cefTAZidime/Avibactam (Monograph)

Drug class: Third Generation Cephalosporins
Chemical name: [6R-[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
Molecular formula: C₂₂H₂₂N₆O₇S₂ • 5H₂OC₇H₁₀N₃O₆SNa
CAS number: 78439-06-2

Introduction

Antibacterial; β-lactam antibiotic; fixed combination of ceftazidime (a third generation cephalosporin) and avibactam (a non-β-lactam β-lactamase inhibitor).

Uses for cefTAZidime/Avibactam

Intra-abdominal Infections

Treatment of complicated intra-abdominal infections caused by susceptible Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, Providencia stuartii, or Pseudomonas aeruginosa; used in conjunction with metronidazole.

Reserve for use in patients with limited or no alternative treatment options; clinical safety and efficacy data are limited.

Urinary Tract Infections

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.

Reserve for use in patients with limited or no alternative treatment options; clinical safety and efficacy data are limited.

cefTAZidime/Avibactam Dosage and Administration

Administration

Administer by IV infusion.

IV Administration

For solution compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute single-dose vials of ceftazidime and avibactam labeled as containing 2.5 g (ceftazidime 2 g and avibactam 0.5 g) by adding 10 mL of 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; mix gently.

Volume of reconstituted solution is approximately 12 mL; approximate concentration is ceftazidime 167 mg/mL and avibactam 42 mg/mL.

Dilution

Prior to IV infusion, reconstituted solutions must be further diluted.

To prepare indicated dose, withdraw appropriate volume of reconstituted solution from the vial and add to a compatible IV solution to achieve a total final volume of 50–250 mL in an IV infusion bag. (See Table 1.) Solution should appear clear and colorless to light yellow.

With the exception of sterile water for injection, dilute using same IV solution used for reconstitution; dilute with any other compatible IV solution if sterile water for injection was used for reconstitution.

Mix diluted solution gently to ensure the drug is completely dissolved.

Rate of Administration

Administer by IV infusion over 2 hours.

Dispensing and Dosage and Administration Precautions

FDA alerted healthcare professionals about risk of medication errors with ceftazidime and avibactam. Errors occurred during preparation of solutions for IV infusion, resulted in administration of incorrect dosage (higher than intended), and were due to confusion about how dosage of the fixed combination 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. To prevent such errors, vial labels and carton packaging were revised to indicate strength of the fixed combination as the total the 2 active components.

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). Consider this dosage convention when prescribing, preparing, and dispensing ceftazidime and avibactam. FDA urges healthcare professionals and patients to report medication errors and adverse effects involving the drug to the FDA MedWatch program.

Dosage

Available as fixed combination containing 4:1 ratio of ceftazidime to avibactam.

Ceftazidime component provided as mixture of ceftazidime pentahydrate and sodium carbonate (dosage of this component expressed in terms of anhydrous ceftazidime); avibactam component provided as avibactam sodium (dosage of this component expressed in terms of avibactam).

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

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

Adults

Intra-abdominal Infections

IV

2.5 g (ceftazidime 2 g and avibactam 0.5 g) every 8 hours given in conjunction with metronidazole.

Treatment duration is 5–14 days.

Urinary Tract Infections

IV

2.5 g (ceftazidime 2 g and avibactam 0.5 g) every 8 hours.

Treatment duration is 7–14 days.

Special Populations

Hepatic Impairment

Dosage adjustments not needed in adults with hepatic impairment.

Renal Impairment

Adjust dosage in adults with Cl_cr ≤50 mL/minute, including those undergoing hemodialysis. (See Table 2.)

Monitor Cl_cr at least once daily in patients with changing renal function; adjust dosage accordingly.

On hemodialysis days, give the dose after dialysis.

Geriatric Patients

Dosage adjustments based solely on age not needed. Select dosage with caution and monitor renal function since geriatric patients more likely to have decreased renal function than younger adults.

Cautions for cefTAZidime/Avibactam

Contraindications

• Known serious hypersensitivity to ceftazidime and/or avibactam, avibactam-containing preparations, or other cephalosporins.

