Piperacillin Tazobactam

Piperacillin tazobactam is a broad-spectrum antipseudomonal penicillin combined with a beta-lactamase inhibitor. It is a first-line empirical drug for hospital-acquired sepsis, intra-abdominal infection, nosocomial pneumonia and febrile neutropenia where Pseudomonas aeruginosa or mixed anaerobic flora are likely.

Classification. Beta-lactam, ureidopenicillin plus penicillanic acid sulphone inhibitor. Doses are written as the combined weight: 4.5 g contains 4 g piperacillin and 0.5 g tazobactam.

Mechanism. Piperacillin blocks penicillin-binding proteins; tazobactam inactivates many class A beta-lactamases and some class C enzymes. Killing is time-dependent, so time over MIC drives efficacy.

Spectrum. Streptococci, MSSA, Enterococcus faecalis, Enterobacterales (including many beta-lactamase producers), Pseudomonas aeruginosa, Bacteroides fragilis and other anaerobes. Not reliably active against ESBL producers, AmpC-hyperproducing organisms, MRSA, Enterococcus faecium or carbapenemase producers.

Pharmacokinetics. IV only. Half-life about 1 hour, longer in renal failure. Protein binding about 30%. Eliminated mainly by the kidney with a biliary component. Good tissue penetration; CSF penetration is poor.

Dose is expressed as the combination. Maximum 18 g of the combination (16 g piperacillin) daily in adults; higher doses are given only under specialist direction. Titration is by site, pathogen MIC, kidney function and critical illness.

Usual adult regimen. 4.5 g IV every 6 hours (or 4.5 g every 8 hours in less severe infection where susceptibility is clear). Duration: intra-abdominal infection 4 to 7 days after source control; pneumonia 7 days; bacteraemia 7 to 14 days.

Extended infusion (critical illness, Pseudomonas, high MIC). Give 4.5 g over 30 minutes as a loading dose, then 4.5 g over 4 hours every 8 hours, starting within 4 hours of the loading dose. Use full loading doses in renal impairment.

Febrile neutropenia. 4.5 g IV every 6 hours, reassessed at 48 to 72 hours.

Children 2 months to 17 years. 112.5 mg/kg (100 mg piperacillin plus 12.5 mg tazobactam) every 8 hours; every 6 hours for neutropenia or Pseudomonas; maximum 4.5 g a dose. Neonates under 1 month: 90 mg/kg every 8 to 12 hours depending on gestation.

Alternatives. Meropenem for ESBL infection; cefepime plus metronidazole; ceftazidime or ceftriaxone plus metronidazole in community-onset infection.

Contraindications. Penicillin or beta-lactamase inhibitor hypersensitivity.

Adverse effects. Diarrhoea, rash, Clostridioides difficile infection, injection-site phlebitis. Serious: anaphylaxis, severe cutaneous reactions, cytopenias (neutropenia and thrombocytopenia with courses over 10 days), interstitial nephritis, hepatitis, seizures in renal failure, and hypokalaemia.

Kidney injury. Observational data link piperacillin tazobactam combined with vancomycin to more acute kidney injury than vancomycin with cefepime or meropenem. Avoid the combination unless needed and monitor creatinine daily.

Interactions. - Aminoglycosides are inactivated if mixed in the same bag or line; give separately. - Methotrexate toxicity increases; probenecid raises levels. - Vecuronium and similar muscle relaxants are prolonged; warfarin INR can rise. - Some older preparations gave false-positive galactomannan assays.

Common prescribing errors. Failing to adjust for kidney function after the first 24 to 48 hours, mixing with gentamicin, assuming cover of ESBL organisms, and continuing after de-escalation is possible.

Special groups.

• Pregnancy and breastfeeding: acceptable.
• Older adults: adjust by creatinine clearance.
• Kidney impairment (conventional dosing):
  • Creatinine clearance over 40 mL/min: no change.
  • 20 to 40 mL/min: 3.375 g every 6 hours (2.25 g every 6 hours if not nosocomial pneumonia or Pseudomonas).
  • Under 20 mL/min: 2.25 g every 8 hours (2.25 g every 6 hours in nosocomial pneumonia).
  • Haemodialysis: 2.25 g every 12 hours with 0.75 g extra after each session (2.25 g every 8 hours in nosocomial pneumonia).
  • Keep the first 24 hours at full dose in sepsis.
• Liver impairment: no adjustment.
• Obesity: use the full dose; extended infusion is favoured.
• Region: tertiary East African hospitals use it for sepsis and febrile neutropenia; local Enterobacterales ESBL rates determine whether a carbapenem is needed first.

Preparation. Reconstitute each 4.5 g vial with 20 mL of water for injection or 0.9% sodium chloride, then dilute to 50 to 150 mL. Infuse over 30 minutes (or 4 hours in extended regimens). Sodium load is significant at high doses.

Baseline and monitoring. - Baseline: allergy history, cultures before the first dose, creatinine, full blood count, liver tests. - During treatment: creatinine and potassium daily in acute illness; full blood count twice weekly beyond 5 days; liver tests weekly. - No routine therapeutic drug monitoring; where available, targeting free drug levels over 4 times the MIC for the whole interval is used in critical illness.

Stop rules. Stop for anaphylaxis, severe skin reaction, unexplained cytopenia or acute kidney injury attributed to the drug.

Referral and escalation. Refer to infectious diseases for failure to improve at 48 to 72 hours, Pseudomonas bacteraemia, febrile neutropenia that persists, and need for prolonged courses.