Ceftazidime/ Avibactam

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Infections caused by designated susceptible gram-negative microorganisms
  - Complicated intra-abdominal infections (cIAI) caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa
  - Complicated urinary tract infections (cUTI), including pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Pseudomonas aeruginosa
  - Hospital-acquired bacterial pneumonia (HABP) caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa
  - Ventilator associated bacterial pneumonia (VABP) caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to any cephalosporin antibacterial agent
• Immediate and/or severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems)

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment (CrCl≤50ml/min)
• Hepatic impairment (South African recommendations) 
• History of non-severe hypersensitivity to penicillins, monobactams or carbapenems
• Prolonged use
• Sodium-controlled diet 
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: poi

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

Infections caused by: Gram-negative microorganisms, including Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Serratia marcescens 

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African registered indications and dosages

Ceftazidime/avibactam should be reserved for the treatment of gram-negative infections caused by gram-negative sensitive bacteria where other antimicrobials approved for similar infections and to which a causative bacteria are sensitive, were considered not to be an appropriate treatment option, have failed, are contraindicated or were not tolerated

Complicated intra-abdominal infections (cIAI) (Additional agent is required)
- Caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 120mins, 8hrly; Treatment duration: 5-14 days 

Complicated urinary tract infections (cUTI), including pyelonephritis 
- Caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Pseudomonas aeruginosa

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 120mins, 8hrly; Treatment duration: 5-10 days

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Treatment duration for cUTI includes IV plus oral treatment. The time to switch from IV to oral treatment with another antibiotic depends on the clinical situation but is normally after about 5 days

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Hospital-acquired bacterial pneumonia (HABP)
- Caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa
Ventilator associated bacterial pneumonia (VABP) 
- Caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 120mins, 8hrly; Treatment duration: 7-14 days

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Prescribers should adhere to the principles of antimicrobial stewardship

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To reduce the development of drug-resistant bacteria and maintain the effectiveness ceftazidime/avibactam, should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. It is recommended that ceftazidime/avibactam be used only after consultation with a medical practitioner with appropriate experience in the management of infectious diseases

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Dosing above is for adults with CrCl>50ml/min.  See special populations for dosing in renal impairment

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Ceftazidime/avibactam should be used in combination with metronidazole for the indication for cIAI

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For cUTI including pyelonephritis, the total duration of treatment could be increased to 14 days for patients with bacteraemia

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Duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient’s clinical and bacteriological progress

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Indications and dosages registered in other jurisdictions

Infections caused by: Gram-negative microorganisms, including Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Serratia marcescens 

Complicated intra-abdominal infections (cIAI) (Additional agent is required)
- Caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa 

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 2hrs, 8hrly; Treatment duration: 5-14 days

Complicated urinary tract infections (cUTI), including pyelonephritis (Additional agent may be required)
- Caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Pseudomonas aeruginosa

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 2hrs, 8hrly; Treatment duration: 5-10 days 

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Treatment duration for cUTI may include IV followed by appropriate oral therapy

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Hospital-acquired bacterial pneumonia (HAP), including  ventilator associated pneumonia (VAP) (Additional agent may be required)
- Caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 2hrs, 8hrly; Treatment duration: 7-14 days

Bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 2hrs, 8hrly; Treatment duration: In accordance with site of infection

Infections due to aerobic gram-negative organisms with limited treatment options (Additional agent may be required)

Ceftazidime/ Avibactam
2/0.5 (g)

• IV: 2g/0.5g, as an infusion over 2hrs, 8hrly; Treatment duration: Should be guided by severity of the infection, the pathogen(s) and patient's clinical and bacteriological progress

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Consideration should be given to official guidance on the appropriate use of antibacterial agents

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It is recommended that ceftazidime/avibactam should be used to treat infections due to aerobic gram-negative organisms with limited treatment options only after consultation with a physician with appropriate experience in the management of infectious disease

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For indications of cIAI, cUTI, HAP/VAP and infections due to aerobic gram-negative organisms in patients with limited treatment options: To be used in combination with an antibacterial agent active against gram-positive pathogens when these are known or suspected to be contributing to the infectious process (e.g. metronidazole for cIAI)

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Dosing above is for adults with CrCl>50 ml/min estimated using the Cockcroft-Gault formula. See additional prescribing points for dosing in renal impairment

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There is very limited experience with use for more than 14 days

Paed. form avail. in SA and covered in this monograph: poi

Paed. dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

Infections caused by: Gram-negative microorganisms, including Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Serratia marcescens 

South African registered indications and dosages

• Not established for use

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Indications and dosages registered in other jurisdictions

Complicated intra-abdominal infections (cIAI) (Additional agent is required)
- Caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa
Complicated urinary tract infections (cUTI), including pyelonephritis (Additional agent may be required)
- Caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Pseudomonas aeruginosa

Ceftazidime/ Avibactam
2/0.5 (g)

