Ceftolozane/tazobactam 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.

Ceftolozane, tazobactam and the tazobactam metabolite M1 are eliminated from the body by renal excretion. In a subgroup analysis of a Phase 3 cIAI trial, clinical cure rates were lower in patients with baseline creatinine clearance (CrCl) of 30 to <=50 mL/min compared to those with CrCl >50 mL/min. Dosage adjustment is required in patients with moderate (CrCl 30 to 50 mL/min) or severe (CrCl 15 to 29 mL/min) renal impairment and in patients with ESRD on HD as per manufacturer recommendations. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of the compound accordingly.