AHFS Class:

• Third Generation Cephalosporins 8:12.06.12

Generic Name(s):

• cefTAZidime and Avibactam Sodium

• cefTAZidime

• Avibactam Sodium

Chemical Name:

• [6 R -[6α,7β(Z)]]-1-[[7-[[(2-Amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-pentahydrate, inner salt, hydroxide, pyridinium

• (2 S ,5 R )-2-Carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate

Molecular Formula:

• C₂₂H₂₂N₆O₇S₂ • 5H₂O

• C₇H₁₀N₃O₆SNa

Ceftazidime and avibactam sodium is a fixed combination of ceftazidime (a third generation cephalosporin) and avibactam (a non-β-lactam β-lactamase inhibitor);1,2 avibactam inactivates certain bacterial β-lactamases and expands ceftazidime's spectrum of activity against some bacteria that produce these β-lactamases.1,5,6,10,11,13,16,17,18,19

Intra-abdominal Infections

Ceftazidime and avibactam is used in conjunction with metronidazole for the treatment of complicated intra-abdominal infections caused by susceptible Enterobacter cloacae , Escherichia coli , Klebsiella oxytoca , K. pneumoniae , Proteus mirabilis , Providencia stuartii , or Pseudomonas aeruginosa .1

Use of ceftazidime and avibactam for the treatment of complicated intra-abdominal infections should be reserved for patients with limited or no alternative treatment options since only limited data are available regarding safety and efficacy of the drug.1

Clinical Experience

Efficacy and safety of ceftazidime and avibactam for the treatment of complicated intra-abdominal infections is based on results from a phase 2, randomized, double-blind, active-controlled study in 204 adults with evidence of intra-abdominal infection requiring surgical intervention and anti-infective treatment.3 Patients were randomized in a 1:1 ratio to receive 5-14 days of treatment with the fixed combination of ceftazidime and avibactam (2.5 g [ceftazidime 2 g and avibactam 0.5 g] given by IV infusion every 8 hours) in conjunction with metronidazole (500 mg given by IV infusion every 8 hours) or treatment with meropenem (1 g given by IV infusion every 8 hours) in conjunction with placebo.3 Baseline characteristics were generally similar between groups (mean age 43 years, 69-79% male, 55-64% white, 83-87% with peritonitis, 39-44% with visceral perforation, 26-28% with abscess).3 Clinical response (defined as complete resolution or substantial improvement of signs and symptoms of infection with no requirement for additional antibiotics or surgery at the test-of-cure visit [2 weeks after the last treatment dose]) in the microbiologically evaluable population was achieved by 91.2% of patients treated with ceftazidime and avibactam in conjunction with metronidazole and 93.4% of those treated with meropenem.3

Urinary Tract Infections

Ceftazidime and avibactam is used for the treatment of complicated urinary tract infections, including pyelonephritis, caused by susceptible E. coli , Citrobacter freundii , C. koseri , E. aerogenes , E. cloacae , K. pneumoniae , Proteus , or Ps. aeruginosa .1

Use of ceftazidime and avibactam for the treatment of complicated urinary tract infections should be reserved for patients with limited or no alternative treatment options since only limited data are available regarding safety and efficacy of the drug.1

Clinical Experience

Efficacy and safety of ceftazidime and avibactam for the treatment of complicated urinary tract infections is based on results from a phase 2, randomized, double-blind study in 137 adults with complicated urinary tract infection, including pyelonephritis, caused by gram-negative bacteria and requiring parenteral anti-infective treatment.4 Patients were randomized in a 1:1 ratio to receive treatment with the fixed combination of ceftazidime and avibactam (625 mg [ceftazidime 500 mg and avibactam 125 mg] given by IV infusion every 8 hours) or the fixed combination of imipenem and cilastatin (500 mg of imipenem given by IV infusion every 6 hours).4 Dosage of ceftazidime and avibactam used in this study is lower than the usually recommended dosage of the drug.1 After at least 4 days of IV treatment, patients with clinical improvement (afebrile for at least 24 hours, with resolution of nausea and vomiting and improved signs and symptoms) who had pathogens susceptible to both study anti-infectives were permitted to switch to oral ciprofloxacin (500 mg twice daily).4 The total duration of IV and/or oral anti-infective treatment was 7-14 days.4 Baseline characteristics were generally similar between groups (mean age 46-48 years, 25-27% male, 59-61% white, 61-65% diagnosed with acute pyelonephritis).4 Favorable microbiologic response (defined as eradication of all uropathogens at the test-of-cure visit 5-9 days after the last treatment dose) in the microbiologically evaluable population was achieved by 70.4% of patients treated with ceftazidime and avibactam and 71.4% of those treated with imipenem and cilastatin.4

Administration

Ceftazidime and avibactam is administered by IV infusion.1

IV Infusion

Reconstitution and Dilution

Ceftazidime and avibactam powder must be reconstituted and further diluted prior to IV infusion.1

