What is the treatment for carbapenem-resistant Klebsiella pneumoniae (CR-KP) susceptible to colistin?

Treatment of Carbapenem-Resistant Klebsiella pneumoniae Susceptible to Colistin

For carbapenem-resistant Klebsiella pneumoniae (CRKP) susceptible to colistin, use combination therapy with colistin PLUS a second active agent rather than colistin monotherapy, as this reduces mortality by approximately 50% in high-risk patients. 1

Immediate Management Steps

• Obtain infectious disease consultation immediately, as this is strongly recommended and improves outcomes for all CRKP infections 2
• Identify the carbapenemase type (KPC, NDM, VIM, or OXA-48) through genotypic testing, as this determines optimal therapy selection 2
• Assess infection severity using the INCREMENT score: patients with scores 8-15 benefit most from combination therapy (adjusted HR 0.56 for mortality reduction), while those with lower scores show less benefit 1

Preferred Combination Regimens

First-Line: Colistin + High-Dose Extended-Infusion Meropenem

Use this regimen when meropenem MIC ≤8 mg/L:

• Colistin: Loading dose 9 million units IV, then 4.5 million units IV every 12 hours 2
• Meropenem: 2 g IV every 8 hours infused over 3 hours 1, 2
• This combination showed lower 14-day mortality in retrospective cohorts of KPC-producing K. pneumoniae bloodstream infections 1
• The extended infusion maximizes time above MIC for high-MIC pathogens 2

Alternative: Colistin + Tigecycline

Use when meropenem MIC >8 mg/L or carbapenem contraindicated:

• Tigecycline: 100 mg IV loading dose, then 50 mg IV every 12 hours 2
• Colistin: Same dosing as above
• Meta-analysis showed OR 1.88 for survival benefit with this combination 2
• Polymyxin and tigecycline are the antimicrobials for which companion drug addition is most advisable 1

Alternative: Colistin + Fosfomycin

Consider for urinary tract infections or when other options unavailable:

• High-dose IV fosfomycin plus colistin demonstrated synergistic activity and reduced mortality in observational studies 2
• Monitor serum potassium daily, as severe hypokalemia is common with this combination 2

Site-Specific Modifications

Bloodstream Infections

• Combination therapy is strongly preferred over monotherapy (OR 1.93 for mortality reduction) 2
• Treatment duration: 10-14 days 2
• Use of two or more in vitro active antibiotics was independently associated with 30-day survival in critically ill patients with septic shock 1

Pneumonia/Respiratory Tract Infections

• Add adjunctive inhaled colistin (1-2 million units every 8-12 hours via nebulizer) in addition to IV colistin 1, 2
• IV colistin achieves negligible concentrations in epithelial lining fluid, making adjunctive inhalation therapy beneficial 1, 2
• Aerosolized colistin plus IV therapy may reduce clinical treatment failure by 77 per 1000 patients treated (RR 0.82) 1
• Treatment duration: 7-10 days for uncomplicated pneumonia, 2-4 weeks for complicated pneumonia or empyema 2

Urinary Tract Infections

• Colistin achieves excellent urinary concentrations, making monotherapy potentially acceptable for uncomplicated UTI 3
• For complicated UTI, combination therapy remains preferred 2

Critical Dosing Considerations

Colistin Dosing Optimization

• Loading dose is mandatory: 9 million units IV to achieve rapid therapeutic levels 2
• Maintenance dose: 4.5 million units IV every 12 hours (adjust for renal function) 2
• Target average steady-state concentration ≥1 mg/L 2

Therapeutic Drug Monitoring (TDM)

• Perform TDM for all patients receiving polymyxins, as this optimizes efficacy and reduces toxicity 2
• Check colistin levels at steady state (after 3rd dose) and adjust dosing to maintain target concentrations 2

Monitoring for Toxicity

Nephrotoxicity Surveillance

• Monitor serum creatinine every 2-3 days, as nephrotoxicity occurs in 20-30% of patients receiving polymyxins 2
• Acute kidney injury occurred in 52% of patients in a recent cohort, with no difference between colistin and polymyxin B 4

Electrolyte Monitoring

• Check serum potassium daily when using IV fosfomycin or polymyxins 2

Critical Pitfalls to Avoid

Colistin Heteroresistance

• Be aware that isolates reported as colistin-susceptible may harbor resistant subpopulations that are not detected by standard susceptibility testing 5
• This heteroresistance can lead to treatment failure despite reported susceptibility 5
• If clinical failure occurs despite susceptibility, consider switching to alternative agents rather than increasing colistin dose 5

Monotherapy Failure

• Never use colistin monotherapy for severe infections or high-risk patients (INCREMENT score ≥8), as combination therapy reduces mortality by 44% in this population 1
• Lower efficacy of single-drug regimens is attributed to suboptimal dosing and unsuitable pharmacokinetics for some infection sites 1

Carbapenem Combination Controversy

• Two RCTs (AIDA and OVERCOME) showed no statistically significant mortality benefit for colistin-meropenem versus colistin monotherapy in CRE subgroups 1
• However, retrospective cohorts demonstrate benefit when meropenem MIC ≤8 mg/L and high-dose extended-infusion dosing is used 1
• The key is using high-dose extended-infusion meropenem (6 g/day over 3-hour infusions), not standard dosing 1

When Newer Agents Are Available

• If the isolate is KPC-producing, ceftazidime-avibactam 2.5 g IV every 8 hours is preferred over colistin-based therapy (clinical success rates 60-80%) 2
• For MBL-producing strains, use ceftazidime-avibactam PLUS aztreonam, which showed significant mortality reduction in a prospective study of 102 patients 2
• These newer agents should be prioritized when available and the organism is susceptible 2