Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: Time for harmonization of CLSI and EUCAST broth microdilution methods

BackgroundBoth the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have MIC clinical breakpoints (CBPs) for fluconazole (FLU) and Candida. EUCAST CBPs are species-specific, and apply only to C. albicans, C. tropicalis and C. parapsilosis, while CLSI CBPs apply to all species. We reassessed the CLSI CBPs for FLU and Candida in light of recent data.MethodsWe examined (1) molecular mechanisms of resistance and cross-resistance profiles, (2) wild-type (WT) MICs and epidemiological cutoff values (ECVs) for FLU and major Candida species by both CLSI and EUCAST methods, (3) determination of essential (EA) and categorical agreement (CA) between CLSI and EUCAST methods, (4) correlation of MICs with outcomes from previously published data using CLSI and EUCAST methods, and (5) pharmacokinetic and pharmacodynamic considerations. We applied these findings to propose new species-specific CLSI CBPs for FLU and Candida.ResultsWT distributions from large collections of Candida revealed similar ECVs by both CLSI and EUCAST methods (0.5–1 mcg/ml for C. albicans, 2 mcg/ml for C. parapsilosis and C. tropicalis, 32 mcg/ml for C. glabrata, and 64–128 for C. krusei). Comparison of CLSI and EUCAST MICs reveal EA and CA of 95% and 96%, respectively. Datasets correlating CLSI and EUCAST FLU MICs with outcomes revealed decreased response rates when MICs were >4 mcg/ml for C. albicans, C. tropicalis and C. parapsilosis, and >16 mcg/ml for C. glabrata.ConclusionsAdjusted CLSI CBPs for FLU and C. albicans, C. parapsilosis, C. tropicalis (S, ≤2 mcg/ml; SDD, 4 mcg/ml; R, ≥8 mcg/ml), and C. glabrata (SDD, ≤32 mcg/ml; R, ≥64 mcg/ml) should be more sensitive for detecting emerging resistance among common Candida species and provide consistency with EUCAST CBPs.     

Data warehouse implementation with clinical pharmacokinetic/pharmacodynamic data

OBJECTIVES: We have created a data warehouse for human pharmacokinetic (PK) and pharmacodynamic (PD) data generated primarily within the Clinical PK Group of the Drug Metabolism and Pharmacokinetics (DM&PK) Department of DuPont Pharmaceuticals. METHODS: Data which enters an Oracle-based LIMS directly from chromatography systems or through files from contract research organizations are accessed via SAS/PH.Kinetics, GLP-compliant data analysis software residing on individual users' workstations. Upon completion of the final PK or PD analysis, data are pushed to a predefined location. Data analyzed/created with other software (i.e., WinNonlin, NONMEM, Adapt, etc.) are added to this file repository as well. The warehouse creates views to these data and accumulates metadata on all data sources defined in the warehouse. The warehouse is managed via the SAS/Warehouse Administrator product that defines the environment, creates summarized data structures, and schedules data refresh. RESULTS: The clinical PK/PD warehouse encompasses laboratory, biometric, PK and PD data streams. Detailed logical tables for each compound are created/updated as the clinical PK/PD data warehouse is populated. The data model defined to the warehouse is based on a star schema. Summarized data structures such as multidimensional data bases (MDDB), infomarts, and datamarts are created from detail tables. Data mining and querying of highly summarized data as well as drill-down to detail data is possible via the creation of exploitation tools which front-end the warehouse data. Based on periodic refreshing of the warehouse data, these applications are able to access the most current data available and do not require a manual interface to update/populate the data store. Prototype applications have been web-enabled to facilitate their usage to varied data customers across platform and location. The warehouse also contains automated mechanisms for the construction of study data listings and SAS transport files for eventual incorporation into an electronic submission. CONCLUSIONS: This environment permits the management of online analytical processing via a single administrator once the data model and warehouse configuration have been designed. The expansion of the current environment will eventually connect data from all phases of research and development ensuring the return on investment and hopefully efficiencies in data processing unforeseen with earlier legacy systems.     

磷霉素的药动学、药效学及临床应用新进展

近年磷霉素在临床抗感染治疗中日益受到重视,磷霉素PK/PD理论的研究以及在预防感染、多重耐药菌严重感染等方面都有了许多新的成果,本文对磷霉素的药动学、药效学研究及临床应用最新进展作一综述。     

Methodology for pharmacokinetic/pharmacodynamic data analysis

This review will highlight the role of exploratory data analysis and nonlinear regression software in pharmacokinetic–pharmacodynamic (PK/PD) data analysis. Kinetic and dynamic modelling situations typical to the pharmacokineticist in the drug industry will be addressed, and two case studies, including single-dose intravenous bolus plasma data and multiple-dose response-time data will be analysed. Approaches to assessing the suitability of model fit to the observed data will be discussed, and a summary of the key features of available commercial PK software will be given. Specific emphasis will be placed on the application of WinNonlin.     

