Antifungal pharmacokinetics and pharmacodynamics: bridging from the bench to bedside

This review considers a way in which experimental data can be used to identify safe and effective antifungal regimens for humans. The process begins with experimental models of invasive fungal infections that enable definition of optimal dosages and schedules of antifungal drug administration to be defined. These preclinical models also enable the identification of drug exposure targets that are associated with therapeutic outcomes of interest. Human pharmacokinetic variability results in a considerable range of drug exposures following the use of fixed antifungal drug regimens. This variability can be quantified using population pharmacokinetic modeling techniques. Monte Carlo simulation can then be used to simulate pharmacokinetic variability and thereby estimate the proportion of patients with a therapeutic outcome of interest. Effective and safe regimens can thus be studied appropriately in clinical settings. This approach can, and should, be used to optimize antifungal therapy for a large number of clinical scenarios.     

Relationship between pharmacokinetics and pharmacodynamics of β-lactams and outcome

The in-vitro susceptibility of an organism and the pharmacokinetics of an antimicrobial agent are two basic factors on which the choice of standardised treatment regimens is based. However, the inter-individual variability of these factors, which modifies the exposure of bacteria to an antibiotic in terms of time and quantity, is not usually taken into account. In 87 patients treated with beta-lactams (ceftriaxone, cefepime or piperacillin), the probability of failure was greater when the infectious process was located in tissues with barriers to the distribution of beta-lactams. Mean MICs of piperacillin and cefepime, but not ceftriaxone, were below the breakpoints in cases of both recovery and failure, but organisms isolated from patients with a poor outcome had higher MICs. Therefore, the use of breakpoints to determine the susceptibility of microorganisms was not satisfactory in predicting the outcome for a large number of patients. If MICs are determined and plasma concentrations are monitored, dosages can be adjusted according to these parameters, thereby allowing antibiotic treatment to be individualised.     

The contribution of pharmacokinetic–pharmacodynamic modelling with Monte Carlo simulation to the development of susceptibility breakpoints for Neisseria meningitidis

This study used pharmacokinetic-pharmacodynamic (PK-PD) modelling and MICs of 15 antimicrobial agents, derived from testing a large international culture collection, to assist in the development of interpretative criteria, i.e., breakpoints, for Neisseria meningitidis. PK parameters, protein binding, percentage penetration into cerebrospinal fluid (CSF), and the variability of these values, were extracted from the published literature for the 15 agents. PK-PD parameters have not been developed specifically for N. meningitidis in animal or human studies. Thus, it was necessary to invoke PK-PD targets from other organisms that cause infections at similar sites. The PK-PD targets utilised were: time above the MIC for at least 50% of the dosing interval for all beta-lactams, chloramphenicol, sulphafurazole and trimethoprim-sulphamethoxazole; an AUC/MIC ratio of >or=25 for the tetracyclines and macrolides; and an AUC/MIC ratio of >or=125 for the fluoroquinolones. A 10 000-subject Monte Carlo simulation was designed with the usual dosing regimens of each antimicrobial agent at MIC values of 0.03-64 mg/L in both serum and CSF. The PK-PD breakpoint was defined as the MIC at which the calculated target attainment was >or=95%. Using these assumptions, the proposed PK-PD breakpoints were: azithromycin, 0.125 mg/L; doxycycline, 0.25 mg/L; cefotaxime, ciprofloxacin and levofloxacin, 0.5 mg/L; penicillin G, meropenem, rifampicin, tetracycline and minocycline, 1 mg/L; chloramphenicol and sulphafurazole, 2 mg/L; and ampicillin, ceftriaxone and trimethoprim-sulphamethoxazole, 4 mg/L. Proposed PK-PD breakpoints applicable to CSF were: penicillin and cefotaxime, 0.06 mg/L; rifampicin, 0.125 mg/L; ceftriaxone, meropenem and trimethoprim-sulphamethoxazole, 0.25 mg/L; ampicillin, 0.5 mg/L; and chloramphenicol, 1 mg/L.     