Single-dose vials of ceftazidime and avibactam labeled as containing 2.5 g (ceftazidime 2 g and avibactam 0.5 g) should be reconstituted by adding 10 mL of a compatible IV solution (sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 2.5% dextrose and 0.45% sodium chloride injection, lactated Ringer's injection) to the vial and gently mixing.1 The volume of the reconstituted solution is approximately 12 mL and the approximate concentration is ceftazidime 167 mg/mL and avibactam 42 mg/mL.1 Reconstituted ceftazidime and avibactam solution may be stored for up to 30 minutes prior to transfer and dilution.1

Prior to IV infusion, reconstituted ceftazidime and avibactam solution must be further diluted.1 To prepare the indicated dose, the appropriate volume of reconstituted solution should be withdrawn from the vial and added to a compatible IV solution to achieve a total final volume of 50-250 mL in an IV infusion bag.1 (See Table 1.) With the exception of sterile water for injection, the same IV solution used for reconstitution should be used for dilution;1 any other compatible IV solution should be used for dilution if sterile water for injection was used for reconstitution.1 The diluted solution should be mixed gently to ensure that the drug is completely dissolved.1

The reconstituted and diluted solution of ceftazidime and avibactam should be inspected visually for particulate matter and discoloration prior to administration;1 the solution should appear clear and colorless to light yellow.1

Following reconstitution and dilution, ceftazidime and avibactam solutions may be stored in the IV infusion bag at room temperature for up to 12 hours.1 Alternatively, these solutions may be stored at 2-8°C for up to 24 hours and then used within 12 hours after removal from refrigeration to room temperature.1

Rate of Administration

IV infusions of ceftazidime and avibactam should be given over 2 hours.1

Dispensing and Dosage and Administration Precautions

FDA alerted healthcare professionals about the risk of medication errors with ceftazidime and avibactam.22 There have been reports of errors occurring during preparation of IV solutions of the drug that resulted in administration of incorrect dosage (higher than intended); the errors were due to confusion about how dosage of ceftazidime and avibactam is expressed (total of the dosage of each of the 2 active components) and how drug strength was displayed on vial labels and carton packaging.22 To prevent such errors, vial labels and carton packaging have been revised to indicate the strength of the fixed combination as the total of the 2 active components.22

Healthcare professionals should be aware that dosage of ceftazidime and avibactam is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of ceftazidime plus dosage of avibactam).1,22 This dosage convention should be considered when prescribing, preparing, and dispensing ceftazidime and avibactam.1,22 FDA urges healthcare professionals and patients to report any medication errors and adverse effects involving the drug to the FDA MedWatch program.22

Dosage

Ceftazidime and avibactam is a fixed combination containing a 4:1 ratio of ceftazidime to avibactam.1

The ceftazidime component is provided as a mixture of ceftazidime pentahydrate and sodium carbonate (dosage of this component is expressed in terms of anhydrous ceftazidime);1 the avibactam component is provided as avibactam sodium (dosage of this component is expressed in terms of avibactam).1

Dosage of the fixed combination of ceftazidime and avibactam is expressed in terms of the total of the ceftazidime and avibactam content.1

Each single-dose vial of ceftazidime and avibactam contains a total of 2.5 g (i.e., 2 g of ceftazidime and 0.5 g of avibactam).1

Adult Dosage

Intra-abdominal Infections

The recommended dosage of ceftazidime and avibactam for the treatment of complicated intra-abdominal infections in adults is 2.5 g (ceftazidime 2 g and avibactam 0.5 g) every 8 hours given in conjunction with metronidazole.1 The duration of treatment is 5-14 days.1

Urinary Tract Infections

The recommended dosage of ceftazidime and avibactam for the treatment of complicated urinary tract infections, including pyelonephritis, in adults is 2.5 g (ceftazidime 2 g and avibactam 0.5 g) every 8 hours.1 The duration of treatment is 7-14 days.1

Dosage in Renal Impairment

Dosage of ceftazidime and avibactam must be adjusted in adults with creatinine clearances of 50 mL/minute or less, including those undergoing hemodialysis.1 (See Table 2.)

Creatinine clearance should be monitored at least once daily in patients with changing renal function and dosage of ceftazidime and avibactam adjusted accordingly.1

Dosage in Hepatic Impairment

Dosage adjustments are not needed when ceftazidime and avibactam is used in adults with hepatic impairment.1

Dosage in Geriatric Patients

Dosage adjustments based solely on age are not needed when ceftazidime and avibactam is used in geriatric patients.1 However, because geriatric patients are more likely to have decreased renal function and because dosage of ceftazidime and avibactam needs to be adjusted based on renal impairment, dosage should be selected with caution and it may be useful to monitor renal function.1

Adverse Effects

Adverse effects reported in 5% or more of patients receiving ceftazidime and avibactam in phase 2 clinical trials include GI effects (nausea,1,3 vomiting,1,3 diarrhea,4 abdominal pain,1,3,4 constipation1,4 ), pyrexia,3 increased AST,3 increased ALT,1,3 increased blood alkaline phosphatase,1,3 increased leukocyte count,3 headache,4 dizziness,1,4 chest pain,4 hypertension,4 cough,3 anxiety,1,4 insomnia,4 and infusion site reactions.4