Mobile genes coding for efflux-mediated antimicrobial resistance in Gram-positive and Gram-negative bacteria

Efflux mechanisms that account for resistance to a variety of antimicrobial agents are commonly found in a wide range of bacteria. Two major groups of efflux systems are known, specific exporters and transporters conferring multidrug resistance (MDR). The MDR systems are able to remove antimicrobials of different classes from the bacterial cell and occasionally play a role in the intrinsic resistance of some bacteria to certain antimicrobials. Their genes are commonly located on the bacterial chromosome. In contrast, the genes coding for specific efflux systems are often associated with mobile genetic elements which can easily be interchanged between bacteria. Specific efflux systems have mainly been identified with resistances to macrolides, lincosamides and/or streptogramins, tetracyclines, as well as chloramphenicol/florfenicol in Gram-positive and Gram-negative bacteria. In this review, we focus on the molecular biology of antimicrobial resistance mediated by specific efflux systems and highlight the association of the respective resistance genes with mobile genetic elements and their distribution across species and genus borders.     

Trimethoprim/sulfametrole: evaluation of the available clinical and pharmacokinetic/pharmacodynamic evidence

Emergence of resistance to widely used trimethoprim/sulfamethoxazole (TMP/SMX) as well as common adverse events in human immunodeficiency virus (HIV)-infected patients casts interest on combinations of TMP with other sulfonamides. Sulfametrole (SMT) combined with TMP could provide a choice for difficult-to-treat infections, particularly when administered intravenously. The objective of this review was to evaluate the available clinical and pharmacokinetic/pharmacodynamic (PK/PD) evidence regarding TMP/SMT, particularly in comparison with TMP/SMX. We reviewed the available evidence retrieved from searches in PubMed/Scopus/Google Scholar and by bibliography hand-searching. In total, 46 eligible studies (most published before 1997) were identified, 7 regarding intravenous (i.v.) TMP/SMT, 24 regarding oral TMP/SMT and 15 providing comparative data for TMP/SMT versus TMP/SMX. The antimicrobial activity of TMP/SMT was similar to TMP/SMX for Gram-positive isolates. A greater percentage of Escherichia coli and Proteus spp. isolates were susceptible to TMP/SMT compared with TMP/SMX. PK/PD data suggest a dosage adjustment of i.v. TMP/SMT in patients with seriously impaired renal function. Four randomised controlled trials and 16 non-comparative studies reported good effectiveness/safety outcomes for oral TMP/SMT in genital ulcers (mainly chancroid), respiratory tract infections and urinary tract infections (UTIs). Moreover, i.v. TMP/SMT was effective against Pneumocystis jiroveci infection in HIV-infected patients, severe pneumonia and UTIs. In one study, hypersensitivity reactions occurred in 18/52 (34.6%) of HIV-infected patients; 2/52 (3.8%) developed psychosis. Gastrointestinal adverse events were mild and rare. Excipients in i.v. TMP/SMT formulations might be less toxic compared with i.v. TMP/SMX formulations, particularly for children. In conclusion, despite the scarcity of contemporary evidence, available data suggest that TMP/SMT could be an alternative treatment option to TMP/SMX, even in serious infections, when administered intravenously.     

动物源性细菌抗生素耐药判定标准的研究现状

抗生素在解决了许多细菌感染性疾病治疗问题的同时,其广泛不合理的应用以及细菌自身适应性的改变也加速了细菌耐药性的产生,对全球经济和公共健康带来严重危害。为了能够很好地监测细菌耐药性的变化和有效的指导临床用药,控制细菌的耐药性,建立细菌的耐药判定标准成为了一项具有实践意义的重要任务。建立耐药判定标准需要收集大量的信息,包括野生型细菌的最小抑菌浓度(minimal inhibitory concentration, MIC)分布,体外药效学和体内药动学的数据以及临床治疗相关的数据,主要包括野生型临界值、药效学临界值和临床临界值3个方面。本文综述了动物源性耐药判定标准的研究进展,总结了目前应用最广泛的两个折点制定组织美国临床实验室标准化协会(CLSI)和欧洲药敏实验标准化委员会(EUCAST)建立耐药判定标准的方法,为建立符合我国耐药现状的耐药判定标准提供理论基础。     

Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic parameters

Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered. When pharmacokinetic and pharmacodynamic values are combined, the area under the inhibitory curve (AUIC) and peak concentration:MIC ratio predict clinical cure for fluoroquinolones. Clinical data and animal models indicate that a peak:MIC of 10:1 and above and an AUIC of 125 and above are predictive of a clinical cure for this class of antimicrobials against gram-negative organisms. The values may be used to compare and contrast fluoroquinolones to determine which would be best for treating a specific microorganism. Pharmacodynamic data also can be used to design regimens that minimize the risk of suboptimal drug levels. Ensuring the optimal fluoroquinolone dosage based on pharmacodynamic principles would diminish the emergence of resistant organisms and prevent treatment failures.     