Warnings/Precautions

Sensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions reported in patients receiving β-lactam antibacterials. Before initiating therapy, carefully inquire about patient's previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems.

Use with caution in patients allergic to penicillin or other β-lactams; cross-sensitivity among β-lactam antibacterials established.

If an allergic reaction occurs, discontinue ceftazidime and avibactam.

Reduced Efficacy in Patients with Moderate Renal Impairment

In a subgroup analysis of patients with complicated intra-abdominal infections, clinical cure rate in patients with baseline moderate renal impairment (Cl_cr of 30–50 mL/minute) receiving ceftazidime and avibactam in conjunction with metronidazole was 45% compared with a clinical cure rate of 85% in those with normal renal function or only mild renal impairment (Cl_cr >50 mL/minute). Reason for reduced efficacy unclear, but protocol-specified dosage in patients with Cl_cr of 30–50 mL/minute was 33% lower than currently recommended dosage for such patients and those with rapidly changing renal function may not have received appropriate dosage.

Monitor Cl_cr at least once daily in patients with changing renal function; adjust dosage accordingly. (See Renal Impairment under Cautions.)

Nervous System Effects

Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia reported in patients receiving ceftazidime, particularly those with renal impairment. Adjust dosage based on Cl_cr. (See Renal Impairment under Dosage and Administration.)

Hematologic Effects

In clinical trials, seroconversion from negative to 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. Adverse reactions representing hemolytic anemia not reported.

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

Possible emergence and overgrowth of nonsusceptible bacteria or fungi. Monitor carefully, institute appropriate therapy if superinfection occurs.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including ceftazidime and avibactam, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; 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.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible. Initiate 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.

Selection and Use of Anti-infectives

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

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

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.

When prescribing, preparing, and dispensing ceftazidime and avibactam, 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). (See Dispensing and Dosage and Administration Precautions under Dosage and Administration.)

Sodium Content

Contains approximately 146 mg (6.4 mEq) of sodium in each single-dose vial.

Specific Populations

Pregnancy

Category B.

Use during pregnancy only if clearly needed.

No adequate controlled studies using ceftazidime and avibactam in pregnant women. In animal studies, no evidence of fetal harm with either ceftazidime or avibactam at dosages tested.

Lactation

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

Use with caution in nursing women.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

Limited data in patients ≥65 years of age; age-related differences in outcomes or specific risks with ceftazidime and avibactam cannot be ruled out.

Ceftazidime and avibactam principally eliminated by kidneys; risk of adverse effects may be greater in those with impaired renal function. Because geriatric patients more likely to have reduced renal function, select dosage with caution and consider renal function monitoring. Adjust dosage in geriatric patients based on renal function.

Hepatic Impairment

Ceftazidime pharmacokinetics not affected by hepatic impairment; because avibactam does not appear to undergo clinically important hepatic metabolism, systemic clearance of the drug not expected to be affected by hepatic impairment.

Renal Impairment

Ceftazidime and avibactam principally eliminated by kidneys; risk of adverse effects may be greater in patients with renal impairment. In addition, lower cure rate reported in some patients with moderate renal impairment. (See Reduced Efficacy in Patients with Moderate Renal Impairment under Cautions.)

Adjust dosage in adults with moderate or severe renal impairment (Cl_cr ≤50 mL/minute), including those undergoing hemodialysis. Monitor Cl_cr at least once daily in patients with changing renal function; adjust dosage accordingly. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (nausea, vomiting, diarrhea, abdominal pain, constipation ), pyrexia, increased AST, increased ALT, increased blood alkaline phosphatase, increased WBC count, headache, dizziness, chest pain, hypertension, cough, anxiety, insomnia, infusion site reactions.

Drug Interactions

Ceftazidime does not induce CYP1A1, 1A2, 2B6, or 3A4/5 in vitro.

Avibactam does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP1A2, 2B6, 2C9, or 3A4 in vitro; shows some potential to induce CYP2E1 at concentrations exceeding clinically relevant exposures.

