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Potentially Fatal Interaction!
Avoid combining TMP-SMX (Septrin) with even low-dose Methotrexate.
The combo increases MTX exposure (reduced clearance + higher free fraction) and adds antifolate toxicity → real risk of pancytopenia, mucositis, and AKI.
Use only if unavoidable, with minimal duration and critical monitoring.

Evidence level (GRADE): Moderate certainty, (based on consistent case series + pharmacologic data, limited RCT evidence).

“Hidden AKI Driver”
In ICU patients with sepsis, the combination of Vanc + Pip-Tazo is associated with a markedly higher risk of Stage 2–3 AKI versus Vanc + other β-lactams.
Risk amplified in:

Vasopressor-dependent shock

High-dose Vanc (AUC > 600)

Obesity

Pre-existing renal hypoperfusion

Prefer Vanc + Cefepime or Vanc + Meropenem in unstable ICU patients unless strong indication.
Evidence (GRADE): Moderate certainty (multiple cohort studies + meta-analyses).

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