Piperacillin and tazobactam
Piperacillin/Tazobactam (Pip-Tazo)
Generic Name
Piperacillin/Tazobactam (Pip-Tazo)
Mechanism
- Piperacillin binds to *penicillin‑binding proteins (PBPs)* on bacterial cell walls, inhibiting *peptidoglycan cross‑linking* → bactericidal effect.
- Tazobactam reversibly inhibits a wide range of *β‑lactamases*, protecting piperacillin from enzymatic degradation and extending its spectrum to β‑lactamase‑producing organisms.
Result: Time‐dependent killing (>40% T > MIC) against susceptible organisms; synergy with tazobactam broadens the antibacterial profile especially against β‑lactamase‑producing pathogens.
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Pharmacokinetics
| Parameter | Typical Value (IV) |
| Absorption | IV only; bioavailability 100% |
| Distribution | Vd 0.4–0.7 L/kg; moderate penetration in tissues; limited CSF unless meningitis |
| Protein Binding | ~35% (piperacillin) |
| Metabolism | Minimal, predominantly renal excretion |
| Half‑life | ~1–1.5 h (renal clearance) |
| Renal | 70–80% excreted unchanged by glomerular filtration & tubular secretion |
| Dosing Adjustments | Renal‑dose interval extended per creatinine clearance; no dose adjustment in mild hepatic impairment |
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Indications
- Complicated intra‑abdominal infections (e.g., peritonitis, appendicitis)
- Complicated urinary tract infections (pyelonephritis, urosepsis)
- Complicated skin and soft‑tissue infections (cellulitis, necrotizing fasciitis)
- Hematogenous bacterial infections (septicemia, endocarditis)
- Nosocomial pneumonia (ventilator‑associated)
- Mixed aerobic/anaerobic infections (surgical prophylaxis in high‑risk patients)
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Contraindications
- Allergy: History of *penicillin or cephalosporin* hypersensitivity (urticaria, anaphylaxis).
- Drug Interactions: May cause elevated *liver aminotransferases* when combined with hepatotoxic agents (e.g., methotrexate).
- Pregnancy & Lactation: Category B; limited data; use only if benefits > risks.
- Renal Function: Dose adjustments required for CrCl < 30 mL/min.
- Severe Hepatic Impairment: Use with caution; no dose adjustment data available.
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Dosing
| Infection | Adult Dose (IV) | Route | Frequency | Special Notes |
| General | 6.3 g (2.1 g pip + 0.9 g taz) every 6 h | IV push/infusion | 4 h infusion | Use 240 mL NS; split 50% pre‑/post‑dose |
| Severe | 13 g (4.3 g pip + 1.9 g taz) every 6 h | IV | 4 h infusion | Continuous infusion (e.g., 0.3–0.5 g/mL over 6 h) in severe infections or Pseudomonas‑positive cases |
| Renal‑Adjusted | 2.1 g / 0.3 g every 6 h (CrCl 10–30 mL/min) | IV | 4 h | 300 mL NS; repeat every 8–12 h if CrCl < 10 mL/min |
Infusion Guidelines: Do not exceed 6 g piperacillin / 1 g tazobactam per infusion to avoid precipitation. Administer in 0.9% sodium chloride over 4–6 h; avoid dilute solutions (≤ 5 mg/mL) to reduce rash incidence.
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Adverse Effects
- Common (≥ 5%)
- Diarrhea (including *Clostridioides difficile* colitis)
- Nausea, vomiting
- Hypersensitivity rash (maculopapular, Stevens‑Johnson)
- Transient ↑ aminotransferases
- Injection‑site reactions (phlebitis)
- Serious (≤ 5%)
- Anaphylaxis (rare)
- Severe hypersensitivity (Stevens‑Johnson, TEN)
- Neutropenia, agranulocytosis
- Hepatotoxicity (transaminases > 5× ULN)
- C. difficile‑associated colitis (severe)
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Monitoring
| Parameter | Frequency | Rationale |
| Renal Function (CrCl/BUN/Cr) | Baseline; weekly in chronic therapy | Adjust dosing |
| Liver Enzymes (AST/ALT) | Baseline; every 2–3 days if > 3× ULN | Detect hepatotoxicity |
| CBC (WBC, neutrophils) | Baseline; every 4–5 days | Detect neutropenia |
| Clinical Signs of C. difficile | Every visit | Early detection of colitis |
| Infusion Reaction | Continuous during infusion | Identify phlebitis/rash |
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Clinical Pearls
- Time‑Dependent Pharmacodynamics: Ensure *T > MIC* ≥ 40% by using prolonged or continuous infusions, especially against *Pseudomonas aeruginosa* where MIC may approach the upper therapeutic limit.
- Allergy Screening: A *penicillin‑negative* skin test (or intradermal) significantly reduces anaphylaxis risk in patients with a past penicillin reaction; those with a positive test must avoid Pip‑Tazo.
- Superinfection Prevention: Use the narrowest effective spectrum and consider *C. difficile* prophylaxis (e.g., oral vancomycin) in patients with a prior CDI history.
- Renal Dosing Algorithms: Commonly cited algorithm:
- CrCl ≥ 50 mL/min – 6.3 g q6h
- CrCl 30–49 mL/min – 4.2 g q8h
- CrCl < 30 mL/min – 2.1 g q12h
*Adjust per local guidelines.*
• Intracellular Penetration: Although Pip‑Tazo achieves good tissue levels, it penetrates the CSF poorly in patients with normal meninges; use in meningitis only if meninges are inflamed or when combined with an agent that penetrates CSF.
• Drug Interactions: It may *decrease the plasma concentration of warfarin* (evidenced by ↓ INR); monitor coagulation status closely.
• Storage: Reconstituted solution should be used within 24 h or stored at 2–8 °C for up to 48 h.
• Infusion Volume: Use infusion volume ≥ 240 mL; lower volumes increase the risk of local irritation and drug precipitation.
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• Key Takeaway: Piperacillin/Tazobactam is the go-to empiric agent for severe, mixed, or gram‑negative infections when broad coverage is required. Master the infusion technique, renal adjustments, and monitoring to maximize efficacy while minimizing toxicity.