Avibactam is a substrate of organic anion transporter (OAT) 1 and OAT3 kidney transporters. Ceftazidime and avibactam do not inhibit OAT1 or OAT3 in vitro; ceftazidime does not inhibit avibactam transport mediated by OAT1 and OAT3.

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 in vitro at clinically relevant concentrations. Avibactam not a substrate for MDR1, BCRP, MRP4, or OCT2.

The following drug interactions are based on studies using ceftazidime and avibactam, ceftazidime alone, or avibactam alone. When ceftazidime and avibactam used, consider interactions associated with both drugs in the fixed combination.

Drugs Affecting or Affected by Organic Anion Transporter

OAT1 and/or OAT3 inhibitors: Possible decreased elimination of avibactam.

Specific Drugs and Laboratory Tests

cefTAZidime/Avibactam Pharmacokinetics

Following IV administration of fixed combination of ceftazidime and avibactam, pharmacokinetic parameters for ceftazidime and avibactam are similar to those reported when each drug is administered alone.

Pharmacokinetic parameters are similar following single or multiple IV doses of the fixed combination.

Absorption

Plasma Concentrations

Peak plasma concentrations of ceftazidime and avibactam were 90.4 and 14.6 mcg/mL, respectively, in healthy adult males 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 over 2 hours every 8 hours for 11 days.

Peak plasma concentrations and AUC of ceftazidime increase in proportion to dose; avibactam demonstrated approximately linear pharmacokinetics after single IV doses ranging from 50 mg to 2 g.

No appreciable accumulation of ceftazidime or avibactam when the fixed combination (2.5 g [ceftazidime 2 g and avibactam 0.5 g]) is given by IV infusion every 8 hours for up to 11 days in healthy adults with normal renal function.

Special Populations

Geriatric adults: AUC in healthy adults ≥65 years of age was 17% higher than that reported in healthy adults 18–45 years of age; peak plasma concentrations not substantially affected by age.

Gender: Peak plasma concentrations of avibactam in males were 18% lower than those reported in females; AUC of avibactam not affected by gender.

Distribution

Extent

Ceftazidime distributes into human milk in low concentrations. In rats, avibactam distributes into milk in dose-dependent manner; not known whether avibactam distributes into human milk.

Plasma Protein Binding

Ceftazidime: <10%.

Avibactam: 5.7–8.2%.

Elimination

Metabolism

Ceftazidime and avibactam do not undergo clinically important metabolism.

Metabolism of avibactam not observed in vitro in human liver preparations (microsomes and hepatocytes).

Elimination Route

Both ceftazidime and avibactam principally eliminated unchanged in urine.

Ceftazidime: Approximately 80–90% of an IV dose excreted unchanged by the kidneys over 24 hours.

Avibactam: Average of 97% of an IV dose eliminated in urine; 0.2% eliminated in feces.

Half-life

Ceftazidime: 2.8 hours following multiple IV doses of ceftazidime and avibactam.

Avibactam: 2.7 hours following multiple IV doses of ceftazidime and avibactam.

Special Populations

Renal impairment: Half-life of ceftazidime prolonged. AUC of avibactam increased by 2.6-, 3.8-, or 7-fold in adults with mild, moderate, or severe renal impairment, respectively.

Both ceftazidime and avibactam removed by hemodialysis. In patients with end-stage renal disease (ESRD), 55% of a ceftazidime dose or 55% of a avibactam dose recovered in dialysate.

Hepatic impairment: Ceftazidime pharmacokinetics not affected. Avibactam pharmacokinetics not established in patients with hepatic impairment; does not appear to undergo clinically important hepatic metabolism and systemic clearance of avibactam not expected to be affected.

Stability

Storage

Parenteral

Powder for IV Infusion

25°C (may be exposed to 15–30°C). Protect from light.

Reconstituted solution may be stored for up to 30 minutes prior to transfer and dilution.

Following reconstitution and dilution, may be stored for up to 12 hours at room temperature. Alternatively, 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.

