Ceftolozane/ Tazobactam

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:

• Complicated intra-abdominal infections (cIAI) (Additional agent required)
  - Caused by Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus and Streptococcus salivarius
• Complicated urinary tract infections (cUTI), including pyelonephritis with or without concurrent bacteremia
  - Caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa
• Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP)
  - Caused by Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella (Enterobacter) aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and Serratia marcescens

• Hypersensitivity to ceftolozane/tazobactam or to any of the inactive excipients
• Hypersensitivity to any cephalosporin antibacterial medicines
• Severe hypersensitivity, such as anaphylactic reaction or severe skin reaction, to any other type of beta-lactam antibacterial medicines, for example, penicillins or carbapenems

• Hypersensitivity to ceftolozane/tazobactam or to any of the excipients
• Hypersensitivity to any cephalosporin antibacterial medicines
• Severe hypersensitivity, such as anaphylactic reaction or severe skin reaction, to any other type of beta-lactam antibacterial medicines, for example, penicillins or carbapenems

South African recommendations

Pregnancy

• Safe use during pregnancy has not been established

Breastfeeding

• Women receiving ceftolozane/ tazobactam should not breastfeed their infants

Antibiotic stewardship

• Follow principles of antibiotic stewardship

Impaired renal function

• Monitor renal function frequently. Adjust ceftolozane/tazobactam dosage based on renal function. Lower cure rates noted in patients with baseline CrCl 30-50ml/min

Hypersensitivity reactions

• Assess prior hypersensitivity reactions to cephalosporins, penicillins or beta-lactams. Exercise caution in case of allergies. Discontinue ceftolozane/tazobactam if anaphylactic reaction occurs

Clostridium difficile-associated diarrhoea (CDAD):

• Diarrhoea may occur due to Clostridium difficile overgrowth. Consider discontinuing ceftolozane/tazobactam and start specific treatment for Clostridium difficile if required

Development of drug-resistant bacteria

• Avoid prescribing ceftolozane/tazobactam for unconfirmed bacterial infections. May lead to development of drug-resistant bacteria

Non-susceptible micro-organisms

• Use of ceftolozane/tazobactam may lead to overgrowth of non-susceptible micro-organisms. Not effective against beta-lactamase producing bacteria not inhibited by tazobactam

Direct antiglobulin test (Coombs test) seroconversion

• Positive direct antiglobulin test (DAGT) may occur during treatment with ceftolozane/tazobactam. No evidence of haemolysis in patients who developed positive DAGT

Limitations of clinical data

• Immunocompromised patients and patients with severe neutropenia were excluded from trials with ceftolozane/tazobactam

Paediatric population

• Safety and efficacy of ceftolozane/tazobactam in children and adolescents below 18 years not yet established. No data available

Recommendations in other jurisdictions

Pregnancy

• Ceftolozane/ tazobactam should only be used during pregnancy if the expected benefit outweighs the possible risks to the pregnant woman and foetus

Breastfeeding

• A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from ceftolozane/tazobactam therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Hypersensitivity reactions

• Discontinue ceftolozane/tazobactam if severe allergic reaction occurs. Use caution if a history of hypersensitivity to cephalosporins, penicillins, or other beta-lactam antibacterial agents

Effect on renal function

• Renal function may decline in patients receiving ceftolozane/tazobactam

Impaired renal function

• Adjust ceftolozane/tazobactam dosage based on renal function. Efficacy is lower in patients with moderate renal impairment. Monitor renal function frequently in patients with renal impairment

Limitations of clinical data

• Immunocompromised patients, patients with severe neutropenia, and patients with end-stage renal disease on hemodialysis were excluded from clinical trials

Complicated intra-abdominal infections

• Clinical cure rates for ceftolozane/tazobactam in patients with complicated intra-abdominal infections vary based on patient age and condition

Complicated urinary tract infections

• Limited efficacy data in patients with complicated lower urinary tract infection. Some patients treated with ceftolozane/tazobactam had bacteraemia at baseline

Clostridioides difficile-associated diarrhoea

• Discontinue ceftolozane/tazobactam and consider specific treatment for Clostridioides difficile in case of diarrhoea occurrence

Non-susceptible micro-organisms

• Ceftolozane/tazobactam may promote the overgrowth of non-susceptible micro-organisms. Ceftolozane/tazobactam is not active against bacteria that produce beta-lactamase enzymes which are not inhibited by tazobactam

