ceftazidime/avibactam

Action and Spectrum

Actions and Spectrum: 

• ceftazidime/avibactam is a combination antibiotic medication that consists of ceftazidime, a third-generation cephalosporin, and avibactam, a beta-lactamase inhibitor. The combination enhances the activity of ceftazidime against certain bacteria that produce beta-lactamase enzymes, which are responsible for resistance to beta-lactam antibiotics. 
• ceftazidime is a beta-lactam antibiotic that inhibits bacterial cell wall synthesis. It binds to and inhibits penicillin-binding proteins (PBPs), enzymes involved in the final steps of peptidoglycan synthesis in bacterial cell walls. By disrupting cell wall formation, ceftazidime weakens the bacterial cell structure, leading to cell lysis and death. 
• avibactam is a non-beta-lactam, beta-lactamase inhibitor. It irreversibly binds to and inhibits certain beta-lactamases produced by bacteria, including some extended-spectrum beta-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs). By inhibiting these enzymes, avibactam prevents the degradation of ceftazidime by beta-lactamases, thereby restoring ceftazidime’s activity against the resistant bacteria. 
• ceftazidime/avibactam exhibits a broad spectrum of activity against Gram-negative and some Gram-positive bacteria. It is particularly effective against multidrug-resistant organisms that produce beta-lactamases. The spectrum of activity includes: 

Gram-Negative Bacteria: 

Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Citrobacter freundii, etc. 

Pseudomonas aeruginosa 

Haemophilus influenzae 

Moraxella catarrhalis 

Burkholderia cepacia complex 

Gram-Positive Bacteria (limited activity): 

Staphylococcus aureus (including methicillin-resistant strains) – ceftazidime/avibactam is inactive against MRSA (methicillin-resistant Staphylococcus aureus) strains. 

Drug Interaction

Adverse Reaction

Frequency defined 

1-10% (cIAI plus metronidazole) 

Nausea (7%) 

Headache (3%) 

Abdominal pain (1%) 

Diarrhea (8%) 

Vomiting (5%) 

Dizziness (2%) 

1-10% (cUTI in pediatric patients) 

Diarrhea (>3%) 

Infusion site phlebitis (>3%) 

Vomiting (>3%) 

Rash (>3%) 

1-10% (cUTI) 

Nausea (3%) 

Upper abdominal pain (1%) 

Diarrhea (3%) 

Constipation (2%) 

1-10% (HABP/VABP) 

Pruritus (2%) 

Nausea (3%)  

Post-marketing reports 

Increased aspartate aminotransferase 

Acute kidney injury 

Rash maculopapular 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

Hypersensitivity 

Caution: 

• Allergic Reactions: Like other antibiotics, ceftazidime/avibactam can cause allergic reactions ranging from mild to severe. It is essential to monitor patients for signs of allergic reactions, such as rash, itching, swelling, or difficulty breathing. If an allergic reaction occurs, treatment should be discontinued, and appropriate medical intervention should be initiated. 
• Clostridium difficile-Associated Diarrhea (CDAD): Antibiotic use, including ceftazidime/avibactam, can disrupt the normal gut flora and lead to the overgrowth of Clostridium difficile bacteria. This can result in severe Clostridium difficile-associated diarrhea (CDAD).  
• Drug Interactions: ceftazidime/avibactam has the potential to interact with other medications.  
• Seizures: ceftazidime, the component of ceftazidime/avibactam, has been associated with an increased risk of seizures, particularly in patients with renal impairment or a history of central nervous system disorders.  
• Impaired Renal Function: Dosage adjustments are necessary for patients with renal impairment. ceftazidime is primarily eliminated through the kidneys, and decreased renal function can lead to increased drug levels and the potential for adverse effects. Dose modifications should be made based on the patient’s estimated creatinine clearance. 

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

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

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: 

• The combination of ceftazidime and avibactam expands the spectrum of activity of ceftazidime to include certain multidrug-resistant Gram-negative bacteria that produce beta-lactamases. Avibactam protects ceftazidime from these beta-lactamases’ degradation, allowing it to exert its antibacterial effects. 
• ceftazidime inhibits bacterial cell wall synthesis by binding to and inhibiting penicillin-binding proteins (PBPs). This disrupts the final steps of peptidoglycan synthesis in bacterial cell walls, leading to cell lysis and bacterial death. 
• avibactam is a non-beta-lactam, beta-lactamase inhibitor. It irreversibly binds to and inhibits certain beta-lactamase enzymes, including extended-spectrum beta-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs). By inhibiting these enzymes, avibactam prevents the degradation of ceftazidime by beta-lactamases, thereby restoring ceftazidime’s activity against resistant bacteria. 

Pharmacokinetics: 

Absorption 

ceftazidime/avibactam is administered intravenously. Both ceftazidime and avibactam are rapidly and completely absorbed into the systemic circulation following intravenous administration. 

Distribution 

ceftazidime exhibits low protein binding (<10%), while avibactam is moderately bound to plasma proteins (5.7-8.2%).The steady-state volume of distribution is 18.1 L for ceftazidime and 23.2 L for avibactam. 

Metabolism 

ceftazidime is primarily eliminated unchanged through the kidneys and undergoes minimal metabolism in the body. avibactam does not undergo significant metabolism. It is eliminated primarily unchanged in the urine. 

Elimination/Excretion 

Approximately 80-90% of the ceftazidime intravenous dose is excreted unchanged in the urine. Nearly 100% of the avibactam intravenous  

the dose is excreted unchanged in the urine. 

The half-life of ceftazidime is approximately 3.27 hours after a single 2.5 g-dose and 2.76 hours after multiple 2.5 g-doses. The half-life of avibactam is approximately 2.22 hours after a single 2.5 g-dose and 2.71 hours after multiple 2.5 g-doses.  

The clearance of ceftazidime is 6.93 L/h after a single 2.5 g-dose and 6.86 L/h after multiple 2.5 g-doses. The clearance of avibactam is 11.9 L/h after a single 2.5 g-dose and 13.1 L/h after multiple 2.5 g-doses. 

Adminstartion

Administration: 

ceftazidime/avibactam is administered intravenously (IV). It is typically given as an infusion over a specified period. The specific dosage and administration schedule may vary depending on the indication, the severity of the infection, and individual patient factors. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ceftazidime/avibactam 

Why do we use ceftazidime/avibactam? 

ceftazidime/avibactam is a combination antibiotic used to treat various infections caused by susceptible bacteria. It is primarily indicated for the following: 

• Complicated Intra-abdominal Infections (cIAI): ceftazidime/avibactam is used in adults and pediatric patients (age 3 months and older) for the treatment of appendicitis, peritonitis, and intra-abdominal abscesses. 
• Complicated Urinary Tract Infections (cUTI), including Pyelonephritis: ceftazidime/avibactam is indicated for the treatment of kidney infections (pyelonephritis), in adults and pediatric patients (age 3 months and older). 
• Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia (HABP/VABP): ceftazidime/avibactam is used in adults for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, which are serious infections occurring in patients who are hospitalized or on mechanical ventilation.