Piperacillin/ 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:

• Community acquired pneumonia due to Haemophilus influenzae
• Intra-abdominal infections caused by piperacillin resistant beta-lactamase producing strains of Escherichia coli and Bacteroides fragilis
• Skin and skin structure infections caused by piperacillin resistant beta-lactamase producing strains of Staphylococcus aureus
• Gynaecological infections including endometritis caused by piperacillin resistant beta-lactamase producing strains of E.coli
• Bacterial infections in neutropenic patients, in combination with an aminoglycoside

Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Hypersensitivity to any other penicillin-antibacterial agent
• History of acute severe allergic reaction to any other beta-lactam active substances (e.g. cephalosporin, monobactam or carbapenem)

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment (CrCl ≤40ml/min for adults, CrCl ≤50ml/min for children)
  - Haemodialysis patients
• History of sensitivity to multiple allergens
• Prolonged use
• High doses
• Low potassium reserves
• Coagulopathy and bleeding disorders
• Coadministration with medicinal products that may lower potassium levels
• Coadministration with vancomycin or any other nephrotoxic agent
• Controlled sodium diet

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

Dosages below include:

• General dosing range
• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

Infections caused by: Some aerobic gram-positive micro-organisms such as Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, methicillin-susceptible, Staphylococcus species, coagulase negative, methicillin-susceptible, Streptococcus pyogenes, Group B streptococci; Some aerobic gram-negative micro-organisms such as Citrobacter koseri, Haemophilus influenza, Moraxella catarrhalis, Proteus mirabilis; Some anaerobic gram-positive micro-organisms such as Clostridium species, Eubacterium species, Peptostreptococcus species; Some anaerobic Gram-negative micro-organisms such as Bacteroides fragilis group, Fusobacterium species, Porphyromonas species, Prevotella species; C freundii, Capnocytophagia

General dosing range

• IV: 4.5g, 6-8hrly

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For nosocomial pneumonia and bacterial infections in neutropenic patients, the 6hrly dose frequency is recommended. This regimen may also be applicable to treat patients with other indicated infections when particularly severe

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See additional prescribing points for administration directions

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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 Standard Treatment Guidelines indications and dosages

Febrile neutropenia (Additional agent required)
- If fever develops after 48hrs of hospital admission

• IV: 4.5g, 8hrly; Treatment duration: 2 days after fever has settled if neutrophil count increases to >0.5 X10⁹/l or 7 days if neutrophil count remains ≤0.5 X10⁹/l
  (STG, Adult 2019)

Hospital-acquired pneumonia (Additional agent required)
- With prior intravenous antibiotic use within 90 days and ventilator-associated pneumonia

• IV: 4.5g, 8hrly; Treatment duration: 10 days  
  (STG, Adult 2019)

Surgical wound infections (Additional agent(s) required)
- Gram negative organism

• IV: 4.5g, 8hrly; Treatment duration: ≤7 days 
  (STG, Adult 2019)

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South African registered indications and dosages

Community acquired pneumonia due to Haemophilus influenzae
Intra-abdominal infections caused by piperacillin resistant beta-lactamase producing strains of Escherichia coli and Bacteroides fragilis
Skin and skin structure infections caused by piperacillin resistant beta-lactamase producing strains of Staphylococcus aureus
Gynaecological infections including endometritis caused by piperacillin resistant beta-lactamase producing strains of E.coli

• IV: 4.5g, 8hrly, as a slow infusion over 30min; Treatment duration: 7-10 days

Bacterial infections in neutropenic patients (Additional agent required)
Bacterial infections in immunocompromised patients (Additional agent required) 

• IV: 4.5g, 6hrly, as a slow infusion over 30min; Treatment duration: 7-10 days

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In acute infections, treatment with piperacillin/tazobactam should be for a minimum of 5 days and continued for 48hrs beyond resolution of clinical symptoms or the fever 

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Indications and dosages registered in other jurisdictions

Severe pneumonia
Neutropenic adults with fever suspected to be due to a bacterial infection 

• IV: 4.5g, 6hrly, as an infusion over 30min; Treatment duration: 5-14 days

Complicated urinary tract infections
- Pyelonephritis
Complicated intra-abdominal infections
Skin and soft tissue infections
- Diabetic foot infections

• IV: 4.5g, 8hrly, as an infusion over 30min; Treatment duration: 5-14 days

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The duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress

Paed. forms avail. in SA and covered in this monograph: inj

Dosages below include:

• General dosing range
• South African Standard Treatment Guidelines indications and dosages
• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

Infections caused by: Some aerobic gram-positive micro-organisms such as Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, methicillin-susceptible, Staphylococcus species, coagulase negative, methicillin-susceptible, Streptococcus pyogenes, Group B streptococci; Some aerobic gram-negative micro-organisms such as Citrobacter koseri, Haemophilus influenza, Moraxella catarrhalis, Proteus mirabilis; Some anaerobic gram-positive micro-organisms such as Clostridium species, Eubacterium species, Peptostreptococcus species; Some anaerobic Gram-negative micro-organisms such as Bacteroides fragilis group, Fusobacterium species, Porphyromonas species, Prevotella species; C freundii, Capnocytophagia

