Recent scientific reports on the use of high dose tigecycline monotherapy\nas a â??drug of last resortâ? warrant further research into the use of this regimen for the treatment of\nsevere multidrug-resistant, Gram-negative bacterial infections. In the current study, the therapeutic\nefficacy of tigecycline monotherapy was investigated and compared to meropenem monotherapy in a\nnewly developed rat model of fatal lobar pneumoniaâ??septicemia. Methods: A Klebsiella pneumoniae\nproducing extended-spectrum Beta-lactamase (ESBL) and an isogenic variant producing K. pneumoniae\ncarbapenemase (KPC) were used in the study. Both strains were tested for their in vitro antibiotic\nsusceptibility and used to induce pneumoniaâ??septicemia in rats, which was characterized using\ndisease progression parameters. Therapy with tigecycline or meropenem was initiated at the moment\nthat rats suffered from progressive infection and was administered 12-hourly over 10 days. The\npharmacokinetics of meropenem were determined in infected rats. Results: In rats with ESBL\npneumoniaâ??septicemia, the minimum dosage of meropenem achieving survival of all rats was\n25 mg/kg/day. However, in rats with KPC pneumoniaâ??septicemia, this meropenem dosage was\nunsuccessful. In contrast, all rats with KPC pneumoniaâ??septicemia were successfully cured by\nadministration of high-dose tigecycline monotherapy of 25 mg/kg/day (i.e., the minimum tigecycline\ndosage achieving 100% survival of rats with ESBL pneumoniaâ??septicemia in a previous study).\nConclusions: The current study supports recent literature recommending high-dose tigecycline as a\nlast resort regimen for the treatment of severe multidrug-resistant bacterial infections. The use of\nESBL- and KPC-producing K. pneumoniae strains in the current rat model of pneumoniaâ??septicemia\nenables further investigation, helping provide supporting data for follow-up clinical trials in patients\nsuffering from severe multidrug-resistant bacterial respiratory infections.
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