Direct antiglobulin test (Coombs test) seroconversion

• Positive direct antiglobulin test (DAGT) may occur during treatment with ceftolozane/tazobactam, but no evidence of haemolysis in patients who developed positive DAGT

Sodium content

• Ceftolozane/tazobactam contains significant sodium content. Consideration should be given to patients' sodium intake

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

South African registered indications and dosages

Infections caused by: Gram-negative bacteria such as Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Haemophilus influenzae, Klebsiella (Enterobacter) aerogenes, Serratia marcescens; and Gram-positive bacteria such as Streptococcus anginosus, Streptococcus constellatus and Streptococcus salivarius

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

Complicated intra-abdominal infections (cIAI) (Additional agent required)
- Caused by Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus and Streptococcus salivarius
- Used in conjunction with metronidazole 500mg IV 8hrly

1.5g (ceftolozane 1g/tazobactam 0.5g)

• IV: 1.5g, 8hrly infused over 1hr; Treatment duration: 4-14 days

Complicated urinary tract infections (cUTI), including pyelonephritis with or without concurrent bacteremia
- Caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa

1.5g (ceftolozane 1g/tazobactam 0.5g)

• IV: 1.5g, 8hrly infused over 1hr; Treatment duration: 7 days

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP)
- Caused by Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella (Enterobacter) aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and Serratia marcescens

1.5g (ceftolozane 1g/tazobactam 0.5g)

• IV: 3g, 8hrly infused over 1hr; Treatment duration: 8-14 days

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Ceftolozane/tazobactam should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. Culture and susceptibility information should be considered when selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy

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The duration of therapy should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress

Not established for use in children and adolescents below of 18 years

Pregnancy

South African recommendations

• Caution; not established for use
• Safe use during pregnancy has not been established for ceftolozane/tazobactam

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• There are no data on the use of ceftolozane/tazobactam in pregnant women
• Tazobactam crosses the placenta, but it is not known if ceftolozane does
• Animal studies with tazobactam have shown reproductive toxicity without evidence of teratogenic effects
• Studies with ceftolozane in mice and rats have not shown evidence of reproductive toxicity or teratogenicity
• Ceftolozane administered to rats during pregnancy and breastfeeding was associated with a decrease in auditory startle response in postnatal day 60 male pups
• Ceftolozane/tazobactam should only be used during pregnancy if the expected benefit outweighs the possible risks to the pregnant woman and foetus

Breastfeeding

South African recommendations

• Caution; not recommended
• Women receiving ceftolozane/tazobactam should not breastfeed their infants

Recommendations in other jurisdictions

• Caution; not recommended
• It is unknown whether ceftolozane and tazobactam are 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 ceftolozane/tazobactam therapy, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• The effects of ceftolozane and tazobactam on fertility in humans have not been studied
• Fertility studies in rats showed no effect on fertility and mating after administration of tazobactam or ceftolozane

South African recommendations & Recommendations in other jurisdictions

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

Estimated CrCl (ml/min) using Cockcroft-Gault formula	cIAI and cUTI including pyelonephritis
30-50	IV: 750mg (500mg and 250mg), 8hrly
15-29	IV: 375mg (250mg and 125mg), 8hrly
End stage renal disease (ESRD) on haemodialysis (HD)	IV: Initial: 750mg (500mg and 250mg), as a single dose; Maintenance: 150mg (100mg and 50mg), 8hrly; With haemodialysis, the dose should be administered immediately following completion of dialysis

Estimated CrCl (ml/min) using Cockcroft-Gault formula	HABP and VABP
30-50	IV: 1.5g (1g and 0.5g), 8hrly
15-29	IV: 750mg (500mg and 250mg), 8hrly
End stage renal disease (ESRD) on haemodialysis (HD)	IV: Initial loading dose: 2.25g (1.5g and 0.75g) as a single dose; Maintenance: 450mg (300mg and 150mg), 8hrly; On haemodialysis days, administer the dose at the earliest possible time following completion of dialysis

• For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of accordingly
• All doses are administered over 1-hour

South African recommendations & Recommendations in other jurisdictions

• No dose adjustment recommended

South African recommendations & Recommendations in other jurisdictions

• No dose adjustment recommended
  No dose adjustment is necessary for the elderly based on age alone