Compatibility

Parenteral

Solution Compatibility

Actions and Spectrum

• Ceftazidime and avibactam is a fixed combination of ceftazidime (a third generation cephalosporin antibiotic) and avibactam (a non-β-lactam β-lactamase inhibitor).

• Like other cephalosporins, antibacterial activity of ceftazidime results from inhibition of mucopeptide synthesis in the bacterial cell wall and is mediated by penicillin-binding proteins (PBPs). Ceftazidime has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins, and is distinguished from many other cephalosporins by its activity against Ps. aeruginosa.

• Avibactam is a non-β-lactam β-lactamase inhibitor; differs structurally and pharmacologically from β-lactam β-lactamase inhibitors (e.g., sulbactam, clavulanic acid, tazobactam). Avibactam inactivates many β-lactamases in Ambler class A (e.g., some extended-spectrum β-lactamases [ESBLs], carbapenemases such as K. pneumoniae carbapenemases [KPCs]), class C (e.g., cephalosporinases such as AmpC), and class D (e.g., some oxacillinases [OXAs]). Cannot inactivate Ambler class B metallo-β-lactamases (MBLs) or certain OXA-type carbapenemases.

• Because avibactam inactivates certain β-lactamases, concomitant use with ceftazidime can protect ceftazidime from degradation by these β-lactamases and expand its spectrum of activity to include many β-lactamase-producing bacteria resistant to ceftazidime alone. Avibactam does not decrease antibacterial activity of ceftazidime against ceftazidime-susceptible bacteria.

• Ceftazidime and avibactam is bactericidal in action.

• Active in vitro against many Enterobacteriaceae, including C. freundii, C. koseri, E. coli, E. aerogenes, E. cloacae, K. pneumoniae, K. oxytoca, Morganella morganii, Proteus (including P. mirabilis and P. vulgaris ), P. rettgeri, P. stuartii, and Serratia marcescens.

• Active in vitro against many strains of Ps. aeruginosa, including some multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains.

• Active in vitro against some Enterobacteriaceae that produce certain TEM, SHV, CTX-M, KPC, AmpC, or OXA β-lactamases and active in vitro against some Ps. aeruginosa that produce certain AmpC β-lactamases.

• Has only limited activity in vitro against most anaerobic bacteria.

• Resistance or reduced susceptibility to ceftazidime and avibactam can occur. Mechanism of resistance may be multifactorial.

• Bacteria that produce metallo-β-lactamases are resistant to ceftazidime and avibactam; bacterial strains producing certain OXA β-lactamases (e.g., Acinetobacter, Ps. aeruginosa) also resistant to ceftazidime and avibactam.

• Bacteria resistant to ceftazidime because of altered PBPs may also be resistant to ceftazidime and avibactam. Some strains of gram-negative bacteria (e.g., Ps aeruginosa, S. marcescens) that over-express efflux pumps or have porin mutations that result in resistance to ceftazidime may also have reduced susceptibility or resistance to ceftazidime and avibactam.

• Cross-resistance between ceftazidime and avibactam and other classes of anti-infectives not reported. Some bacteria resistant to carbapenems, other cephalosporins (including ceftazidime alone), or fluoroquinolones may be susceptible to ceftazidime and avibactam.

Advice to Patients

• Advise patients 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).

• Importance of completing full course of therapy, even if feeling better after a few days.

• Advise patients that skipping doses or not completing the full course of 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.

• Advise patients that allergic reactions, including serious allergic reactions, requiring immediate treatment could occur. Importance of informing clinicians about any previous hypersensitivity reactions to ceftazidime and avibactam, other β-lactams (including cephalosporins), or other allergens.

• Advise patients that adverse neurologic reactions can occur while receiving ceftazidime and avibactam. Importance of immediately informing a clinician if any neurologic signs and symptoms, including encephalopathy (disturbance of consciousness such as confusion, hallucinations, stupor, coma), myoclonus, and seizures, occur; immediate treatment, dosage adjustment, or discontinuance of ceftazidime and avibactam may be necessary.

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting 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.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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