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Ceftazidime and Avibactam

Pronunciation

(SEF tay zi deem & a vi BAK tam)

Index Terms

  • Avibactam and Ceftazidime
  • Ceftazidime/Avibactam

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Avycaz: 2.5 g: Ceftazidime 2 g and avibactam 0.5 g (1 ea)

Brand Names: U.S.

  • Avycaz

Pharmacologic Category

  • Cephalosporin Combination

Pharmacology

Ceftazidime inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Avibactam inactivates some beta-lactamases and protects ceftazidime from degradation.

Distribution

Vd: Ceftazidime: 17 L; Avibactam: 22.2 L

Metabolism

Ceftazidime: ~80% to 90% of dose eliminated as unchanged drug; Avibactam: Not metabolized

Excretion

Ceftazidime: Urine (~80% to 90% as unchanged drug); Avibactam: Urine (97%)

Half-Life Elimination

Ceftazidime: 2.76 hours; Avibactam: 2.71 hours

Protein Binding

Ceftazidime: <10%; Avibactam: 5.7% to 8.2%

Special Populations: Renal Function Impairment

Half-life increases in patients with impaired renal function; AUC of avibactam increases 2.6-fold, 3.8-fold, and 7-fold in patients with mild, moderate or severe renal impairment, respectively.

Use: Labeled Indications

Intra-abdominal infections, complicated: Treatment of complicated intra-abdominal infections (cIAI) in patients 18 years and older, in combination with metronidazole, caused by Citrobacter freundii complex, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

Urinary tract infections, complicated (including pyelonephritis): Treatment of complicated urinary tract infections (cUTI) (including pyelonephritis) in patients 18 years and older, caused by Citrobacter freundii, C. koseri, Enterobacter aerogenes, E. cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus spp, and Pseudomonas aeruginosa.

Contraindications

Serious hypersensitivity to ceftazidime, avibactam, other cephalosporins, or any component of the formulation

Dosing: Adult

Note: Dosage recommendations are expressed as total grams of the ceftazidime/avibactam combination.

Intra-abdominal infections, complicated: IV: 2.5 g every 8 hours in combination with metronidazole for 5 to 14 days.

Urinary tract infections, complicated (including pyelonephritis): IV: 2.5 g every 8 hours for 7 to 14 days.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Note: Estimation of renal function for the purpose of drug dosing should be done using the Cockcroft-Gault formula. Dosage recommendations are expressed as total grams of the ceftazidime/avibactam combination:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 31 to 50 mL/minute: 1.25 g every 8 hours

CrCl 16 to 30 mL/minute: 0.94 g every 12 hours

CrCl 6 to 15 mL/minute: 0.94 g every 24 hours

CrCl ≤5 mL/minute: 0.94 g every 48 hours

End stage renal disease (ESRD) on intermittent hemodialysis (IHD): Administer after hemodialysis on dialysis days; base dose upon patient's estimated renal function (eg, CrCl 6 to 15 mL/minute or CrCl ≤5 mL/minute ).

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Reconstitution

IV: Reconstitute vial with 10 mL of NS, D5W, SWFI or other compatible solution listed in the manufacturer’s labeling (resulting approximate concentration: ceftazidime 167 mg/mL and avibactam 42 mg/mL) and further dilute in 50 to 250 mL of a compatible IV infusion fluid; mix gently. Solution ranges in color from clear to light yellow.

Administration

IV: Administer by intermittent infusion over 2 hours.

Compatibility

Stable in NS, D5W, LR, and all combinations of dextrose and sodium chloride injection containing up to dextrose 2.5% and sodium chloride 0.45%.

Storage

Vials: Store intact vials at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect from light.

Intermittent IV infusion: Admixed solutions in NS, D5W, LR, or any combination of dextrose and sodium chloride injection containing up to dextrose 2.5% and sodium chloride 0.45% are stable up to 12 hours at 20°C to 25°C (68°F to 77°F) and 24 hours at 2°C to 8°C (36°F to 46°F). Use solutions previously stored at 2°C to 8°C (36°F to 46°F) within 12 hours of subsequent storage at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Aminoglycosides: Cephalosporins (3rd Generation) may enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Chloramphenicol: May diminish the therapeutic effect of CefTAZidime. Management: Consider using a different combination of antimicrobials, especially if bactericidal activity is desired. If these agents are combined, monitor for reduced antimicrobial effectiveness and/or therapeutic failure. Consider therapy modification

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Probenecid: May increase the serum concentration of Avibactam. Avoid combination

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Teriflunomide: May increase the serum concentration of OAT3 Substrates. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Cephalosporins may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

Ceftazidime: Positive direct Coomb. False-positive reaction for urine glucose with certain methods; use glucose tests based on enzymatic glucose oxidase reactions.

Adverse Reactions

Frequency not always defined.

1% to 10%:

Central nervous system: Anxiety (10%), dizziness (6%)

Dermatologic: Skin rash (<5%)

Endocrine & metabolic: Hypokalemia (<5%), increased gamma-glutamyl transferase (<5%)

Gastrointestinal: Constipation (10%), abdominal pain (7%), upper abdominal pain (7%), nausea (2%), Clostridium difficile associated diarrhea

Hematologic & oncologic: Eosinophilia (<5%), prolonged prothrombin time (<5%), thrombocytopenia (<5%), positive direct coombs test (2%; no hemolytic anemia reactions reported)

Hepatic: Increased serum alkaline phosphatase (3%), increased serum ALT (3%)

Renal: Acute renal failure (<5%), renal impairment (<5%)

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam drugs. Before initiating therapy, carefully investigate previous penicillin, cephalosporin, or carbapenem hypersensitivity. Use caution if given to a patient with a penicillin or other beta-lactam allergy because cross sensitivity among beta-lactam antibacterial drugs has been established. If an allergic reaction occurs, discontinue and institute appropriate therapy.

• Neurotoxicity: Severe neurological reactions have been reported with ceftazidime, including asterixis, coma, encephalopathy, myoclonus, neuromuscular excitability, seizures, and nonconvulsive status epilepticus. Risk may be increased in the presence of renal impairment; ensure dose adjusted for renal function. Discontinue therapy if patient develops neurotoxicity.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: In clinical trials, patients with a CrCl of 30 to 50 mL/minute had lower clinical cure rates than those with CrCl >50 mL/minute; however, these patients received a daily dose that was 33% lower than what is currently recommended for patients with this degree of renal impairment. Monitor renal function at baseline and at least daily in patients with changing renal function. Adjust the dose accordingly.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Monitor for signs of anaphylaxis during first dose. Monitor renal function at baseline in all patients, and at least daily in patients with renal impairment.

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies conducted with ceftazidime; adverse events have been observed in some animal reproduction studies conducted with avibactam.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience anxiety, constipation, dizziness, nausea, or vomiting. Have patient report immediately to prescriber seizures, muscle rigidity, tremors, abnormal movements, confusion, hallucination, passing out, or signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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