxone are not significantly removed by hemodialysis.

Cases of hepatitis have been reported with the use of certain cephalosporins. Transient rise in AST, ALT, and alkaline phosphatase levels have also been observed. Caution and monitoring are recommended when these agents are prescribed to patients with hepatic disorders.

Cephalosporins have been implicated in triggering seizures. Nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal dysfunction. Dosage should be adjusted based on the degree of renal function. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether treatment should be discontinued.