Precautions and Contraindications

Sensitivity Reactions

Ceftazidime and avibactam is contraindicated in patients with known serious hypersensitivity to ceftazidime and/or avibactam, avibactam-containing preparations, or other cephalosporins.1

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving β-lactam antibacterials.1 Before initiating therapy with ceftazidime and avibactam, the clinician should carefully inquire about the patient's previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems.1 Ceftazidime and avibactam should be used with caution in patients allergic to penicillins or other β-lactams since cross-sensitivity among β-lactams antibacterials has been established.1

Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment.1

If an allergic reaction occurs, ceftazidime and avibactam should be discontinued.1

Reduced Efficacy in Patients with Moderate Renal Impairment

Results of a subgroup analysis of a phase 3 clinical trial in patients with complicated intra-abdominal infections indicated that the clinical cure rate in patients with moderate renal impairment was lower than the clinical cure rate in those with normal renal function or only mild renal impairment, and this difference was more marked in those treated with a regimen of ceftazidime and avibactam in conjunction with metronidazole than in those treated with the comparator drug (meropenem).1 The clinical cure rate in patients treated with ceftazidime and avibactam in conjunction with metronidazole was 45% in those with baseline creatinine clearances of 30-50 mL/minute compared with 85% in those with baseline creatinine clearances greater than 50 mL/minute.1 Although the reason for this reduced efficacy is unclear,25 the dosage of ceftazidime and avibactam used in this study in patients with creatinine clearances of 30-50 mL/minute was 33% lower than the currently recommended dosage of the drug for such patients and it is possible that those with rapidly changing renal function did not receive appropriate dosage.1,25

Creatinine clearance should be monitored at least once daily in patients with changing renal function and dosage of ceftazidime and avibactam adjusted accordingly.1 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Nervous System Effects

Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients receiving ceftazidime, particularly in patients with renal impairment.1 Dosage of ceftazidime and avibactam should be adjusted based on creatinine clearance.1 (See Dosage and Administration: Dosage in Renal Impairment.)

Patients should be advised that adverse neurologic reactions can occur while receiving ceftazidime and avibactam and that they should immediately inform a clinician if any neurologic signs and symptoms, including encephalopathy (disturbance of consciousness such as confusion, hallucinations, stupor, coma), myoclonus, or seizures, occur since immediate treatment, dosage adjustment, or discontinuance of ceftazidime and avibactam may be necessary.1

Hematologic Effects

In clinical trials, seroconversion from a negative to a positive direct Coombs' test result occurred in 7.3% of patients receiving ceftazidime and avibactam in conjunction with metronidazole and in 1.9% of patients receiving ceftazidime and avibactam alone.1 Adverse reactions representing hemolytic anemia were not reported in any treatment group.1

Eosinophilia and thrombocytopenia have been reported in less than 5% of patients receiving ceftazidime and avibactam.1

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Use of ceftazidime and avibactam may result in emergence and overgrowth of nonsusceptible bacteria or fungi.1 The patient should be carefully monitored and appropriate therapy instituted if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,12,14,15 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported in patients receiving nearly all anti-infectives, including ceftazidime and avibactam, and may range in severity from mild diarrhea to fatal colitis.1,12,14,15 C. difficile produces toxins A and B which contribute to development of CDAD;1,12 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,12,14,15 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,12 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1,12,14,15

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually resolves when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of ceftazidime and avibactam and other antibacterials, the drug should be used only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1

Patients should be advised that antibacterials (including ceftazidime and avibactam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with ceftazidime and avibactam or other antibacterials in the future.1

Precautions Related to Use of Fixed Combinations

When ceftazidime and avibactam is used, the cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination must be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug.1 (For additional cautionary information on ceftazidime, see Cautions in Ceftazidime 8:12.06.12.)

When prescribing, preparing, and dispensing ceftazidime and avibactam, healthcare professionals should consider that dosage of the fixed combination is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of ceftazidime plus dosage of avibactam).1 (See Dispensing and Dosage and Administration Precautions under Administration: IV Infusion, in Dosage and Administration.)

Other Precautions and Contraindications

Ceftazidime and avibactam are principally eliminated by the kidneys, and the risk of adverse effects may be greater in patients with renal impairment.1 In addition, a lower cure rate has been reported in some patients with moderate renal impairment (see Reduced Efficacy in Patients with Moderate Renal Impairment under Cautions: Precautions and Contraindications).1 Dosage of ceftazidime and avibactam should be adjusted in patients with moderate or severe renal impairment (creatinine clearances of 50 mL/minute or less), including those undergoing hemodialysis.1 In patients with changing renal function, creatinine clearance should be monitored at least once daily and dosage adjusted accordingly.1 (See Dosage and Administration: Dosage in Renal Impairment.)

