ceftazidime/avibactam (Rx)

Brand and Other Names:Avycaz
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

ceftazidime/avibactam

injection, powder of reconstitution

  • (2g/0.5g)/vial: 2.5g
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Intra-abdominal Infections

Indicated in combination with metronidazole for complicated intra-abdominal infections (cIAIs) caused by the following susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa

2.5 g (2 g/0.5 g) IV q8hr infused over 2 hr for 5-14 days

Urinary Tract Infections

Indicated for complicated urinary tract infections (cUTIs) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus mirabilis, and Pseudomonas aeruginosa

2.5 g (2 g/0.5 g) IV q8hr infused over 2 hr for 7-14 days

Bacteria Pneumonia

Indicated for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible gram negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients ≥18 years

2.5 g (2 g/0.5 g) IV q8hr infused over 2 hr for 7-14 days

Dosage Modifications

Renal impairment

  • CrCl >50 mL/min: No dose adjustment required
  • CrCl 31-50 mL/min: 1.25 g (1 g/0.25 g) IV q8hr
  • CrCl 16-30 mL/min: 0.94 g (0.75 g/0.19 g) IV q12hr
  • CrCl 6-15 mL/min: 0.94 g (0.75 g/0.19 g) IV q24hr
  • CrCl <5 mL/min: 0.94 g (0.75 g/0.19 g) IV q48hr
  • Patients on hemodialysis: Administer after hemodialysis on hemodialysis days

Dosing Considerations

To reduce the development of drug-resistant bacteria and maintain the effectiveness, use only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria

<18 years: Safety and efficacy not established

Carefully monitor renal function in patients aged >65 yr

Dosage adjustment for elderly patients should be based on renal function (see Dosage Modifications)

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Interactions

Interaction Checker

and ceftazidime/avibactam

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            1-10% (in cIAI plus metronidazole)

            Diarrhea (8%)

            Nausea (7%)

            Vomiting (5%)

            Headache (3%)

            Dizziness (2%)

            Abdominal pain (1%)

            1-10% (in cUTI)

            Diarrhea (3%)

            Nausea (3%)

            Constipation (2%)

            Upper abdominal pain (1%)

            1-10% (in HABP/VABP)

            Nausea (3%)

            Pruritus (2%)

            Frequency Not Reported

            Blood and lymphatic disorders: Thrombocytopenia, thrombocytosis, leukopenia

            General disorders and administration site conditions: Injection site phlebitis

            Infections and infestations: Candidiasis

            Investigations:Increased aspartate aminotransferase, increased alanine aminotransferase, increased gamma-glutamyltransferase

            Metabolism and nutrition disorders: Hypokalemia

            Nervous system disorders: Dysgeusia

            Renal and urinary disorders: Acute kidney injury, renal impairment, nephrolithiasis

            Skin and subcutaneous tissue disorders: Rash, rash maculopapular, urticaria

            Psychiatric disorders: Anxiety

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            Warnings

            Contraindications

            Known serious hypersensitivity to avibactam, ceftazidime, or other cephalosporins

            Cautions

            In clinical trials, cure rates were lower in patients with baseline moderate renal impairment (CrCl 30-50 mL/min) who were treated for cIAI with ceftazidime/avibactam plus metronidazole (45% cure rate) compared with meropenem (74% cure rate); during the clinical trial, the ceftazidime/avibactam dose was 33% lower than what is currently recommended for patients with moderate renal impairment (see Dosage Modifications); follow current dosage adjustment recommendations for renal impairment

            Serious and occasionally fatal anaphylactic reactions and serious skin reactions have been reported with beta-lactam antibacterials; caution in patients with history of allergy to cephalosporins, penicillins, or carbapenems

            Clostridium difficile associated diarrhea (CDAD) has been associated with nearly all systemic antibacterials; severity may range from mild diarrhea to fatal colitis; may occur >2 months following antibacterial use; if CDAD suspected, manage fluid and electrolytes levels and monitor antibacterial treatment for CDAD

            Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with ceftazidime, especially in the setting of renal impairment; adjust dose according to CrCl (see Dosage Modifications)

            Confirm suspected bacterial infection when prescribing ceftazidime/avibactam to avoid the risk of developing drug-resistant bacteria

            Drug interactions overview

            • Avibactam is an OAT1/OAT3 substrate; probenecid, a potent OAT inhibitor, inhibits OAT uptake of avibactam by 56-70% and potentially decreases avibactam elimination when coadministered; therefore, coadministration with probenecid is not recommended
            • Ceftazidime administration may result in a false-positive reaction for urine glucose with certain methods; glucose tests based on enzymatic glucose oxidase reactions are recommended
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            Pregnancy & Lactation

            Pregnancy

            There are no adequate and well-controlled studies of ceftazidime/avibactam, ceftazidime, or avibactam in pregnant women

            Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose; in the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam

            Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed

            Lactation

            Ceftazidime is excreted in human milk in low concentrations

            Unknown whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats

            No information is available on the effects of ceftazidime and avibactam on the breastfed child or on milk production

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Ceftazidime: Third-generation cephalosporin with broad-spectrum gram-negative activity, including Pseudomonas; arrests bacterial growth by binding to 1 or more penicillin-binding proteins, and thereby inhibiting final transpeptidation step of peptidoglycan synthesis in bacterial cell-wall synthesis and inhibiting cell-wall biosynthesis

