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.

Keywords: Klebsiella pneumoniae; antibiotic resistance; meropenem; pneumonia; septicemia; tigecycline.

Figure A1

Representative lung histopathology in lung tissue from rats with K. pneumoniae KPC pneumonia–septicemia at 24 h after initiation of infection. (A–C) Sections stained with hematoxylin-eosin at different magnifications. (D) Section stained with Gram stain. An outer hemorrhagic zone of the lesion was observed (in areas next to uninfected tissue), in which the alveoli were filled with mucoid exudates dominated by edema fluid and a light cellular infiltrate. More extensive areas of pneumonia were observed towards the center of the lesion (i.e., in the zone of early consolidation). In these areas, alveoli were packed with predominantly polymorphonuclear leukocytes and alveolar walls were necrotic. Numerous encapsulated Gram-negative bacilli were freely present in the exudates within the hemorrhagic zone of the lesions.

Figure 1

Concentration- and time-dependent bactericidal activity of meropenem (MEM) and tigecycline (TGC) against K. pneumoniae strains. Bacterial cultures of K. pneumoniae ESBL or K. pneumoniae KPC were exposed to two-fold increasing concentrations of antibiotic for 24 h. Shown are the median ± range of in triplicate experiments. The dashed grey line indicates the lower limit of quantification of log 0.7.

Figure 2

Bacterial load of K. pneumoniae in lungs and blood of rats with K. pneumoniae pneumonia–septicemia in the early phase of infection. Bacterial load of K. pneumoniae was determined for total lungs and individual lung lobes and blood (per mL) of rats with K. pneumoniae ESBL pneumonia–septicemia and rats with K. pneumoniae KPC pneumonia–septicemia at 24 h and 48 h after initiation of infection. TL, total lungs; LL, left lobe; RCrL, right cranial lobe; RML, right middle lobe; RCaL, right caudal lobe; RIL, right intermediate lobules. Groups of 6 rats per time point. Bacterial load is expressed as log CFU (median ± range).

Figure 3

Disease progression in rats with K. pneumoniae pneumonia–septicemia. Groups of 11 rats were used for each experiment. (A) Rat survival (Kaplan–Meier curves) of rats reaching humane endpoints. (B) Box plots of pooled body temperatures showing the range of the data; the dashed line at 34 °C represents the humane endpoint. (C) Body weight loss from the onset of the infection (mean ± SD).

Figure 4

Therapeutic efficacy of meropenem (MEM) in rats with ESBL pneumonia–septicemia. Groups of 11 rats were treated 12-hourly for 10 days with placebo (physiological saline) or 25 mg/kg/day meropenem, starting at 24 h after initiation of infection. (A) Rat survival (Kaplan–Meier curves) of rats reaching humane endpoints. (B) Box plots of pooled body temperatures showing the range of the data; the dashed line at 34 °C represents the humane endpoint. (C) Body weight loss (mean ± SD).

Figure 5

Plasma concentrations of total (bound and unbound) meropenem (MEM) in rats with ESBL pneumonia–septicemia. Rats were treated 12-hourly with 3 consecutive doses of 25 mg/kg/day meropenem, starting at 24 h after initiation of infection. The concentration–time curve predicted by a one-compartment model of extravascular administration was imposed over the observed concentrations at each time point in 3 rats (mean ± SEM).

Figure 6

Therapeutic efficacy of meropenem (MEM) or tigecycline (TGC) in rats with KPC pneumonia–septicemia. Groups of 11 rats were treated 12-hourly for 10 days with placebo (physiological saline), 25 mg/kg/day meropenem, or 25 mg/kg/day tigecycline, starting at 24 h after initiation of infection. (A) Rat survival (Kaplan–Meier curves) of rats reaching humane endpoints. (B) Box plots of pooled body temperatures showing the range of the data; the dashed line at 34 °C represents the humane endpoint. (C) Body weight loss (mean ± SD).