Daptomycin in the treatment of enterococcal bloodstream infections and endocarditis: a EUCAST position paper

ScopeThis position paper describes the view adopted by EUCAST on the role of daptomycin in the treatment of serious infections caused by Enterococcus species.BackgroundHigh-dose daptomycin is considered effective in the treatment of enterococcal bloodstream infection (BSI) and endocarditis, although published clinical experience with the latter condition is limited.MethodsEUCAST reviewed the available published data on pharmacokinetics–pharmacodynamics (PK-PD), resistance selection, clinical efficacy and safety for the use of 10–12 mg/kg/day of daptomycin for these conditions, noting that the doses licensed by the European Medicines Agency are only 4–6 mg/kg/day, and only for infections caused by Staphylococcus aureus.Findings and recommendationsThe PK-PD evidence shows that, even with doses of 10–12 mg/kg/day, it is not possible to treat infections caused by isolates at the upper end of the wild-type distributions of Enterococcus faecalis (with MICs of 4 mg/L) and E. faecium (with MICs of 4 or 8 mg/L). For this reason, and because there are ongoing issues with the reliability of laboratory testing, EUCAST lists daptomycin breakpoints for Enterococcus species as “IE”—insufficient evidence. EUCAST advises increased vigilance in the use of high-dose of daptomycin to treat enterococcal BSI and endocarditis. Additional PK-PD studies and prospective efficacy and safety studies of serious Enterococcal infections treated with high-dose daptomycin may permit the setting of breakpoints in the future.     

Gentamicin susceptibility in Escherichia coli related to the genetic background: problems with breakpoints

In total, 120 Escherichia coli isolates positive for one of the gentamicin resistance (GEN(R)) genes aac(3)-II, aac(3)-IV or ant(2')-I were tested for gentamicin susceptibility by the agar dilution method. Isolates positive for aac(3)-IV or ant(2')-I had an MIC distribution of 8-64 mg/L, whereas isolates positive for aac(3)-II had MICs of 32 to >512 mg/L, suggesting a relationship between the distribution of MICs and the specific GEN(R) mechanism. The MIC distribution, regardless of the GEN(R) mechanism, was 8 - >512 mg/L, which supports the clinical breakpoint of MIC >4 mg/L suggested by EUCAST and questions the breakpoint recommended by the CLSI (> or =16 mg/L).     

一金颗粒对动物小肠与急性胰腺炎的药理作用

目的：观察一金颗粒的药效学作用。方法：通过不同动物观察一金颗粒对小肠与急性胰腺炎的药理作用，采用（1）墨汁法观察一金颗粒对小鼠肠蠕动的作用；（2）离体肠肌试验观察一金颗粒对家兔离体肠肌的作用；（3）毛细血管通透性试验观察一金颗粒对小鼠毛细血管通透性的作用；（4）3％牛磺胆酸钠胰腺被膜下注射复制急性胰腺炎模型，观察一金颗粒对急性胰腺炎大鼠的治疗作用。结果：（1）小鼠肠内墨汁的推进率在大、中剂量组明显高于阴性对照组，而小剂量组略有增加；（2）能增加肠肌蠕动的幅度和频率，其中以频率增加为主；（3）各剂量组均可使小鼠毛细血管通透性降低；（4）3、6h各剂量组均可使血淀粉酶较模型有显著降低。结论：一金颗粒具有一定的增加肠蠕动．抗炎及抗胰腺炎的作用。     

The use of sequential silver and quinacrine staining to determine the parental origin and breakpoints of a ring-22 human chromosome

We delineated a G-ring syndrome in 1968 and suggested it was due to a ring-22 (Weleber et al. 1969). We confirmed in 1972 that the ring was derived from chromosome 22 (Magenis et al. 1973). The present report constitutes a new case of the ring-22 syndrome with clinical findings virtually identical to those we described earlier. By sequential staining techniques with silver and quinacrine, it was possible to determine the parental origin of the ring (maternal) and to estimate the breakpoints in the chromosome 22 (22p12 and 22q13) leading to the ring configuration. The clinical abnormalities are due to terminal deletion of 22q distal to the breakpoint in band 22q13. The silver technique, especially in sequence with other stains, provides new and useful data concerning the origin and precise cytology of this, one of the tiniest rings known in humans.     

The role of whole genome sequencing in antimicrobial susceptibility testing of bacteria: report from the EUCAST Subcommittee

Whole genome sequencing (WGS) offers the potential to predict antimicrobial susceptibility from a single assay. The European Committee on Antimicrobial Susceptibility Testing established a subcommittee to review the current development status of WGS for bacterial antimicrobial susceptibility testing (AST).The published evidence for using WGS as a tool to infer antimicrobial susceptibility accurately is currently either poor or non-existent and the evidence / knowledge base requires significant expansion. The primary comparators for assessing genotypic–phenotypic concordance from WGS data should be changed to epidemiological cut-off values in order to improve differentiation of wild-type from non-wild-type isolates (harbouring an acquired resistance). Clinical breakpoints should be a secondary comparator. This assessment will reveal whether genetic predictions could also be used to guide clinical decision making. Internationally agreed principles and quality control (QC) metrics will facilitate early harmonization of analytical approaches and interpretive criteria for WGS-based predictive AST. Only data sets that pass agreed QC metrics should be used in AST predictions. Minimum performance standards should exist and comparative accuracies across different WGS laboratories and processes should be measured. To facilitate comparisons, a single public database of all known resistance loci should be established, regularly updated and strictly curated using minimum standards for the inclusion of resistance loci. For most bacterial species the major limitations to widespread adoption for WGS-based AST in clinical laboratories remain the current high-cost and limited speed of inferring antimicrobial susceptibility from WGS data as well as the dependency on previous culture because analysis directly on specimens remains challenging.For most bacterial species there is currently insufficient evidence to support the use of WGS-inferred AST to guide clinical decision making. WGS-AST should be a funding priority if it is to become a rival to phenotypic AST. This report will be updated as the available evidence increases.     

