Schedule H

Intravenous (IV), Intramuscular (IM)

• Injection: 2 g vial (as piperacillin sodium, powder for reconstitution)

• Injection: 4 g vial (as piperacillin sodium, powder for reconstitution)

Note: Piperacillin monotherapy formulations have limited availability in India. Fixed-dose combination with tazobactam (Piperacillin-Tazobactam) is predominantly used in clinical practice. Refer to separate entry for Piperacillin-Tazobactam.

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

⚠️ Important: Piperacillin monotherapy is rarely used in current Indian practice due to widespread β-lactamase-producing organisms. Most indications now require combination with tazobactam. Monotherapy may be considered only for documented susceptible organisms.

1. Serious Infections due to Susceptible Pseudomonas aeruginosa — Adults

Parameter Recommendation

Starting dose 4 g IV every 6 hours

Titration Not applicable

Usual maintenance dose 4 g IV every 6 hours (16 g/day)

Maximum dose 24 g/day (in severe/life-threatening infections)

Duration 7–14 days; guided by clinical response and cultures

Clinical note Usually combined with aminoglycoside (amikacin/gentamicin) for synergy; confirm susceptibility before monotherapy

1. Hospital-Acquired Pneumonia (Susceptible Organisms) — Adults

Parameter Recommendation

Starting dose 4 g IV every 6 hours

Titration Not applicable

Usual maintenance dose 4 g IV every 6 hours

Maximum dose 18–24 g/day

Duration 7–14 days depending on clinical response

Clinical note Combination with aminoglycoside recommended for empirical Pseudomonas coverage; de-escalate based on culture sensitivity

1. Complicated Urinary Tract Infections / Pyelonephritis (Susceptible Organisms) — Adults

Parameter Recommendation

Starting dose 3 g IV every 6 hours

Titration Increase to 4 g every 6 hours if severe

Usual maintenance dose 3–4 g IV every 6 hours (12–16 g/day)

Maximum dose 18 g/day

Duration 10–14 days; switch to oral based on sensitivity when stable

Clinical note Covers P. aeruginosa and many Enterobacterales if susceptible; confirm no β-lactamase production

1. Complicated Intra-abdominal Infections (Susceptible Organisms) — Adults

Parameter Recommendation

Starting dose 4 g IV every 6 hours

Titration Not applicable

Usual maintenance dose 4 g IV every 6 hours

Maximum dose 18 g/day

Duration 4–7 days with adequate source control

Clinical note Must combine with metronidazole or clindamycin for anaerobic coverage; piperacillin-tazobactam FDC preferred in practice

1. Septicaemia / Bacteraemia (Susceptible Gram-negative Organisms) — Adults

Parameter Recommendation

Starting dose 4 g IV every 4–6 hours

Titration Not applicable

Usual maintenance dose 4 g IV every 6 hours (16 g/day)

Maximum dose 24 g/day

Duration Minimum 7–14 days; guided by source and clinical response

Clinical note Loading dose of 4 g recommended; combination with aminoglycoside for synergy in Pseudomonas bacteraemia

Secondary Indications — Adults (Off-label)

Indication Dose Duration Notes

Febrile neutropenia (empirical therapy, as part of combination) 4 g IV every 6 hours + Aminoglycoside Until neutrophil recovery and afebrile ≥48 hours OFF-LABEL; Specialist only. Piperacillin-tazobactam or cefepime now preferred. Evidence: Historical AIIMS/tertiary centre protocols; largely superseded by FDC

Cystic fibrosis pulmonary exacerbations (P. aeruginosa) 4 g IV every 4–6 hours 14–21 days OFF-LABEL; Specialist only. Always combine with aminoglycoside. Evidence: International guidelines adapted in Indian pulmonology practice

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

⚠️ Important: Piperacillin monotherapy in paediatrics is uncommon; piperacillin-tazobactam is standard practice. Use monotherapy only for documented susceptible organisms under specialist supervision.

Minimum age: No absolute restriction; can be used in neonates under specialist care

Serious Susceptible Gram-negative Infections (including Pseudomonas)

Preterm neonates (<37 weeks) 75 mg/kg/dose Every 12 hours 150 mg/kg/day

Term neonates <7 days 75 mg/kg/dose Every 12 hours 150 mg/kg/day

Term neonates ≥7 days 75–100 mg/kg/dose Every 8 hours 300 mg/kg/day

Infants 1–12 months 75–100 mg/kg/dose Every 6–8 hours 300 mg/kg/day

Children 1–12 years 100 mg/kg/dose Every 6–8 hours 400 mg/kg/day (max 16 g/day)

Adolescents >12 years or >40 kg Adult dosing Every 6 hours 24 g/day

Duration: 7–14 days; guided by infection type and response

Clinical note: For Pseudomonas infections, combine with aminoglycoside for synergy

