Last update:
27-Mar-2018

OBJECTIVE Infections by multidrug resistant carbapenemase producing Klebsiella pneumoniae isolates (CP-Κp) are associated with a high mortality rate, particularly in immunocompromised patients. Because of an increase in resistance rates to carbapenems and the lack of new active antibacterial drugs, combination therapy is often used against CP-Κp. In the present study, human pharmacokinetics of meropenem, colistin and tigecycline monotherapy and combination therapy (double and triple) were simulated in an in vitro pharmacokinetic-pharmacodynamic model. Antibacterial activity against CP-Κp isolates with different resistance mechanisms and reduced susceptibility to meropenem was assessed.

METHOD The effect was studied of the triple combination meropenem+colistin+tigecycline against a wild-type susceptible and six CP-Kp isolates (two producing VIM, one KPC, one NDM, one KPC+VIM and one KPC+VIM+SHV-5) with MIC of meropenem 0.06 mg/L and 16–512 mg/L, respectively. The human plasma concentration-time profiles of 100 mg tigecycline q12, 4.5 MU colistin q12 και 1 g meropenem q8 as one hour' infusion were simulated for 48 hours. Drug levels were measured by microbiological assay. Bacterial burden (log₁₀ CFU/mL) was determined with quantitative cultures at regular time intervals and the reduction from the initial inoculum of 10⁷ CFU/ mL was calculated at 48 hours. The bactericidal activity (>3 log₁₀ CFU/mL reduction)-MIC relationship of monotherapy and combination therapy regimens was analyzed using the Emax model.

RESULTS The wild-type isolate was killed by meropenem monotherapy and combination therapy regimens. Tigecycline and colistin alone and in combination were not active. Against the CP-Kp isolates, meropenem was not effective alone but its activity was enhanced by tigecycline, colistin and tigecycline+colistin. The highest MIC of meropenem where bactericidal activity was found against CP-Kp isolates were 1 mg/L, 8 mg/L, 128 mg/L and 256 mg/L for meropenem monotherapy, the double combinations meropenem+tigecycline and meropenem+colistin and the triple combination meropenem+tigecycline+colistin, respectively.

CONCLUSIONS The double combinations meropenem+tigecycline and meropenem+colistin and the triple combination meropenem+tigecycline+colistin were effective against CP-Kp isolates with MIC ≥8 mg/L. Combination therapy may increase the efficacy of antimicrobial therapy and can provide an alternative effective approach for the treatment of multidrug resistant infections.

Key words: Colistin, Combination therapy, Klebsiella pneumoniae, Meropenem, Tigecycline.