脑脊液CK-BB、ADA和IgM在脑膜炎患者中的表达及意义

目的探讨脑脊液肌酸激酶同工酶BB(CK-BB)、腺苷脱氨酶(ADA)和免疫球蛋白lgM在脑膜炎患者中的表达及意义。方法选取2016年1月至2017年10月在我院治疗的脑膜炎患者110例,其中病毒性脑膜炎32例,结核性脑膜炎40例,细菌性脑膜炎38例,同时选取40例健康志愿者作为对照组,检测各组脑脊液CK-BB、ADA和lgM水平。结果结核性脑膜炎CK-BB、ADA和lgM分别为(7.81±1.51)U/L、(9.87±2.27)U/L和(13.04±1.27)mg/L,明显高于病毒性脑膜炎、细菌性脑膜炎和对照组(P0.05);病毒性脑膜炎预后不良患者CK-BB和lgM分别为(2.41±0.77)U/L和(9.41±1.40)mg/L,明显高于预后良好患者(P0.05);结核性脑膜炎预后不良患者CK-BB、ADA和lgM分别为(9.22±1.82)U/L、(10.75±2.55)U/L和(14.64±1.97)mg/L,明显高于预后良好患者(P0.05);细菌性脑膜炎预后不良患者CK-BB为(7.89±1.30)U/L,明显高于预后良好患者(P0.05)。结论不同类型脑膜炎患者脑脊液CK-BB、ADA和IgM水平有所差异,且与疾病预后有一定关系。     

脑脊液中免疫球蛋白、乳酸脱氢酶及腺苷脱氨酶检测鉴别脑膜炎

目的探讨脑脊液中免疫球蛋白(immunoglobulin,Ig)、乳酸脱氢酶(lactatedehydrogenase,LDH)及腺苷脱氨酶(adenosinedeaminase,ADA)对三种脑膜炎的鉴别诊断意义。方法检测结核性脑膜炎15例、化脓性脑膜炎18例、病毒性脑膜炎20例患者的脑脊液中LDH、ADA、Ig的含量,并与对照组进行比较。结果化脓性脑膜炎组脑脊液中LDH为(85.62±18.13)U/L、ADA为(2.58±0.52)U/L、IgM为(63.84±13.43)mg/L、IgG为(92.57±35.19)mg/L、IgA为(20.62±8.74)mg/L;结核性脑膜炎组LDH为(78.83±22.39)U/L、ADA为(11.82±2.64)U/L、IgM为(18.91±8.62)mg/L、IgG为(180.70±42.29)mg/L、IgA为(41.61±11.42)mg/L;病毒性脑膜炎组LDH为(22.42±9.57)U/L、ADA为(2.65±0.64)U/L、IgM为(5.83±1.34)mg/L、IgG为(20.91±10.34)mg/L、IgA为(7.20±2.31)mg/L。三组中枢神经系统感染性疾病中,结核性脑膜炎组与化脓性脑膜炎组脑脊液中IgM、IgG、IgA、LDH含量均较病毒性脑膜炎组显著增高(P<0.01),其中结核性脑膜炎组以IgG、IgA升高最明显,化脓性脑膜炎组以IgM升高最明显;结核性脑膜炎组脑脊液ADA活性与对照组和其它两组相比明显增高(P<0.01);病毒性脑膜炎组与对照组比较,各项指标差异无统计学意义(P>0.05)。结论中枢神经系统感染患者的血脑屏障受到不同程度损伤,脑脊液中免疫球蛋白、LDH检测有助临床对三种脑膜炎的诊断与鉴别诊断;ADA在早期诊断结核性脑膜炎时具有较高的临床价值。     

结核性脑膜炎患者脑脊液基质金属蛋白酶-9及其抑制剂检测

目的:探讨结核性脑膜炎患者脑脊液中基质金属蛋白酶-9(MMP-9)和基质金属蛋白酶组织抑制剂1(TIMP-1)水平的变化意义。方法:选取5例非肿瘤非感染性头痛患者脑脊液作对照,9例病毒性脑膜炎,12例结核性脑膜炎患者。12例结核性脑膜炎根据有无意识障碍或脑实质损害的症状分为两组,A组有意识障碍或脑实质损害症状,7例;B组无意识障碍或脑实质损害症状,5例。酶联免疫吸附测定(ELISA)方法检测脑脊液MMP-9和TIMP-1水平。结果:结核性脑膜炎脑脊液MMP-9的水平及MMP-9/TIMP-1比例显著增高,A组增高得更显著。结论:脑脊液MMP-9水平及MMP-9/TIMP-1比例对结核性脑膜炎的诊断和预后有参考价值。     

