Tigecycline-Amikacin Combination Effectively Suppresses the Selection of Resistance in Clinical Isolates of KPC-Producing Klebsiella pneumoniae

Abstract

By far, only tigecycline, colistin, and some aminoglycosides still show favorable in vitro activities against carbapenem-resistant Enterobacteriaceae. However, rapid emergence of resistance often occurs during long-term treatment in clinic, challenging these last resort antimicrobials. In this study, we measured mutant prevention concentration (MPC) and mutant selection window (MSW) of tigecycline, colistin and amikacin alone and in combination for clinical isolates of KPC-producing K. pneumoniae, and characterized the resistant mutants recovered. The MPC90 of 30 tested isolates for tigecycline, colistin, and amikacin were 16, >128, and 128 mg/L, respectively. The average MSW of tigecycline-amikacin, tigecycline-colistin, and amikacin-colistin combinations for four representative strains were 11.99, 200.13, and 372.38, respectively. A strong correlation was found between the MSWcombination and the product of MSW of each single drug. Combinations of 1 minimal inhibitory concentration (MIC) multiple tigecycline and 1 MIC multiple amikacin could result in 1000- to 10000-fold reduction in mutational frequency relative to their individual mutational frequencies, and combinations of 1 MIC multiple amikacin and 1.5–2 MIC multiple tigecycline could successfully restrict the recovery of resistant mutants on agar plates. However, 2 MIC multiple colistin in combination with 2 MIC multiple tigecycline or amikacin merely resulted in approximately 10-fold decrease in the mutational frequency. In conclusion, this study showed tigecycline-amikacin combination could effectively suppress the selection of resistance at low concentrations compared with the colistin-tigecycline and colistin-amikacin combinations, suggesting that this combination may be useful in clinical therapy.

Evaluation of automated systems for aminoglycosides and fluoroquinolones susceptibility testing for Carbapenem-resistant Enterobacteriaceae

“…The most optimal treatment options for CRE infections have not been well defined. Current treatment options include the use of some older agents either in monotherapy or in combination therapy, such as aminoglycosides and fluoroquinolones [ 7 , 8 ]. Aminoglycosides and fluoroquinolones are two different important types of antimicrobial agents for the treatment of life-threatening bacterial infections.…”

Infections with Carbapenem-Resistant Gram-Negative Bacteria are a Serious Problem Among Critically Ill Children: A Single-Centre Retrospective Study

“…In a recent study showed that triple or double combination of meropenem, colistin and tigecycline were bactericidal against carbapenem-resistant Klebsiella pneumoniae isolates [18]. In another study, it was reported that combination antibiotic therapy including colistin and tigecycline may have better ability in preventing the evolution of resistance in CRIs [19]. However, another two studies reported that resistant strains were isolated during the combination therapy of colistin and tigecycline [20,21].…”

Synergistic Combination of Linezolid and Fosfomycin Closing Each Other’s Mutant Selection Window to Prevent Enterococcal Resistance

“…The MSW comprises a specific drug concentration range in which mutant strains with reduced susceptibility can be selected ( Drlica and Zhao, 2007 ; Blondeau, 2009 ). It has been confirmed in many antibiotics such as fluoroquinolones ( Strukova et al, 2016 ), oxazolidinones ( Alieva et al, 2018 ), aminoglycosides ( Ni et al, 2016 ). MPC is defined as the lowest concentration that blocks the emergence of first-step resistant mutants in a large susceptible population, usually more than 10 10 colony forming unit (CFU)/mL bacteria ( Drlica, 2003 ).…”

“…In practice, high exposure was related to higher incidence of side effects. Fortunately, combination therapy at a low concentration could prevent the selection of resistant mutants by narrowing or closing the MSW ( Díez-Aguilar et al, 2015 ; Ni et al, 2016 ). Theoretically, the more likely the combination is to shut off each other’s MSW at the same time, the stronger its ability to prevent bacterial resistance.…”