Pediatric Precautions

Safety and efficacy of ceftazidime and avibactam have not been established in patients younger than 18 years of age.1

Geriatric Precautions

In phase 2 clinical trials evaluating ceftazidime and avibactam for the treatment of complicated intra-abdominal infections or complicated urinary tract infections, 10.7% of patients were 65 years of age or older.1 Since only limited data are available, age-related differences in outcomes or specific risks with ceftazidime and avibactam cannot be ruled out.1

Ceftazidime and avibactam are eliminated principally by the kidneys, and the risk of adverse effects may be greater in those with impaired renal function.1 Because geriatric patients are more likely to have reduced renal function, dosage should be selected with caution and renal function monitoring should be considered.1 Dosage adjustments in geriatric patients should be based on renal function.1

Mutagenicity and Carcinogenicity

Ceftazidime was not mutagenic in a microbial (i.e., Ames test) or mammalian cell (i.e., mouse micronucleus) test.1 Avibactam was not genotoxic in the Ames assay, unscheduled DNA synthesis test, chromosomal aberration assay, or a rat micronucleus study.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in mice and rats using ceftazidime dosages up to 40 times the usual human dose have not revealed evidence of harm to the fetus.1 Avibactam was not teratogenic in rats or rabbits.1 In rats, there was no evidence of embryofetal toxicity at an avibactam dosage of 1 g/kg daily (approximately 9 times the human dosage based on area under the concentration-time curve [AUC]) and no effects on pup growth and viability at a dosage of 825 mg/kg daily.1 In rabbits, there was no evidence of embryofetal toxicity at an avibactam dosage of 100 mg/kg, but increased implantation loss, lower mean fetal weights, delayed ossification of bones, and other anomalies were observed at higher dosages.1

There are no adequate and controlled studies using ceftazidime and avibactam in pregnant women, and the drug should be used during pregnancy only if clearly needed.1

Fertility

Avibactam had no adverse effects on fertility in male and female rats using dosages up to 1 g/kg daily (approximately 20 times higher than the recommended human dosage based on body surface area).1 In female rats, IV avibactam dosages of 0.5 g/kg or higher resulted in dose-related increases in the percentage of pre- and post-implantation loss compared with controls.1

Lactation

Ceftazidime is distributed into human milk in low concentrations.1 It is not known whether avibactam is distributed into human milk.1 (See Pharmacokinetics: Distribution.)

Ceftazidime and avibactam should be used with caution in nursing women.1

The following drug interactions are based on studies using the fixed combination containing ceftazidime and avibactam, ceftazidime alone, or avibactam alone.1 When ceftazidime and avibactam is used, interactions associated with both drugs in the fixed combination should be considered.1

Ceftazidime does not induce cytochrome P-450 (CYP) 1A1, 1A2, 2B6, or 3A4/5 when tested in vitro in human hepatocytes.1

In vitro, avibactam does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5 and does not induce CYP1A2, 2B6, 2C9, or 3A4.1 At concentrations exceeding clinically relevant exposures, avibactam shows some potential to induce CYP2E1.1

Drugs Affecting or Affected by Organic Anion Transporters

In vitro, avibactam is a substrate of organic anion transporter (OAT) 1 and OAT3 kidney transporters.1 In vitro, probenecid (a potent OAT1/OAT3 inhibitor) inhibits uptake of avibactam by 56-70% and has the potential to decrease elimination of avibactam.1 (See Drug Interactions: Probenecid.)

Ceftazidime and avibactam do not inhibit OAT1 or OAT3 and ceftazidime does not inhibit avibactam transport mediated by OAT1 and OAT3.1

Drugs Affecting or Affected by Other Membrane Transporters

In vitro, ceftazidime and avibactam do not inhibit multidrug-resistance transporter (MDR) 1, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 4, organic cation transporter (OCT) 1, or OCT2 at clinically relevant concentrations.1 Avibactam is not a substrate of MDR1, BCRP, MRP4, or OCT2.1

Anti-infectives

Metronidazole

In healthy males, administration of ceftazidime and avibactam (2.5 g [ceftazidime 2 g and avibactam 0.5 g] given by IV infusion over 2 hours) following metronidazole (500 mg given by IV infusion over 1 hour every 8 hours for 3 days) had no effect on peak plasma concentrations or area under the plasma concentration-time curve (AUC) of ceftazidime or avibactam compared with use of ceftazidime and avibactam alone.1,30 Similarly, administration of metronidazole (500 mg given by IV infusion over 1 hour) followed by ceftazidime and avibactam (2.5 g [ceftazidime 2 g and avibactam 0.5 g] given by IV infusion over 2 hours every 8 hours for 3 days) in healthy males had no effect on peak plasma concentrations and AUC of metronidazole compared with use of metronidazole alone.1,30

There is no in vitro evidence of antagonistic antibacterial effects between ceftazidime and avibactam and metronidazole.1

Other Anti-infectives

There is no in vitro evidence of antagonistic antibacterial effects between ceftazidime and avibactam and colistin (commercially available in US as colistimethate sodium), levofloxacin, linezolid, tigecycline, tobramycin, or vancomycin.1,7