脑脊液置换联合鞘内给药治疗结核性脑膜炎24例疗效分析

目的探讨脑脊液置换加鞘内注药治疗结核性脑膜炎的临床疗效。方法采用脑脊液置换联合鞘内注药加常规治疗结核性脑膜炎24例(治疗组)和常规抗结核药物及激素、脱水剂等治疗22例(对照组)。对两组的疗效和脑脊液压力、蛋白、糖、氯化物及细胞数恢复时间进行比较。结果治疗组有效率(91.66%)与对照组有效率(72.72%)比较差异有统计学意义(P0.05);治疗组脑脊液蛋白、压力、糖、氯化物、细胞数恢复正常时间均较对照组明显缩短,差异有统计学意义(P0.01)。结论脑脊液置换联合鞘内注药可明显缓解结核性脑膜炎的症状,缩短疗程,该方法是治疗结核性脑膜炎的一种简单、有效、安全的方法 。     

腺苷脱氨酶检测对结核性脑膜炎诊断的临床价值

目的评价脑脊液中腺苷脱氨酶(ADA)检测对结核性脑膜炎诊断的应用价值。方法采用酶显色法检测102例4组病例(结核性脑膜炎组30例,化脓性脑膜炎组34例,病毒性脑膜炎组15例,头痛症状组23例)脑脊液中ADA的活性水平。结果30例结核性脑膜炎组脑脊液中ADA活性明显增高,ADA6.0U/L26例,与化脓性脑膜炎组比较差异有统计学意义(P0.01),敏感性为86.7%(26/30),特异性为91.7%(66/72)。化脓性脑膜炎组和病毒性脑膜炎组与头痛症状组(对照组)比较差异也具有统计学意义(P0.05)。结论检测脑脊液中ADA的活性对于结核性脑膜炎诊断和鉴别诊断有重要的临床价值。     

脑脊液腺苷脱氨酶测定对结核性脑膜炎的诊断意义

目的探讨脑脊液腺昔脱氨酶(ADA)活性测定对结核性脑膜炎诊断的临床意义。方法对确诊的50例结核性脑膜炎、46例病毒性脑膜炎、42例化脓性脑膜炎及40例非脑炎患者采用LX20全自动生化分析仪检测脑脊液ADA活性。结果结核性脑膜炎患者组脑脊液ADA活性明显高于其它非结核性脑膜炎患者,平均为(12.69±5.08)U/L,最高达27.33U/L。病毒性脑膜炎、化脓性脑膜炎和其它非脑膜炎患者脑脊液ADA分别为(3.26±1.03)U/L(、4.52±2.11)U/L、(2.99±1.22)U/L,最高9.04U/L,与结核性脑膜炎患者相比差别有统计学意义(P<0.01)。结核性脑膜炎组43例患者治疗6周后脑脊液中ADA活性比刚入院时明显降低,差别有统计学意义(P<0.01)。结论脑脊液腺苷脱氨酶可作为诊断结核性脑膜炎的重要参考指标。     

