Ceftolozane/tazobactam
Introduction
Ceftolozane/tazobactam is a combination antibiotic used in the treatment of various bacterial infections. It consists of ceftolozane, a cephalosporin antibiotic, and tazobactam, a β-lactamase inhibitor. This combination is particularly effective against Gram-negative bacteria, including multidrug-resistant strains. It is marketed under the trade name Zerbaxa.
Composition and Mechanism of Action
Ceftolozane is a fifth-generation cephalosporin that inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This action disrupts the peptidoglycan cross-linking, leading to cell lysis and death. Tazobactam, on the other hand, is a β-lactamase inhibitor that protects ceftolozane from degradation by β-lactamase enzymes produced by certain bacteria. This combination enhances the spectrum of activity of ceftolozane, making it effective against β-lactamase-producing organisms.
Pharmacokinetics
Ceftolozane/tazobactam is administered intravenously. The pharmacokinetics of ceftolozane and tazobactam are similar, with both components exhibiting linear pharmacokinetics. After administration, ceftolozane and tazobactam are distributed widely in body tissues and fluids. The elimination half-life of both drugs is approximately 2.5 to 3 hours. They are primarily excreted unchanged in the urine, making dose adjustment necessary in patients with renal impairment.
Clinical Uses
Ceftolozane/tazobactam is approved for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI), including pyelonephritis. It is often used in combination with metronidazole for the treatment of cIAI. The combination is also being investigated for its efficacy in treating hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP).
Spectrum of Activity
Ceftolozane/tazobactam has a broad spectrum of activity against Gram-negative bacteria, including:
- Pseudomonas aeruginosa
- Escherichia coli
- Klebsiella pneumoniae
- Enterobacter cloacae
- Proteus mirabilis
It is also effective against some Gram-positive bacteria, although its primary use is against Gram-negative pathogens. The combination is particularly valuable in treating infections caused by multidrug-resistant Pseudomonas aeruginosa.
Resistance Mechanisms
Despite its broad spectrum of activity, resistance to ceftolozane/tazobactam can occur. Mechanisms of resistance include:
- Production of β-lactamases that are not inhibited by tazobactam.
- Alterations in PBPs that reduce the binding affinity of ceftolozane.
- Efflux pumps that expel the antibiotic from bacterial cells.
- Reduced permeability of the bacterial outer membrane.
Adverse Effects
Common adverse effects of ceftolozane/tazobactam include:
- Nausea
- Diarrhea
- Headache
- Pyrexia (fever)
- Phlebitis at the injection site
Serious adverse effects, although rare, may include hypersensitivity reactions, Clostridioides difficile-associated diarrhea, and renal impairment.
Dosage and Administration
The recommended dosage of ceftolozane/tazobactam for adults with normal renal function is 1.5 grams (1 gram of ceftolozane and 0.5 grams of tazobactam) administered every 8 hours. The duration of therapy depends on the type and severity of the infection. Dose adjustments are necessary for patients with renal impairment, and the dosage should be reduced based on the degree of renal function.
Drug Interactions
Ceftolozane/tazobactam has minimal drug-drug interactions. However, it should be used with caution in patients receiving other nephrotoxic agents, as the risk of renal impairment may be increased. Additionally, co-administration with probenecid can increase the plasma concentrations of tazobactam, although this is not considered clinically significant.
Clinical Trials and Studies
Several clinical trials have demonstrated the efficacy and safety of ceftolozane/tazobactam in treating cIAI and cUTI. In a phase 3 trial for cIAI, the combination of ceftolozane/tazobactam with metronidazole was found to be non-inferior to meropenem. Similarly, in a phase 3 trial for cUTI, ceftolozane/tazobactam was non-inferior to levofloxacin. Ongoing studies are evaluating its use in treating HABP and VABP.
Regulatory Status
Ceftolozane/tazobactam was approved by the U.S. Food and Drug Administration (FDA) in December 2014 for the treatment of cIAI and cUTI. It has also been approved by the European Medicines Agency (EMA) and other regulatory bodies worldwide.
Conclusion
Ceftolozane/tazobactam is a valuable antibiotic combination for the treatment of serious Gram-negative bacterial infections, particularly those caused by multidrug-resistant organisms. Its broad spectrum of activity, coupled with the β-lactamase inhibiting properties of tazobactam, makes it a potent option in the antimicrobial arsenal. Ongoing research and clinical trials will continue to define its role in the management of bacterial infections.