Ceftazidime-Avibactam
Avycaz — ceftazidime 2 g / avibactam 0.5 g per vial
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Complicated intra-abdominal infections (cIAI) | Adults & pediatrics ≥31 weeks GA | Combination with metronidazole | FDA Approved |
| Complicated urinary tract infections (cUTI) including pyelonephritis | Adults & pediatrics ≥31 weeks GA | Monotherapy | FDA Approved |
| Hospital-acquired / ventilator-associated bacterial pneumonia (HABP/VABP) | Adults & pediatrics ≥31 weeks GA | Monotherapy | FDA Approved |
Ceftazidime-avibactam provides coverage against a broad range of gram-negative pathogens including E. coli, K. pneumoniae, P. mirabilis, E. cloacae, K. oxytoca, C. freundii complex, S. marcescens, P. aeruginosa, and H. influenzae. The addition of avibactam restores ceftazidime activity against organisms producing Ambler class A beta-lactamases (ESBLs, KPC carbapenemases), class C (AmpC), and some class D (OXA-48). Critically, avibactam does not inhibit class B metallo-beta-lactamases (NDM, VIM, IMP), and ceftazidime-avibactam is not active against MRSA, Enterococcus, Acinetobacter, or Stenotrophomonas.
KPC-producing carbapenem-resistant Enterobacterales (CRE) infections beyond approved indications: Ceftazidime-avibactam is widely used off-label as a preferred agent for KPC-producing CRE infections at various sites (e.g., bloodstream infections, non-HABP pneumonia) per IDSA 2023 AMR guidance. Evidence quality: High — supported by observational studies and IDSA guidance documents.
Dosing
Adults (CrCl >50 mL/min)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| cIAI | 2.5 g (2 g/0.5 g) IV q8h | Same | 7.5 g/day | 5–14 days Must combine with metronidazole 500 mg IV q8h; infuse over 2 hours |
| cUTI including pyelonephritis | 2.5 g (2 g/0.5 g) IV q8h | Same | 7.5 g/day | 7–14 days Infuse over 2 hours |
| HABP/VABP | 2.5 g (2 g/0.5 g) IV q8h | Same | 7.5 g/day | 7–14 days Infuse over 2 hours |
Pediatric Patients (by Age Band)
| Age Group | Dose (All Indications) | Maximum Dose | Notes |
|---|---|---|---|
| 2 years to <18 years | 62.5 mg/kg IV q8h | 2.5 g (adult max) | = ceftazidime 50 mg/kg + avibactam 12.5 mg/kg For cIAI: add metronidazole 10 mg/kg IV q8h |
| 6 months to <2 years | 62.5 mg/kg IV q8h | Weight-based | = ceftazidime 50 mg/kg + avibactam 12.5 mg/kg |
| 3 months to <6 months | 50 mg/kg IV q8h | Weight-based | = ceftazidime 40 mg/kg + avibactam 10 mg/kg |
| >28 days to <3 months | 37.5 mg/kg IV q8h | Weight-based | = ceftazidime 30 mg/kg + avibactam 7.5 mg/kg |
| ≤28 days (GA ≥31 weeks) | 25 mg/kg IV q8h | Weight-based | = ceftazidime 20 mg/kg + avibactam 5 mg/kg |
Adult Renal Impairment
| CrCl (mL/min) | Dose | Frequency | Notes |
|---|---|---|---|
| >50 | 2.5 g (2 g/0.5 g) | q8h | Normal dosing |
| 31–50 | 1.25 g (1 g/0.25 g) | q8h | FDA PI Table 3 |
| 16–30 | 0.94 g (0.75 g/0.19 g) | q12h | FDA PI Table 3 |
| 6–15 | 0.94 g (0.75 g/0.19 g) | q24h | FDA PI Table 3 |
| ≤5 (including HD) | 0.94 g (0.75 g/0.19 g) | q48h | Both components hemodialyzable; administer after HD on HD days |
In the Phase 3 cIAI trial, patients with baseline CrCl 30–50 mL/min had substantially lower clinical cure rates with AVYCAZ plus metronidazole (45%) compared to meropenem (74%). Mortality was also higher in this subgroup (19.5% vs 7.0%). These patients had received a 33% lower daily dose than is currently recommended. The FDA PI now specifies 1.25 g q8h for CrCl 31–50. Monitor CrCl at least daily and adjust dosing accordingly.
