Ceftazidime and avibactam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: AKT
Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Overview
Ceftazidime and avibactam is a combination of a cephalosporin and a beta-lactamase inhibitor that is FDA approved for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. Common adverse reactions include diarrhea and nausea.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Complicated Intra-abdominal Infections (cIAI)
AVYCAZ in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa in patients 18 years or older.
- The recommended dosage of AVYCAZ is 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older in patients with normal renal function.
- Metronidazole should be given concurrently.
- Duration of treatment should range from 5 to 14 days.
- The recommended AVYCAZ dosage in patients with varying degrees of renal function is presented in TABLE 2. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of AVYCAZ accordingly.
Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
AVYCAZ is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa in patients 18 years or older.
- The recommended dosage of AVYCAZ is 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours by intravenous (IV) infusion over 2 hours in patients 18 years of age and older in patients with normal renal function.
- Duration of treatment should range from 7 to 14 days.
- The recommended AVYCAZ dosage in patients with varying degrees of renal function is presented in TABLE 2. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of AVYCAZ accordingly.
- The recommended AVYCAZ dosage in patients with varying degrees of renal function is presented in TABLE 2. For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of AVYCAZ accordingly.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftazidime and avibactam in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftazidime and avibactam in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ceftazidime and avibactam FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftazidime and avibactam in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftazidime and avibactam in pediatric patients.
Contraindications
AVYCAZ is contraindicated in patients with known serious hypersensitivity to ceftazidime or avibactam, avibactam-containing products, or other members of the cephalosporin class.
Warnings
- Decreased Clinical Response in cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min
- In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline CrCl of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min (TABLE 4). The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min.
- The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials.
- Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly.
- Hypersensitivity Reactions
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made.
- Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs.
- Clostridium difficile-associated Diarrhea
- Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.
- CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.
- If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
- Central Nervous System Reactions
- Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment.
- Adjust dosing based on creatinine clearance
- Development of Drug-Resistant Bacteria
- Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. AVYCAZ was evaluated in five active-controlled clinical trials in patients with cIAI or cUTI, including pyelonephritis. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as three Phase 3 trials, one in cIAI, one in cUTI (Trial 1), and one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2). Data from Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling, but provided supportive information. The five clinical trials included a total of 1373 adult patients treated with AVYCAZ and 1375 patients treated with comparators.
Complicated Intra-abdominal Infections
The Phase 3 cIAI trial included 529 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours plus 0.5 grams metronidazole administered intravenously over 60 minutes every 8 hours and 529 patients treated with meropenem. The median age of patients treated with AVYCAZ was 50 years (range 18 to 90 years) and 22.5% of patients were 65 years of age or older. Patients were predominantly male (62%) and Caucasian (76.6%).
Treatment discontinuation due to an adverse reaction occurred in 2.6% (14/529) of patients receiving AVYCAZ plus metronidazole and 1.3% (7/529) of patients receiving meropenem. There was no specific adverse reaction leading to discontinuation.
Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea and vomiting.
TABLE 5 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial.
Increased Mortality:
In the Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ plus metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCl 30 to less than or equal to 50 mL/min, death occurred in 19.5% (8/41) of patients who received AVYCAZ plus metronidazole and in 7.0% (3/43) of patients who received meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min.\
In patients with normal renal function or mild renal impairment (baseline CrCl greater than 50 mL/min), death occurred in 1.0% (5/485) of patients who received AVYCAZ plus metronidazole and in 1.0% (5/484) of patients who received meropenem. The causes of death varied and contributing factors included progression of underlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention.
Complicated Urinary Tract Infections, Including Pyelonephritis Trial 1 included 511 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours and 509 patients treated with doripenem; in some patients parenteral therapy was followed by a switch to an oral antimicrobial agent [see Clinical Studies (14.2)]. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years). Patients were predominantly female (68.3%) and Caucasian (82.4%). Patients with CrCl less than 30 mL/min were excluded.
There were no deaths in Trial 1. Treatment discontinuation due to adverse reactions occurred in 1.4% (7/511) of patients receiving AVYCAZ and 1.2% (6/509) of patients receiving doripenem. There was no specific adverse reaction leading to discontinuation.
The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea.
TABLE 6 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1.
Other Adverse Reactions of AVYCAZ and Ceftazidime
The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in the Phase 3 trials.
- Blood and lymphatic disorders - Thrombocytopenia
- 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 renal failure, Renal impairment, Nephrolithiasis
- Skin and subcutaneous tissue disorders - Rash, Rash maculo-papular, Urticaria, Pruritus
- Psychiatric disorders - Anxiety
Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below:
- Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Leukopenia, Lymphocytosis, Neutropenia, Thrombocytosis, Eosinophilia
- General disorders and administration site conditions - Infusion site inflammation, Injection site hematoma, Injection site thrombosis
- Hepatobiliary disorders – Jaundice
- Investigations - Increased blood lactate dehydrogenase, Prolonged prothrombin time
- Nervous system disorders - Paresthesia
- Renal and urinary disorders - Tubulointerstitial nephritis
- Reproductive and breast disorders - Vaginal inflammation
- Skin and subcutaneous tissue disorders - Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis
Laboratory Changes
Seroconversion from a negative to a positive direct Coombs' test result at any time up to the last visit occurred in 31/240 (12.9%) of patients receiving AVYCAZ plus metronidazole with initial negative Coombs' test and at least one follow up test and in 7/235 (3.0%) of patients receiving meropenem in the Phase 3 cIAI trial. Seroconversion from a negative to a positive direct Coombs' test result at any time up to the last visit occurred in 7/216 (3.2%) of patients receiving AVYCAZ with initial negative Coombs' test and at least one follow up test and 2/214 (0.9%) of patients receiving doripenem in the Phase 3 cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment group.