Probenecid

In vitro studies indicate probenecid (a potent OAT1/OAT3 inhibitor) has the potential to decrease elimination of avibactam by inhibiting renal uptake of the drug.1 Therefore, concomitant use of probenecid with ceftazidime and avibactam is not recommended.1

Tests for Urinary Glucose

Administration of ceftazidime may result in a false-positive reaction for urine glucose when certain testing methods are used.1 Urine glucose tests based on enzymatic glucose oxidase reactions should be used in patients receiving ceftazidime and avibactam.1

Mechanism of Action

Ceftazidime and avibactam is bactericidal in action.1,13

Like other cephalosporins, the antibacterial activity of ceftazidime results from inhibition of mucopeptide synthesis in the bacterial cell wall and is mediated through binding to penicillin-binding proteins (PBPs).1,5 (For information on the mechanism of action of cephalosporins, see Mechanism of Action in the Cephalosporins General Statement 8:12.06.)

Avibactam is a non-β-lactam β-lactamase inhibitor that inactivates certain β-lactamases, including some extended-spectrum β-lactamases (ESBLs).1,5,6,26,27,28 Avibactam inactivates many β-lactamases in Ambler class A (e.g., ESBLs, carbapenemases such as Klebsiella pneumoniae carbapenemases [KPCs]), class C (e.g., cephalosporinases such as AmpC), and class D (e.g., some oxacillinases [OXAs]).1,5,6,10,25,26,27,28 Avibactam binds to the β-lactamase active site serine residue by covalent acylation, which is partially reversible;5,6,26,27 subsequently, deacylation can occur resulting in release of intact avibactam allowing additional β-lactamase inhibition.5,6,26,27 This mechanism of action differs from that of some other β-lactamase inhibitors (e.g., clavulanic acid, sulbactam, tazobactam) that can form covalent, irreversible, acyl-enzyme intermediates that may undergo hydrolysis, resulting in decomposition of the β-lactamase inhibitor.5,6,26,27,28 Avibactam cannot inactivate Ambler class B metallo-β-lactamases (MBLs)5,26,28 or certain OXA-type carbapenemases.5,9,26

Because avibactam inactivates certain β-lactamases, concomitant use with ceftazidime can protect ceftazidime from degradation by these β-lactamases and expand the spectrum of activity of the cephalosporin to include many β-lactamase-producing bacteria that are resistant to ceftazidime alone.1,5,6,10,11,13,16,17,18,19 Avibactam does not decrease the antibacterial activity of ceftazidime against ceftazidime-susceptible bacteria.1

Spectrum

Based on its spectrum of activity, ceftazidime and avibactam is classified as a third generation cephalosporin.1,2 (For information on the classification of cephalosporins and closely related β-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06.)

Like other currently available parenteral third generation cephalosporins (e.g., cefotaxime, ceftriaxone), ceftazidime generally is less active against staphylococci but has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins.2 Ceftazidime is distinguished from many other cephalosporins by its activity against Pseudomonas aeruginosa .2 (For information on the spectrum of activity of ceftazidime used alone, see Spectrum in Ceftazidime 8:12.06.12.)

Ceftazidime and avibactam has a wider spectrum of activity than ceftazidime alone.1,5,6,10,11,13,16,17,18,19 Ceftazidime and avibactam is active against many β-lactamase-producing gram-negative bacteria that are resistant to ceftazidime alone, including many strains that produce extended-spectrum β-lactamases (ESBLs).1,5,6,9,10,11,13,16,17,18,19 The fixed combination is active in vitro against Enterobacteriaceae that produce TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPC), AmpC, and certain oxacillinase (OXA) β-lactamases and also is active in vitro against Ps. aeruginosa that produce certain AmpC β-lactamases.1,5,6,8,9,10,11,13,16,18,20,21

Ceftazidime and avibactam is active in vitro against some Enterobacteriaceae and Ps. aeruginosa that are resistant to carbapenems, other cephalosporins (including ceftazidime alone), or fluoroquinolones.1,8,8

In Vitro Susceptibility Testing

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), clinical isolates identified as susceptible to ceftazidime and avibactam are inhibited by drug concentrations usually achievable when dosage recommended for the site of infection is used.1 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to ceftazidime and avibactam, the strain is not likely to be inhibited by drug concentrations generally achievable with usual dosage schedules and other anti-infective therapy should be selected.1

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ceftazidime and avibactam, a disk containing 30 mcg of ceftazidime and 20 mcg of avibactam is used.1

When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures, Enterobacteriaceae with growth inhibition zones of 21 mm or greater are susceptible to ceftazidime and avibactam and those with zones of 20 mm or less are resistant to the drug.1 Ps. aeruginosa with growth inhibition zones of 18 mm or greater are susceptible to ceftazidime and avibactam and those with zones of 17 mm or less are resistant to the drug.1