• Younger than 3 months: Not established for use
• Between 3-6 months: IV: 40mg/kg/10mg/kg, as an infusion over 2hrs, 8hrly; Treatment duration: 5-14 days 
• Older than 6 months: IV: 50mg/kg/12.5mg/kg, as an infusion over 2hrs, 8hrly; Max dose: 2g/0.5g; Treatment duration: 5-14 days

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Treatment duration for cUTI may include IV followed by appropriate oral therapy

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Hospital-acquired bacterial pneumonia (HAP), including  ventilator associated pneumonia (VAP) (Additional agent may be required) 
- Caused by Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa

Ceftazidime/ Avibactam
2/0.5 (g)

• Younger than 3 months: Not established for use
• Between 3-6 months: IV: 40mg/kg/10mg/kg, as an infusion over 2hrs, 8hrly; Treatment duration: 7-14 days
• Older than 6 months: IV: 50mg/kg/12.5mg/kg, as an infusion over 2hrs, 8hrly; Max dose: 2g/0.5g; Treatment duration: 7-14 days

Infections due to aerobic gram-negative organisms with limited treatment options (Additional agent may be required) 

Ceftazidime/ Avibactam
2/0.5 (g)

• Younger than 3 months: Not established for use
• Between 3-6 months : IV: 40mg/kg/10mg/kg, as an infusion over 2hrs, 8hrly; Treatment duration: Should be guided by severity of the infection, the pathogen(s) and patient's clinical and bacteriological progress
• Older than 6 months: IV: 50mg/kg/12.5mg/kg, as an infusion over 2hrs, 8hrly; Max dose: 2g/0.5g; Treatment duration: Should be guided by severity of the infection, the pathogen(s) and patient's clinical and bacteriological progress

---

Consideration should be given to official guidance on the appropriate use of antibacterial agents

---

It is recommended that ceftazidime/avibactam should be used to treat infections due to aerobic gram-negative organisms with limited treatment options only after consultation with a physician with appropriate experience in the management of infectious disease

---

For indications of cIAI, cUTI, HAP/VAP and limited treatment options: To be used in combination with an antibacterial agent active against gram-positive pathogens when these are known or suspected to be contributing to the infectious process (e.g. metronidazole for cIAI)

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Dosing above is for paediatrics with CrCl>50ml/min/1.73m² estimated using the Schwartz bedside formula. See additional prescribing points for dosing in renal impairment

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There is very limited experience with use for more than 14 days

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There is limited experience with the use of ceftazidime/avibactam in paediatric patients 3 months to <6 months 

Pregnancy 

South African recommendations

• Caution
• Safe use during pregnancy has not been established
• Following administration of avibactam throughout pregnancy and lactation in the rat at maternal exposures greater than or equal to approximately 1,5 times human therapeutic exposures, there were minor changes in the morphology of the kidney and ureters in the rat pups. Greater than or equal to approximately 1,5 times human therapeutic exposures, there were minor changes in the morphology of the kidney and ureters in the rat pups
• Should not be used during pregnancy unless clearly necessary

Recommendations in other jurisdictions

• Caution
• Animal studies with ceftazidime do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Animal studies with avibactam have shown reproductive toxicity without evidence of teratogenic effects 
• Ceftazidime/avibactam should only be used during pregnancy if the potential benefit outweighs the possible risk

Breastfeeding

South African recommendations

• Caution; not recommended 
• Ceftazidime is excreted in human milk. Avibactam is excreted in rodent milk, it is unknown whether avibactam is excreted in human milk
• Women should not breastfeed their infants

Recommendations in other jurisdictions

• Caution; not recommended
• Ceftazidime is excreted in human milk in small quantities. It is unknown whether avibactam is excreted in human milk. A risk to newborns/infants cannot be excluded
• A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from ceftazidime/avibactam therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• The effects of ceftazidime/avibactam on fertility in humans have not been studied. No data are available on animal studies with ceftazidime. Animal studies with avibactam do not indicate harmful effects with respect to fertility

Renal Impairment

South African recommendations

• CrCl>50ml/min: No dose adjustment recommended 
• CrCl≤50ml/min: Caution; dose adjustment recommended 

Adults with estimated CrCl≤50ml/min

Estimated CrCl (ml/min) using Cockcroft-Gault formula	Dosage ceftazidime/avibactam
31-50	IV: 1g/0.25g, as an infusion over 2hrs, 8hrly
16-30	IV: 0.75g/0.1875g, as an infusion over 2hrs, 12hrly
6-15	IV: 0.75g/0.1875g, as an infusion over 2hrs, 24hrly
<6	IV: 0.75g/0.1875g, as an infusion over 2hrs, 48hrly

Dosing on haemodialysis days should occur after completion of haemodialysis
Information on dosing for patients requiring dialysis is in the setting of intermittent haemodialysis. There is insufficient data to make specific dosage adjustment recommendations for patients undergoing continuous veno-venous haemofiltration and peritoneal dialysis. For other types of dialysis, it is suggested that the dose/frequency should follow local label/local guidelines for dosing of ceftazidime
Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment

