Pharmacokinetics And Pharmacokinetic/Pharmacodynamic Study Of Cefoperazone/Sulbactam In The Treatment Of Adult Patients With Hospital-Acquired Pneumonia Caused By Multidrug Resistant Nonfermentative Bacilli

In recent years, the drug resistance of bacteria to available therapeutic options has increased rapidly due to widely use of antibiotics. Patients worldwide have been exposed to the rapid emergence and uncontrolled spread of multidrug-resistant (MDR) and pandrug-resistant (PDR) microorganisms. Nonfermenters(Acinetobacter baumannii and Pseudomonas aeruginosd) are one of them play an important role in hospital acquired infection, especially hospital acquired pneumonia (HAP). Furthermore, infections caused by MDR nonfermenters, which associated with high mortality and treatment failures, have enhanced in the past few years. Since therapeutic options are increasingly narrowed, mainly due to widespread resistance and a shortage of new antimicrobial compounds, the managements of those infections become challenging.Agents known active against most MDR A. baumannii and/or P. aeruginosa are polymyxins, carbapenems, aztreonam, quinolones, aminoglycosides, and sulbactam (commercially available in combination with otherβ-lactams, mainly ampicillin and cefoperazone).Cefoperazone is a third-generation cephalosporin antibiotic with a broad spectrum of activity against most gram-positive and gram-negative bacteria. Sulbactam, a (3-lactamase inhibitor, has intrinsic activity against Acinetobacter spp. In vitro, the combination of cefoperazone and sulbactam shows a marked degree of synergetic effect against some cefoperazone-resistant organisms, especially MDR A. baumannii.Patients who received cefoperazone/sulbactam may be physiologically compromised and therefore may not distribute or eliminate these drugs as healthy subjects do. These altered pharmacokinetics (PK) may be correlated with poor outcomes and lead to the probability of resistance. It was very important to understand the PK/PD targets for treatments before we started the regimen, which could maximize the clinical and microbiological response as well as minimize the probability for exposure related toxicitiesThe data of the PK/PD of cefoperazone/sulbactam in HAP patients were limited so far, therefore, we carried out a study to investigate the clinical and microbiological response, PK/PD of cefoperazone/sulbactam regimens in HAP patients caused by A. baumannii and P. aeruginosa to guide dosing in this difficult patient population to lower the probability of resistance and maintain the utility of the drugs currently in our therapeutic armamentarium.The study consists of the following4parts:Part I Clinical analyze on cefoperazone/sulbactam treatment in HAP patients caused by MDR nonfermentersPart II Liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of cefoperazone and sulbactam in plasmaPart III Pharmacokinetics of cefoperazone/sulbactam in HAP patients caused by MDR nonfermentersPart IV Pharmacokinetics/Pharmacodynamics of cefoperazone/sulbactam in HAP patients caused by MDR nonfermentersPart I Clinical analyze on cefoperazone/sulbactam treatment in HAP patients caused by MDR nonfermenters[Objective] To investigate the clinical, microbiological efficacy and safety of cefoperazone/sulbactam in HAP patients caused by MDR nonfermenters.[Methods] This was a prospective, open label, and non-comparative study performed in Huashan Hospital in Shanghai from Jan2009to Dec2012. Adult patients who met the criteria for HAP including ventilator-associated pneumonia (VAP) caused by MDR nonfermenters which susceptive to cefoperazone/sulbactam were enrolled. All the eligible patients received intravenous infusion of cefoperazone/sulbactam. The demographic and baseline data were collected. Clinical and microbiological responses were followed up, as well as the safety data.[Results]54patients completed the study, and53patients can be evaluated by microbiological response.43patients were with tube inserted after tracheotomy but without ventilator, while7patients assisted by ventilator. The clinical cure rate of54evaluable cases was74.1%, and the microbiological cure rate of53evaluable cases was47.2%. Among29cases of A. baumannii infection,23cases were clinical cure, 20cases were microbiological cure, and body mass index (BMI) was the independent risk factor of clinical efficacy. Among22cases of P. aeruginosa infection,15cases were clinical cure,4cases were microbiological cure, and concentration of albumin was the independent risk factor of clinical efficacy. There were2cases of mild adverse events related to the therapy. Susceptibility of5strains was found decreased during the follow up.