Pharmacokinetic/pharmacodynamic assessment of the in-vivo efficacy of imipenem alone or in combination with amikacin for the treatment of experimental multiresistant Acinetobacter baumannii pneumonia

A guinea-pig pneumonia model involving imipenem-susceptible and imipenem-resistant strains of Acinetobacter baumannii was developed to assess the in-vitro and in-vivo activities of imipenem, alone or in combination with amikacin, and the pharmacokinetic and pharmacodynamic parameters. Serum levels were measured by bioassay (imipenem) or immunoassay (amikacin), followed by calculation of pharmacokinetic and pharmacodynamic parameters (Cmax, AUC, t1/2, Cmax/MIC, AUC/MIC, and Deltat/MIC). In-vivo efficacy was evaluated by comparing bacterial counts in the lungs of treatment groups with end-of-therapy controls by anova and post-hoc tests. Decreases in the Cmax (13.4%), AUC (13%), t1/2 (25%) and Deltat/MIC (11.8-32.2%) of imipenem were observed when it was administered with amikacin, compared with administration of imipenem alone. Similarly, decreases in the Cmax (34.5%), AUC (11.6%), Cmax/MIC (34.5%) and AUC/MIC (11.7%) of amikacin were observed when it was administered with imipenem. Bacterial counts in lungs were reduced by imipenem (p 0.004) with the imipenem-susceptible strain, and by amikacin (p 0.001) with the imipenem-resistant strain. The combination of imipenem plus amikacin was inferior to imipenem alone with the imipenem-susceptible strain (p 0.01), despite their in-vitro synergy, and was inferior to amikacin alone with the imipenem-resistant strain (p < 0.0001). In summary, combined use of imipenem with amikacin was less efficacious than monotherapy, probably because of a drug-drug interaction that resulted in decreased pharmacokinetic and pharmacodynamic parameters for both antimicrobial agents.     

How to interpret MICs of antifungal compounds according to the revised clinical breakpoints v. 10.0 European committee on antimicrobial susceptibility testing (EUCAST)

BackgroundEUCAST has revised the definition of the susceptibility category I from ‘Intermediate’ to ‘Susceptible, Increased exposure’. This implies that I can be used where the drug concentration at the site of infection is high, either because of dose escalation or through other means to ensure efficacy. Consequently, I is no longer used as a buffer zone to prevent technical factors from causing misclassifications and discrepancies in interpretations. Instead, an Area of Technical Uncertainty (ATU) has been introduced for MICs that cannot be categorized without additional information as a warning to the laboratory that decision on how to act has to be made. To implement these changes, the EUCAST-AFST (Subcommittee on Antifungal Susceptibility Testing) reviewed all, and revised some, clinical antifungal breakpoints.ObjectivesThe aim was to present an overview of the current antifungal breakpoints and supporting evidence behind the changes.SourcesThis document is based on the ten recently updated EUCAST rationale documents, clinical breakpoint and breakpoint ECOFF documents.ContentThe following breakpoints (in mg/L) have been revised or established for Candida species: micafungin against C. albicans (ATU = 0.03); amphotericin B (S ≤/> R = 1/1), fluconazole (S ≤/> R = 2/4), itraconazole (S ≤/> R = 0.06/0.06), posaconazole (S ≤/> R = 0.06/0.06) and voriconazole (S ≤/> R = 0.06/0.25) against C. dubliniensis; fluconazole against C. glabrata (S ≤/> R = 0.001/16); and anidulafungin (S ≤/> R = 4/4) and micafungin (S ≤/> R = 2/2) against C. parapsilosis. For Aspergillus, new or revised breakpoints include itraconazole (ATU = 2) and isavuconazole against A. flavus (S ≤/> R = 1/2, ATU = 2); amphotericin B (S ≤/> R = 1/1), isavuconazole (S ≤ /> R = 1/2, ATU = 2), itraconazole (S ≤/> R = 1/1, ATU = 2), posaconazole (ATU = 0.25) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. fumigatus; itraconazole (S ≤/> R = 1/1, ATU = 2) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. nidulans; amphotericin B against A. niger (S ≤/> R = 1/1); and itraconazole (S ≤/> R = 1/1, ATU = 2) and posaconazole (ATU = 0.25) against A. terreus.ImplicationsEUCAST-AFST has released ten new documents summarizing existing and new breakpoints and MIC ranges for control strains. A failure to adopt the breakpoint changes may lead to misclassifications and suboptimal or inappropriate therapy of patients with fungal infections.     

