What are the potential side effects of Ceftazidime (Ceftazidime) avibactam in patients, particularly those with a history of impaired renal function or seizure disorders?

Ceftazidime-Avibactam Side Effects

Ceftazidime-avibactam is generally well-tolerated with a favorable safety profile comparable to other beta-lactam antibiotics, but patients with renal impairment face significant risk of neurotoxicity including seizures, encephalopathy, and coma if doses are not appropriately adjusted. 1

Common Side Effects (Occurring in <2% of Patients)

Local reactions:

• Phlebitis and inflammation at injection site (approximately 1 in 69 patients) 1

Hypersensitivity reactions (2% of patients):

• Pruritus, rash, and fever 1
• Immediate reactions manifested by rash and/or pruritus (1 in 285 patients) 1
• Rare but serious: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, and anaphylaxis with bronchospasm and/or hypotension 1

Gastrointestinal symptoms (<2% of patients):

• Diarrhea (1 in 78 patients) 1
• Nausea (1 in 156 patients) 1
• Vomiting (1 in 500 patients) 1
• Abdominal pain (1 in 416 patients) 1
• Clostridium difficile-associated diarrhea (CDAD), which can range from mild diarrhea to fatal colitis and may occur up to 2 months after treatment 1

Central nervous system reactions (<1%):

• Headache, dizziness, and paresthesia 1

Critical Safety Concerns in Renal Impairment

Neurotoxicity is the most serious adverse effect in patients with renal dysfunction, occurring when ceftazidime accumulates to toxic levels. 1, 2, 3

Specific neurological manifestations include:

• Seizures 1
• Non-convulsive status epilepticus (NCSE) 1
• Encephalopathy and progressive loss of consciousness 1, 3
• Coma 1
• Asterixis (flapping tremor) 1
• Neuromuscular excitability 1
• Myoclonia and myoclonic seizures 1, 3

A neurotoxicity threshold of 78 mg/L for ceftazidime plasma concentration has been proposed based on case analysis, though prospective validation is needed. 3

Laboratory Abnormalities

Hematologic changes (transient):

• Eosinophilia (1 in 13 patients) 1
• Positive Coombs test without hemolysis (1 in 23 patients) 1
• Thrombocytosis (1 in 45 patients) 1
• Rare cases of hemolytic anemia 1
• Very rare: transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and lymphocytosis 1

Hepatic enzyme elevations (transient):

• AST elevation (1 in 16 patients) 1
• ALT elevation (1 in 15 patients) 1
• LDH elevation (1 in 18 patients) 1
• GGT elevation (1 in 19 patients) 1
• Alkaline phosphatase elevation (1 in 23 patients) 1

Renal function changes:

• Transient elevations of blood urea nitrogen and/or serum creatinine 1

Comparative Safety Profile

Multiple observational studies and guidelines confirm that ceftazidime-avibactam demonstrates no significant differences in adverse event frequency compared to other antimicrobial regimens, with notably lower nephrotoxicity than colistin-based therapies. 4

In the TANGO-II trial, meropenem-vaborbactam showed reduced nephrotoxicity compared to best available therapy, and retrospective comparisons found no difference in adverse events between meropenem-vaborbactam and ceftazidime-avibactam. 4

Critical Dosing Considerations for Renal Impairment

Dose adjustment is mandatory in renal impairment to prevent neurotoxicity while maintaining efficacy. 1, 5, 6

Key dosing principles:

• Total daily dosage must be reduced when creatinine clearance is decreased 1
• Modified dosage adjustments (50% increase in total daily dose compared to original recommendations) were implemented during phase 3 trials to reduce risk of subtherapeutic exposures with rapidly improving renal function 5
• The 4:1 ratio of ceftazidime:avibactam should be maintained across all renal function categories, as both drugs demonstrate similar linear relationships between clearance and creatinine clearance 6
• For hemodialysis patients, >50% of avibactam is removed during a 4-hour session, requiring administration after dialysis 6

Monitoring Requirements

For patients with renal impairment receiving ceftazidime-avibactam:

• Monitor renal function (serum creatinine) regularly during therapy 1
• Consider therapeutic drug monitoring (TDM) of ceftazidime plasma concentrations in patients with severe renal impairment or those undergoing renal replacement therapy to avoid neurotoxicity while ensuring therapeutic levels 2, 3
• Maintain vigilance for neurological symptoms, particularly altered mental status, seizures, or myoclonus 2, 3

Special Populations

Patients with seizure disorders:

• Exercise extreme caution, as ceftazidime can lower seizure threshold, particularly when drug levels are elevated 1
• Ensure meticulous dose adjustment for renal function 1

Cross-reactivity concerns:

• Cross-hypersensitivity with penicillins occurs in up to 10% of patients with penicillin allergy 1
• Careful inquiry about prior hypersensitivity reactions to ceftazidime, cephalosporins, or penicillins is mandatory before initiation 1

Common Pitfalls to Avoid

Never use standard dosing in patients with any degree of renal impairment - this is the primary cause of ceftazidime neurotoxicity, as demonstrated by case reports showing plasma concentrations exceeding 200 mg/L in patients receiving unadjusted doses. 2, 3

Do not administer ceftazidime-avibactam before hemodialysis - both components are significantly removed during dialysis, resulting in subtherapeutic levels and treatment failure. 6

Avoid concurrent nephrotoxins (aminoglycosides, potent diuretics like furosemide) as nephrotoxicity risk increases with combination therapy. 1

Do not dismiss neurological symptoms as unrelated in patients receiving ceftazidime-avibactam with renal impairment - obtain ceftazidime levels and consider discontinuation if encephalopathy, seizures, or myoclonus develop. 2, 3

Never reduce the ceftazidime:avibactam ratio when adjusting for renal function - maintain the 4:1 ratio to preserve the pharmacodynamic relationship between the beta-lactam and beta-lactamase inhibitor. 6