            Avibactam: Diazabicyclooctanone, non-β-lactam, β-lactamase inhibitor; alone has no antibacterial activity at clinically relevant doses; when combined with ceftazidime, avibactam protects ceftazidime from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of ceftazidime to include many gram-negative bacteria normally not susceptible to ceftazidime

            Absorption

            Ceftazidime

            • Peak plasma concentration: 88.1 mg/L (single 2.5 g-dose); 90.4 mg/L (multiple 2.5 g-dose)
            • AUC: 289 mg·h/L (single 2.5 g-dose); 291 mg·h/L (multiple 2.5 g-dose)

            Avibactam

            • Peak plasma concentration: 15.2mg/L (single 2.5 g-dose); 14.6 mg/L (multiple 2.5 g-dose)
            • AUC: 42.1 mg·h/L (single 2.5 g-dose); 38.2 mg·h/L (multiple 2.5 g-dose)

            Distribution

            Protein bound: <10% (ceftazidime); 5.7-8.2% (avibactam)

            Ceftazidime

            • Vd (steady-state): 18.1 L (single 2.5 g-dose); 17 L (multiple 2.5 g-dose)

            Avibactam

            • Vd (steady-state): 23.2 L (single 2.5 g-dose); 22.2 L (multiple 2.5 g-dose)

            Metabolism

            80-90% of ceftazidime IV dose is eliminated unchanged via the urine

            Nearly 100% of avibactam IV dose is eliminated unchanged via the urine

            Elimination

            Ceftazidime

            • Half-life: 3.27 hr (single 2.5 g-dose); 2.76 hr (multiple 2.5 g-dose)
            • Clearance (L/h): 6.93 L/h (single 2.5 g-dose); 6.86 L/h (multiple 2.5 g-dose)
            • Excretion: Urine (~80- 90% as unchanged drug)

            Avibactam

            • Half-life: 2.22 hr (single 2.5 g-dose); 2.71hr (multiple 2.5 g-dose)
            • Clearance (L/h): 11.9 L/h (single 2.5 g-dose); 13.1 L/h (multiple 2.5 g-dose)
            • Excretion, single 0.5 g-dose: Urine (97%); feces (0.2%)
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            Administration

            IV Compatibilities

            0.9% NaCl

            D5W

            All combinations of dextrose and sodium chloride injection containing up to 2.5% dextrose and 0.45% NaCl

            Lactated Ringer injection

            Y-site compatibility

            • Compatible drugs for use with 0.9% NaCl, D5W or Lactated Ringer injection as diluents
              • Daptomycin
              • Dexmedetomidine HCl
              • Dopamine HCl
              • Furosemide
              • Gentamicin sulfate
              • Imipenem-cilastatin
              • Magnesium sulfate
              • Norepinephrine bitartrate
              • Phenylephrine HCl
              • Vasopressin
              • Vecuronium bromide
            • Compatible drugs for use with 0.9% NaCl or D5W as diluents
              • Ertapenem sodium
              • Potassium phosphate
              • Sodium glycerophosphate
            • Compatible drugs for use with D5W or Lactated Ringer injection as diluents
              • Heparin sodium
              • Linezolid
              • Tobramycin sulfate
            • Compatible drugs for use with one compatible diluent only
              • Meropenem (0.9% NaCl diluent only)
              • Sodium bicarbonate (D5W diluent only)
              • Tedizolid phosphate (D5W diluent only)
              • Potassium chloride (Lactated Ringer injection diluent only)

            IV Preparation

            Reconstitute powder with 10 mL of one of the following solutions

            • Sterile water for injection
            • 0.9% NaCl
            • D5W
            • All combinations of dextrose and sodium chloride injection containing up to 2.5% dextrose and 0.45% NaCl
            • Lactated Ringer injection
            • Upon constitution, solution may be held for no longer than 30 minutes before transferring and further diluting in a suitable infusion bag

            Additional dilution required

            • Mix vial gently with 10 mL of a solution listed above
            • Reconstituted solution results in ~0.167 g/mL of ceftazidime and ~0.042 g/mL avibactam
            • Further dilute with the same diluent used for reconstitution (except sterile water for injection), to achieve a total volume of 50-250 mL before infusion
            • Volume to withdraw from constituted vial for further dilution
              • 2.5 g (2 g/0.5 g): 12 mL (entire contents)
              • 1.25 g (1 g/0.25 g): 6 mL
              • 0.94 g (0.75 g/0.19 g): 4.5 mL
            • Mix gently and ensure contents are dissolved completely
            • Visually inspect for particulate matter and discoloration (color ranges from clear to light yellow)
            • Use diluted infusion bags within 12 hr when stored at room temperature or under refrigeration at 2-8°C (36- 46°F) up to 24 hr following dilution and used within 12 hr of subsequent storage at room temperature

            IV Administration

            Infuse IV over 2 hr

            Storage

            Unopened vials

            • Store at 25°C (77°F); excursion permitted between 15-30°C (59-86°F)
            • Protect from light

            Diluted solution

            • Stored at room temperature, 25°C (77°F) for up to 12 hr
            • Refrigerate at 2-8°C (36- 46°F) up to 24 hr following dilution and used within 12 hr of subsequent storage at room temperature
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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