What is the recommended treatment for multi-drug resistant (MDR) infections?

Treatment of Multidrug-Resistant (MDR) Infections

The treatment of MDR infections requires pathogen-specific regimens guided by susceptibility testing, with combination therapy generally preferred over monotherapy for severe infections, and infectious disease consultation strongly recommended for all cases. 1, 2

General Principles for All MDR Infections

• Obtain antimicrobial susceptibility testing or genotypic resistance characterization before initiating therapy to guide appropriate antibiotic selection 2
• Consult infectious disease specialists for all MDR infections to optimize treatment outcomes and reduce mortality 2
• Reassess all antibiotic regimens at 48-72 hours and de-escalate based on clinical response and microbiological data 2
• Avoid unnecessary prolonged use of empiric broad-spectrum antibiotics, as interval antibiotic therapy between initial intervention and reoperation is the strongest risk factor for emergence of MDR bacteria (OR 5.1) 1, 3

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

Pneumonia

• First-line: Colistin-based combination therapy with or without carbapenem, PLUS adjunctive inhaled colistin for at least 7 days 1, 4, 2
• Alternative: Sulbactam 6-9 g/day IV in 3-4 divided doses (preferred when MIC ≤4 mg/L due to better safety profile) 4
• Alternative combination: Colistin + tigecycline + sulbactam 4
• AVOID tigecycline monotherapy for pneumonia due to poor outcomes and higher mortality 4, 2, 5

Bloodstream Infections

• First-line: Colistin-carbapenem combination therapy (especially when carbapenem MIC ≤32 mg/L) for 10-14 days 1, 4, 2
• Alternative: Colistin + tigecycline 4
• Colistin-carbapenem combinations show the best outcomes in network meta-analyses 4

Dosing Considerations

• Colistin: 2.5-5 mg CBA/kg/day IV in 2 or 4 divided doses (maximum 100 mg CBA/dose) with careful monitoring for nephrotoxicity 1, 4
• Inhaled colistin: 4 mg CBA/kg/dose every 12 hours (maximum 150 mg CBA/dose) 1

Carbapenem-Resistant Enterobacterales (CRE)

Bloodstream Infections

• First-line: Ceftazidime-avibactam 2.5g IV every 8 hours infused over 3 hours 2
• Alternative: Polymyxin-based combination therapy based on susceptibility testing 2
• Alternative: Meropenem-vaborbactam 4g IV every 8 hours 2
• Duration: 7-14 days 6

Complicated Urinary Tract Infections

• Ceftazidime-avibactam 2.5g IV every 8 hours 2
• Meropenem-vaborbactam 4g IV every 8 hours 2
• Imipenem-cilastatin-relebactam 1.25g IV every 6 hours 2
• Plazomicin 15 mg/kg IV every 12 hours 2
• Fosfomycin IV formulations preferred over oral for complicated UTIs 6
• Duration: 5-7 days 1, 6

Uncomplicated Urinary Tract Infections

• Fosfomycin 3g PO single dose OR 3g PO every other day for 3-7 days 1, 6

Important Considerations

• For severe CRE infections resistant to newer antibiotics, use fosfomycin in combination with other agents, not as monotherapy 6
• Perform therapeutic drug monitoring (TDM) when possible, especially for prolonged courses 6

Vancomycin-Resistant Enterococci (VRE)

Pneumonia

• Linezolid 600 mg IV every 12 hours for at least 7 days (strong recommendation) 1, 2

Bloodstream Infections

• First-line: Linezolid 600 mg IV every 12 hours for 10-14 days (strong recommendation) 1, 2
• Alternative: High-dose daptomycin 8-12 mg/kg IV daily alone or in combination with β-lactams 1, 2
• Consider β-lactam combination when daptomycin MIC is high (3-4 mg/mL) - options include penicillins, carbapenems, and cephalosporins (excluding cefotaxime and cefazolin) 1
• For infective endocarditis: cardiac surgery combined with antimicrobial therapy should be considered 1

Complicated Intra-Abdominal Infections

• First-line: Linezolid 600 mg IV every 12 hours for 5-7 days (strong recommendation) 1
• Alternative: Tigecycline 100 mg IV loading dose, then 50 mg IV every 12 hours for 5-7 days 1, 2

Complicated Urinary Tract Infections

• Linezolid 600 mg IV every 12 hours for 5-7 days (strong recommendation) 1
• Daptomycin 6-12 mg/kg IV daily for 5-7 days 1

Uncomplicated Urinary Tract Infections

• Fosfomycin 3g PO single dose OR 3g PO every other day for 3-7 days 1, 6
• Nitrofurantoin 100 mg PO four times daily for 3-7 days 1
• High-dose ampicillin 18-30 g/day IV in divided doses for 3-7 days (achieves sufficient urinary concentrations regardless of ampicillin susceptibility) 1
• Amoxicillin 500 mg PO/IV every 8 hours for 3-7 days 1

Critical Considerations

• Differentiate colonization from true infection before prescribing anti-VRE agents 1
• Daptomycin is preferred for serious VRE infections due to bactericidal activity 1

Multidrug-Resistant Tuberculosis (MDR-TB)

Regimen Composition

• Use at least 5 drugs in the intensive phase and 4 drugs in the continuation phase 1
• MUST include: Later-generation fluoroquinolone (levofloxacin or moxifloxacin) - strong recommendation 1
• MUST include: Bedaquiline - strong recommendation 1
• Suggested additions: Linezolid, clofazimine, cycloserine 1
• Include pyrazinamide when isolate not resistant to pyrazinamide 1
• Include ethambutol ONLY when other more effective drugs cannot be assembled to achieve 5 drugs 1

Treatment Duration

• Intensive phase: 5-7 months after culture conversion 1
• Total treatment: 15-21 months after culture conversion for MDR-TB 1
• Total treatment: 15-24 months after culture conversion for pre-XDR-TB and XDR-TB 1

Optimizing β-Lactam Administration for MDR Infections

• Administer β-lactams by prolonged IV infusion (3-4 hours) for severe infections, especially with high MIC pathogens 2
• Consider continuous infusion for carbapenems, ceftazidime, and piperacillin-tazobactam when risk of pharmacodynamic failure exists 2
• For meropenem: 500 mg every 8 hours for skin/soft tissue, 1 gram every 8 hours for intra-abdominal infections, infused over 15-30 minutes 7

Empiric Therapy Considerations

• Use empiric combination treatment for patients with shock, neutropenia, or suspected MDR infections 2
• For postoperative peritonitis without prior broad-spectrum antibiotic exposure: Imipenem/cilastatin monotherapy provides >80% adequacy 3
• For postoperative peritonitis with prior broad-spectrum antibiotic exposure: Combination of imipenem/cilastatin or piperacillin/tazobactam + amikacin + glycopeptide achieves 94-99% adequacy 3

Common Pitfalls to Avoid

• Never use tigecycline monotherapy for pneumonia or bloodstream infections - associated with increased all-cause mortality (risk difference 0.6%, 95% CI 0.1-1.2) 4, 2, 5
• Do not use fosfomycin oral formulations for pyelonephritis or perinephric abscess 6
• Avoid fosfomycin monotherapy for severe systemic MDR infections outside uncomplicated UTIs 6
• Do not use minocycline monotherapy for severe infections, particularly pneumonia and bloodstream infections 4
• Tigecycline is reserved for situations when alternative treatments are not suitable due to increased mortality risk 5