General dosing range

Older than 28 days

• IV: 300mg/kg/24hrs, in 4 divided doses (6hrly)

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Dose in general dosing range is the sum of the piperacillin/tazobactam (mg)

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See additional prescribing points for administration directions

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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 Standard Treatment Guidelines indications and dosages

Pneumonia (Additional agent required)
- Poor response to first line empiric therapy
Nosocomial pneumonia (Additional agent required)
- Bacterial infection empiric therapy 

• IV: 100mg/kg/dose, 8hrly
  (STG, Paed. 2023)

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South African registered indications and dosages

Neutropenia (Additional agent required)

Younger than 12 years and <50kg

• IV: 80/10mg/kg, 6hrly

Older than 12 years and >50kg

• See adult dosage

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In South Africa, piperacillin/tazobactam is only recommended for the treatment of children with neutropenia

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Indications and dosages registered in other jurisdictions

Neutropenia with fever suspected to be due to bacterial infections

Younger than 2 years

• Not established for use

Between 2-12 years

• IV: 80/10mg/kg, 6hrly, as an infusion over 30min; Max: 4.0/0.5g/dose over 30min; Treatment duration: 5-14 days

Older than 12 years

• See adult dosage

Complicated intra-abdominal infections

Younger than 2 years

• Not established for use

Between 2-12 years

• IV: 100/12.5mg/kg, 8hrly, as an infusion over 30min; Max: 4.0/0.5g/dose over 30min; Treatment duration: 5-14 days

Older than 12 years

• See adult dosage

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The duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress

Pregnancy

• Caution
• There are no or a limited amount of data from the use of piperacillin/tazobactam in pregnant women. Studies in animals have shown developmental toxicity, but no evidence of teratogenicity at doses that are maternally toxic
• Piperacillin/tazobactam cross the placenta. Piperacillin/tazobactam should only be used during pregnancy if clearly indicated, i.e. only if the expected benefit outweighs the possible risks to the pregnant woman and foetus

Breastfeeding

• Caution
• Piperacillin is excreted in low concentrations in human milk, tazobactam concentrations in human milk have not been studied. Women who are breastfeeding should be treated only if the expected benefit outweighs the possible risks to the woman and child

Fertility

• A fertility study in rats showed no effect on fertility and mating after intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam

Renal Impairment

Adults

• CrCl >40ml/min: No dose adjustment recommended
• CrCl ≤40ml/min: Caution; dose adjustment recommended 

CrCl (ml/min)	Dose
>40	No dose adjustment recommended
20-40	Max. 4.0/0.5g, 8hrly
<20	Max. 4.0/0.5g, 12hrly
Haemodialysis	Additional 2.0/0.25g after dialysis

Children

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

CrCl (ml/min)	Dose
>50	No dose adjustment recommended
≤50	70/8.75mg/kg, 8hrly
Haemodialysis	Additional 40/5mg/kg, after dialysis

Hepatic Impairment

• No dose adjustment recommended

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Insomnia

Cardiovascular Disorders

• Hypotension
• Thrombophlebitis
• Phlebitis
• Flushing

Respiratory Disorders

• Epistaxis
• Eosinophilic pneumonia

Gastrointestinal Disorders

• Diarrhoea
• Abdominal pain
• Nausea and vomiting
• Constipation
• Dyspepsia
• Pseudomembranous colitis
• Stomatitis

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Increased gamma-glutamyltransferase
• Hepatitis
• Jaundice
• Increased bilirubin

Genitourinary Disorders

• Increased blood creatinine
• Increased blood urea
• Renal failure
• Tubulointerstitial nephritis

Endocrine and Metabolic Disorders

• Decreased total protein
• Decreased albumin
• Hypokalaemia
• Decreased blood glucose

Musculoskeletal Disorders

• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Erythema multiforme
• Urticaria
• Maculopapular rash
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Exfoliative dermatitis
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Acute generalised exanthematous pustulosis (AGEP)
• Bullous dermatitis
• Purpura  
• Injection site reaction

Immune, Blood and Lymphatic System Disorders

• Candidal superinfection
• Thrombocytopenia
• Thrombocytosis
• Anaemia
• Prolonged activated partial thromboplastin time
• Leukopenia
• Agranulocytosis
• Pancytopenia
• Neutropenia
• Prolonged prothrombin time
• Prolonged bleeding time
• Haemolytic anaemia
• Eosinophilia
• Anaphylactic reaction
• Anaphylactic shock
• Anaphylactoid reaction
• Anaphylactoid shock
• Hypersensitivity
• Fever
• Chills

