| Objective:The paper was designed to select for proper antimicrobial agents to treat Stenotrophomonas maltophilia (Sm) infections through susceptibility testing, Monte-Carlo simulation and time-killing experiments. Futhermore, we determined mutant prevention concentration (MPC) of candidate antimicrobials both single and combinations against susceptible isolates and determined potential resistance genes for tigecycline to provide a reference for reasonable use of antimicrobials.Method:The agar dilution method was used to test susceptibility of nine candidate antimicrobials. One hundred and two strains of clinical isolated Sm were used in this study. Based on the MICs and the population pharmacokinetic parameters of the investigated antimicrobials, a Monte Carlo simulation was performed to simulate the pharmacokinetic/pharmacodynamic (PK/PD) indices of different regimens. The probability of target attainment (PTA) was estimated at each MIC value and the cumulative fraction of response (CFR) were calculated to evaluate the efficacy of these chosen regimens. And time-killing experiments were carried out to evaluate the efficacy of SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, and ceftazidime both alone and in combinations at clinically relevant antimicrobial concentrations. Then, we determined MPC of minocycline, tigecycline, moxifloxacin and levofloxacin both single and combinations against susceptible isolates. Finally, we carried out qRT-PCR to test the potential resistance mechanism for tigecycline.Result:(1) The susceptibility to SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, ticarcillin-clavulanate, chloramphenicol, polymyxin E, and ceftazidime were 93.8%,95.0%,83.8%,80.0%,76.3%,76.3%,37.5%,22.5%, and 20.0% against 80 clinical consecutively isolated strains, respectively. Minocycline and tigecycline showed consistent active against 22 SXT-resistant strains. However, resistance rates were high in the remaining antimicrobial agents against SXT-resistant strains. (2) The estimated CFR were 96.2% for minocycline 100 mg twice daily (q12h),50.8/67.1/75.4% for tigecycline 50/75/100 mg ql2h,34.3/48.0/56.6% for levofloxacin 500/750/1000 mg once daily (q24h), and 45.7% for moxifloxacin 400mg q24h, respectively. (3) In time-kill experiments, there were no synergisms in most drug combinations in time-kill experiments. SXT plus moxifloxacin displayed synergism when strains with low moxifloxacin MICs. Moxifloxacin plus Minocycline and moxifloxacin plus tigecycline displayed synergism in few strains. No antagonisms were found in these combinations. Overall, compared with single drug, the drug combinations demonstrated lower bacterial concentrations. Some combinations showed bactericidal activity. (4) The MPC range of minocycline was 4-32 μg/mL and the SI range was 4-32; The MPC range of tigecycline was 4-32 μg/mL and the SI range was 4-128; The MPC range of moxifloxacin was 4-64 μg/mL and the SI range was 8-64; The MPC range of levofloxacin was 8-32ug/mL and the SI range was 8-64; Minocycline or tigecycline with an addition of 4μg/mL moxifloxacin/levofloxacin, the MPCs of combinations didn’t change for most strains. (5)The relative quantitative expression of SmeC、SmeF、 SmeK、SmeW and SmeP efflux pump genes increased at different minocycline and tigecycline resistant isolates.Conclusion:(1) Our susceptibility testing results suggest that SXT and minocycline may be considered as first-line therapeutic choices in Sm infections; tigecycline, moxifloxacin, levofloxacin, and ticarcillin-clavulanate may serve in the second-line setting; And ceftazidime, colistin, and chbramphenicol do not appear to be appropriate choices in any setting. (2) Minocycline predicts high probabilities of achieving adequate pharmacodynamic exposures when given approved regimen for the treatment of HAP caused by Sm. It may serve as a good alternative option for minocycline when SXT is contra indicated or ineffective. Whereas tigecycline, moxifloxacin and levofloxacin though demonstrate good in vitro activity but get suboptimal probabilities of drug exposures as therapeutic options regarding Sm pneumonia. (3) The candidates of tigecycline, moxifloxacin and levofloxacin should be used with caution especially using as monotherapy. Monotherapy is inadequate in infection management, especially in case of immunocompromised patients. Combination therapy, especially SXT plus moxifloxacin, may benefit than monotherapy in inhibiting or killing Sm. (4) The MPCs of minocycline, tigecycline, moxifloxacin and levofloxacin were quite high and the MSWs were wide, indicating that the drug-resistant mutant strains are easy to select; Combination of tetracyc lines and quinobnes is no better than single drug. (5) Decreased susceptibility to tigecycline in Sm is associated with the overexpressian of SmeC、SmeF、 SmeK、SmeW and SmeP efflux pump genes. |
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