In vitro and in vivo synergistic effects of tigecycline combined with aminoglycosides on carbapenem-resistant Klebsiella pneumoniae

Abstract

Objectives Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections represent severe threats to public health worldwide. The aim of this study was to assess potential synergistic interaction between tigecycline and aminoglycosides via in vitro and in vivo studies. Methods Antibiotic resistance profiles and molecular characteristics of 168 CR-KP clinical isolates were investigated by susceptibility testing, PCR and MLST. Chequerboard tests and time–kill assays were performed for 20 CR-KP isolates to evaluate in vitro synergistic effects of tigecycline combined with aminoglycosides. A tissue-cage infection model of rats was established to evaluate in vivo synergistic effects. Different doses of tigecycline and aminoglycosides alone or in combination were administered for 7 days via tail vein injection. Antibiotic efficacy was evaluated in tissue-cage fluid and emergence of resistance was screened. Results The chequerboard tests showed that this combination displayed synergistic or partial synergistic activity against CR-KP. The time–kill assays further demonstrated that strong synergistic effects of such a combination existed against isolates that were susceptible to both drugs but for resistant isolates no synergy was observed if clinical pharmacokinetics were taken into consideration. The in vivo study showed that the therapeutic effectiveness of combination therapies was better than that of monotherapy for susceptible isolates, suggesting in vivo synergistic effects. Furthermore, combinations of tigecycline with an aminoglycoside showed significant activity in reducing the occurrence of tigecycline-resistant mutants. Conclusions Compared with single drugs, tigecycline combined with aminoglycosides could exert synergistic effects and reduce the emergence of tigecycline resistance. Such a combination might be an effective alternative when treating CR-KP infections in clinical practice.

Novel synergistic combinations of last-line antibiotics and FDA-approved drugs against Klebsiella pneumoniae revealed by in vitro synergy screenings

“…Moreover, synergy was demonstrated between tigecycline and aminoglycosides (34)(35)(36), colistin and levofloxacin (37,38), fosfomycin and cephalosporins (31) or doripenem (39,40) against K. pneumoniae. Principe et al also reported synergy between tigecycline and levofloxacin against Acinetobacter baumanii strains (41).…”

A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae

“…Carbapenems have been widely used to against MDR Enterobacteriaceae . Unfortunately, with the increased use, carbapenem-resistant Enterobacteriaceae has been emerged and spread rapidly, especially in K. pneumoniae ( Ni et al., 2021 ). Infections induced by CRKP have been considered a great challenge in clinical practices ( Agyeman et al., 2020 ).…”

Heteroresistance Is Associated With in vitro Regrowth During Colistin Treatment in Carbapenem-Resistant Klebsiella pneumoniae

“…In our previous study, we tested the susceptibility of 168 non-duplicate CR-KP clinical strains collected from different patients during June 2014–December 2018 in four tertiary hospitals in Beijing, China ( Ni et al, 2021 ). Among them, 98 CR-KP strains from three tertiary hospitals were used in this study.…”

“…The time-kill assays for colistin monotherapy and combination therapy were performed as previously described ( Ni et al, 2021 ). The concentration of colistin and other antibiotics used in time-kill assays was 1 × MIC of each tested strain that was obtained from the susceptibility testing.…”