ceftazidime/avibactam (Rx)

1-10% (cIAI plus metronidazole)

Diarrhea (8%)

Nausea (7%)

Vomiting (5%)

Headache (3%)

Dizziness (2%)

Abdominal pain (1%)

1-10% (cUTI in pediatric patients)

Vomiting (>3%)

Diarrhea (>3%)

Rash (>3%)

Infusion site phlebitis (>3%)

1-10% (cUTI)

Diarrhea (3%)

Nausea (3%)

Constipation (2%)

Upper abdominal pain (1%)

1-10% (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

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 decrease the elimination of avibactam when coadministered; therefore, coadministration of ceftazidime/avibactam with probenecid is not recommended
• Ceftazidime administration may result in a false-positive reaction for glucose in the urine with certain methods; glucose tests based on enzymatic glucose oxidase reactions be used

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.

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%)

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 reconstitution, 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
• For adults and pediatric patient (≥40 kg), reconstituted solution results in 167 mg/mL of ceftazidime and 42 mg/mL of avibactam; final volume is ~12 mL
• For pediatric patients (<40 kg), reconstitute solution with a final concentration of ceftazidime 167 mg/mL and avibactam 42 mg/mL
• 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 reconstituted vial for further dilution for patients (≥40 kg)

  • 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)

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