Dosing and uses of Avycaz (ceftazidime/avibactam)
Adult dosage forms and strengths
ceftazidime/avibactam
powder for reconstitution for IV administration
- (2g/0.5g)/vial
- Powder must be reconstituted and further diluted before IV infusion
Intra-abdominal Infections
Indicated in combination with metronidazole for complicated intra-abdominal infections (cIAIs) caused by the following susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa
2.5 g (2 g/0.5 g) IV q8hr infused over 2 hr for 5-14 days
Urinary Tract Infections
Indicated for complicated urinary tract infections (cUTIs) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus spp., and Pseudomonas aeruginosa
2.5 g (2 g/0.5 g) IV q8hr infused over 2 hr for 7-14 days
Dosage modifications
Renal impairment
- CrCl estimated with Cockcroft-Gault formula
- CrCl >50 mL/min: No dose adjustment required
- CrCl 31-50 mL/min: 1.25 g (1 g/0.25 g) IV q8hr
- CrCl 16-30 mL/min: 0.94 g (0.75 g/0.19 g) IV q12hr
- CrCl 6-15 mL/min: 0.94 g (0.75 g/0.19 g) IV q24hr
- CrCl <5 mL/min: 0.94 g (0.75 g/0.19 g) IV q48hr
Hemodialysis
- Both ceftazidime and avibactam are removed by dialysis
- Administer ceftazidime/avibactam following hemodialysis on hemodialysis days
- 55% of the ceftazidime dose is removed by hemodialysis
- 55% of the avibactam dose is removed by hemodialysis
- Monitor CrCl daily and adjust ceftazidime/avibactam dose accordingly
Dosing Considerations
To reduce the development of drug-resistant bacteria and maintain the effectiveness, use only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Geriatric dosage forms and strengths
Carefully monitor renal function in patients aged >65 yr
See adult dosing section for dose adjustment based on CrCL
Avycaz (ceftazidime/avibactam) adverse (side) effects
1-10% (in cIAI plus metronidazole)
Diarrhea (8%)
Nausea (7%)
Vomiting (5%)
Headache (3%)
Dizziness (2%)
Abdominal pain (1%)
1-10% (in cUTI)
Constipation (10%)
Anxiety (10%)
Abdominal pain (7%)
Upper abdominal pain (7%)
Dizziness (6%)
<1% in cIAI
Blood and lymphatic disorders -Eosinophilia, thrombocytopenia
General disorders and administration site conditions -Injection site phlebitis
Infections and infestations -Candidiasis
Investigations -Increased aspartate aminotransferase, increased alanine aminotransferase, increased gamma-glutamyltransferase, prolonged prothrombin time
Metabolism and nutrition disorders -Hypokalemia
Nervous system disorders -Dysgeusia
Renal and urinary disorders -Acute renal failure, renal impairment
Skin and subcutaneous tissue disorders -Rash, rash maculo-papular, urticaria, pruritus
Warnings
Contraindications
Known serious hypersensitivity to avibactam, ceftazidime, or other cephalosporins
Cautions
In clinical trials, cure rates were lower in patients with baseline moderate renal impairment (CrCl 30-50 mL/min) who were treated for cIAI with ceftazidime/avibactam plus metronidazole (45% cure rate) compared with meropenem (74% cure rate); during the clinical trial, the ceftazidime/avibactam dose was 33% lower than what is currently recommended for patients with moderate renal impairment (see Dosage modifications); follow current dosage adjustment recommendations for renal impairment
Serious and occasionally fatal anaphylactic reactions and serious skin reactions have been reported with beta-lactam antibacterials; caution in patients with history of allergy to cephalosporins, penicillins, or carbapenems
Clostridium difficile associated diarrhea (CDAD) has been associated with nearly all systemic antibacterials; severity may range from mild diarrhea to fatal colitis; may occur >2 months following antibacterial use; if CDAD suspected, manage fluid and electrolytes levels and monitor antibacterial treatment for CDAd
Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with ceftazidime, especially in the setting of renal impairment; adjust dose according to CrCl (see Dosage modifications)
Confirm suspected bacterial infection when prescribing ceftazidime/avibactam to avoid the risk of developing drug-resistant bacteria
Pregnancy and lactation
Pregnancy category: B
Animal reproductive toxicity studies in rats and rabbits using doses approximately 9 times the human dose have not shown teratogenic effects
Lactation: Ceftazidime is excreted in human milk in low concentrations; unknown if avibactam distributed in human breast milk; caution advised if breast feeding
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Avycaz (ceftazidime/avibactam)
Mechanism of action
Ceftazidime: Third-generation cephalosporin with broad-spectrum gram-negative activity, including Pseudomonas; arrests bacterial growth by binding to 1 or more penicillin-binding proteins, and thereby inhibiting final transpeptidation step of peptidoglycan synthesis in bacterial cell-wall synthesis and inhibiting cell-wall biosynthesis
Avibactam: Diazabicyclooctanone, non-β-lactam, β-lactamase inhibitor; alone has no antibacterial activity at clinically relevant doses; when combined with ceftazidime, avibactam protects ceftazidime from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of ceftazidime to include many gram-negative bacteria normally not susceptible to ceftazidime
Absorption
Bioavailability: 100%
Peak plasma time: 2 hr after initiating the infusion
Peak plasma concentration: ceftazidime 90.4 mg/L; avibactam 14.6 mg/L
AUC: ceftazidime 291 mg•hr/L; avibactam 38.2 mg•hr/L
Distribution
Protein bound: ceftazidime <10%; avibactam 5.7-8.2%
Vd: ceftazidime 17 L; avibactam 22.2 L
Metabolism
80-90% of ceftazidime IV dose is eliminated unchanged via the urine
Nearly 100% of avibactam IV dose is eliminated unchanged via the urine
Elimination
Half-life: ceftazidime 2.76 hr; avibactam 2.71 hr
Plasma clearance: ceftazidime 6.86 L/hr; avibactam 13.1 L/hr
Excretion: Nearly 100% in urine for both ceftazidime and avibactam
Administration
IV Compatibilities
0.9% NaCL
5% dextrose
All combinations of dextrose and sodium chloride injection containing up to 2.5% dextrose and 0.45% NaCL
Lactated Ringer injection
IV Preparation
Reconstitute powder with 10 mL of one of the following solutions
- Sterile water for injection
- 0.9% NaCl
- 5% dextrose
- All combinations of dextrose and sodium chloride injection containing up to 2.5% dextrose and 0.45% NaCl
- Lactated Ringer injection
Additional dilution required
- Mix vial gently with 10 mL of a solution listed above
- Reconstituted solution results in ~0.167 g/mL of ceftazidime and ~0.042 g/mL avibactam
- Further dilute with the same diluent used for reconstitution (except sterile water for injection), to achieve a total volume of 50-250 mL before infusion
- Mix gently and ensure contents are dissolved completely
- Visually inspect for particulate matter and discoloration (color ranges from clear to light yellow)
IV Administration
Infuse IV over 2 hr
Storage
Unreconstituted viaL
- Store at 25°C (77°F); excursion permitted between 15-30°C (59-86°F)
- Protect from light
Diluted solution
- Diluted solution (ie, final dilution of 50-250 mL) should be used within 12 hr if stored at room temperature
- May store refrigerated (2-8°C [36-46°F]) for up to 24 hr and use within 12 hr of subsequent storage at room temperature