Pharmacology
Mechanism of Action
Ceftazidime-avibactam combines a third-generation cephalosporin (ceftazidime) with a novel non-beta-lactam, beta-lactamase inhibitor (avibactam). Ceftazidime acts bactericidally by binding to PBPs and inhibiting cell wall peptidoglycan synthesis. Avibactam protects ceftazidime from enzymatic degradation by covalently and reversibly binding to a broad range of beta-lactamases. Unlike older inhibitors (clavulanate, sulbactam, tazobactam), avibactam inhibits Ambler class A (including ESBLs and KPC carbapenemases), class C (AmpC), and some class D enzymes (notably OXA-48). This makes ceftazidime-avibactam a key agent against carbapenem-resistant Enterobacterales (CRE) that produce KPC or OXA-48. Avibactam does not inhibit class B metallo-beta-lactamases (NDM, VIM, IMP), so infections caused by MBL-producing organisms are not expected to respond.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV only; Cmax dose-proportional for both components; linear PK (avibactam 50–2000 mg); no accumulation over 11 days of q8h dosing | 2-hour infusion optimizes time-dependent killing for ceftazidime |
| Distribution | Ceftazidime: Vss 17 L, protein binding <10%. Avibactam: Vss 22.2 L, protein binding 5.7–8.2% | Very low protein binding for both = high free drug concentrations; good tissue penetration |
| Metabolism | Ceftazidime: not metabolized. Avibactam: not metabolized; no CYP involvement. Avibactam is a substrate of OAT1/OAT3 kidney transporters | No hepatic dose adjustment needed; probenecid inhibits avibactam renal elimination via OAT1/OAT3 (56–70%) — co-admin not recommended |
| Elimination | Both renally excreted unchanged. Ceftazidime t½ ~2.8 h; Avibactam t½ ~2.7 h. Both hemodialyzable: 55% of each removed during 4-hour HD session | Dosing is highly dependent on renal function; monitor CrCl at least daily; administer post-HD on dialysis days |
Side Effects
No individual clinical adverse reaction reached ≥10% incidence in ceftazidime-avibactam pivotal trials at recommended doses. Diarrhea (8% in cIAI) was the most frequent.
| Adverse Effect | Incidence (AVYCAZ + Metro) | Comparator (Meropenem) | Clinical Note |
|---|---|---|---|
| Diarrhea | 8% | 3% | Most common overall; higher than meropenem; monitor for C. difficile |
| Nausea | 7% | 5% | Usually mild and self-limiting |
| Vomiting | 5% | 2% | More frequent with AVYCAZ than comparator |
| Headache | 3% | 2% | Mild; monitor for CNS toxicity in renal impairment |
| Dizziness | 2% | 1% | Assess neurological status regularly |
| Abdominal pain | 1% | 1% | Similar to comparator |
In the cUTI trial, the most common adverse reactions were diarrhea (3%) and nausea (3%). In the HABP/VABP trial, diarrhea and vomiting were most common (≥5%). In pediatric patients ≥3 months, vomiting, diarrhea, rash, and infusion site phlebitis were each reported in ≥3%. In neonates <3 months, vomiting and increased transaminases (>3%) were the most common findings.
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Neurotoxicity (seizures, NCSE, encephalopathy, myoclonus) | Uncommon; higher in renal impairment | Variable; days into therapy | Discontinue or reduce dose; anticonvulsant therapy; EEG for NCSE; verify renal dosing |
| Anaphylaxis / serious hypersensitivity | Rare | Minutes to hours | Discontinue immediately; epinephrine and emergency supportive care |
| C. difficile-associated diarrhea / colitis | Uncommon | During or up to 2+ months after therapy | Discontinue AVYCAZ if confirmed; stool toxin testing; treat with oral vancomycin or fidaxomicin |
| Increased mortality in cIAI patients with CrCl 30–50 | 19.5% vs 7% (historical; with underdosing) | During treatment course | Use current PI-recommended dose (1.25 g q8h for CrCl 31–50); monitor CrCl at least daily |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| All adverse reactions (cIAI) | 2.6% (14/529) | Phase 3 cIAI trial; comparator (meropenem) was 1.3% |
Drug Interactions
Neither ceftazidime nor avibactam is metabolized via CYP enzymes. Avibactam is a substrate of renal OAT1 and OAT3 transporters, which is the basis of the probenecid interaction. Ceftazidime does not inhibit avibactam transport. No PK interaction was observed with metronidazole.
AVYCAZ has extensive Y-site compatibility data in the FDA PI (Tables 6–9). Compatible drugs include gentamicin, amikacin, tobramycin, metronidazole, daptomycin, furosemide, norepinephrine, vasopressin, levofloxacin, azithromycin, and others in specific diluents. Always verify diluent compatibility before Y-site co-administration. Drugs not listed in the PI tables should not be co-administered through the same line.
Monitoring
- Renal FunctionAt least daily
RoutineCrCl (adults) or eGFR (pediatrics) must be monitored at least daily due to the critical relationship between renal function and both drug exposure and clinical outcomes. Adjust dose immediately when CrCl changes. The FDA PI explicitly warns of decreased cure rates and increased mortality in cIAI patients who were underdosed for their renal function. - Neurological StatusDaily assessment
RoutineMonitor for seizures, myoclonus, altered consciousness, or NCSE, particularly in patients with renal impairment. Ceftazidime is associated with CNS toxicity in the setting of supratherapeutic levels. - Clinical Response48–72 h
RoutineAssess for clinical improvement. If inadequate response, reassess cultures, consider resistance (especially MBL-producing organisms which are not covered), and adjust therapy. - Hepatic PanelBaseline + weekly
Trigger-basedIncreased transaminases reported in neonates (>3%) and in adult trials. Monitor particularly in neonates and patients on prolonged courses. - GI Symptoms / StoolThroughout therapy
RoutineDiarrhea was the most common adverse event (8% in cIAI). Test for C. difficile if diarrhea is persistent, bloody, or accompanied by fever.