脑脊液IgA、IgG、IgM和CRP水平在感染性脑膜炎中的临床意义

目的探讨脑脊液中免疫球蛋白和C反应蛋白(CRP)水平在感染性脑膜炎中的临床意义。方法选取2014年2月至2017年3月在我院治疗的感染性脑膜炎患儿102例,其中化脓性脑膜炎41例,病毒性脑膜炎35例,结核性脑膜炎26例,同时选取健康体检儿童40例作为对照,检测各组脑脊液中免疫球蛋白和CRP水平,同时比较不同预后患儿脑脊液免疫球蛋白和CRP水平。结果结核性脑脑膜炎患儿脑脊液中lgA和lgG分别为(89.10±18.38)mg/L和(280.04±34.37)mg/L,明显高于化脓性脑膜炎和病毒性脑膜炎(P0.05);化脓性脑膜炎患儿脑脊液中lgM和CRP分别为(73.10±25.58)mg/L和(6.83±2.32)mg/L,明显高于病毒性脑膜炎和结核性脑膜炎(P0.05);化脓性脑膜炎预后不良患儿脑脊液lgA和CRP分别为(56.40±12.18)mg/L和(8.34±1.38)mg/L,明显高于预后良好患儿(P0.05);病毒性脑膜炎、结核性脑膜炎预后不良和预后良好患儿脑脊液lgA、lgG、lgM和CRP比较差异无统计学意义(P0.05);化脓性脑膜炎患儿lgA、CRP与预后呈负相关(P0.05)。结论脑脊液免疫球蛋白和CRP在鉴别诊断感染性脑膜炎中有一定价值;在化脓性脑膜炎中,免疫球蛋白和CRP在判断预后方面有一定作用。     

早期鉴别小儿结核性脑膜炎和病毒性脑膜炎的回顾性研究

[目的]探讨小儿病毒性脑膜炎和结核性脑膜炎(TBM)早期鉴别因素.[方法]回顾性分析确诊为病毒性脑膜炎患儿262例和TBM患儿55例的临床和实验室特征.[结果]比较两种疾病临床和实验室特征,多变量分析表明:入院前症状持续时间(DSBA)、DSBA≥5d、死亡、脑脊液(CSF)与血浆葡萄糖比值＜0.5、CSF氯化物浓度、CSF氯化物浓度低于正常、CSF蛋白值、CSF蛋白值＞1 g/L有统计学意义(P＜0.05)；多变量logistic回归方程分析,进入logistic回归方程的因素:DSBA≥5d、CSF与血浆葡萄糖比值＜0.5、CSF氯化物浓度低于正常、CSF蛋白值＞1 g/L；ROC曲线提示:DSBA、CFS氯化物浓度、CFS蛋白值灵敏度高.[结论]早期获得的DSBA、CSF与血浆葡萄糖比值、CSF氯化物浓度、CSF蛋白值等临床和实验室的数据对于鉴别结核性脑膜炎和病毒性脑膜炎有重要意义.     

实时荧光定量聚合酶链反应技术在结核性脑膜炎中的诊断价值

目的 用涂片、实时荧光定量聚合酶链反应(RT-PCR)法检测结核分枝杆菌,探讨其临床应用价值.方法 对临床确诊的结核性脑膜炎(n =110)、可疑结核性脑膜炎(n=205)和非结核性脑膜炎(n=100)患者的脑脊液标本分别采用涂片、RT-PCR两种方法进行检测,对结果进行对比分析.结果 415例脑脊液标本中,脑脊液涂片检查阳性率为2.4％(10/415),PCR检测阳性率为12.5％(52/415);脑脊液涂片、PCR法检测110例临床确诊的结核性脑膜炎患者脑脊液标本阳性率分别为6.4％(7/110)、26.4％(29/110);检测205例临床可疑结核性脑膜炎患者脑脊液标本阳性率分别为1.5％(3/205)、11.2％(23/205).比较两种方法的阳性检测率,差异有统计学意义(P＜0.05),检测100例非结核患者脑脊液标本,涂片及PCR检测均为阴性.结论 RT-PCR法检测脑脊液中TB-DNA对结核性脑膜炎的诊断有决定意义,具有较高临床应用价值.     

结核性脑膜炎患者脑脊液腺苷脱氨酶变化的临床意义

目的 探讨脑脊液腺苷脱氨酶(ADA)活性对结核性脑膜炎诊断的临床意义.方法 选取本院住院患者47例,用酶法测定其活性.病例分为二组,确诊为结核性脑膜炎组27例,对照组20例.结果 以ADA > 8 U/L为阳性阈值,结核性脑膜炎组患者脑脊液ADA活性明显高于对照组,差异有统计学意义.结论 脑脊液ADA测定可作为诊断结核性脑膜炎的重要参考指标.     