Secondary Indications — Paediatrics (Off-label)

Indication Dose Duration Notes

Cystic fibrosis pulmonary exacerbations 100 mg/kg/dose IV every 6 hours (max 4 g/dose) 14–21 days OFF-LABEL; Specialist only. Combine with tobramycin. Evidence: Adapted from international CF guidelines used in Indian pulmonology practice

Safety Monitoring in Paediatrics:

• Renal function (serum creatinine, urea) at baseline and during therapy

• CBC with differential (weekly if therapy >7 days)

• Serum electrolytes (sodium load from formulation)

• Hepatic function in prolonged therapy

• Signs of superinfection

Age restriction statement: No minimum age restriction; neonatal use requires specialist (neonatologist/paediatric ID) supervision with appropriate gestational age-based dosing

40 No adjustment required

20–40 4 g IV every 8 hours (maximum 12 g/day)

<20 4 g IV every 12 hours (maximum 8 g/day)

Haemodialysis 2–4 g IV every 12 hours; administer additional 1 g after each dialysis session (approximately 30–40% removed)

CAPD 2 g IV every 12 hours; use with caution; limited data

CRRT 4 g every 8 hours; adjust based on effluent rate; consult ID/nephrology

Note: Accumulation increases risk of neurotoxicity (seizures) and bleeding; monitor closely in renal impairment

• Known hypersensitivity to piperacillin, any penicillin, or any excipient

• History of immediate/severe hypersensitivity reaction (anaphylaxis, angioedema, severe urticaria) to any β-lactam antibiotic

• History of piperacillin-induced cholestatic jaundice or hepatic dysfunction

• History of non-severe penicillin or cephalosporin allergy — monitor closely for allergic reactions

• Renal impairment — mandatory dose adjustment; increased risk of accumulation and neurotoxicity

• History of seizure disorder — high-dose piperacillin may lower seizure threshold

• Congestive heart failure or hypertension — significant sodium load (approximately 1.85 mEq sodium per gram of piperacillin); may exacerbate fluid retention

• Bleeding disorders or thrombocytopenia — piperacillin may cause platelet dysfunction and prolong bleeding time

• Concurrent aminoglycoside therapy — additive nephrotoxicity risk

• Hypokalaemia — may worsen with prolonged therapy

• History of antibiotic-associated colitis

• Critically ill patients with unstable renal function — frequent dose adjustment needed

Aspect Recommendation

Overall safety Generally considered safe; crosses placenta in therapeutic concentrations

Risk category US FDA Category B equivalent; no evidence of teratogenicity in animal or human studies

Preferred alternatives Piperacillin-tazobactam (provides better coverage); Ceftriaxone, Cefotaxime for many indications

When to use May be used when indicated, including obstetric sepsis, when susceptible organism documented

Monitoring Maternal renal function; fluid status (sodium load); signs of hypersensitivity

Aspect Recommendation

Compatibility Compatible with breastfeeding

Drug levels in milk Low (excreted in small amounts)

Preferred alternatives Piperacillin-tazobactam if broader coverage needed; penicillins generally acceptable

Infant monitoring GI disturbance (diarrhoea, loose stools), oral thrush, allergic sensitisation (rare)

• Starting dose: Standard adult dosing unless renal impairment present

• Titration: Adjust based on renal function (mandatory CrCl/eGFR calculation)

• Special considerations:

• Assess renal function before initiating — serum creatinine alone may underestimate renal impairment

• Increased risk of neurotoxicity (confusion, myoclonus, seizures) if drug accumulates

• Monitor for bleeding complications — elderly more susceptible to platelet dysfunction

• Significant sodium load may exacerbate heart failure or hypertension

• Higher risk of C. difficile colitis

• Ensure adequate hydration

Drug Interaction Management

Methotrexate Piperacillin reduces renal clearance of methotrexate → severe haematological and mucosal toxicity Avoid combination; if essential, monitor methotrexate levels closely and reduce methotrexate dose

Aminoglycosides (Amikacin, Gentamicin, Tobramycin) Physical incompatibility if mixed in same IV line; piperacillin inactivates aminoglycosides in vitro Never mix in same IV line or syringe; administer separately; flush line between drugs

Probenecid Inhibits tubular secretion of piperacillin → increased serum levels and prolonged half-life Reduce piperacillin dose by 25–50% if concurrent probenecid; or avoid combination

Warfarin/Acenocoumarol Piperacillin may enhance anticoagulant effect (vitamin K reduction, platelet dysfunction) Monitor INR closely during and after therapy; may need anticoagulant dose reduction

Drug Interaction Management

Vancomycin Additive nephrotoxicity when used concurrently Monitor renal function daily; ensure adequate hydration

