Dosing & Uses
Dosage Forms & Strengths
ceftazidime/avibactam
injection, powder of reconstitution
- (2g/0.5g)/vial: 2.5g
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 mirabilis, and Pseudomonas aeruginosa
2.5 g (2 g/0.5 g) IV q8hr infused over 2 hr for 7-14 days
Bacteria Pneumonia
Indicated for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible gram negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients ≥18 years
2.5 g (2 g/0.5 g) IV q8hr infused over 2 hr for 7-14 days
Dosage Modifications
Renal impairment
- 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
- Patients on hemodialysis: Administer after hemodialysis on hemodialysis days
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
<18 years: Safety and efficacy not established
Carefully monitor renal function in patients aged >65 yr
Dosage adjustment for elderly patients should be based on renal function (see Dosage Modifications)
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
1-10% (in cIAI plus metronidazole)
Diarrhea (8%)
Nausea (7%)
Vomiting (5%)
Headache (3%)
Dizziness (2%)
Abdominal pain (1%)
1-10% (in cUTI)
Diarrhea (3%)
Nausea (3%)
Constipation (2%)
Upper abdominal pain (1%)
1-10% (in HABP/VABP)
Nausea (3%)
Pruritus (2%)
Frequency Not Reported
Blood and lymphatic disorders: Thrombocytopenia, thrombocytosis, leukopenia
General disorders and administration site conditions: Injection site phlebitis
Infections and infestations: Candidiasis
Investigations:Increased aspartate aminotransferase, increased alanine aminotransferase, increased gamma-glutamyltransferase
Metabolism and nutrition disorders: Hypokalemia
Nervous system disorders: Dysgeusia
Renal and urinary disorders: Acute kidney injury, renal impairment, nephrolithiasis
Skin and subcutaneous tissue disorders: Rash, rash maculopapular, urticaria
Psychiatric disorders: Anxiety
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
Drug interactions overview
- Avibactam is an OAT1/OAT3 substrate; probenecid, a potent OAT inhibitor, inhibits OAT uptake of avibactam by 56-70% and potentially decreases avibactam elimination when coadministered; therefore, coadministration with probenecid is not recommended
- Ceftazidime administration may result in a false-positive reaction for urine glucose with certain methods; glucose tests based on enzymatic glucose oxidase reactions are recommended
Pregnancy & Lactation
Pregnancy
There are no adequate and well-controlled studies of ceftazidime/avibactam, ceftazidime, or avibactam in pregnant women
Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose; in the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam
Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed
Lactation
Ceftazidime is excreted in human milk in low concentrations
Unknown whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats
No information is available on the effects of ceftazidime and avibactam on the breastfed child or on milk production
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
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
Ceftazidime
- Peak plasma concentration: 88.1 mg/L (single 2.5 g-dose); 90.4 mg/L (multiple 2.5 g-dose)
- AUC: 289 mg·h/L (single 2.5 g-dose); 291 mg·h/L (multiple 2.5 g-dose)
Avibactam
- Peak plasma concentration: 15.2mg/L (single 2.5 g-dose); 14.6 mg/L (multiple 2.5 g-dose)
- AUC: 42.1 mg·h/L (single 2.5 g-dose); 38.2 mg·h/L (multiple 2.5 g-dose)
Distribution
Protein bound: <10% (ceftazidime); 5.7-8.2% (avibactam)
Ceftazidime
- Vd (steady-state): 18.1 L (single 2.5 g-dose); 17 L (multiple 2.5 g-dose)
Avibactam
- Vd (steady-state): 23.2 L (single 2.5 g-dose); 22.2 L (multiple 2.5 g-dose)
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
Ceftazidime
- Half-life: 3.27 hr (single 2.5 g-dose); 2.76 hr (multiple 2.5 g-dose)
- Clearance (L/h): 6.93 L/h (single 2.5 g-dose); 6.86 L/h (multiple 2.5 g-dose)
- Excretion: Urine (~80- 90% as unchanged drug)
Avibactam
- Half-life: 2.22 hr (single 2.5 g-dose); 2.71hr (multiple 2.5 g-dose)
- Clearance (L/h): 11.9 L/h (single 2.5 g-dose); 13.1 L/h (multiple 2.5 g-dose)
- Excretion, single 0.5 g-dose: Urine (97%); feces (0.2%)
Administration
IV Compatibilities
0.9% NaCl
D5W
All combinations of dextrose and sodium chloride injection containing up to 2.5% dextrose and 0.45% NaCl
Lactated Ringer injection
Y-site compatibility
- Compatible drugs for use with 0.9% NaCl, D5W or Lactated Ringer injection as diluents
- Daptomycin
- Dexmedetomidine HCl
- Dopamine HCl
- Furosemide
- Gentamicin sulfate
- Imipenem-cilastatin
- Magnesium sulfate
- Norepinephrine bitartrate
- Phenylephrine HCl
- Vasopressin
- Vecuronium bromide
- Compatible drugs for use with 0.9% NaCl or D5W as diluents
- Ertapenem sodium
- Potassium phosphate
- Sodium glycerophosphate
- Compatible drugs for use with D5W or Lactated Ringer injection as diluents
- Heparin sodium
- Linezolid
- Tobramycin sulfate
- Compatible drugs for use with one compatible diluent only
- Meropenem (0.9% NaCl diluent only)
- Sodium bicarbonate (D5W diluent only)
- Tedizolid phosphate (D5W diluent only)
- Potassium chloride (Lactated Ringer injection diluent only)
IV Preparation
Reconstitute powder with 10 mL of one of the following solutions
- Sterile water for injection
- 0.9% NaCl
- D5W
- All combinations of dextrose and sodium chloride injection containing up to 2.5% dextrose and 0.45% NaCl
- Lactated Ringer injection
- Upon constitution, solution may be held for no longer than 30 minutes before transferring and further diluting in a suitable infusion bag
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
- Volume to withdraw from constituted vial for further dilution
- 2.5 g (2 g/0.5 g): 12 mL (entire contents)
- 1.25 g (1 g/0.25 g): 6 mL
- 0.94 g (0.75 g/0.19 g): 4.5 mL
- Mix gently and ensure contents are dissolved completely
- Visually inspect for particulate matter and discoloration (color ranges from clear to light yellow)
- Use diluted infusion bags within 12 hr when stored at room temperature or under refrigeration at 2-8°C (36- 46°F) up to 24 hr following dilution and used within 12 hr of subsequent storage at room temperature
IV Administration
Infuse IV over 2 hr
Storage
Unopened vials
- Store at 25°C (77°F); excursion permitted between 15-30°C (59-86°F)
- Protect from light
Diluted solution
- Stored at room temperature, 25°C (77°F) for up to 12 hr
- Refrigerate at 2-8°C (36- 46°F) up to 24 hr following dilution and used within 12 hr of subsequent storage at room temperature
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Patient Handout
Formulary
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