Note: Dosage recommendations are expressed as total grams of the ceftazidime/avibactam combination. Not recommended for routine empiric use. Reserve use for patients with or at risk for certain extensively drug-resistant gram-negative pathogens (nonsusceptible to ≥1 agent in all but 2 or fewer antimicrobial classes) (eg, carbapenem-resistant Enterobacterales, extensively drug-resistant P. aeruginosa) (IDSA [Tamma 2021]; Magiorakos 2012; Yahav 2020).
Intra-abdominal infections (alternative agent):
IV: 2.5 g every 8 hours in combination with metronidazole (Mazuski 2016; SIS [Mazuski 2017]). Total duration of therapy (which may include transition to oral antibiotics) is 4 to 5 days following adequate source control (Gomi 2018; Sawyer 2015; SIS [Mazuski 2017]).
Pneumonia, hospital-acquired or ventilator-associated (alternative agent): IV: 2.5 g every 8 hours (Torres 2018). Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days (IDSA/ATS [Kalil 2016]).
Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms):
IV: 2.5 g every 8 hours (IDSA [Tamma 2021]; Wagenlehner 2016). Switch to an appropriate oral regimen once symptoms improve, if culture and susceptibility results allow. Total duration of therapy ranges from 5 to 14 days and depends on clinical response and the antimicrobial chosen to complete the regimen (Hooton 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Dosage recommendations are expressed as total grams of the ceftazidime/avibactam combination.
Altered kidney function (Li 2019; manufacturer’s labeling):
Note: Estimation of renal function for the purpose of drug dosing should be done using the Cockcroft-Gault formula.
IV:
CrCl >50 to <130 mL/minute: No dosage adjustment necessary.
CrCl >30 to 50 mL/minute: 1.25 g every 8 hours.
CrCl >15 to 30 mL/minute: 0.94 g every 12 hours.
CrCl >5 to 15 mL/minute: 0.94 g every 24 hours.
CrCl ≤5 mL/minute: 0.94 g every 48 hours.
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):
Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Bilbao-Meseguer 2018; Udy 2010).
IV: 2.5 g every 8 hours (Das 2019; Gatti 2021; Li 2020; Stein 2019).
Hemodialysis, intermittent (thrice weekly): Dialyzable (~57% ceftazidime; 55% avibactam [Merdjan 2017; Pistolesi 2019; manufacturer’s labeling]): 0.94 g every 24 hours; in patients with minimal residual kidney function and less severe infections, may consider administering 0.94 g every 48 hours. When scheduled dose falls on a dialysis day, administer after hemodialysis (expert opinion; manufacturer’s labeling).
Peritoneal dialysis:
IV: 0.94 g every 24 hours; in patients with minimal residual kidney function and less severe infections, may consider administering 0.94 g every 48 hours (expert opinion).
CRRT:
Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.
IV: 1.25 g every 8 hours (Pistolesi 2019; Wenzler 2017).
PIRRT (eg, sustained, low-efficiency diafiltration):
Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.
IV:
On PIRRT days: 1.25 g every 12 hours (administer 1 of the twice-daily doses after PIRRT session). Patients receiving prolonged daily treatments (eg, 12 hours a day) may require dosing every 8 hours (expert opinion).
On non-PIRRT days: Dose as for CrCl ≤15 mL/minute (expert opinion).
No dosage adjustment necessary.
(For additional information see "Ceftazidime and avibactam: Pediatric drug information")
Note: Avycaz (ceftazidime and avibactam) is a combination product; each 2.5 g vial contains 2 g ceftazidime and 0.5 g avibactam sodium in a 4:1 ratio. Dosage recommendations are based on the ceftazidime component. Dosing presented is based on traditional infusion method (IV infusion over 2 hours).
Intra-abdominal infections, complicated (cIAI): Note: Use in combination with metronidazole; treat for 5 to 14 days depending upon severity and clinical response:
Infants ≥3 months to <6 months: IV: 40 mg ceftazidime/kg/dose every 8 hours.
Infants ≥6 months, Children, and Adolescents <18 years: IV: 50 mg ceftazidime/kg/dose every 8 hours; maximum dose: 2,000 mg ceftazidime/dose.