Ocular pharmacokinetic/pharmacodynamic modeling for multiple anti-glaucoma drugs

We have constructed a new ocular pharmacokinetic pharmacodynamic (PK/PD) model for anti-glaucoma drugs to describe ocular hypotensive effects on intraocular pressure (IOP) after instillation of a combination of an alpha(1)-adrenergic antagonist, bunazosin, and a beta-adrenergic antagonist, timolol, into rabbits. This model was constructed by the combination of two ocular PK/PD models for bunazosin and timolol by including aqueous humor dynamics based on both action mechanisms. We also verified the reliability of this model by confirming the drug concentrations in aqueous humor and ocular hypotensive effects after instillation of the drug combination. The aqueous humor concentrations of timolol and bunazosin were determined by an HPLC, and ocular hypotensive effect-time profiles were measured using a telemetry system, which was able to record automatically detailed effects. The combined model could simulate the aqueous humor concentrations of both drugs and the additive IOP-lowering effect after instillation of the combination using the MULTI (RUNGE) program and PK/PD parameters which were obtained from ocular hypotensive effects after instillation of bunazosin alone or timolol alone. The theoretical concentration curves of both drugs in the aqueous humor and the theoretical ocular hypotensive effect curves almost agreed with both the observed concentrations and ocular hypotensive effects after instillation of the drug combination. These results indicate the reliability and usefulness of PK/PD modeling considering aqueous humor dynamics to predict IOP in multidrug therapy. This is the first study to develop a PK/PD model for multidrug therapy for the eye.     

Donepezil for Alzheimer's disease: pharmacodynamic, pharmacokinetic, and clinical profiles

Donepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a piperidine-based, reversible acetylcholinesterase inhibitor, that is chemically unrelated to other cholinesterase inhibitors. It was developed for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is highly selective for acetylcholinesterase with a significantly lower affinity for butyrylcholinesterase, which is present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favorable pharmacokinetic, pharmacodynamic and safety profile. There is no need to modify the dose of donepezil in the elderly or in patients with renal and hepatic failure. Pivotal phase-III trials in the US, European countries, and Japan showed that donepezil significantly improved cognition and global function in patients with mild to moderate AD. In long-term trials, donepezil maintained cognitive and global function for up to 1 year prior to the resumption of gradual deterioration. Donepezil is generally well tolerated; most of its adverse events are mild, transient and cholinergic in nature. Donepezil produces no clinically significant changes in laboratory parameters, including liver function. The drug is approved for the treatment of mild to moderate Alzheimer's disease, but donepezil therapy does not have to be discontinued if a patient continues to deteriorate. Possible new indications for donepezil in psychiatric and neurologic diseases, other than AD, include dementia with Lewy bodies, brain injury, attention deficit hyperactivity, multiple sclerosis, Down's syndrome, delirium, mood disorders, Huntington's disease and sleep disorders.     

The influence of cardiovascular physiology on dose/pharmacokinetic and pharmacokinetic/pharmacodynamic relationships

Inter- and intraindividual variability in the relationship between dose and clinical--or pharmacodynamic--response of a drug can be analysed in two steps: firstly, by considering the plasma pharmacokinetic response to a given dose and, secondly, by the connection between both pharmacokinetic and pharmacodynamic responses. As the cardiovascular system is the means of transport of endogenous and exogenous substances, blood flow fraction destined to each organ determines the relative mass of solute in plasma, which is constantly in contact with the tissue. Hence, not only the rate but also the extent of drug transfer would be increased when tissues are irrigated by a higher fraction of cardiac output. Aging and circadian rhythms present similar cardiac output distribution patterns when moving from young to aged adult and from nocturnal to diurnal hours. These two changes lead to an increased blood flow delivery to the extra-splanchnic-renal region in the elderly and in the morning, but with a decreased cardiac output in aged individuals and an increased one during the day. This scenario allows us to forecast substance concentrations outside the blood vessels, which are responsible for the extent of drug elimination and the intensity of drug effect. So available data on disposition and pharmacodynamics of drugs might be explained from another point of view that challenges current knowledge. Furthermore, the administration of cardiovascular active drugs might reverse the chronological sequence between pharmacokinetic and pharmacodynamic responses, since they could modify blood flow distribution.     