Loop diuretics (Furosemide) May enhance nephrotoxicity, especially with concurrent aminoglycosides Monitor renal function and electrolytes

Vecuronium / Neuromuscular blocking agents Piperacillin may prolong neuromuscular blockade Monitor recovery from anaesthesia carefully

Heparin Additive bleeding risk due to platelet dysfunction Monitor for bleeding; check coagulation parameters

Live oral typhoid vaccine Antibiotics may reduce vaccine efficacy Complete antibiotic course 3 days before vaccination or delay vaccine

Oral contraceptives Theoretical reduction in efficacy (gut flora disruption) Counsel regarding backup contraception during therapy

• Diarrhoea and loose stools

• Nausea and vomiting

• Injection site reactions (pain, phlebitis, thrombophlebitis)

• Skin rash and pruritus

• Transient elevation of hepatic transaminases (ALT, AST)

• Eosinophilia

• Headache

• Hypokalaemia (with prolonged therapy)

• Anaphylaxis and severe hypersensitivity reactions — discontinue immediately; emergency management required

• Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis — rare; discontinue immediately

• Seizures — especially with high doses, renal impairment, or CNS pathology; reduce dose or discontinue

• Bleeding and platelet dysfunction — prolonged bleeding time; discontinue if significant bleeding occurs

• Neutropenia / Agranulocytosis / Thrombocytopenia — with prolonged therapy (>10–14 days); usually reversible

• Clostridioides difficile colitis — may occur during or after therapy; discontinue and initiate specific treatment

• Cholestatic hepatitis / Hepatotoxicity — rare; discontinue and investigate

• Interstitial nephritis — presents with fever, rash, eosinophilia, rising creatinine

• Haemolytic anaemia — rare; Coombs-positive

During therapy (days 3–5) Clinical response; signs of hypersensitivity; diarrhoea; injection site for phlebitis

Prolonged therapy (>7–10 days) CBC with differential (weekly); renal function; LFTs; serum potassium; bleeding time if clinically indicated

If on anticoagulants INR/aPTT at days 3–5 and weekly

Concurrent aminoglycosides Daily renal function; aminoglycoside levels

Piperacillin Monotherapy (Limited Availability):

• Pipracil (Pfizer — availability variable)

• Piprapen (Ranbaxy/Sun Pharma — availability variable)

• Generic piperacillin — select public sector hospitals

Note: Standalone piperacillin is rarely stocked; most facilities use piperacillin-tazobactam combinations

Piperacillin-Tazobactam FDCs (More Commonly Available — separate monograph):

• Tazact (Alkem)

• Tazopen (Cipla)

• Zosyn (Pfizer)

• Pipzo (Zydus)

• Multiple branded generics

Strength Price Range

• NPPA status: Not under direct price control; not in NLEM as monotherapy

• Availability: Limited in private retail; may be available through hospital pharmacies and public sector procurement

• Note: Piperacillin-tazobactam FDCs are more widely available and cost approximately ₹200–₹600 per vial depending on strength

1. Monotherapy is largely obsolete — due to widespread β-lactamase-producing organisms, piperacillin-tazobactam combination has replaced monotherapy in almost all clinical situations in India

1. Never mix with aminoglycosides — physical incompatibility leads to inactivation of aminoglycoside; always administer separately with line flush between drugs

1. High sodium content warning — each gram of piperacillin contains approximately 1.85 mEq sodium; at 16 g/day, this adds nearly 30 mEq sodium daily — significant for CHF patients or those on fluid restriction

1. Extended infusion may improve outcomes — infusing each dose over 3–4 hours (instead of 30 minutes) optimises time above MIC; consider for severe infections or elevated MIC pathogens

1. Watch for bleeding — piperacillin causes dose-dependent platelet dysfunction; monitor bleeding time or clinical bleeding, especially with concurrent anticoagulants or in renal impairment

1. Hypokalaemia with prolonged use — piperacillin is a non-reabsorbable anion that promotes potassium wasting; monitor potassium especially in ICU patients

piperacillin; penicillin; ureidopenicillin; extended-spectrum penicillin; Pseudomonas; Gram-negative; injectable antibiotic; renal-adjustment; sodium-load; bleeding-risk; Schedule H

RxIndia v1.0 — 05 Jan 2025

• CDSCO Approved Drug Formulations List

• Indian Pharmacopoeia (IP)

• API Textbook of Medicine (2022)

• AIIMS Antimicrobial Stewardship Guidelines

• ICMR Guidelines on Antimicrobial Use and Resistance

• IAP Drug Formulary (paediatric dosing)

• Goodman & Gilman's Pharmacological Basis of Therapeutics (supportive)

• Harrison's Principles of Internal Medicine (supportive)