What is the treatment for multidrug-resistant (MDR) Klebsiella infection?

From the Guidelines

For treating multidrug-resistant (MDR) Klebsiella infections, combination therapy with Ceftazidime/Avibactam is recommended, administered as 2.5g IV every 8 hours, as it has demonstrated consistent activity against Klebsiella pneumoniae carbapenemases (KPCs) producers 1.

Treatment Options

• Ceftazidime/Avibactam 2.5g IV every 8 hours is a preferred option for MDR Klebsiella infections, especially for carbapenemase-producing strains 1.
• Ceftolozane/Tazobactam 1.5g IV every 8 hours + Metronidazole 500mg IV every 6 hours is an alternative option, although its effectiveness against KPC-producing strains is not as well established as Ceftazidime/Avibactam 1.

Considerations

• Treatment should always be guided by susceptibility testing, as resistance patterns vary significantly 1.
• Dosing adjustments are required for patients with renal impairment.
• Source control through drainage of abscesses or removal of infected devices is crucial for treatment success.
• These newer agents are preferred over older combinations due to improved efficacy against carbapenemase-producing strains and better safety profiles compared to nephrotoxic agents like colistin, which should be reserved for cases with limited alternatives 1.

From the FDA Drug Label

At baseline, 111 patients in the mMITT population had Gram-negative isolates that were not susceptible to ceftazidime, including 61 patients with E. coli and 26 patients with K. pneumoniae isolates. Cure rates were 39/47 (83.0%) in patients who received AVYCAZ and 55/64 (85. 9%) of patients who received meropenem. In a subset of Gram-negative pathogens from both arms of the Phase 3 cIAI trial that met phenotypic screening criteria for the presence of a beta-lactamase, genotypic testing identified certain ESBL groups (e.g., TEM-1, SHV-12, CTX-M-15, OXA-48) and AmpC that were expected to be inhibited by avibactam in isolates from 105 (12. 8%) of the 823 patients in the mMITT population. Clinical cure rates in this subset were similar to the overall results.

Treatment of MDR Klebsiella

• The drug label provides information on the treatment of complicated intra-abdominal infections (cIAI) with AVYCAZ (avibactam and ceftazidime) plus metronidazole.
• The cure rate for Klebsiella pneumoniae was 78.4% (40/51) in the AVYCAZ plus metronidazole group and 75.5% (37/49) in the meropenem group.
• The presence of certain ESBL groups and AmpC was identified in a subset of Gram-negative pathogens, and avibactam was expected to inhibit these enzymes.
• Clinical cure rates in this subset were similar to the overall results, suggesting that AVYCAZ plus metronidazole may be effective in treating MDR Klebsiella infections 2.

From the Research

Treatment Options for Multidrug-Resistant Klebsiella

• Multidrug-resistant (MDR) Klebsiella pneumoniae is a significant threat to human health, causing difficult-to-treat infections with high mortality rates 3.
• Treatment options for MDR Klebsiella pneumoniae include tigecycline, gentamicin, fosfomycin, and ceftazidime/avibactam, with the choice of antimicrobial depending on pharmacokinetics/pharmacodynamics properties, site of infection, and susceptibility profile of the isolated strain 3.
• Novel antimicrobial options, such as plazomicin and cefiderocol, are being developed to address the challenge of colistin resistance in MDR Klebsiella pneumoniae 3.

Mechanisms of Resistance

• MDR Klebsiella pneumoniae develops resistance to various antimicrobials, including β-lactam antibiotics, due to constant selective pressure from multiple antibiotics 4.
• Understanding the mechanisms of resistance is crucial to improving the efficacy of current antimicrobials and designing novel therapeutic agents that can circumvent resistance mechanisms 4.

Challenges in Treatment and Prevention

• Management of antimicrobial resistance in MDR Klebsiella pneumoniae is a major challenge for clinicians, with optimal treatment options still not well established 5.
• Combination therapies, including high-dose meropenem, colistin, fosfomycin, tigecycline, and aminoglycosides, are widely used but often have suboptimal results 5.
• Coordinated strategies and common efforts in infection control and stewardship programs are essential for limiting the spread of MDR Klebsiella pneumoniae 5.

Novel Antimicrobial Agents

• Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem/cilastatin-relebactam are novel β-lactam/β-lactamase inhibitor combinations that have shown improved safety and efficacy in treating Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC) infections 6.
• Meropenem-vaborbactam has shown decreased rates of resistance to KPC compared to ceftazidime-avibactam, making it a potential alternative for treating KPC infections 6.

Case Studies and Treatment Strategies

• A case study of a multidrug-resistant Klebsiella urinary tract infection (UTI) highlights the importance of susceptibility testing and treatment strategies, including combination therapy with a carbapenem and synergy using polymyxin 7.
• The use of fosfomycin and colistin has been reported in treating MDR Klebsiella UTIs, but treatment outcomes can be limited by the development of adverse effects, such as acute kidney injury 7.