[Conclusions] If A. baumannii wassusceptible to cefoperazone/sulbactam, the treatment can gain satisfied clinical and microbiological efficacy. While encounter P. aeruginosa infection, cefoperazone/sulbactam was not recommended to administrate alone in patients who were tracheotomy with tube inserted, regardless of whether the strain is susceptible or not.Part II Liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of cefoperazone and sulbactam in plasma[Objective] To develop a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for simultaneous determination of cefoperazone sodium and sulbactam sodium in human plasma.[Methods] The cefoperazone sodium, sulbactam sodium and internal standard (IS), cefuroxime sodium, were extracted from human plasma via liquid-liquid extraction with ethyl acetate and separated on a Waters Xterra C18column within3.0min. Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in selected reaction monitoring (SRM) and negative ion mode. The precursor to product ion transitions monitored for cefoperazone, sulbactam and IS were m/z644.1→528.0,232.1→140.0, and423.0→362.0, respectively.[Results] The assay was validated in the linear range of (0.1-20) μg/mL for cefoperazone and (0.02-4) μg/mL for sulbactam. The intra-and inter-day precisions (CV%) were within8.4%for each analyte. The recoveries were (91.26±8.7)%for cefoperazone and (88.55±4.71)%for sulbactam. Cefoperazone sodium was found to be unstable for9hours at room temperature in plasma samples. Sulbactam sodium was found to be unstable for12hours at room temperature in extracted plasma samples. Sulbactam was found unstable under three freeze-thaw cycles. Both analytes spiked plasma samples stored at-70℃were found to be stable for30days, but unstable beyond30days.[Conclusions] A simple, specific, rapid and sensitive analytical method for simultaneous determination of cefoperazone and sulbactam in human plasma had been developed and validated.Part III Pharmacokinetics of cefoperazone/sulbactam in HAP patients caused by MDR nonfermenters[Objective] To investigated the pharmacokinetics characteristics of cefoperazone/sulbactam in HAP patients caused by MDR nonfermenters.[Methods] Blood samples were collected in54cases enrolled in Part Ⅰ. Cefoperazone/sulbactam concentrations were determined using LC-MS/MS method explained in Part Ⅱ. Pharmacokinetic parameters were determined by non-compartmental methods using Phoenix WinNonlin (6.0, Pharsight Corp.CA USA).[Results]51cases (38male and13female) were get their PK parameters. Patient demographics were as follows (mean±standard deviation):age (46±14.7) years; and body mass index (22.0±2.1) kg/m2. The calculated creatinine clearance was (117.0±44.8) mL/min. The alanine aminotransferase was (27.2±20.5) U/L, and the albumin was (36.4±4.1) g/L. PK parameters for cefoperazone/sulbactam were as follows:Cmax was (120.78±46.41) mg/L and (30.98±20.99)mg/L, AUC0.τ was (521.48±204.19) mg·h/L and (80.77±41.87) mg·h/L, CLss was (4.72±1.76) L/h and (16.88±15.69)L/h, Vss was (1.04±7.88)L and (28.93±15.73)L, T1/2was(3.62±1.24)h and (1.66±0.61)h, and MRT0-∞was (4.70±1.64)h and (1.93±0.86)h, respectively. Difference of T1/2of sulbactam between creatinine clearance over90ml/min group and below90ml/min group was significant. Difference of Vss of cefoperazone between ALT normal or abnormal group was significant.[Conclusions] T1/2of cefoperazone/sulbactam was longer in HAP patients than it was reported in health volunteers, and AUCo-T andVss were larger. CLss of cefoperazone was less, while which of sulbactam was more in HAP patients than it reported in health volunteers. After several doses, cefoperazone was accumulated. Decrease dosing interval, the accumulation of sulbactam increased. The liver and kidney function can affect the PK of cefoperazone/sulbactam. Part IV Pharmacokinetics/Pharmacodynamics of cefoperazone/sulbactam in HAP patients caused by MDR nonfermenters[Objective] To develop the PK/PD parameter of cefoperazone/sulbactam in HAP patients caused by MDR nonfermenters, and to optimize dosing in these kinds of patients.[Methods] The bacteria isolated from all eligible patients were collected. The minimum inhibitory concentrations (MICs) of cefoperazone/sulbactam for these isolates were determined by agar dilution according to CLSI guideline. The percentage time that the free-drug concentration remained above the MIC (%fT>mic) was calculated. Receiver Operating Characteristic (ROC) curves were applied to found the target of%fT>MIC which indicated clinical and microbiological efficacy.[Results]57strains were collected, and the MIC50of32A. baumannii and25P. aeruginosa were16/8mg/L and8/4mg/L, MIC90were64/32mg/L and32/16mg/L, respectively. Through ROC curves, the target of%fT>MIC of sulbactam in treatment of A. baumannii HAP were found at32.3%. Using50%and32.3%as target of%fT>MIC of cefoperazone/sulbactam, we found if shorten the dosing interval; we may achieve better clinical efficacy in MDR A. baumannii HAP.[Conclusions%fT>mic of sulbactam in the cefoperazone/sulbactam treatment of MDR A. baumannii HAP should be≥32.3%, that satisfied clinical efficacy could be achieved. Shorten the dosing interval, may achieve better clinical efficacy in MDR A. baumannii HAP.