Antipseudomonal Penicillins

Antipseudomonal penicillins are extended-spectrum penicillins with activity against Pseudomonas aeruginosa and a wide range of Enterobacterales and anaerobes. Carboxypenicillins (ticarcillin) and the ureidopenicillins azlocillin and mezlocillin have been withdrawn or largely replaced. Piperacillin, almost always given with tazobactam, is the working agent.

Mechanism. PBP binding with time-dependent killing. Piperacillin has high affinity for PBP3 and good penetration through porins. Tazobactam inhibits many class A beta-lactamases (TEM, SHV, some CTX-M) and some class C enzymes weakly.

Pharmacokinetics. Not absorbed orally. Half-life about 1 hour; renal elimination of both components. Good penetration into peritoneal fluid, lung, bile and bone; limited into CSF.

Spectrum. Streptococci, MSSA, E. faecalis, Enterobacterales, P. aeruginosa and anaerobes including Bacteroides fragilis. Unreliable for ESBL-producing and AmpC-producing organisms, and inactive against MRSA, E. faecium, metallo-beta-lactamase producers, Stenotrophomonas maltophilia and atypicals.

• Piperacillin-tazobactam: 4.5 g vial contains piperacillin 4 g and tazobactam 0.5 g. Doses are expressed as the combined weight.
• Ticarcillin-clavulanate and older agents: no longer marketed in most countries.
• Alternatives with antipseudomonal activity: ceftazidime, cefepime, meropenem, ciprofloxacin, aztreonam, aminoglycosides, colistin, ceftolozane-tazobactam, ceftazidime-avibactam.

Adult regimens (normal renal function).

• Serious infection with possible Pseudomonas (hospital-acquired pneumonia, febrile neutropenia, intra-abdominal infection with healthcare contact, bacteraemia): piperacillin-tazobactam 4.5 g IV every 6 hours over 30 minutes, or 4.5 g every 8 hours as a 4-hour extended infusion after a 4.5 g loading dose over 30 minutes.
• Community-acquired intra-abdominal infection, diabetic foot infection: 4.5 g every 6 to 8 hours (3.375 g every 6 hours in some regimens).
• Renal adjustment: creatinine clearance 20 to 40 mL/min, 2.25 g every 6 hours (4.5 g every 6 hours is retained by some regimens for pseudomonal pneumonia); under 20 mL/min, 2.25 g every 8 hours; haemodialysis, 2.25 g every 8 hours with an additional 0.75 g after dialysis.
• Children: 80 to 100 mg/kg of the piperacillin component every 6 to 8 hours (maximum 4 g piperacillin each dose); infants under 2 months are dosed by a specialist.

Selection. Use for empirical cover of mixed Gram-negative and anaerobic infection in unwell patients, then narrow on culture. Where ESBL is possible (known colonisation, recent cephalosporin or travel), a carbapenem is preferred for bacteraemia. Combination with an aminoglycoside is not routine, and when used is limited to 3 to 5 days.

Contraindications. Immediate hypersensitivity to penicillins; caution with cephalosporin allergy.

Serious effects. Acute kidney injury, especially with vancomycin (the combination carries a higher risk than vancomycin with cefepime or meropenem); neutropenia and thrombocytopenia with courses over 2 weeks; platelet dysfunction and bleeding with high doses; hypokalaemia; seizures in renal failure; C. difficile infection; sodium load.

Interactions. Vancomycin (nephrotoxicity), methotrexate (reduced clearance), probenecid, vecuronium (prolonged blockade), warfarin. Aminoglycosides are inactivated if mixed in the same bag or line.

Monitoring. Renal function and electrolytes every 2 to 3 days; full blood count weekly; clinical review at 48 to 72 hours with de-escalation.

Special groups.

• Pregnancy and breastfeeding: acceptable when indicated.
• Hepatic impairment: no adjustment needed.
• Obesity: extended infusion preserves target attainment; dose by total body weight is not required.
• Critical illness with augmented clearance: extended or continuous infusion rather than higher single doses.