What is the recommended treatment for a patient with a severe or high-risk infection suspected or confirmed to be caused by multi-drug resistant bacteria, specifically using carbapenem (carbapenem) antibiotics such as meropenem or imipenem/cilastatin?

Carbapenem Treatment for Severe Multi-Drug Resistant Infections

First-Line Therapy Selection

For carbapenem-resistant Enterobacterales (CRE) infections, ceftazidime-avibactam 2.5 g IV every 8 hours is the preferred first-line agent, with imipenem-cilastatin-relebactam 1.25 g IV every 6 hours or meropenem-vaborbactam 4 g IV every 8 hours as alternatives. 1, 2

When Traditional Carbapenems Remain Appropriate

For carbapenem-susceptible organisms or carbapenem-resistant Pseudomonas aeruginosa (CRPA) with carbapenem MIC ≤8 mg/L, high-dose extended-infusion meropenem (1-2 g IV every 8 hours infused over 3 hours) can be used as part of combination therapy. 1, 3

• Imipenem/cilastatin 500 mg IV every 6 hours or meropenem 2 g IV every 8 hours (extended infusion) should be combined with colistin for carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia when carbapenem MIC is ≤32 mg/L 1
• Standard dosing for meropenem in adults with normal renal function ranges from 500 mg every 6 hours to 1,000 mg every 6-8 hours, depending on infection severity 4, 5

Infection-Specific Carbapenem Recommendations

Bloodstream Infections

• For CRE bloodstream infections, use ceftazidime-avibactam 2.5 g IV every 8 hours, meropenem-vaborbactam 4 g IV every 8 hours, or imipenem-cilastatin-relebactam 1.25 g IV every 6 hours for 7-14 days 1, 2
• For CRAB bloodstream infections, colistin 5 mg CBA/kg IV loading dose followed by maintenance dosing ± high-dose extended-infusion carbapenem (if MIC ≤32 mg/L) for 10-14 days 1
• Never use tigecycline monotherapy for bloodstream infections due to worse outcomes 3

Pneumonia (Hospital-Acquired/Ventilator-Associated)

• For CRAB pneumonia, use colistin 5 mg CBA/kg IV loading dose with maintenance dosing plus imipenem/cilastatin 500 mg IV every 6 hours or meropenem 2 g IV every 8 hours (extended infusion), with adjunctive inhaled colistin for at least 7 days 1
• For CRPA pneumonia, use ceftolozane-tazobactam 3 g IV every 8 hours or ceftazidime-avibactam 2.5 g IV every 8 hours 1
• Meropenem demonstrates excellent lung tissue penetration and is preferred over tigecycline for hospital-acquired/ventilator-associated pneumonia 3, 5

Complicated Intra-Abdominal Infections

• For CRE complicated intra-abdominal infections, use ceftazidime-avibactam 2.5 g IV every 8 hours plus metronidazole 500 mg IV every 6 hours for 5-7 days 1, 2
• Alternative: imipenem-cilastatin-relebactam 1.25 g IV every 6 hours (provides anaerobic coverage without additional metronidazole) 1, 2
• Treatment duration is 5-7 days with adequate source control 1, 2

Complicated Urinary Tract Infections

• For CRE complicated urinary tract infections, aminoglycosides (gentamicin 5-7 mg/kg/day IV once daily or amikacin 15 mg/kg/day IV once daily) are preferred over carbapenems for 5-7 days 1, 3
• Alternative: ceftazidime-avibactam 2.5 g IV every 8 hours or meropenem-vaborbactam 4 g IV every 8 hours 1

Critical Combination Therapy Principles

When to Use Combination Therapy

For severe or high-risk CRAB infections, use combination therapy with two in vitro active antibiotics (polymyxin, aminoglycoside, tigecycline, sulbactam, or carbapenem if MIC ≤8 mg/L). 1

• For CRPA infections treated with polymyxins, aminoglycosides, or fosfomycin, use two in vitro active drugs 1
• Do NOT use polymyxin-rifampin or polymyxin-meropenem combinations for CRAB, as these have been shown ineffective 1

Extended-Infusion Strategy

Administer carbapenems via 3-hour extended infusion for CRE infections, high MIC organisms (≥8 mg/L), and critically ill patients to maximize time above MIC. 2, 3

Dosing Adjustments for Renal Impairment

• Reduce carbapenem doses when creatinine clearance is <90 mL/min 4
• Do NOT use imipenem/cilastatin in patients with creatinine clearance <15 mL/min unless hemodialysis is instituted within 48 hours 4
• Meropenem requires dosage adjustment in renal impairment but has a safer renal profile with reduced nephrotoxicity compared to colistin 3, 5

Critical Pitfalls to Avoid

• Never use carbapenem monotherapy for documented CRE infections; newer beta-lactam/beta-lactamase inhibitor combinations are strongly preferred 2, 3
• Never use polymyxin monotherapy for severe CRE infections; always combine with at least one other active agent 2
• Avoid tigecycline for bloodstream infections or hospital-acquired/ventilator-associated pneumonia due to worse outcomes 3
• Do NOT use imipenem/cilastatin for meningitis or CNS infections due to seizure risk 4
• Avoid standard-dose carbapenems for high-MIC organisms (≥8 mg/L); use extended infusion strategy 2, 3

Special Considerations

Seizure Risk Management

• Seizures and CNS adverse reactions (confusional states, myoclonic activity) can occur with carbapenems, particularly imipenem 4
• If focal tremors, myoclonus, or seizures occur, evaluate neurologically, initiate anticonvulsant therapy, and consider decreasing carbapenem dose or discontinuing 4
• Meropenem has lower seizure propensity than imipenem, making it suitable for most serious infections 5, 6

Drug Interactions

• Co-administration of imipenem/cilastatin with valproic acid or divalproex sodium reduces valproic acid concentrations below therapeutic range, increasing breakthrough seizure risk 4
• Consider alternative antibiotics or closely monitor valproic acid levels with supplementation 4

Antimicrobial Stewardship

• Carbapenems are "Watch" category antibiotics reserved for severe infections with multidrug-resistant organisms 3
• Obtain infectious disease consultation for all MDR organism infections to optimize outcomes 2
• Resistance to carbapenems can emerge during treatment of Pseudomonas aeruginosa infections 7, 6

Treatment Duration by Infection Type

• Bloodstream infections: 7-14 days 1, 2
• Pneumonia: at least 7 days (10-14 days for hospital-acquired/ventilator-associated) 1
• Complicated intra-abdominal infections: 5-7 days with source control 1, 2
• Complicated urinary tract infections: 5-7 days 1
• Extend duration to 7-14 days if inadequate source control or persistent infection signs 2