Others

• Positive result for Coombs direct test

• Non-depolarising muscle relaxants
• Vecuronium
• Oral anticoagulants
• Heparin
• Other agents that may affect the blood coagulation system including thrombocyte function
• Methotrexate
• Probenecid
• Tobramycin (in severe renal impairment)
• Gentamicin (in severe renal impairment)

Other interactions

• Non-enzymatic methods of measuring urinary glucose
• Some chemical urine protein measurement methods
• Direct Coombs test
• Platelia Aspergillus EIA test

None routine. Specific cases may require

• Renal function
• Full blood count with differential
• Hepatic function
• Prothrombin time
• Blood urea nitrogen
• Urinalysis
• Haematopoietic function
• Clotting time
• Platelet aggregation
• Partial thromboplastin time
• Electrolytes

Additional observations

• Signs of bleeding
• Monitor for signs of anaphylaxis during first dose

Administration directions

• The reconstitution and dilution is to be made under aseptic conditions
• The solution is to be inspected visually for particulate matter and discolouration prior to administration
• The solution should only be used if the solution is clear and free from particles

Intravenous use

• Reconstitute each vial/bottle with 20ml of compatible solvent (see list below)
• Swirl until dissolved. When swirled constantly, reconstitution generally occurs within 3 minutes

Compatible solvents for reconstitution

• Water for injection
• Sodium chloride 9 mg/ml (0.9 %) solution in water for injection
• Glucose 50mg/ml (5%) solution in water for injection
• Glucose 50mg/ml (5%) solution in sodium chloride 9mg/ml (0.9%) solution
• The reconstituted solutions should be withdrawn from the vial/bottle by syringe
• When reconstituted as directed, the vial/bottle contents withdrawn by syringe will provide the labelled amount of piperacillin and tazobactam

The reconstituted solutions may be further diluted to the desired volume (e.g. 50ml to 150ml) with one of the following compatible solvents

• Sodium chloride 9 mg/ml (0.9 %) solution in water for injection
• Glucose 50 mg/ml (5 %) solution in water for injection
• Dextran (grade 40) 60 mg/ml (6%) solution in sodium chloride 9 mg/ml (0.9%) solution

Incompatibilities

• Piperacillin/tazobactam must not be mixed or coadministrated with any aminoglycoside
• The mixing of beta-lactam antibiotics with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside
• Piperacillin/tazobactam should not be mixed with other substances in a syringe or infusion bottle since compatibility has not been established
• Piperacillin/tazobactam should be administered through an infusion set separately from any other drugs unless compatibility is proven
• Due to chemical instability, piperacillin/tazobactam should not be used in solutions containing only sodium bicarbonate
• Lactated Ringer's (Hartmann's) solution is not compatible with piperacillin/tazobactam
• Piperacillin/tazobactam should not be added to blood products or albumin hydrolysates

Effects on laboratory tests

• Non-enzymatic methods of measuring urinary glucose may lead to false-positive results, as with other penicillins. Therefore, enzymatic urinary glucose measurement is required under piperacillin/tazobactam therapy
• A number of chemical urine protein measurement methods may lead to false-positive results. Protein measurement with dipsticks is not affected
• The direct Coombs test may be positive
• Bio-Rad Laboratories Platelia Aspergillus EIA tests may lead to false-positive results for patients receiving piperacillin/tazobactam
• Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported
• Positive test results for the assays listed above in patients receiving piperacillin/tazobactam should be confirmed by other diagnostic methods

Piperacillin, a broad-spectrum, semisynthetic penicillin exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporins, but it does not inhibit AmpC enzymes or metallo beta-lactamases. Tazobactam extends the antibiotic spectrum of piperacillin to include many beta-lactamase-producing bacteria that have acquired resistance to piperacillin alone.

Spectrum of activity: Some aerobic gram-positive micro-organisms such as Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus (methicillin-susceptible), Staphylococcus species (coagulase negative, methicillin-susceptible), Streptococcus pyogenes, Group B streptococci; Some aerobic gram-negative micro-organisms such as Citrobacter koseri, Haemophilus influenza, Moraxella catarrhalis, Proteus mirabilis; Some anaerobic gram-positive micro-organisms such as Clostridium species, Eubacterium species, Peptostreptococcus species; Some anaerobic Gram-negative micro-organisms such as Bacteroides fragilis group, Fusobacterium species, Porphyromonas species, Prevotella species; C freundii, Capnocytophagia

COMBINATION PREPARATIONS

Piperacillin/ Tazobactam

Injection (per vial) 0.5g/4g

• Caplin (Xixia)
• Curitaz (Sandoz)
• Litha Piperacillin CO (Litha) 
• Pirabax (Accord) 
• Piperacillin/Tazobactam Fresenius (Fresenius Kabi)
• Razobin 4 (Aurobindo)
• Tazobax (Litha Pharma)
• Tazocin 4 EF (Pfizer) originator
• Tazogen (Ranbaxy)