Adolescents ≥18 years: 2,000 mg ceftazidime every 8 hours.
Urinary tract infections, complicated (cUTI) (including pyelonephritis): Note: Treat for 7 to 14 days depending upon severity and clinical response:
Infant ≥3 months to <6 months: IV: 40 mg ceftazidime/kg/dose every 8 hours.
Infants ≥6 months, Children, and Adolescents <18 years: IV: 50 mg ceftazidime/kg/dose every 8 hours; maximum dose: 2,000 mg ceftazidime/dose.
Adolescents ≥18 years: 2,000 mg ceftazidime every 8 hours.
Pneumonia, hospital-acquired and ventilator-associated (HAP/VAP): Adolescents ≥18 years: IV: 2,000 mg ceftazidime every 8 hours for 7 to 14 days.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: Dosage recommendations are based on the ceftazidime component.
Infants ≥3 months and Children <2 years: There are no dosage adjustments provided in the manufacturer's labeling; insufficient data to provide any recommendations for use in patients with eGFR <50 mL/minute/1.73 m2; use with caution.
Children ≥2 years and Adolescents <18 years: IV: Note: Use bedside Schwartz formula to estimate renal function for the purpose of drug dosing.
eGFR >50 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 31 to 50 mL/minute/1.73 m2: 25 mg ceftazidime/kg/dose every 8 hours; maximum dose: 1,000 mg ceftazidime/dose.
eGFR 16 to 30 mL/minute/1.73 m2: 19 mg ceftazidime/kg/dose every 12 hours; maximum dose: 750 mg ceftazidime/dose.
eGFR 6 to 15 mL/minute/1.73 m2: 19 mg ceftazidime/kg/dose every 24 hours; maximum dose: 750 mg ceftazidime/dose.
eGFR ≤5 mL/minute/1.73 m2: 19 mg ceftazidime/kg/dose every 48 hours; maximum dose: 750 mg ceftazidime/dose.
End-stage renal disease (ESRD) on intermittent hemodialysis (IHD): Administer after hemodialysis on dialysis days; base dose upon patient's estimated renal function (eg, eGFR 6 to 15 mL/minute/1.73 m2 or eGFR ≤5 mL/minute/1.73 m2). Approximately 55% (based on a ceftazidime 1,000 mg dose and avibactam 100 mg dose) is removed following a 4-hour dialysis session.
Adolescents ≥18 years: IV: Note: Use Cockcroft-Gault formula to estimate renal function for the purpose of drug dosing.
CrCl >50 mL/minute: No dosage adjustment necessary.
CrCl 31 to 50 mL/minute: 1,000 mg ceftazidime every 8 hours.
CrCl 16 to 30 mL/minute: 750 mg ceftazidime every 12 hours.
CrCl 6 to 15 mL/minute: 750 mg ceftazidime every 24 hours.
CrCl ≤5 mL/minute: 750 mg ceftazidime every 48 hours.
End-stage renal disease (ESRD) on intermittent hemodialysis (IHD): Administer after hemodialysis on dialysis days; base dose upon patient's estimated renal function (eg, CrCl 6 to 15 mL/minute or CrCl ≤5 mL/minute). Approximately 55% (based on a ceftazidime 1,000 mg dose and avibactam 100 mg dose) is removed following a 4-hour dialysis session.
Infants ≥3 months, Children, and Adolescents: No dosage adjustment necessary.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Avycaz: Ceftazidime 2 g and avibactam 0.5 g (1 ea)
No
IV: Administer by intermittent infusion over 2 hours.
IV: Administer by intermittent IV infusion over 2 hours.
Intra-abdominal infections: Treatment of complicated intra-abdominal infections (cIAI) in adult and pediatric patients ≥3 months of age, in combination with metronidazole, caused by Citrobacter freundii complex, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.
Pneumonia, hospital-acquired and ventilator-associated: Treatment of hospital-acquired bacterial pneumonia and ventilator-associated (HAP/VAP) bacterial pneumonia in adult patients caused by ceftazidime/avibactam-susceptible K. pneumoniae, E. cloacae, E. coli, Serratia marcescens, P. mirabilis, P. aeruginosa, and Haemophilus influenzae.
Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms): Treatment of complicated urinary tract infections (including pyelonephritis) in adult and pediatric patients ≥3 months of age, caused by C. freundii complex, E. cloacae, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see ceftazidime monograph.
>10%: Hematologic & oncologic: Positive direct coombs test (3% to 21%)
1% to 10%:
Dermatologic: Injection site phlebitis (children and adolescents: >3%; adults: <1%), skin rash (children and adolescents: >3%; adults: <1%), pruritus (2%)
Gastrointestinal: Vomiting (>3%), diarrhea (≥3%), nausea (3%), constipation (2%), upper abdominal pain (1%)
<1%, postmarketing, and/or case reports: Acute renal failure, anxiety, candidiasis, Clostridioides difficile-associated diarrhea, dysgeusia, hypokalemia, increased gamma-glutamyl transferase, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, leukopenia, maculopapular rash, nephrolithiasis, renal insufficiency, thrombocythemia, thrombocytopenia, urticaria
Known serious hypersensitivity to ceftazidime, avibactam, other cephalosporins, or any component of the formulation
Concerns related to adverse effects:
• Hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam drugs. Before initiating therapy, carefully investigate previous penicillin, cephalosporin, or carbapenem hypersensitivity. Use caution if given to a patient with a penicillin or other beta-lactam allergy; cross sensitivity has been established. If an allergic reaction occurs, discontinue and institute appropriate management.
• Neurotoxicity: Severe neurological reactions have been reported with ceftazidime, including asterixis, coma, encephalopathy, myoclonus, neuromuscular excitability, seizures, and nonconvulsive status epilepticus. Risk may be increased in the presence of renal impairment; ensure dose adjusted for renal function. Discontinue therapy if patient develops neurotoxicity.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns:
• Renal impairment: In a complicated intra-abdominal infection clinical trial, adult patients with a CrCl of 30 to 50 mL/minute had lower clinical cure rates than those with CrCl >50 mL/minute; however, these patients received a daily dose that was 33% lower than what is currently recommended for patients with this degree of renal impairment. Decreased clinical response was not seen in patients with a baseline CrCl of 30 to 50 mL/minute in complicated UTI clinical trials. Monitor renal function at baseline and at least daily in adult and pediatric patients with changing renal function. Adjust the dose accordingly.
Refer to individual components.
Aminoglycosides: Cephalosporins may enhance the nephrotoxic effect of Aminoglycosides. Cephalosporins may decrease the serum concentration of Aminoglycosides. Risk C: Monitor therapy
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Chloramphenicol (Systemic): May diminish the therapeutic effect of CefTAZidime. Management: Consider using a different combination of antimicrobials, especially if bactericidal activity is desired. If these agents are combined, monitor for reduced antimicrobial effectiveness and/or therapeutic failure. Risk D: Consider therapy modification
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Management: Avoid use of fexinidazole with OAT1/3 substrates when possible. If combined, monitor for increased OAT1/3 substrate toxicities. Risk D: Consider therapy modification
Immune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Nitisinone: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Pretomanid: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Avibactam. Risk X: Avoid combination
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Teriflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Cephalosporins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Adverse events have not been observed in animal reproduction studies conducted with ceftazidime; adverse events have been observed in some animal reproduction studies conducted with avibactam.
Ceftazidime is excreted in breast milk. It is not known if avibactam is excreted in breast milk. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother.
Monitor for signs of anaphylaxis during first dose. Monitor renal function at baseline in all patients, and at least daily in patients with changing renal function.
Ceftazidime inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.
Avibactam inactivates some beta-lactamases and protects ceftazidime from degradation.
