In an adult postoperative ICU patient with severe sepsis, cholestatic‑hepatocellular injury (bilirubin 8.4 mg/dL, AST 320 U/L, ALT 183 U/L, elevated INR) and electrolyte abnormalities, who is receiving meropenem and polymyxin B, should meropenem be discontinued or continued, and what dosing regimen is recommended?

Clarification: Meropenem Should Be Continued in Combination with Polymyxin B

In this clinical scenario of severe sepsis with carbapenem-resistant gram-negative infection, meropenem should be continued as part of combination therapy with polymyxin B, not discontinued. The apparent conflict arises from different clinical contexts: meropenem monotherapy would be inappropriate, but meropenem as part of polymyxin-based combination therapy is strongly recommended by current guidelines. 1

Why Meropenem Should Be Continued

Guideline-Based Rationale for Combination Therapy

• Polymyxin combination therapy is strongly recommended over monotherapy for carbapenem-resistant gram-negative bacilli (CRGNB) infections, with moderate-quality evidence showing 119 fewer treatment failures per 1000 patients and 74 fewer pathogen eradication failures compared to polymyxin monotherapy. 1

• Polymyxin-meropenem combination is specifically recommended for carbapenem-resistant Acinetobacter baumannii (CRAB) infections when meropenem MIC is ≤32 mg/L, and for carbapenem-resistant Enterobacteriaceae (CRE) when meropenem MIC is ≤8 mg/L, using high-dose extended-infusion meropenem (3-hour infusion). 1

• Network meta-analysis demonstrates that colistin-carbapenem combinations ranked first in improving clinical cure (SUCRA 91.7%) and second in microbiological cure (SUCRA 68.7%) among various treatment regimens for CRAB pneumonia. 1

Clinical Evidence Supporting Continuation

• Six randomized controlled trials (N=876) comparing polymyxin combination therapy versus monotherapy showed 14 fewer deaths per 1000 patients (RR 0.97), with no apparent differences in renal toxicity or hepatotoxicity between groups. 1

• The AIDA study specifically reported that colistin-meropenem combination reduced the incidence of mild renal failure (20% vs 30% with monotherapy), though it increased diarrhea incidence (27% vs 16%). 1

Recommended Dosing Regimen for This Patient

High-Dose Extended-Infusion Protocol

• Administer meropenem 2 grams IV every 8 hours as a 3-hour extended infusion in combination with polymyxin B for this critically ill ICU patient with severe sepsis and suspected CRAB or CRE infection. 1, 2

• Extended infusion over 3 hours is mandatory when treating resistant organisms with MIC ≥8 mg/L or for carbapenem-resistant infections to optimize pharmacodynamic targets (time above MIC). 1, 2

Dosing Adjustments for Hepatic Dysfunction

• No dosage adjustment is required for hepatic impairment with meropenem, as it undergoes predominantly renal excretion with low protein binding. 3

• Monitor renal function closely during polymyxin treatment, as the combination may affect renal clearance; therapeutic drug monitoring (TDM) is encouraged where possible. 1

Addressing the Hepatic Injury Concern

Meropenem and Liver Toxicity

• Meropenem-induced liver injury is rare but documented, presenting as mixed hepatocellular-cholestatic patterns with rapid enzyme elevation within 48 hours of administration. 4

• However, the current cholestatic-hepatocellular injury (bilirubin 8.4 mg/dL, AST 320 U/L, ALT 183 U/L) is more likely multifactorial in a postoperative ICU patient with severe sepsis, including sepsis-associated cholestasis, shock liver, total parenteral nutrition, and multiple hepatotoxic medications. 4

• Polymyxin-meropenem combination therapy showed no apparent differences in hepatotoxicity compared to polymyxin monotherapy in RCTs (N=779). 1

Clinical Decision Algorithm

Do NOT discontinue meropenem if:

• Patient has documented or suspected CRAB/CRE infection requiring polymyxin therapy
• Meropenem MIC is ≤32 mg/L for CRAB or ≤8 mg/L for CRE
• Liver enzymes are stable or improving
• No alternative explanation for hepatic injury has been excluded 1, 4

Consider discontinuation only if:

• Liver enzymes are rapidly rising (>3× baseline within 48 hours of meropenem initiation)
• Other causes of hepatotoxicity have been systematically excluded
• Alternative antimicrobial regimens are available (e.g., ceftazidime-avibactam, ceftolozane-tazobactam for susceptible organisms) 1, 4

Critical Pitfalls to Avoid

• Never use polymyxin monotherapy when combination therapy is feasible, as this significantly increases treatment failure rates and mortality in CRGNB infections. 1

• Do not assume meropenem is ineffective against carbapenem-resistant organisms—when used at high doses with extended infusion in combination therapy, meropenem demonstrates synergistic activity and prevents resistance emergence. 1

• Avoid ototoxic and nephrotoxic drugs in combination with polymyxin (including aminoglycosides unless absolutely necessary), but meropenem does not fall into this category. 1

• Do not prematurely attribute hepatic dysfunction to meropenem in critically ill septic patients without excluding more common causes: sepsis-associated cholestasis, shock liver, ischemic hepatitis, and drug-drug interactions. 4

Monitoring and Duration

• Continue combination therapy for 10-14 days for severe sepsis with bloodstream infection or pneumonia, depending on source control adequacy and clinical response. 1, 2

• Monitor liver enzymes every 48-72 hours during therapy; if enzymes continue rising despite clinical improvement, consider infectious disease consultation for alternative regimens. 4

• Assess clinical stability criteria daily: temperature ≤37.8°C, heart rate ≤100 bpm, respiratory rate ≤24 breaths/min, systolic BP ≥90 mmHg, oxygen saturation ≥90%, ability to maintain oral intake, and normal mental status before considering de-escalation. 2