Ceftazidime and Avibactam Sodium

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;1 used in conjunction with metronidazole.1 3

Reserve for use in patients with limited or no alternative treatment options;1 clinical safety and efficacy data are limited.1

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.1 4

Reserve for use in patients with limited or no alternative treatment options;1 clinical safety and efficacy data are limited.1

Contraindications

• Known serious hypersensitivity to ceftazidime and/or avibactam, avibactam-containing preparations, or other cephalosporins.1

Warnings/Precautions

Sensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions reported in patients receiving β-lactam antibacterials.1 Before initiating therapy, carefully inquire about patient's previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems.1

Use with caution in patients allergic to penicillin or other β-lactams;1 cross-sensitivity among β-lactam antibacterials established.1

If an allergic reaction occurs, discontinue ceftazidime and avibactam.1

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 (Clcr 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 (Clcr >50 mL/minute).1 Reason for reduced efficacy unclear,25 but protocol-specified dosage in patients with Clcr 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.1 25

Monitor Clcr at least once daily in patients with changing renal function;1 adjust dosage accordingly.1 (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.1 Adjust dosage based on Clcr.1 (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.1 Adverse reactions representing hemolytic anemia not reported.1

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

Possible emergence and overgrowth of nonsusceptible bacteria or fungi.1 Monitor carefully, institute appropriate therapy 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) reported with 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

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 12 14 15 Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.1

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible.1 12 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.1 12 14 15

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.1

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

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.1

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).1 (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.1

Specific Populations

Category B.1

Use during pregnancy only if clearly needed.1

No adequate controlled studies using ceftazidime and avibactam in pregnant women.1 In animal studies, no evidence of fetal harm with either ceftazidime or avibactam at dosages tested.1

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

Use with caution in nursing women.1

Safety and efficacy not established in patients <18 years of age.1

Limited data in patients ≥65 years of age;1 age-related differences in outcomes or specific risks with ceftazidime and avibactam cannot be ruled out.1

Ceftazidime and avibactam principally eliminated by kidneys;1 risk of adverse effects may be greater in those with impaired renal function.1 Because geriatric patients more likely to have reduced renal function, select dosage with caution and consider renal function monitoring.1 Adjust dosage in geriatric patients based on renal function.1

Ceftazidime pharmacokinetics not affected by hepatic impairment;1 because avibactam does not appear to undergo clinically important hepatic metabolism, systemic clearance of the drug not expected to be affected by hepatic impairment.1

Ceftazidime and avibactam principally eliminated by kidneys;1 risk of adverse effects may be greater in patients with renal impairment.1 In addition, lower cure rate reported in some patients with moderate renal impairment.1 (See Reduced Efficacy in Patients with Moderate Renal Impairment under Cautions.)

Adjust dosage in adults with moderate or severe renal impairment (Clcr ≤50 mL/minute), including those undergoing hemodialysis.1 Monitor Clcr at least once daily in patients with changing renal function;1 adjust dosage accordingly.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

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 WBC count,3 headache,4 dizziness,1 4 chest pain,4 hypertension,4 cough,3 anxiety,1 4 insomnia,4 infusion site reactions.4

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

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;1 shows some potential to induce CYP2E1 at concentrations exceeding clinically relevant exposures.1

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

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.1 Avibactam not a substrate for MDR1, BCRP, MRP4, or OCT2.1

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

Drugs Affecting or Affected by Organic Anion Transporter

OAT1 and/or OAT3 inhibitors: Possible decreased elimination of avibactam.1

Specific Drugs and Laboratory Tests

• Ceftazidime and avibactam is a fixed combination of ceftazidime (a third generation cephalosporin antibiotic) and avibactam (a non-β-lactam β-lactamase inhibitor).1 2

• 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).1 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.2

• Avibactam is a non-β-lactam β-lactamase inhibitor;1 5 6 25 26 27 differs structurally and pharmacologically from β-lactam β-lactamase inhibitors (e.g., sulbactam, clavulanic acid, tazobactam).5 6 25 26 27 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]).1 5 6 10 25 26 27 28 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 its spectrum of activity to include many β-lactamase-producing bacteria resistant to ceftazidime alone.1 5 6 10 11 13 16 17 18 19 Avibactam does not decrease antibacterial activity of ceftazidime against ceftazidime-susceptible bacteria.1

• Ceftazidime and avibactam is bactericidal in action.1 13

• Active in vitro against many Enterobacteriaceae, including C. freundii,1 8 11 16 18 C. koseri,1 16 19 E. coli,1 8 9 11 13 16 18 E. aerogenes,1 E. cloacae,1 8 11 16 18 19 K. pneumoniae,1 8 9 11 16 18 K. oxytoca,1 18 19 Morganella morganii,1 11 18 Proteus1 11 (including P. mirabilis1 8 11 16 19 and P. vulgaris19 ), P. rettgeri,1 11 P. stuartii,1 and Serratia marcescens.1 8 18 19

• 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) strains.10 21

• 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.1 5 6 8 9 10 11 13 16 18 20 21

• Has only limited activity in vitro against most anaerobic bacteria.5 31

• Resistance or reduced susceptibility to ceftazidime and avibactam can occur.1 5 13 16 17 19 26 29 Mechanism of resistance may be multifactorial.20

• Bacteria that produce metallo-β-lactamases are resistant to ceftazidime and avibactam;5 13 26 bacterial strains producing certain OXA β-lactamases (e.g., Acinetobacter, Ps. aeruginosa) also resistant to ceftazidime and avibactam.5 9 13 26

• Bacteria resistant to ceftazidime because of altered PBPs may also be resistant to ceftazidime and avibactam.5 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.1 5 8 16 20

• Cross-resistance between ceftazidime and avibactam and other classes of anti-infectives not reported.1 Some bacteria resistant to carbapenems, other cephalosporins (including ceftazidime alone), or fluoroquinolones may be susceptible to ceftazidime and avibactam.1 8

• 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).1

• Importance of completing full course of therapy, even if feeling better after a few days.1

• 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.1

• Advise patients that allergic reactions, including serious allergic reactions, requiring immediate treatment could occur.1 Importance of informing clinicians about any previous hypersensitivity reactions to ceftazidime and avibactam, other β-lactams (including cephalosporins), or other allergens.1

• Advise patients that adverse neurologic reactions can occur while receiving ceftazidime and avibactam.1 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;1 immediate treatment, dosage adjustment, or discontinuance of ceftazidime and avibactam may be necessary.1

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 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.1

• 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.1

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)