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is used to test susceptibility to ceftazidime and avibactam, tests should be performed using serial dilutions of ceftazidime combined with a fixed avibactam concentration of 4 mcg/mL.1 If a broth dilution test is used, results should be read within 18 hours because degradation of ceftazidime activity occurs by 24 hours.1

When dilution susceptibility testing is performed according to CLSI standardized procedures, Enterobacteriaceae and Ps. aeruginosa with MICs of 8 mcg/mL or less of ceftazidime and 4 mcg/mL or less of avibactam are susceptible to ceftazidime and avibactam and those with MICs of 16 mcg/mL or greater of ceftazidime and 4 mcg/mL or greater of avibactam are resistant to the drug.1

Gram-negative Aerobic Bacteria

Ceftazidime and avibactam is active in vitro against many Enterobacteriaceae, including Citrobacter freundii ,1,8,11,16,18 C. koseri ,1,16,19 Enterobacter aerogenes ,1 E. cloacae ,1,8,11,16,18,19 Escherichia coli ,1,8,9,11,13,16,18 K. pneumoniae ,1,8,9,11,16,18 K. oxytoca ,1,18,19 Morganella morganii ,1,11,18 Proteus 1,11 (including P. mirabilis 1,8,11,16,19 and P. vulgaris 19 ), Providencia rettgeri ,1,11 P. stuartii ,1 and Serratia marcescens .1,8,18,19

Ceftazidime and avibactam is active in vitro against many strains of Ps. aeruginosa ,1,8,9,10,13,16,18,20,21 including some multidrug-resistant (MDR) and extensively drug-resistant (XDR) Ps. aeruginosa .10,21

Anaerobic Bacteria

Although ceftazidime and avibactam has been active in vitro against a few strains of Bacteroides fragilis , Prevotella , and Porphyromonas ,31 the fixed combination shows only limited in vitro activity against most anaerobic bacteria.5,31

Pharmacokinetics

Following IV administration of the fixed combination of ceftazidime and avibactam sodium, pharmacokinetic parameters for ceftazidime and avibactam are similar to those reported when each drug is administered alone.1 In addition, pharmacokinetic parameters are similar following single or multiple IV doses of the fixed combination.1

Absorption

In healthy adult males with normal renal function receiving multiple doses of ceftazidime and avibactam (2.5 g [ceftazidime 2 g and avibactam 0.5 g]) given by IV infusion over 2 hours every 8 hours for 11 days, peak plasma concentrations of ceftazidime were 90.4 mcg/mL and peak plasma concentrations of avibactam were 14.6 mcg/mL.1

Peak plasma concentrations and area under the plasma concentration-time curve (AUC) of ceftazidime increase in proportion to the dose;1 avibactam demonstrated approximately linear pharmacokinetics when single IV doses ranging from 50 mg to 2 g were given alone.1,23

There is no appreciable accumulation of ceftazidime or avibactam in healthy adults with normal renal function following multiple doses of ceftazidime and avibactam (2.5 g [ceftazidime 2 g and avibactam 0.5 g]) given by IV infusion every 8 hours for up to 11 days.1,23

In healthy adults 65 years of age or older who received a single 0.5-g IV dose of avibactam, the AUC of the drug was 17% higher than the AUC reported in healthy adults 18-45 years of a 1,24 peak plasma concentrations of avibactam in these adults were not substantially affected by age.1

In a study in healthy adults who received a single 0.5-g IV dose of avibactam, peak plasma concentrations of the drug in males were 18% lower than in females;1,24 gender did not affect the AUC of avibactam.1

Distribution

The steady-state volumes of distribution of ceftazidime and avibactam are 17 and 22.2 L, respectively, in healthy adults following multiple doses of ceftazidime and avibactam (2.5 g [ceftazidime 2 g and avibactam 0.5 g]) given by IV infusion every 8 hours for 11 days.1

Ceftazidime is less than 10% protein bound;1 avibactam is approximately 5.7-8.2% bound to plasma proteins.1

Ceftazidime is distributed into human milk in low concentrations.1 In rats, avibactam is distributed into milk in a dose-dependent manner;1 it is not known whether avibactam is distributed into human milk.1

Elimination

Ceftazidime and avibactam do not undergo clinically important metabolism, and both drugs are principally eliminated unchanged in urine.1

There was no evidence of metabolism of avibactam in vitro in human liver preparations (microsomes and hepatocytes),1 and unchanged avibactam was the major component in human plasma and urine after a single IV dose of 0.5 g of avibactam.1

Following an IV dose of ceftazidime, approximately 80-90% of the dose is excreted unchanged by the kidneys over 24 hours.1 Following an IV dose of avibactam, an average of 97% of the dose is eliminated in urine and 0.2% is eliminated in feces.1

The plasma elimination half-lives of ceftazidime and avibactam are 2.8 and 2.7 hours, respectively, in healthy adult males with normal renal function receiving multiple doses of ceftazidime and avibactam (2.5 g [ceftazidime 2 g and avibactam 0.5 g]) given by IV infusion over 2 hours every 8 hours.1