Postmarketing Experience
There is limited information regarding Ceftazidime and avibactam Postmarketing Experience in the drug label.
Drug Interactions
- Probenecid
- In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion.
- As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered.
- Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended.
- Drug/Laboratory Test Interactions
- The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods.
- It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
Use in Specific Populations
Pregnancy
- Risk Summary
- There are no adequate and well-controlled studies of AVYCAZ, 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.
- The background risk of major birth defects and miscarriage for the indicated population is unknown.
- The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. **Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.
- Data
- Animal Data
- Ceftazidime
- Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime.
- Avibactam
- Avibactam was not teratogenic in rats or rabbits.
- In the rat, intravenous studies with 0, 250, 500 and 1000 mg/kg/day avibactam during gestation days 6-17 showed no embryofetal toxicity at doses up to 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC).
- In a rat pre- and post-natal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability.
- A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults.
- Rabbits administered intravenous avibactam on gestation days 6-19 at 0, 100, 300 and 1000 mg/kg/day showed no effects on embryofetal development at a dose of 100 mg/kg, twice the human exposure (AUC).
- At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed.
- Ceftazidime
- Animal Data
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftazidime and avibactam in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ceftazidime and avibactam during labor and delivery.
Nursing Mothers
- Risk Summary
- Ceftazidime is excreted in human milk in low concentrations. It is not known 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 breast-fed child or on milk production.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AVYCAZ and any potential adverse effects on the breastfed child from AVYCAZ or from the underlying maternal conditions.
- Data
- In a rat pre- and post-natal study at doses up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), the exposure to avibactam was minimal in the pups in comparison to the dams.
- Exposure to avibactam was observed in both pups and milk on PND 7.
Pediatric Use
Safety and effectiveness in patients less than 18 years of age have not been established.
Geriatic Use
Of the 1373 patients treated with AVYCAZ in the Phase 2 and Phase 3 clinical trials 385 (28%) were 65 years of age and older, including 173 (15.3 %) patients 75 years of age and older.
In the pooled Phase 2 and Phase 3 cIAI AVYCAZ clinical trials, 20% (126/630) of patients treated with AVYCAZ were 65 years of age and older, including 49 (7.8%) patients 75 years of age and older. The incidence of adverse reactions in both treatment groups was higher in older patients (≥ 65 years of age) and similar in both treatment groups; clinical cure rates for patients 65 years of age or older were 73.0% (73/100) in the AVYCAZ plus metronidazole arm and 78.6% (77/98) in the meropenem arm.
In the Phase 3 cUTI trial, 30.7% (157/511) of patients treated with AVYCAZ were 65 years of age or older, including 78 (15.3%) patients 75 years of age or older. The incidence of adverse reactions in both treatment groups was lower in older patients (≥ 65 years of age) and similar between treatment groups. Among patients 65 years of age or older in the Phase 3 cUTI trial, 66.1% (82/124) of patients treated with AVYCAZ had symptomatic resolution at Day 5 compared with 56.6% (77/136) of patients treated with doripenem. The combined response (microbiological cure and symptomatic response) observed at the test-of-cure (TOC) visit for patients 65 years of age or older were 58.1% (72/124) in the AVYCAZ arm and 58.8% (80/136) in the doripenem arm.
Ceftazidime and avibactam are known to be substantially excreted by the kidney; therefore, the risk of adverse reactions to ceftazidime and avibactam may be greater in patients with decreased renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function.
Gender
There is no FDA guidance on the use of Ceftazidime and avibactam with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ceftazidime and avibactam with respect to specific racial populations.
Renal Impairment
Dosage adjustment is required in patients with moderately or severely impaired renal function (CrCl 50 mL/min or less). For patients with changing renal function, CrCl should be monitored at least daily, particularly early in treatment, and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days.
Hepatic Impairment
There is no FDA guidance on the use of Ceftazidime and avibactam in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ceftazidime and avibactam in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ceftazidime and avibactam in patients who are immunocompromised.
Administration and Monitoring
Administration
AVYCAZ is supplied as a dry powder, which must be constituted and subsequently diluted, using aseptic technique prior to intravenous infusion.
- p
- p
Monitoring
There is limited information regarding Ceftazidime and avibactam Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Ceftazidime and avibactam and IV administrations.
Overdosage
There is limited information regarding Ceftazidime and avibactam overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Ceftazidime and avibactam Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Ceftazidime and avibactam Mechanism of Action in the drug label.
Structure
There is limited information regarding Ceftazidime and avibactam Structure in the drug label.
Pharmacodynamics
There is limited information regarding Ceftazidime and avibactam Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Ceftazidime and avibactam Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Ceftazidime and avibactam Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Ceftazidime and avibactam Clinical Studies in the drug label.
How Supplied
There is limited information regarding Ceftazidime and avibactam How Supplied in the drug label.
Storage
There is limited information regarding Ceftazidime and avibactam Storage in the drug label.
Images
Drug Images
{{#ask: Page Name::Ceftazidime and avibactam |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
{{#ask: Label Page::Ceftazidime and avibactam |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
There is limited information regarding Ceftazidime and avibactam Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Ceftazidime and avibactam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Ceftazidime and avibactam Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Ceftazidime and avibactam Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.