Successful High-Dosage Monotherapy of Tigecycline in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia–Septicemia Model in Rats

Abstract

Background: 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. Methods: A Klebsiella pneumoniae producing extended-spectrum β-lactamase (ESBL) and an isogenic variant producing K. pneumoniae 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. Results: 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). Conclusions: 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 K. pneumoniae 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.

Machine perfusion combined with antibiotics prevents donor-derived infections caused by multidrug-resistant bacteria

“…53 Some studies have suggested that monotherapy with a high dose of tigecycline is safe and optimally effective and can improve the outcome. [53][54][55][56][57] Nevertheless, other opinions have…”

Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

“…The present study shows that although both nanomedicines resulted in significantly improved therapeutic efficacy in terms of increased rat survival time compared with free AA139, survival of all infected rats was not achieved. In relation to this, it should be noted that the pneumonia-septicemia rat model used in this study is representative of multidrug-resistant bacterial infections that are associated with very high mortality rates in patients and are particularly challenging to treat successfully (38). Furthermore, there is published evidence that rats may be more sensitive to the innate immune activation known to be caused by AMPs, including histamine release (39)(40)(41).…”

“…Bacterial strains. The ESBL-positive strain K. pneumoniae ESBL EMC2003 (referred to in this publication as K. pneumoniae ESBL) used in this study has previously been characterized in terms of its genotype and antimicrobial susceptibility profile and was used to establish pneumonia-septicemia in rats (38). The stability of the plasmid-containing K. pneumoniae ESBL strain was confirmed through five consecutive passages in Mueller-Hinton II (MH-II) broth (Becton, Dickinson BV, Vianen, The Netherlands).…”

“…Rat model of pneumonia-septicemia. Bilateral K. pneumoniae ESBL pneumonia-septicemia was induced as described previously (38). In short, suspensions of washed bacteria in the logarithmic phase of growth were used to prepare inocula.…”

Antimicrobial Peptides Epinecidin-1 and Beta-Defesin-3 Are Effective against a Broad Spectrum of Antibiotic-Resistant Bacterial Isolates and Increase Survival Rate in Experimental Sepsis

“…In each group, the dosage of substances used was the same: hBD-3 and Epi-1, 10 mg/kg; and meropenem, 25 mg/kg. Meropenem dosage was chosen in accordance with previous study of H. Van der Weide et al [ 41 ].…”