The serum half-life of ceftazidime is prolonged in patients with renal impairment.1 Following a single 100-mg IV dose of avibactam in adults with mild, moderate, or severe renal impairment not requiring hemodialysis, the AUC of avibactam was 2.6-, 3.8-, or 7-fold higher, respectively, compared with the AUC reported in healthy adults with normal renal function.1 In adults with end-stage renal disease (ESRD) who received a single 100-mg IV dose of avibactam 1 hour after hemodialysis, the AUC of avibactam was 19.5-fold higher than the AUC reported in healthy adults with normal renal function.1

Both ceftazidime and avibactam are removed by hemodialysis.1 In patients with ESRD who received 1 g of ceftazidime or 100 mg of avibactam prior to a 4-hour hemodialysis session, 55% of the ceftazidime dose or 55% of the avibactam dose was recovered in the dialysate.1

There was no effect on ceftazidime pharmacokinetics when ceftazidime was given in a dosage of 2 g IV every 8 hours for 5 days in adults with hepatic impairment.1 Pharmacokinetics of avibactam have not been established in patients with hepatic impairment;1 however, avibactam does not appear to undergo clinically important hepatic metabolism and systemic clearance of the drug is not expected to be affected by hepatic impairment.1

Chemistry and Stability

Chemistry

Ceftazidime and avibactam sodium is a fixed combination of ceftazidime (a third generation cephalosporin antibiotic) and avibactam (a non-β-lactam β-lactamase inhibitor);1,2 avibactam inactivates certain bacterial β-lactamases and expands ceftazidime's spectrum of activity against some bacteria that produce these β-lactamases.1,5,6,10,11,13,16,17,18,19

Ceftazidime contains an aminothiadiazole ring that enhances antibacterial activity against gram-negative bacteria, a carboxypropyl-oxyimino group that contributes to stability in the presence of β-lactamases, and a methylpyridinium group responsible for the drug's antipseudomonal activity.5 (For additional information on ceftazidime, see Ceftazidime 8:12.06.12.)

Avibactam is a diazabicyclooctanone derivative non-β-lactam β-lactamase inhibitor that differs structurally and pharmacologically from β-lactam β-lactamase inhibitors (e.g., sulbactam, clavulanic acid, tazobactam).1,5,6,25,26,27 Avibactam does not contain a β-lactam core, but does resemble β-lactams in key areas (i.e., carbonyl at position 7, sulfate at position 6, carboxamide at position 2), which allows binding to and inactivation of certain β-lactamases produced by bacteria.1,5,6,26,27

Ceftazidime and avibactam is commercially available as a white to yellow sterile powder for IV infusion containing a 4:1 ratio of ceftazidime to avibactam.1 The ceftazidime component is provided as a mixture of ceftazidime (as the pentahydrate) and sodium carbonate (facilitates dissolution of ceftazidime);1,217 the avibactam component is provided as avibactam sodium.1 Drug strength and dosage are expressed as the total of the 2 active components.1 (See Dispensing and Dosage and Administration Precautions under Administration: IV Infusion, in Dosage and Administration.)

Each single-dose vial of ceftazidime and avibactam contains 2.5 g (2 g of ceftazidime [equivalent to 2.635 g of the ceftazidime pentahydrate and sodium carbonate mixture] and 0.5 g of avibactam [equivalent to 0.551 g of avibactam sodium]).1 The total sodium content is approximately 146 mg (6.4 mEq) per single-dose vial.1

Stability

Ceftazidime and avibactam powder for IV infusion should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1 Vials should be protected from light.1

Following reconstitution and dilution, ceftazidime and avibactam solutions should be used within 12 hours when stored at room temperature.1 Alternatively, reconstituted and diluted solutions of the drug may be stored for up to 24 hours at 2-8°C and then used within 12 hours after removal from refrigeration to room temperature.1

Additional Information

For further information on chemistry, mechanism of action, spectrum, resistance, uses, cautions, acute toxicity, drug interactions, or laboratory test interferences of cephalosporins, see the Cephalosporins General Statement 8:12.06.

1. Forest Pharmaceuticals, Inc. Avycaz^® (ceftazidime and avibactam sodium) for injection prescribing information. Cincinnati, OH; 2015 Sep.

2. Andes DR, Craig WA. Cephalosporins. In: Bennett JE, Dolin R, Blaser MJ eds. Mandell, Douglas and Bennett's principles and practices of infectious disease. 8th ed. Philadelphia, PA: Saunders, Elsevier; 2015:278-91.