Correlation between CLSI, EUCAST and Etest methodologies for amphotericin B and fluconazole antifungal susceptibility testing of Candida spp. clinical isolates

This study analyzed the correlation between the results obtained through two microdilution methods: Clinical and Laboratory Standard Institute (CLSI) (M27-A2) and European Committee on Antibiotic Susceptibility Testing (EUCAST) (document E. Dis. 7.1) and an agar base method Etest for determining minimmun inhibitory concentration (MIC) for amphotericin B and fluconazole against 30 clinical isolates of Candida spp. The agreement between Etest, CLSI and EUCAST MICs within +/- 2 log2 dilutions was higher for amphotericin B than for fluconazole However, Pearson correlation demonstrated a greater agreement for fluconazole. The categorical agreement between MICs provided by the Etest/ CLSI and Etest/EUCAST methodologies was high for both amphotericin B (100%) and fluconazole (> or = 96.66%). This study demonstrated the adequacy of Etest method using Mueller Hinton agar to evaluate amphotericin B and fluconazole susceptibility of clinical isolates of Candida spp.     

Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus

Expanding the cytokine paradigm beyond the use of calcineurin inhibitors as baseline therapy provides new strategies in immunosuppression. Drugs such as FTY720 alter the sensitivity of lymphocytes to homing chemokines, and agents such as sirolimus (SRL) disrupt downstream cytokine signal transduction. Confirming studies in rodents and nonhuman primates, administration of either FTY720 or both of these drugs afford synergistic interactions with cyclosporine to renal transplant patients to rapidly and dramatically deplete peripheral blood lymphocytes (PBL) but neither granulocytes nor monocytes. Present information suggests that FTY720 facilitates lymphocyte homing mechanisms, leading to T and B cell sequestration in secondary lymphoid structures. Interestingly, FTY720 displays pharmacokinetic characteristics suggesting that therapeutic drug monitoring (TDM) will not be essential for clinical applications. In contrast, SRL is a critical-dose drug that requires TDM. SRL disrupts costimulatory and cytokine-stimulated T cell activation by inhibiting a multifunctional kinase, mammalian target of sirolimus (mTOR). Two pivotal trials including more than 1,300 patients demonstrated that addition of SRL to a CsA-based regimen reduces the incidence, time to onset, and severity of acute rejection episodes. When used alone, SRL seems therapeutically equivalent to CsA. In the coming decade, SRL is likely to be used in a variety of drug combination regimens both simultaneously and sequentially, not only to avert acute rejection episodes, but also to forestall chronic nephropathic processes. These two new agents are likely to usher in a new era of transplant therapy.     

Application of novel quantitative bioanalytical methods for pharmacokinetic and pharmacokinetic/pharmacodynamic assessments of antisense oligonucleotides

The development of antisense therapeutic agents has required the development of a number of novel bioanalytical methods for their quantitation. The success of these methods has enabled characterization of the pharmacokinetic and pharmacokinetic/ pharmacodynamic behavior of antisense agents. Specific quantitative bioanalytical methods addressed in this review include radiotracer methods, high-performance liquid chromatography (HPLC) methods, capillary gel electrophoresis with UV detection or with laser-induced fluorescence detection, matrix-assisted laser-induced desorption/ionization mass spectrometry, HPLC-mass spectrometry, and hybridization-based enzyme-linked immunosorbent assays. The most important bioanalytical techniques have been summarized in view of their general and specific features, the possibilities and extent of their application, and characteristics of operation and limitations.     