结核分枝杆菌Rv1009结构域多肽的免疫学特性研究

目的 研究结核分枝杆菌Rv1009结构域多肽的免疫学特性.方法 用原核表达的Rv1009结构域多肽免疫BALB/c小鼠3次.每次间隔2周.用ELISA法检测免疫小鼠血清中特异性抗体滴度.分离免疫小鼠的脾淋巴细胞,体外用抗原再刺激后,用MTT比色法检测免疫小鼠脾淋巴细胞的增殖指数.ELISA方法检测淋巴细胞悬液中γ干扰素(IFN-γ)、白细胞介素(IL)-10和IL-12的产生水平.另一部分免疫的小鼠经尾静脉感染MTB毒株H37Rv,4周后,计数脾脏细菌负荷数.结果 Rv1009结构域多肽免疫小鼠血清特异性抗体滴度为1:12 800.淋巴细胞增殖指数为2.40±0.18,明显高于生理盐水对照组的0.90±0.21.ELISA方法检测Rv1009结构域多肽免疫组IFN-γ、IL-10和IL-12水平为(1432±30)ng/L、(503±11)ng/L和(311±11)ng/L,显著高于生理盐水对照组的(256±20)ng/L、(76±6)ng/L和(56±8)ng/L(P<0.01).与生理盐水免疫组(细菌负荷6.64±0.13)相比较,Rv1009结构域多肽免疫组小鼠,对攻击感染后抗MTB在脾脏中增殖有显著作用(细菌负荷为4.86±0.14,P<0.05),但不及BCG免疫组的3.81±0.16.结论 Rv1009结构域多肽有可能作为新型结核疫苗的候选组分.     

Rapid, simple in vivo screen for new drugs active against Mycobacterium tuberculosis

We evaluated the use of a simple and easy-to-obtain potential marker of tuberculosis (TB) drug efficacy, body weight, and correlated weight loss or gain with the number of CFU of Mycobacterium tuberculosis in lungs and spleens of infected mice. C3H mice were infected intravenously with 10(6) CFU of virulent M. tuberculosis H37Rv, and body weight was evaluated for several weeks after infection. At day 20, infected untreated mice consistently lost more than 25% of their body weight. Chemotherapy with selected orally active anti-TB drugs was initiated 7 days following infection and continued for 13 days. Drugs that were administered daily by gavage included isoniazid (INH), ethambutol (EMB), rifampin (RIF), and moxifloxacin (MXF). At the most effective doses, each of these drugs inhibited bacterial growth and abolished infection-induced body weight loss. Chemotherapy with 1/10 the standard dose of INH determined in accepted long-term murine models of TB also prevented body weight loss, while chemotherapy with 1/10 the standard dose of RIF did not. With only 2 weeks of chemotherapy, we observed a good reverse correlation between CFU in lung or spleen and body weight of mice. The simple measurement of weight in TB-infected drug-treated mice required only a weight balance, and go/no-go drug efficacy data was available on day 20 without the necessity of prolonged drug treatment and long (3 weeks or more) in vitro culture times to obtain organ CFU values.     

A Systematic Review and Meta-analysis of Isoniazid Pharmacokinetics in Healthy Volunteers and Patients with Tuberculosis

PurposeThis systematic review and meta-analysis assesses the pharmacokinetic (PK) summary estimates of isoniazid (INH) between healthy volunteers and patients with tuberculosis (TB), evaluates whether the current INH dose regimen is appropriate in patients with TB, and evaluates the impact of N-acetyl-transferase-2 (NAT2) status on the PK properties of INH.MethodsA systematic approach was conducted to find studies with relevant INH PK data published in the English language up to February 2018. The PK properties of INH were extracted with their respective INH dosages and were dose normalized to allow a fair comparison between healthy volunteers and patients with TB. Meta-analysis was then performed for the C_max and AUC estimates for all INH dosages.FindingsNinety studies were included in this systematic review. TB status significantly affected the INH C_max and AUC estimates. In healthy volunteers, the dose-normalized INH C_max and AUC were statistically higher than those of patients with TB. No significant differences were found in dose-normalized C_max and AUC between adults with TB and adults with TB/HIV; however, the AUC in pediatric patients was significantly different between patients with TB and patients with TB/HIV. In addition, no significance was observed comparing the dose-normalized C_max and AUC of pediatric patients with TB and TB/HIV with their respective adult counterparts. Dose-normalized INH C_max and AUC in patients with fast and intermediate NAT2 were significantly lower than in patients with slow NAT2.ImplicationsThe current recommended dosages of INH were found to produce less drug exposure in patients with TB when compared with healthy volunteers. NAT2 polymorphism greatly impacts the PK properties of INH; hence, testing for acetylator status is highly recommended, and therapeutic drug monitoring would help reduce INH toxicity.     