3. Lucasti C, Popescu I, Ramesh MK et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother . 2013; 68:1183-92. [PubMed 23391714]

4. Vazquez JA, González Patzán LD, Stricklin D et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin . 2012; 28:1921-31. [PubMed 23145859]

5. Lagacé-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid . 2014; 9:13-25. [PubMedCentral][PubMed 24493994]

6. Lahiri SD, Johnstone MR, Ross PL et al. Avibactam and class C β-lactamases: mechanism of inhibition, conservation of the binding pocket, and implications for resistance. Antimicrob Agents Chemother . 2014; 58:5704-13. [PubMedCentral][PubMed 25022578]

7. Dallow J, Otterson LG, Huband MD et al. Microbiological interaction studies between ceftazidime-avibactam and pulmonary surfactant and between ceftazidime-avibactam and antibacterial agents of other classes. Int J Antimicrob Agents . 2014; 44:552-6. [PubMed 25293578]

8. Pitart C, Marco F, Keating TA et al. Activity of Ceftazidime-Avibactam against Fluoroquinolone-Resistant Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother . 2015; 59:3059-65. [PubMedCentral][PubMed 25753646]

9. Aktas Z, Kayacan C, Oncul O. In vitro activity of avibactam (NXL104) in combination with β-lactams against Gram-negative bacteria, including OXA-48 β-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents . 2012; 39:86-9. [PubMed 22041508]

10. Berkhout J, Melchers MJ, van Mil AC et al. In vitro activity of ceftazidime-avibactam combination in in vitro checkerboard assays. Antimicrob Agents Chemother . 2015; 59:1138-44. [PubMedCentral][PubMed 25487794]

11. Levasseur P, Girard AM, Miossec C et al. In vitro antibacterial activity of the ceftazidime-avibactam combination against enterobacteriaceae, including strains with well-characterized β-lactamases. Antimicrob Agents Chemother . 2015; 59:1931-4. [PubMedCentral][PubMed 25583732]

12. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol . 2010; 31:431-55. [PubMed 20307191]

13. Keepers TR, Gomez M, Celeri C et al. Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother . 2014; 58:5297-305. [PubMedCentral][PubMed 24957838]

14. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50. [PubMed 9149180]

15. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]

16. Yoshizumi A, Ishii Y, Aoki K et al. In-vitro susceptibility of characterized β-lactamase-producing Gram-negative bacteria isolated in Japan to ceftazidime-, ceftaroline-, and aztreonam-avibactam combinations. J Infect Chemother . 2015; 21:148-51. [PubMed 25444674]

17. Winkler ML, Papp-Wallace KM, Bonomo RA. Activity of ceftazidime/avibactam against isogenic strains of Escherichia coli containing KPC and SHV β-lactamases with single amino acid substitutions in the ω-loop. J Antimicrob Chemother . 2015; :. [PubMedCentral]

18. Li H, Estabrook M, Jacoby GA et al. In vitro susceptibility of characterized β-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother . 2015; 59:1789-93. [PubMedCentral][PubMed 25534728]

19. Castanheira M, Mills JC, Costello SE et al. Ceftazidime-Avibactam Activity Tested against Enterobacteriaceae Isolates from U.S. Hospitals (2011 to 2013) and Characterization of β-Lactamase-Producing Strains. Antimicrob Agents Chemother . 2015; 59:3509-17. [PubMedCentral][PubMed 25845862]

20. Levasseur P, Girard AM, Claudon M et al. In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother . 2012; 56:1606-8. [PubMedCentral][PubMed 22214778]

21. Sader HS, Castanheira M, Mendes RE et al. Ceftazidime-Avibactam Activity against Multidrug-Resistant Pseudomonas aeruginosa Isolated in U.S. Medical Centers in 2012 and 2013. Antimicrob Agents Chemother . 2015; 59:3656-9. [PubMedCentral][PubMed 25845861]

22. US Food and Drug Administration. FDA drug safety communication: FDA cautions about dose confusion and medication errors with antibacterial drug Avycaz (ceftazidime and avibactam). 2015 Sept 22. From FDA website. [Web]

23. Merdjan H, Rangaraju M, Tarral A. Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies. Clin Drug Investig . 2015; 35:307-17. [PubMed 25813217]

24. Tarral A, Merdjan H. Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers. Clin Ther . 2015; 37:877-86. [PubMed 25769615]

25. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206494Orig1s000. Summary review. From FDA website. [Web]

26. Drawz SM, Papp-Wallace KM, Bonomo RA. New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother . 2014; 58:1835-46. [PubMedCentral][PubMed 24379206]

27. Stachyra T, Péchereau MC, Bruneau JM et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor. Antimicrob Agents Chemother . 2010; 54:5132-8. [PubMedCentral][PubMed 20921316]

28. Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev . 2010; 23:160-201. [PubMedCentral][PubMed 20065329]

29. Livermore DM, Warner M, Jamrozy D et al. In-vitro selection of ceftazidime-avibactam resistance in Enterobacteriaceae with KPC-3 carbapenemase. Antimicrob Agents Chemother . 2015; :. [PubMedCentral][PubMed 26100712]

30. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206494Orig1s000. Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

31. Citron DM, Tyrrell KL, Merriam V et al. In vitro activity of ceftazidime-NXL104 against 396 strains of beta-lactamase-producing anaerobes. Antimicrob Agents Chemother . 2011; 55:3616-20. [PubMedCentral][PubMed 21537015]

217. Hospira Inc. Tazicef^® (ceftazidime) powder for injection prescribing information. Lake Forest, IL; 2014 Oct.