Background: Cefoperazone/sulbactam (CPZ/SUL) is a beta-lactam and beta lactamase inhibitor combination for the treatment of respiratory tract infection.The aim of this study was to develop population pharmacokinetic/pharmacodynamic (PK/PD) model of CPZ/SUL (2∶1) in patients.Methods: This was a prospective, single center, open label study.Adult patients with hospital-acquired pneumoniae (HAP) or ventilator associated pneumonia caused by multidrug resistant (MDR) Pseudomonas aeruginosa (PA) or Acinetobacter baumannii (Ab) were included.CPZ/SUL was administered at 3g every 6, 8 or 12 hours for 7-14 days.The infusion time was 1.5-2 h.Plasma concentration of CPZ and SUL were determined, and the clinical and microbiological efficacy was recorded.The concentration and covariate data were collected to develop population pharmacokinetic (PPK) model.The PK/PD model was established using multivariate logistic regression, and Monte Carlo simulation was used to optimize dosing regimen.Results: 54 patients were included, and the mean age was 46 years.The PK of CPZ and SUL were all consistent with two compartment model.The clearance (CL) and inter-compartment clearance (Q) of CPZ were 4.51 L/h and 8.15 L/h.The CL was affected by age, and Q was affected by red blood cell count (RBC) and topiramate.For sulbactam, the CL and Q were 14.9 L/h and 2.25 L/h.Body mass index (BMI) and fluconazole were significant covariates on CL, while age and baclofen affected Q significantly.The %T>MIC of CPZ for three dosing regimens were over 90% when MIC ≤ 8mg/L.The %T>MIC for 3g(q6h) could still reach 89% when MIC was 32 mg/L.For patients with Ab infection, the clinical efficacy was affected by %T>MIC and body weight.The %T>MIC target for 90% of cured clinical efficacy is 50.9%.The cumulative fraction of response of %T>MIC could reach 79.8% for 3g(q6h) regimen.The probability of target attainment could achieve 90% when MIC was 16 mg/L.There was no relationship between CPZ %T>MIC and efficacy data for patients with PA infection.Conclusions: For patients with Ab infection, the regimen of 3g(q8h) and 3g(q6h) for 7-14 days could lead to satisfied clinical and microbiological efficacy when MIC ≤16 mg/L.The 3g(q6h) regimen becomes the best choice when MIC is 32 mg/L.