1330株临床分离革兰阳性菌耐药性分析

目的 了解临床分离的革兰阳性菌对不同抗菌药物的耐药情况,为临床医师及时提供抗生素的耐药动向与耐药变迁为临床抗感染治疗提供选药依据.方法 用苯唑西林检测葡萄球菌临床分离株的敏感性,用纸片扩散法检测革兰阳性菌对四环素、红霉素、庆大霉素、氨苄青霉素、环丙沙星、头孢吡肟、复方磺胺甲噁唑、万古霉素、替考拉宁、利福平、克林霉素等抗菌药物的耐药结果.用E-test法检测对苯唑西林耐药的肺炎链球菌青霉素的MIC值.结果 1330株革兰阳性菌中耐甲氧西林的葡萄球菌对抗菌药物的耐药率显著高于对甲氧两林敏感的葡萄球菌.肠球菌属以粪肠球菌和屎肠球菌检出率最高,粪肠球菌对呋喃妥因、氨苄西林耐药率较低,屎肠球菌耐药性较强,仅对氯霉素、四环素耐药率较低.肺炎链球菌对四环素、克林霉素、红霉素有较高的耐药率,青霉素不敏感肺炎链球菌(PNSSP)的E-test检测结果以中介菌株为主,PNSSP的MIC值最高达到6μg/mL.结论 葡萄球菌、肺炎链球菌对万古霉素全部敏感,有仅发现1株耐万古霉素的屎肠球菌,万古霉素是临床治疗重症革兰阳性菌感染的首选药物.加强耐药性监测对指导临床合理使用抗菌药物具有重要意义.     

Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs

Inadequate tissue penetration of antibiotics can lead to therapeutic failure and bacterial resistance. Pharmacokinetic evaluation of antibiotics should therefore be based on tissue rather than serum concentrations. Over several years, tissue concentration data obtained by methods such as tissue biopsies have flawed the correct interpretation of antibiotic tissue distribution. Microdialysis--a semi-invasive catheter-based sampling technique--has been employed for the in vivo measurement of antibiotic tissue pharmacokinetics. Owing to selective access to the target site for most anti-infective drugs, microdialysis satisfies regulatory requirements for pharmacokinetic distribution studies and might become a reference technique for tissue distribution studies in the near future. Furthermore, microdialysis might contribute to the definition of meaningful surrogate markers for antibiotic efficiency during drug development.     

The pharmacokinetic and pharmacodynamic interactions of ramipril with propranolol

Summary We have studied the pharmacodynamic effects of ramipril, propranolol, and their combination, as well as the effect of propranolol on the pharmacokinetics of ramipril in 12 healthy men (age 24 (SD 6) y, weight 72 (7) kg).Propranolol and placebo, ramipril and placebo, or propranolol and ramipril were given orally for four days in a crossover, double-blind fashion. The pharmacokinetics of ramipril and ramiprilat were investigated on day 4. Effects on plasma renin activity, ACE activity, and heart rate and blood pressure both before and after a standardized exercise test were measured on days 1 and 4.On day 4 the combination reduced the mean arterial pressure by 2.8 mmHg compared with propranolol alone and by 3.7 mmHg compared with ramipril alone. Ramipril had no effect on the bradycardia induced by propranolol. Propranolol reduced exercise mean arterial pressure by 9 mmHg (day 4) and heart rate by 7 beats.min^–1 (day 4) compared with ramipril; this was not affected by co-administration of ramipril.On day 4 the average plasma renin activity was not significantly higher than after the combination. ACE activity was not affected by propranolol.The pharmacokinetics of ramipril and ramiprilat were not influenced by propranolol.The combination of ramipril and propranolol has additive pharmacodynamic effects that may be useful in the treatment of hypertension.     

Population pharmacokinetic/pharmacodynamic modeling of valproate in Chinese children with epilepsy

AIM： To establish a population pharmacokinetic/pharmacodynamic （PK/PD） model for valproate （VPA） in children with epilepsy in China, and promote reasonable use of antiepileptic drug in clinical practice. METHODS： Sparse data of VPA serum concentrations from 417 pediatric children were collected. These patients were divided into three groups： Population PK-Index group, n = 317; Population PK-Valid group, n = 100; 115 of the total 417 subjects were also included in the Population PD group. Population PK parameters of VPA were estimated based on the data from population PK-Index group. In the validation procedure, the serum concentrations of VPA from the population PK-Valid group were predicted by base and final models respectively. To assess the accuracy and precision of the predictions, mean prediction error （MPE）, mean squared prediction error （MSPE）, root mean squared prediction error （RMSPE）, weight-residues （WRES） and its 95 % confidence intervals （95 % CI） were all calculated, then compared between the two models. For population PD group, all of the ! 15 patients were VPA monotherapy. Efficacy of epilepsy treatment was divided into 5 grades according to the percentage of seizure frequency decreased （ PSFD% ）. The value of PSFD% 100%, 75% - 100%, 50% - 75%, 25% - 50%, or less than 25 % are corresponding to grade 1 to 5. For population PD group, the quantitative relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by logistic regression.[第一段]     

Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs

Over the last decades, the interest in the relationships between the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents has increased and, therefore, the use of PK/PD indices and expressions has spread widely. The appropriate definition and use of these parameters is a matter of controversy. This paper contains a proposal to use PK/PD expressions for antimicrobial agents and their units in a uniform manner.