Distribution: Vd:
Single dose: Adults: Mean: Ceftazidime: 18.1 L; Avibactam: 23.2 L
Multiple dose: Adults: Mean: Ceftazidime: 17 L; Avibactam: 22.2 L
Protein binding: Ceftazidime: <10%; Avibactam: 5.7% to 8.2%
Metabolism: Ceftazidime: ~80% to 90% of dose eliminated as unchanged drug; Avibactam: Not metabolized
Half-life elimination:
Single dose:
Ceftazidime:
Children ≥6 years to <12 years: Median: 1.6 hours (0.9 to 1.8 hours) (Bradley 2016)
Children ≥12 years and Adolescents: Median: 1.7 hours (0.9 to 2.8 hours) (Bradley 2016)
Adults: Mean: 3.27 hours
Avibactam:
Children ≥6 years to <12 years: Median: 1.7 hours (0.9 to 2 hours) (Bradley 2016)
Children ≥12 years and Adolescents: Median: 1.6 hours (0.9 to 2.8 hours) (Bradley 2016)
Adults: Mean: 2.22 hours
Multiple dose: Adults: Mean: Ceftazidime: 2.76 hours; Avibactam: 2.71 hours
Excretion: Ceftazidime: Urine (~80% to 90% as unchanged drug); Avibactam: Urine (97%)
Renal function impairment: Half-life increases in patients with impaired renal function; AUC of avibactam increases 2.6-fold, 3.8-fold, and 7-fold in patients with mild, moderate or severe renal impairment, respectively.
Anti-infective considerations:
Parameters associated with efficacy:
Ceftazidime (data on monotherapy for susceptible organisms): Time dependent; associated with time free drug concentration (fT) > minimum inhibitory concentration (MIC):
Organism specific: Gram-negative bacteria (including P. aeruginosa): Goal: 35% to 40% fT > MIC (bacteriostatic in vitro); 60% to 70% fT > MIC (bactericidal in vitro); ~45% to 53% fT > MIC (microbiological response) (Craig 1995; MacVane 2014; Muller 2013).
Population specific: In critically ill patients in the ICU, minimum goal: ≥50% fT > MIC; preferred goal: ≥100% fT > MIC (Abdul-Aziz 2020; Al-Shaer 2020; Roberts 2014); some experts favor ≥100% fT >4 times the MIC (Guilhaumou 2019).
Ceftazidime (in combination with avibactam): Interrelationship between ceftazidime exposure, avibactam exposure, MIC, and efficacy is not fully elucidated; at avibactam exposures that were associated with bacteriostatic and bactericidal activity, mean ceftazidime fT > MIC (ceftazidime MIC in the presence of a fixed avibactam concentration): ~50% (Berkhout 2015; Nichols 2018).
Avibactam (in combination with ceftazidime): Time dependent, associated with fT > threshold concentration (threshold concentration: 1 mg/L); goal: ≥ ~20% to 50% (Berkhout 2015; Coleman 2014; Crass 2019; Nichols 2018).
Postantibiotic effect: Generally little to no postantibiotic effect (Berkhout 2021; Pillar 2016).
Expected drug concentrations in patients with normal renal function:
Pediatric patients (hospitalized): Single dose (2-hour infusion): Cmax (peak): IV:
Infants and children 3 months to <2 years of age: Ceftazidime 50 mg/avibactam 12.5 mg per kg: Ceftazidime: 91.7 mg/L; Avibactam: 16.3 mg/L (Bradley 2016).
Children 2 to <12 years of age: Ceftazidime 50 mg/avibactam 12.5 mg per kg (maximum ceftazidime 2,000 mg/avibactam 500 mg): Ceftazidime: ~80 mg/L; Avibactam: ~14 mg/L (Bradley 2016).
Children and adolescents 12 to <18 years of age: Ceftazidime 2,000 mg/avibactam 500 mg: Ceftazidime: 79.8 mg/L; Avibactam: 15.1 mg/L (Bradley 2016).
Adults: Cmax (peak): IV:
Note: Adult doses are expressed as the combined amount of ceftazidime and avibactam.
Single dose, 30-minute infusion (healthy volunteers): 2.5 g: Ceftazidime: 93.17 mg/L; Avibactam: 23.33 mg/L (Merdjan 2015).
Steady state, 30-minute infusion (healthy volunteers): 2.5 g every 8 hours: Ceftazidime: 114.53 mg/L; Avibactam: 22.22 mg/L (Merdjan 2015).
Steady state, 2-hour infusion (patients with nosocomial pneumonia, including ventilator-associated): 2.5 g every 8 hours: Ceftazidime: 61.9 to 79 mg/L; Avibactam: 12 to 15.5 mg/L (Li 2019).
Solution (reconstituted) (Avycaz Intravenous)
2.5 (2-0.5) g (per each): $430.57
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