Infections and infestations

• Clostridioides difficile colitis² (Common)
• Candidiasis including oropharyngeal and vulvovaginal, fungal urinary tract infection (Uncommon)¹
• Clostridium difficile colitis¹
• Clostridioides difficile infection² (Uncommon)

Blood and the lymphatic system disorders

• Thrombocytosis¹ (Common)
• Anaemia¹ (Uncommon)

Metabolism and nutrition disorders

• Hypokalaemia¹ (Common)
• Hyperglycaemia¹ (Uncommon)
• Hypomagnesaemia¹ (Uncommon)
• Hypophosphatemia¹ (Uncommon)

Psychiatric disorders

• Insomnia¹ (Common)
• Anxiety¹ (Common)

Nervous system disorders

• Headache¹ (Common)
• Dizziness¹ (Common)
• Ischaemic stroke¹ (Uncommon)

Cardiac disorders

• Atrial fibrillation¹ (Uncommon)
• Tachycardia¹ (Uncommon)
• Angina pectoris¹ (Uncommon)

Vascular disorders

• Hypotension¹ (Common)
• Phlebitis¹ (Uncommon)
• Venous thrombosis¹ (Uncommon)

Respiratory, thoracic and mediastinal disorders

• Dyspnoea¹ (Uncommon)

Gastrointestinal disorders

• Nausea¹ (Common)
• Vomiting (across all indications) (Common)
• Diarrhoea (across all indications) (Common)
• Constipation¹ (Common)
• Abdominal pain¹ (Common)
• Gastritis¹ (Uncommon)
• Abdominal distension¹ (Uncommon)
• Dyspepsia¹ (Uncommon)
• Flatulence¹ (Uncommon)
• Paralytic ileus¹ (Uncommon)

Skin and subcutaneous tissue disorders

• Rash¹ (Common)
• Urticaria¹ (Uncommon)

Renal and urinary disorders

• Renal impairment¹ (Uncommon)
• Renal failure¹ (Uncommon)

General disorders and administration site conditions

• Pyrexia¹ (Common)
• Infusion site reactions¹ (Common)

Investigations

• Increased alanine aminotransferase (across all indications) (Common)
• Increased aspartate aminotransferase (across all indications) (Common)
• Increased transaminases² (Common)
• Abnormal liver function test² (Common)
• Increased blood alkaline phosphatase² (Common)
• Increased gamma-glutamyl transferase² (Common)
• Positive Coombs test (across all indications) (Uncommon)
• Increased serum gamma-glutamyl transpeptidase (GGT)¹ (Uncommon)
• Increased serum alkaline phosphatase¹ (Uncommon)
• Positive Clostridioides test² (Uncommon)

¹Specific for the complicated intra-abdominal infections, acute pyelonephritis and complicated urinary tract infections indications treated with ceftolozane/ tazobactam (1 g/0.5g intravenously every 8 hours) for up to 14 days
²Specific for the hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia indication treated with ceftolozane/ tazobactam (2g/1g intravenously every 8 hours) for up to 14 days

• Active substances that inhibit OAT1 or OAT3
• Probenecid

• Serum creatinine
• Creatinine clearance
  - At baseline and daily in patients with changing renal function

Ceftolozane
Ceftolozane belongs to the cephalosporin class of antimicrobials. Ceftolozane exerts bactericidal activity through binding to important penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell-wall synthesis and subsequent cell death. Ceftolozane is an inhibitor to PBPs of P. aeruginosa (e.g. PBP1b, PBP1c and PBP3) and E.coli (e.g. PBP3).

Tazobactam
Tazobactam, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Tazobactam is a beta-lactam structurally related to penicillin. It is an inhibitor of many molecular Class A beta-lactamases, including CTX-M, SHV, and TEM enzymes.

Spectrum of activity: 

Gram-negative bacteria such as Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Serratia marcescens. Gram-positive bacteria such as Streptococcus anginosus, Streptococcus constellatus, Streptococcus salivarius. Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to ceftolozane/tazobactam in the absence of acquired mechanisms of resistance: Citrobacter freundii, Citrobacter koseri, Klebsiella (Enterobacter) aerogenes, Morganella morganii, Proteus vulgaris.