Successful High-Dosage Monotherapy of Tigecycline in a Multidrug-Resistant <i>Klebsiella pneumoniae</i> Pneumonia–Septicemia Model in Rats
oleh: Hessel Van der Weide, Marian T. Ten Kate, Denise M. C. Vermeulen-de Jongh, Aart Van der Meijden, Rixt A. Wijma, Stefan A. Boers, Mireille Van Westreenen, John P. Hays, Wil H. F. Goessens, Irma A. J. M. Bakker-Woudenberg
| Format: | Article |
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| Diterbitkan: | MDPI AG 2020-03-01 |
Deskripsi
<b>Background:</b> Recent scientific reports on the use of high dose tigecycline monotherapy as a “drug of last resort” warrant further research into the use of this regimen for the treatment of severe multidrug-resistant, Gram-negative bacterial infections. In the current study, the therapeutic efficacy of tigecycline monotherapy was investigated and compared to meropenem monotherapy in a newly developed rat model of fatal lobar pneumonia−septicemia. <b>Methods:</b> A <i>Klebsiella pneumoniae</i> producing extended-spectrum β-lactamase (ESBL) and an isogenic variant producing <i>K. pneumoniae</i> carbapenemase (KPC) were used in the study. Both strains were tested for their in vitro antibiotic susceptibility and used to induce pneumonia−septicemia in rats, which was characterized using disease progression parameters. Therapy with tigecycline or meropenem was initiated at the moment that rats suffered from progressive infection and was administered 12-hourly over 10 days. The pharmacokinetics of meropenem were determined in infected rats. <b>Results:</b> In rats with ESBL pneumonia−septicemia, the minimum dosage of meropenem achieving survival of all rats was 25 mg/kg/day. However, in rats with KPC pneumonia−septicemia, this meropenem dosage was unsuccessful. In contrast, all rats with KPC pneumonia−septicemia were successfully cured by administration of high-dose tigecycline monotherapy of 25 mg/kg/day (i.e., the minimum tigecycline dosage achieving 100% survival of rats with ESBL pneumonia−septicemia in a previous study). <b>Conclusions:</b> The current study supports recent literature recommending high-dose tigecycline as a last resort regimen for the treatment of severe multidrug-resistant bacterial infections. The use of ESBL- and KPC-producing <i>K. pneumoniae</i> strains in the current rat model of pneumonia−septicemia enables further investigation, helping provide supporting data for follow-up clinical trials in patients suffering from severe multidrug-resistant bacterial respiratory infections.