What is the recommended treatment for Klebsiella pneumoniae lower respiratory tract infections (LRTI) with doripenem?

Doripenem for Klebsiella pneumoniae Lower Respiratory Tract Infections

For Klebsiella pneumoniae lower respiratory tract infections (LRTI), high-dose, extended-infusion doripenem (4-hour infusion) may be effective against strains with intermediate susceptibility (MIC 4-8 mg/L), particularly when combined with another active agent such as fosfomycin. However, newer treatment options are preferred for carbapenem-resistant strains.

Treatment Approach Based on Resistance Pattern

For Carbapenem-Susceptible K. pneumoniae

• Carbapenems (including doripenem) are highly effective first-line options
• Doripenem dosing: Standard dose with adjustment for renal function
• Duration: 7-14 days for pneumonia, typically 10 days 1

For Carbapenem-Resistant K. pneumoniae (CRKP)

1. First-line options (preferred over doripenem):

   • Ceftazidime-avibactam (2.5g IV q8h) - particularly for KPC-producing strains 1
   • Combination therapy with polymyxin B plus at least one other in vitro active antibiotic 1

2. Alternative for intermediate susceptibility to doripenem:

   • High-dose, 4-hour infusion of doripenem combined with fosfomycin has shown similar outcomes to colistin plus fosfomycin in a small retrospective study of nosocomial pneumonia 2

Evidence for Doripenem in K. pneumoniae LRTI

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines note that for CRKP with intermediate susceptibility to doripenem (MIC 4-8 mg/L), high-dose extended infusion doripenem may be effective when combined with other agents 2. However, the evidence is limited to small retrospective studies.

In vitro studies have demonstrated synergistic activity when doripenem is combined with polymyxins against KPC-producing K. pneumoniae, showing rapid bactericidal activity within 4 hours that was sustained for 24 hours 3. This suggests potential benefit for combination therapy in resistant infections.

Combination Therapy Considerations

For severe CRKP infections:

• Combination therapy is associated with improved survival compared to monotherapy 4
• Common effective combinations include:
  • Polymyxin B or colistin plus a carbapenem (including doripenem) 1, 4
  • Doripenem plus fosfomycin for strains with intermediate susceptibility 2

Important Clinical Considerations

• Resistance testing: Always obtain susceptibility testing before initiating therapy
• Extended infusion: For doripenem against strains with elevated MICs, use extended infusion (4-hour) to optimize pharmacodynamics 5
• Monitoring: Regular clinical and microbiological assessment during treatment
• Duration: 7-14 days for pneumonia, with longer courses for immunocompromised patients 1

Pitfalls to Avoid

1. Monotherapy failure: Monotherapy with polymyxins or tigecycline has been associated with higher mortality rates (66.7%) compared to combination therapy (12.5%) in bacteremia due to KPC-producing K. pneumoniae 4

2. Re-growth phenomenon: In vitro studies show significant bacterial re-growth by 24 hours with polymyxin monotherapy against KPC-producing K. pneumoniae, highlighting the importance of combination therapy 3

3. Resistance development: Doripenem monotherapy against carbapenem-resistant strains may lead to treatment failure and further resistance

For Klebsiella pneumoniae LRTI, the treatment approach should be guided by susceptibility testing, with doripenem being a viable option for susceptible strains or as part of combination therapy for strains with intermediate susceptibility.