What is the best antibiotic treatment for a patient with a multidrug-resistant Gram-negative infection sensitive to Amikacin, Gentamicin, Colistin, Fosfomycin, and Polymyxin B?

Treatment of Multidrug-Resistant Gram-Negative Infection

For this extensively drug-resistant Gram-negative organism with sensitivity only to aminoglycosides (amikacin, gentamicin), polymyxins (colistin, polymyxin B), and fosfomycin, combination therapy with an aminoglycoside plus a polymyxin is the recommended treatment approach, with the specific regimen determined by infection site and severity. 1

Primary Treatment Recommendations by Clinical Scenario

For Bloodstream Infections or Severe Sepsis

• Colistin 5 mg CBA/kg IV loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) IV every 12 hours PLUS Gentamicin 5-7 mg/kg IV once daily 1, 2
• Alternative: Polymyxin B 2.5 mg/kg/day IV in 2 divided doses PLUS Amikacin 15 mg/kg IV once daily 1, 3
• Treatment duration: 7-14 days depending on source control and clinical response 1, 2

For Urinary Tract Infections

• Fosfomycin 3 grams IV every 8 hours as monotherapy may be adequate for uncomplicated UTI 4, 5
• For complicated UTI or pyelonephritis: Gentamicin 5-7 mg/kg IV once daily PLUS Fosfomycin 3 grams IV every 8 hours 1, 4
• Treatment duration: 5-7 days for uncomplicated, 10-14 days for complicated UTI 1

For Pneumonia or Respiratory Infections

• Colistin 5 mg CBA/kg IV loading dose, then maintenance dosing PLUS Gentamicin 5-7 mg/kg IV once daily PLUS aerosolized colistin 2 MIU twice daily 1, 3
• The addition of inhaled polymyxin to IV therapy may reduce mortality (RR=0.86) and clinical treatment failure (RR=0.82) for respiratory infections 3
• Treatment duration: 10-14 days 1

For Intra-Abdominal Infections

• Gentamicin 5-7 mg/kg IV once daily PLUS Colistin 5 mg CBA/kg IV loading dose, then maintenance dosing PLUS Metronidazole 500 mg IV every 8 hours (for anaerobic coverage) 1
• Treatment duration: 5-7 days with adequate source control 1, 2

Rationale for Combination Therapy

Combination therapy is strongly preferred over monotherapy for this resistance pattern because it reduces mortality, prevents resistance emergence, and improves microbiological cure rates. 1, 3

• Meta-analysis of carbapenem-resistant infections showed combination therapy reduced 28-30 day mortality from 55.5% to 35.7% (OR 0.46,95% CI 0.30-0.69) 3
• Combination therapy was independently associated with lower 30-day mortality (HR 0.33,95% CI 0.17-0.64) compared to polymyxin monotherapy 3
• Polymyxin-aminoglycoside combinations demonstrate synergistic effects in vitro and prevent emergence of resistant subpopulations 3

Choice Between Aminoglycosides

Gentamicin is preferred over amikacin for most systemic infections due to equivalent efficacy, lower cost, and extensive clinical experience, though amikacin may be reserved for gentamicin-resistant strains or when gentamicin resistance is suspected. 1, 6

• Both aminoglycosides should be dosed once daily: gentamicin 5-7 mg/kg/day, amikacin 15 mg/kg/day 1, 2
• Monitor trough levels and renal function closely due to nephrotoxicity risk 6
• Avoid aminoglycosides in combination with other nephrotoxic drugs when possible 1

Choice Between Polymyxins

Polymyxin B may be preferred over colistin due to lower nephrotoxicity risk (adjusted HR 2.27 for colistin vs polymyxin B, 95% CI 1.35-3.82) and more predictable pharmacokinetics without requiring conversion from prodrug. 3, 7, 8

• Polymyxin B demonstrates significantly lower MICs than colistin against Klebsiella pneumoniae (p<0.02), Acinetobacter baumannii (p<0.001), and Pseudomonas aeruginosa (p<0.01) 7
• Colistin requires loading dose for rapid therapeutic levels, while polymyxin B does not require loading dose 3, 9
• Both polymyxins have similar antimicrobial spectrum and clinical efficacy 10, 8

Fosfomycin Considerations

Fosfomycin should be reserved primarily for urinary tract infections or as a third agent in combination therapy for systemic infections, as it achieves poor plasma concentrations and has limited evidence for non-urinary infections. 1, 4, 5

• Fosfomycin susceptibility was 96% for Klebsiella pneumoniae and 100% for Enterobacter species using CLSI criteria 5
• For systemic infections, fosfomycin 3 grams IV every 8 hours can be added as a third agent to polymyxin-aminoglycoside combinations 1
• Fosfomycin monotherapy should be avoided for bacteremia or severe infections due to inadequate serum concentrations 1

Critical Monitoring Parameters

Monitor renal function daily during the first week, then every 2-3 days, as both polymyxins and aminoglycosides are nephrotoxic. 6, 9

• Baseline creatinine clearance must be established before initiating therapy 9
• Adjust polymyxin and aminoglycoside doses based on renal function 1, 6
• Monitor aminoglycoside trough levels (target <1 mcg/mL for gentamicin) 6
• Watch for neurotoxicity signs including paresthesias, dizziness, or respiratory depression 9

Common Pitfalls to Avoid

• Never use tigecycline for bacteremia or pneumonia as monotherapy due to inadequate serum concentrations and poor outcomes 1
• Do not use aminoglycoside monotherapy for systemic infections—it is only appropriate for uncomplicated urinary tract infections 1
• Avoid concurrent use of curariform muscle relaxants with polymyxins due to risk of respiratory paralysis 9
• Do not delay loading dose of colistin in severe infections, as therapeutic levels are not achieved rapidly without it 1, 3
• Ensure adequate source control before expecting clinical improvement, as antibiotics alone are insufficient for abscesses or undrained collections 1, 2

When to Consider Infectious Disease Consultation

Obtain infectious disease consultation for all patients with this resistance pattern, as management requires specialized expertise in dosing, monitoring, and optimizing combination regimens. 2