西藏地区169例复治失败肺结核病例耐药状况检测

目的 了解西藏地区复治肺结核患者中的结核分枝杆菌对抗结核化学药物的耐药状况,为有效防治肺结核病提供科学依据.方法 收集西藏自治区结核病防治所2000-2005年复治失败病例169例痰标本,用改良罗氏培养基分离培养结核分枝杆菌,绝对浓度法检测分离菌株对4种抗结核药物[链霉素(SM)、异烟肼(INH)、乙氨丁醇(EMB)、利福平(RFP)]的耐药性测定.结果 共检测169株结核分枝杆菌,其中耐药株165株,总耐药率高达97.63%,其中耐多药(所耐药物中含R和H)133例,耐多药率为78.70%.复治失败的耐药率和耐多药率明显高于全国46.50%的水平.对RFP、INH、SM和EMB的耐药率分别为91.12%(154/169)、84.02%(142/169)、75.15%(127/169)和21.30%(36/169).结论 西藏地区属高耐药区,应加强结核分枝杆菌的耐药监测和控制.     

Preliminary Pharmacokinetic Study of Repeated Doses of Rifampin and Rifapentine in Guinea Pigs

Substitution of rifapentine (RFP) for rifampin (RIF) in the standard antituberculous regimen reduces the time required to cure chronic tuberculosis (TB) infection in mice, but not in guinea pigs. In order to gain insight into these discrepant findings, we conducted a steady-state pharmacokinetic (PK) study in healthy guinea pigs to study the metabolism and autoinduction of RIF and RFP. Both RFP and RIF 25-desacetyl metabolites (desRFP and desRIF, respectively), were detected at low concentrations in the serum of guinea pigs. The metabolite concentrations in guinea pigs are much lower than those seen in humans at steady state.     

Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint

One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial agents is dose selection. The choice is often based on preclinical data from pharmacokinetic (PK) studies with animals and healthy volunteers but is rarely linked directly to the target organisms except by the MIC, an in vitro measure of antimicrobial activity with many limitations. It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model which uses four data sets: (i) the distribution of MICs for clinical isolates, (ii) the distribution of the values of the PK parameters for the test drug in the population, (iii) the PD target(s) developed from animal models of infection, and (iv) the protein binding characteristics of the test drug. In performing this study with the new anti-infective agent evernimicin, we collected a large number (n = 4,543) of recent clinical isolates of gram-positive pathogens (Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium, and Staphylococcus aureus) and determined the MICs using E-test methods (AB Biodisk, Stockholm, Sweden) for susceptibility to evernimicin. Population PK data were collected from healthy volunteers (n = 40) and patients with hypoalbuminemia (n = 12), and the data were analyzed by using NPEM III. PD targets were developed with a neutropenic murine thigh infection model with three target pathogens: S. pneumoniae (n = 5), E. faecalis (n = 2), and S. aureus (n = 4). Drug exposure or the ratio of the area under the concentration-time curve/MIC (AUC/MIC) was found to be the best predictor of microbiological efficacy. There were three possible microbiological results: stasis of the initial inoculum at 24 h (10(7) CFU), log killing (pathogen dependent, ranging from 1 to 3 log(10)), or 90% maximal killing effect (90% E(max)). The levels of protein binding in humans and mice were similar. The PK and PD of 6 and 9 mg of evernimicin per kg of body weight were compared; the population values for the model parameters and population covariance matrix were used to generate five Monte Carlo simulations with 200 subjects each. The fractional probability of attaining the three PD targets was calculated for each dose and for each of the three pathogens. All differences in the fractional probability of attaining the target AUC/MIC in this PD model were significant. For S. pneumoniae, the probability of attaining all three PD targets was high for both doses. For S. aureus and enterococci, there were increasing differences between the 6- and 9-mg/kg evernimicin doses for reaching the 2 log killing (S. aureus), 1 log killing (enterococci), or 90% E(max) AUC/MIC targets. This same approach may also be used to set preliminary in vitro MIC breakpoints.     

Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis

OBJECTIVES: To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs). METHODS: Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. RESULTS: Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. CONCLUSIONS: There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.     

Determination of [11C]Rifampin Pharmacokinetics within Mycobacterium tuberculosis-Infected Mice by Using Dynamic Positron Emission Tomography Bioimaging

Information about intralesional pharmacokinetics (PK) and spatial distribution of tuberculosis (TB) drugs is limited and has not been used to optimize dosing recommendations for new or existing drugs. While new techniques can detect drugs and their metabolites within TB granulomas, they are invasive, rely on accurate resection of tissues, and do not capture dynamic drug distribution in the tissues of interest. In this study, we assessed the in situ distribution of ¹¹C-labeled rifampin in live, Mycobacterium tuberculosis-infected mice that develop necrotic lesions akin to human disease. Dynamic positron emission tomography (PET) imaging was performed over 60 min after injection of [¹¹C]rifampin as a microdose, standardized uptake values (SUV) were calculated, and noncompartmental analysis was used to estimate PK parameters in compartments of interest. [¹¹C]rifampin was rapidly distributed to all parts of the body and quickly localized to the liver. Areas under the concentration-time curve for the first 60 min (AUC_0–60) in infected and uninfected mice were similar for liver, blood, and brain compartments (P > 0.53) and were uniformly low in brain (10 to 20% of blood values). However, lower concentrations were noted in necrotic lung tissues of infected mice than in healthy lungs (P = 0.03). Ex vivo two-dimensional matrix-assisted laser desorption ionization (MALDI) imaging confirmed restricted penetration of rifampin into necrotic lung lesions. Noninvasive bioimaging can be used to assess the distribution of drugs into compartments of interest, with potential applications for TB drug regimen development.     

Prediction of neutropenia-related effects of a new combination therapy with the anticancer drugs BI 2536 (a Plk1 inhibitor) and pemetrexed

This study investigated the feasibility of predicting the neutropenia-related effects of a therapy that combines the investigational drug BI 2536 (inhibitor of Polo-like kinase 1) and pemetrexed, an approved anticancer drug. Predictions were arrived at using the pharmacokinetic/pharmacodynamic (PK/PD) parameters of each of the drugs obtained from monotherapy studies and assuming that the neutropenic effect is additive when the drugs are administered as a combination therapy. Subsequently, a PK/PD model was developed to determine whether this assumption of additive effect was reasonable in relation to these two drugs. All analyses and simulations were performed using the population approach in NONMEM, version VI.     

Clinical pharmacokinetic and pharmacodynamic analysis of daptomycin and the necessity of high-dose regimen in Japanese adult patients

The objective of this study was to explore the optimal dosage regimen of daptomycin and to determine the necessity and validity of a high-dose regimen from the perspectives of PK/PD parameters using Monte Carlo Simulation (MCS) and therapeutic drug monitoring (TDM) in a Japanese clinical setting. The volume of distribution (0.13 ± 0.012 L/kg) in this study was greater than that in healthy volunteers reported in Japan. The range of half-lives was between 8.9 and 34.9 h, which were gradually prolonged as creatinine clearance decreased. In MCS, the cumulative fractions of response (CFR) of the peak/MIC ≧ 60 and the AUC/MIC ≧ 666 at the 6 mg/kg q 24 h were 72.0% and 78.8% but at the 10 mg/kg q 24 h, the CFRs improved to both 99%. In TDM with 6 mg/kg q 24 h regimen, the patients who reached the peak and AUC target were 40% (2 out of 5 patients), respectively. The intraindividual variability in daptomycin PK may indicate the necessity of TDM and high-dose regimen, such as over 8 mg/kg, may be needed to ensure the effectiveness especially on Japanese patients with normal renal function.