Tigecycline in combination with other antibiotics against clinical isolates of carbapenem-resistant Klebsiella pneumoniae in vitro

Jisheng Zhang, Lan Yu, Yanjun Fu, Yongxin Zhao, Yong Wang, Jing Zhao, Yuhang Guo, Chunjiang Li, Xiaoli Zhang


Background: To investigate the activity of 5 antibiotic monotherapies, including colistin (COL), meropenem (MEM), amikacin (AMK), levofloxacin (LEV), and tigecycline (TGC), when combined with 4 other antibiotics against clinical isolates of carbapenem-resistant Klebsiella pneumoniae (CRKP) in vitro.
Methods: The minimum inhibitory concentrations (MICs) of 5 antibiotics against 40 CRKP isolates were determined by micro-broth dilution method. There were synergistic effects between TGC combinations in the 10 CRKP isolates detected with checkerboard microdilution method. Time-kill assay was used to assess the monotherapies and the TGC combinations against 4 distinct sequence typing (STs) CRKP isolates. Polymerase chain reaction (PCR) tests were used to detect the carbapenemase genes, extended-spectrum beta lactamase (ESBL) genes, colistin resistance gene, and quinolone resistance genes, while multilocus sequence typing (MLST) was performed for 10 CRKP isolates.
Results: The MICs of TGC, COL, MEM, AMK, and LEV were 0.5–2, 2–32, 4–256, 1–16,384, and 0.5–64 μg/mL, respectively. The combinations exerted a significant synergism or additive effect via the checkerboard technique for most tested CRKP isolates, but a portion of the CRKP isolates had an indifferent effect except for the TGC-AMK combination. In addition, time-kill assays revealed that TGC enhanced the bactericidal activity of the 4 other antibiotics. Among 10 CRKP isolates, blaKPC-2 (90%), blaSHV (100%), and blaacc(6’)-Ib (100%) were the most common carbapenemase genes, ESBL genes, and quinolone resistance genes, respectively. ST76 (70%) was the most predominant clone, followed by ST11 (10%), ST375 (10%), and ST530 (10%).
Conclusions: In contrast to the currently recommended TGC therapy, our in vitro data suggest that TGC combinations may be a valid therapeutic option against CRKP, even in the presence of 1 antibiotic resistant isolate in TGC combination therapy. TGC-AMK combination is a cost-effective option for treating CRKP in the eastern region of Heilongjiang Province. In addition, TGC combinations might circumvent the overuse of carbapenems during the era of multi-drug resistance in Klebsiella pneumoniae (KP).