Recommendations in other jurisdictions

• CrCl>50ml/min: No dose adjustment recommended 
• CrCl≤50ml/min: Caution; dose adjustment recommended 

Adults with estimated CrCl≤50ml/min

Estimated CrCl (ml/min) using Cockcroft-Gault formula	Dosage ceftazidime/avibactam
31-50	IV: 1g/0.25g, as an infusion over 2hrs, 8hrly
16-30	IV: 0.75g/0.1875g, as an infusion over 2hrs, 12hrly
6-15	IV: 0.75g/0.1875g, as an infusion over 2hrs, 24hrly
End-stage renal disease including on haemodialysis	IV: 0.75g/0.1875g, as an infusion over 2hrs, 48hrly

Paediatrics ≥2 years of age with CrCl≤50ml/min/1.73m²

Estimated CrCl (ml/min) using Schwartz bedside formula	Dosage ceftazidime/avibactam
31-50	25mg/kg/6.25mg/kg, as an infusion over 2hrs, 8hrly; Max dose: 1g/0.25g
16-30	18.75mg/kg/4.7mg/kg, as an infusion over 2hrs, 12hrly; Max dose: 0.75g/0.1875g
6-15	18.75mg/kg/4.7mg/kg, as an infusion over 2hrs, 24hrly; Max dose: 0.75g/0.1875g
End-stage renal disease including on haemodialysis	18.75mg/kg/4.7mg/kg, as an infusion over 2hrs, 48hrly; Max dose: 0.75g/0.1875g

Paediatrics <2 years of age with CrCl≤50ml/min/1.73m²

Age group	Estimated CrCl (ml/min) using Schwartz bedside formula	Dosage ceftazidime/avibactam
Between 3-6 months	31-50	20mg/kg/5mg/kg, as an infusion over 2hrs, 8hrly
Between 6 months-2 years	31-50	25mg/kg/6.25mg/kg, as an infusion over 2hrs, 8hrly
Between 3-6 months	16-30	15mg/kg/3.75mg/kg, as an infusion over 2hrs, 12hrly
Between 6 months-2 years	16-30	18.75mg/kg/4.7mg/kg, as an infusion over 2hrs, 12hrly

Insufficient information to recommend dosage regimen for paediatric patients <2 years of age with CrCl<16ml/min/1.73m
Dosing on haemodialysis days should occur after completion of haemodialysis
Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment

Hepatic Impairment 

South African recommendations

• Caution; no dose adjustment recommended  
  Close clinical monitoring for safety and efficacy is advised

Recommendations in other jurisdictions

• No dose adjustment recommended  

Elderly

• No dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Paraesthesia

Gastrointestinal Disorders

• Oral candidiasis
• Diarrhoea
• Abdominal pain
• Nausea and vomiting

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase 
• Increased gamma-glutamyltransferase 
• Increased blood lactate dehydrogenase 
• Jaundice 

Genitourinary Disorders

• Vulvovaginal candidiasis
• Increased blood creatinine
• Increased blood urea
• Acute renal injury
• Tubulointerstitial nephritis

Skin and Subcutaneous Tissue Disorders

• Maculo-papular rash
• Urticaria
• Pruritus
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Erythema multiforme
• Angioedema
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders

• Candidiasis
• Clostridioides difficile colitis
• Pseudomembranous colitis
• Positive Coombs direct test
• Eosinophilia
• Thrombocytosis
• Thrombocytopenia
• Neutropenia
• Leukopenia
• Lymphocytosis
• Agranulocytosis
• Haemolytic anaemia
• Anaphylactic reaction 
• Infusion site thrombosis
• Infusion site phlebitis
• Pyrexia

Sensory Disorders

• Dysgeusia

• Probenecid
• Nephrotoxic medicinal agents
• Aminoglycosides
• Potent diuretics
• Furosemide
• Chloramphenicol

Other interactions

• Copper reduction methods (Benedict's, Fehling's, Clinitest) (See additional prescribing points)

• Renal function

Additional observations

• Signs of anaphylaxis (during first dose)

Interference with laboratory tests

• Ceftazidime may interfere with copper reduction methods (Benedict's, Fehling's, Clinitest) for detection of glycosuria leading to false positive results
• Ceftazidime does not interfere with enzyme-based tests for glycosuria

Ceftazidime inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin binding proteins (PBPs), which leads to bacterial cell lysis and death. Avibactam is a non beta-lactam, beta-lactamase inhibitor that acts by forming a covalent adduct with the enzyme that is stable to hydrolysis. It inhibits both Ambler class A and class C beta-lactamases and some class D enzymes, including extended-spectrum beta-lactamases (ESBLs), KPC and OXA-48 carbapenemases, and AmpC enzymes. Avibactam does not inhibit class B enzymes (metallo-beta-lactamases) and is not able to inhibit many class D enzymes. 

Spectrum of activity: Gram-negative microorganisms including Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Serratia marcescens

COMBINATION PREPARATIONS

Ceftazidime/ Avibactam

Powder for injection (per vial) 2g/0.5g

• Zavicefta (Pfizer) originator