Contraindications & Cautions
Absolute Contraindications
- Known serious hypersensitivity to ceftazidime, avibactam, avibactam-containing products, or any cephalosporin
Relative Contraindications (Specialist Input Recommended)
- Renal impairment (CrCl ≤50) without appropriate dose adjustment — associated with decreased clinical cure rates and increased mortality in the cIAI trial
- Infections caused by MBL-producing organisms (NDM, VIM, IMP) — avibactam does not inhibit class B beta-lactamases; use of ceftazidime-avibactam would be expected to fail
Use with Caution
- History of seizure disorder or CNS disease — ceftazidime-associated seizure risk, especially with renal impairment
- Penicillin or carbapenem allergy history — cross-hypersensitivity may occur
- History of GI disease, especially colitis — C. difficile risk
- Concurrent probenecid — co-administration not recommended (impairs avibactam elimination)
In the Phase 3 cIAI trial, clinical cure rates in patients with baseline CrCl 30–50 mL/min were 45% for AVYCAZ plus metronidazole compared to 74% for meropenem. Mortality was 19.5% vs 7.0%. These patients received a lower dose than currently recommended. The current PI specifies 1.25 g q8h for CrCl 31–50. Monitor CrCl at least daily in patients with changing renal function.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. Cross-sensitivity may occur in patients with penicillin allergy. If an allergic reaction occurs, discontinue AVYCAZ.
Patient Counselling
Purpose of Therapy
Ceftazidime-avibactam (Avycaz) is a powerful IV antibiotic used to treat serious bacterial infections that are resistant to many other antibiotics. It combines an antibiotic (ceftazidime) with a protective agent (avibactam) that prevents bacteria from destroying the antibiotic. It is administered as an IV infusion over 2 hours, typically every 8 hours.
Sources
- AVYCAZ (ceftazidime and avibactam) Prescribing Information. AbbVie Inc. Revised April 2025. Drugs.comCurrent FDA PI; source for all dosing tables (adults, pediatrics, renal), adverse events, PK parameters, and warnings.
- AVYCAZ (ceftazidime and avibactam) FDA Label, NDA 206494. FDA.gov2024 label revision with HABP/VABP indication, updated pediatric dosing, and expanded age range down to 31 weeks GA.
- AVYCAZ (ceftazidime and avibactam) FDA Label, NDA 206494 (2019). FDA.govLabel that added HABP/VABP indication for adults with Phase 3 REPROVE trial data.
- Mazuski JE, Gasink LB, Armstrong J, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a Phase 3 study (RECLAIM). Clin Infect Dis. 2016;62(11):1380-1389. DOIPhase 3 cIAI trial (RECLAIM); source for clinical cure rates, mortality data in renal impairment subgroup, and adverse event incidence rates.
- Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE. Clin Infect Dis. 2016;63(6):754-762. DOIPhase 3 cUTI trial (RECAPTURE); demonstrated non-inferiority to doripenem.
- Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE). Lancet Infect Dis. 2018;18(3):285-295. DOIPhase 3 HABP/VABP trial (REPROVE); established non-inferiority to meropenem; basis for HABP/VABP approval.
- Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis. 2023;ciad428. DOIIDSA AMR guidance recommending ceftazidime-avibactam as preferred therapy for KPC-producing CRE infections and OXA-48-producing infections.
- Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the IDSA and ATS. Clin Infect Dis. 2016;63(5):e61-e111. DOIATS/IDSA HAP/VAP guideline; ceftazidime-avibactam relevant as anti-pseudomonal option.
- Ehmann DE, Jahic H, Ross PL, et al. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci USA. 2012;109(29):11663-11668. DOIFoundational mechanistic study characterizing avibactam’s unique covalent-reversible binding to serine beta-lactamases (class A, C, and some class D).
- Shields RK, Nguyen MH, Chen L, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother. 2017;61(8):e00883-17. DOIKey observational study demonstrating improved outcomes with ceftazidime-avibactam vs other regimens for KPC-producing K. pneumoniae bacteremia.
- Das S, Li J, Armstrong J, et al. Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. Pharmacol Res Perspect. 2015;3(1):e00172. DOIPK study confirming no interaction between AVYCAZ and metronidazole, and characterizing single/multiple-dose PK parameters.
- Merdjan H, Rangaraju M, Engel AM. In vitro study of the interaction of probenecid with avibactam through renal organic anion transporters. Antimicrob Agents Chemother. 2017;61(3):e01717-16. DOIIn vitro study demonstrating probenecid inhibition of avibactam uptake by OAT1/OAT3 (56–70%), supporting the co-administration contraindication.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. DOICrCl estimation formula referenced in the AVYCAZ PI for adult renal dose adjustments.