In Vivo And In Vitro Efficacy Of Cefoperazone Sulbactam-based Combination Therapy For MDR-AB And Clinical Evaluation

OBJECTIVE: To explore the antibacterial effects and mechanism on the basis of cefoperazone sulbactam(1:1)on 30 clinical isolates of multidrug-resistant Acinetobacter baumannii(MDR-AB)in vitro and in vivo.Analysis the application of cefoperazone sulbactam in the department of respiration in Yichun People's Hospital,which provide guidance for the treatment of infectious diseases in department of respiration patients.METHODS: The MIC of Cefoperazone sulbactam(CFS)combined doxycycline(DOX),levofloxacin(LEV),fosfomycin(FOS)were measured by the Broth dilution method and checkerboard method and the time-killing curves,then partial inhibitory concentration index(FICI)was calculated to determine the combined effect.The clinical isolates of MDRAB502 mouse pneumonia model was established,and the survival rate of CFS and FOS monotherapy and combination therapy was recorded.The viable count of biofilm carrier were determined by serial dilution method and the semi-quantitative biofilm by crystal violet staining method.Finally,the retrospective investigation and analysis method was used to collect the electronic medical records of inpatients from department of respiratory Yichun People's Hospital from January 2018 to December 2018.The clinical application of Cefoperazone sulbactam was analyzed.RESULTS: In vitro experimental results showed the combination of CFS and DOX displayed synergistic and additive activity on 17% and 63% multidrug-resistant Acinetobacter baumannii,and antagonism activity was 20%.In vitro experimental results showed the combination of CFS and LEV displayed synergistic and additive activity on23% and 57% multidrug-resistant Acinetobacter baumannii,and antagonism activity was 20%.And the combination of CFS and FOS displayed synergistic and additive activity on 70% and 23% multidrug-resistant Acinetobacter baumannii,and antagonism activity was 0.3%.In vitro experimental results showed the combination of CFS and AMI displayed synergistic and additive activity on 27% and 53% multidrug-resistant Acinetobacter baumannii.and antagonism activity was 20%.CFS combined with FOS had the best synergistic effect compared with other groups.The time-killing curves indicated that CFS combined with FOS(1MIC×1MIC)had bactericidal effect on the isolate MDR-AB502 and MDR-AB193.In the MDR-AB502 mouse pneumonia infection model,the 7-day survival rates for mice receiving combination therapy,CFS or FOS monotherapy group were 82%,64% and 55%,respectively.The number of bacterial colonies in the lung tissue of the CFS group and the combined group was significantly lower than that of the control group,and the number of viable bacteria in the combined group compared to the CFS group was significantly reduced.The semi-quantitative and biofilm bacterial counts showed that CFS+FOS group were markedly decreased compared to the CFS group after the biofilm cultivate for 48 h and 72 h.In 2018,the clinical diagnosis of cefoperazone sulbactam in therespiratory department was more common in pulmonary infection,accounting for 63%.The combination of drugs was more frequent,and the frequency of administration was the highest at 3g/q8 h,accounting for 51.1%.The therapeutic efficacy of fusidic acid in patients was 72%.CONCLUSION: The combination of CFS and FOS has synergistic and additive effects on MDR-AB.The mechanism of the combination of two drugs may be that FOS can enhance the inhibiting effect of CFS to biofilm of clinical isolates.The clinical dose and frequency of cefoperazone sulbactam should be adjusted according to the patient's symptoms,signs and severity of infection.At the same time,long-term single use should be avoided,and the combination can not only enhance synergy but also effectively prevent the occurrence of drug resistance.