ceftolozane/​tazobactam

Action and Spectrum

Actions and Spectrum: 

• ceftolozane/tazobactam is an antibiotic combination used to treat various bacterial infections. It consists of two active components: ceftolozane, a cephalosporin antibiotic, and tazobactam, a beta-lactamase inhibitor. Combining these two drugs enhances their effectiveness against a broad spectrum of bacteria. 
• ceftolozane specifically targets the penicillin-binding proteins (PBPs) responsible for constructing the cell walls of bacteria. By binding to PBPs, ceftolozane disrupts the cross-linking process of peptidoglycans, an essential bacterial cell wall component. As a result, the cell wall weakens, leading to cell lysis and bacterial death. 
• tazobactam, on the other hand, is a beta-lactamase inhibitor. Beta-lactamases are enzymes produced by certain bacteria that can inactivate beta-lactam antibiotics like cephalosporins. tazobactam works by irreversibly binding to beta-lactamase enzymes, preventing them from breaking down ceftolozane.  
• ceftolozane/tazobactam has a broad spectrum of activity against Gram-negative and some Gram-positive bacteria. It is particularly effective against multidrug-resistant strains, including certain types of Enterobacteriaceae and Pseudomonas aeruginosa. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% (HABP/VABP) 

Increased hepatic transaminase (11.9%)  

1-10% (cIAI/cUTI) 

Headache (2.5-5.8%) 

Pyrexia (1.7-5.6%) 

Insomnia (1.3-3.5%) 

Nausea (2.8-7.9%) 

Diarrhea (1.9-6.2%) 

Constipation (1.9-3.9%) 

Hypokalemia (0.8-3.3%) 

AST increased (1-1.7%) 

Thrombocytosis (0.4-1.9%) 

Anxiety (0.2-1.9%) 

Vomiting (1.1-3.3%) 

ALT increased (1.7-1.5%) 

Anemia (0.4-1.5%) 

Abdominal pain (0.8-1.2%) 

1-10% (HABP/VABP) 

Diarrhea (6.4%) 

Vomiting (3.3%) 

Renal impairment/failure (8.9%) 

Intracranial hemorrhage (4.4%) 

Clostridioides difficile-associated diarrhea (2.8%) 

Post-marketing reports 

Candidiasis candidiasis 

Renal impairment 

Urticaria 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

Hypersensitivity 

Caution: 

• Clostridium difficile infection: Antibiotic therapy, including ceftolozane/tazobactam, can disrupt the average balance of bacteria in the gastrointestinal tract and potentially lead to the overgrowth of Clostridium difficile bacteria. This can result in severe Clostridium difficile-associated diarrhea (CDAD). 
• Seizures: ceftolozane/tazobactam has been associated with a risk of seizures, particularly in patients with pre-existing risk factors such as a history of seizures, epilepsy, or central nervous system (CNS) disorders.  
• Liver and kidney function: ceftolozane/tazobactam is primarily eliminated from the body through the kidneys. Dosage adjustments may be necessary for patients with impaired renal function.  

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

ceftolozane is a third-generation cephalosporin antibiotic. It exerts its bactericidal effects by inhibiting the bacterial cell wall synthesis. It specifically targets and binds to penicillin-binding proteins (PBPs) in cell wall synthesis. This binding inhibits the transpeptidation step of peptidoglycan cross-linking, resulting in weakened cell walls, cell lysis, and bacterial death. 

tazobactam is a beta-lactamase inhibitor. It irreversibly binds to and inactivates beta-lactamase enzymes produced by certain bacteria. Beta-lactamases are enzymes responsible for the hydrolysis and inactivation of beta-lactam antibiotics, including cephalosporins. By inhibiting beta-lactamases, tazobactam prevents the breakdown of ceftolozane and extends its antibacterial activity. 

Pharmacokinetics: 

Absorption 

Peak plasma time: Approximately 1.02 hours after administration. 

Peak plasma concentration: 

• For cIAI and cUTI indications: 

ceftolozane: 65.7 mcg/mL 

tazobactam: 17.8 mcg/mL

• For HABP/VABP indication: 

ceftolozane: 105 mcg/mL 

tazobactam: 26.4 mcg/mL 

Area Under the Curve: 

• For cIAI and cUTI indications: 

ceftolozane: 186 mcg•h/mL 

tazobactam: 35.8 mcg•h/mL 

• For HABP/VABP indication: 

ceftolozane: 392 mcg•h/mL 

tazobactam: 73.3 mcg•h/mL 

Distribution 

Approximately 16-21% of ceftolozane bound to plasma proteins. 

Approximately 30% of tazobactam bound to plasma proteins. 

Volume of distribution (Vd): 

ceftolozane: 13.5 L 

tazobactam: 18.2 L 

Metabolism 

ceftolozane is not metabolized to a significant extent.tazobactam undergoes hydrolysis of the beta-lactam ring to form the inactive metabolite M1. 

Elimination/Excretion 

The half-life of ceftolozane is approximately 2.77 hours. The half-life of  tazobactam is approximately 0.91 hours. 

The renal clearance ranges from 3.41 to 5.59 L/hr. More than 95% of ceftolozane is excreted unchanged in the urine. Over 80% of tazobactam is excreted as the parent compound in the urine, while the remaining portion is excreted as the M1 metabolite. 

Adminstartion

Administration: 

• Route of administration: ceftolozane/tazobactam is given by intravenous infusion. It should not be administered by other routes such as intramuscularly or subcutaneously. 
• Preparation: ceftolozane/tazobactam is supplied as a powder for reconstitution. According to the instructions, the powder should be reconstituted with the appropriate diluent (usually sterile water for injection).  
• Infusion duration: The infusion duration for ceftolozane/tazobactam can vary depending on the indication and the recommended dosage. It is typically administered over 1 hour 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ceftolozane/tazobactam 

Why do we use ceftolozane/tazobactam? 

ceftolozane/tazobactam is a combination medication used to treat certain bacterial infections. It is indicated for the following: 

• Complicated Intra-abdominal Infections (cIAI): ceftolozane/tazobactam is combined with metronidazole to treat cIAI caused by susceptible Gram-negative and Gram-positive bacteria, including multidrug-resistant pathogens. 
• Complicated Urinary Tract Infections (cUTI), including pyelonephritis: ceftolozane/tazobactam treats cUTI caused by susceptible Gram-negative bacteria, including multidrug-resistant strains. 
• Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia (HABP/VABP): ceftolozane/tazobactam is indicated for the treatment of HABP/VABP caused by susceptible Gram-negative pathogens, including multidrug-resistant strains.