Genetic counsellors in Sweden: their role and added value in the clinical setting

Genetic testing is becoming more commonplace in general and specialist health care and should always be accompanied by genetic counselling, according to Swedish law. Genetic counsellors are members of the multi-disciplinary team providing genetic counselling. This study examined the role and added value of genetic counsellors in Sweden, using a cross-sectional on-line survey. The findings showed that the genetic counsellors added value in the clinical setting by acting as the ‘spider-in-the-web'' regarding case management, having a more holistic, ethical and psychological perspective, being able to offer continuous support and build a relationship with the patient, and being more accessible than medical geneticists. The main difference between a genetic counsellor and medical geneticist was that the doctor had the main medical responsibility. Thus genetic counsellors in Sweden contribute substantially to the care of patients in the clinical genetic setting.     

The pharmacologic profile of desloratadine: a review

Desloratadine is a new agent for the treatment of diseases such as seasonal allergic rhinitis and chronic urticaria. The pharmacologic profile of desloratadine offers particular benefits in terms of histamine H₁-receptor binding potency and H₁ selectivity. Desloratadine has a half-life of 21–24 h, permitting once-daily dosing. No specific cautions are required with respect to administration in renal or hepatic failure, and food or grapefruit juice have no effect on the pharmacologic parameters. No clinically relevant racial or sex variations in the disposition of desloratadine have been noted. In combination with the cytochrome P450 inhibitors, ketoconazole and erythromycin, the AUC and C_max of desloratadine were increased to a small extent, but no clinically relevant drug accumulation occurred. With high-dose treatment (45 mg/day for 10 days), no significant adverse events were observed, despite the sustained elevation of plasma desloratadine levels. Specifically, desloratadine had no effects on the corrected QT interval (QTc) when administered alone, at high dose, or in combination with ketoconazole or erythromycin. Preclinical studies also show that desloratadine does not interfere with HERG channels or cardiac conduction parameters even at high dose. Desloratadine is nonsedating and free of antimuscarinic/anticholinergic effects in preclinical and clinical studies. Novel antiallergic and anti-inflammatory effects have also been noted with desloratadine, a fact which may be relevant to its clinical efficacy.     

Esomeprazole: potent acid suppression in the treatment of acid-related disorders

Esomeprazole (S-omeprazole), an enantiomer of the racemate omeprazole, is the first proton pump inhibitor to be developed as an isomer. This confers improved pharmacokinetics and pharmacodynamics compared with the racemate R/S-omeprazole. The difference in the pharmacokinetics of esomeprazole compared with omeprazole and the R-isomer is due to reductions in total body clearance and first-pass metabolism in the liver. Pharmacodynamic studies showed that esomeprazole 40 mg provides greater intragastric acid control than respective doses of all the other proton pump inhibitors on the market. Several well-designed clinical trials, employing both endoscopic and symptomatic response criteria, have compared the efficacy of esomeprazole with that of other proton pump inhibitors in the management of gastroesophageal reflux disease patients, and in the eradication of Helicobacter pylori. In addition, the efficacy of esomeprazole for the healing and prevention of nonsteroidal anti-inflammatory drug-associated dyspeptic symptoms and ulcers has been established. The aim of this review is to provide an overview of the pharmacokinetics, pharmacodynamics and consequent clinical importance of esomeprazole in the treatment of acid-related disorders.     

Tackling the characterization of canine chromosomal breakpoints with an integrated in-situ/in-silico approach: The canine PAR and PAB

The domestic dog continues to represent an influential model organism for comparative biomedical research owing to the numerous genetic and pathophysiological similarities shared between human and dog diseases. The combined availability of a high-quality genome assembly and a 1 Mb-resolution genome-assembly integrated bacterial artificial chromosome (BAC) panel now provides the essential resources to combine cytogenetic and computational analyses to determine the precise locations of chromosome breakpoint regions within aberrant karyotypes. In this study we demonstrate the synergy of using a such a combined in-situ/in-silico approach to define chromosome breakpoints using the naturally occurring breakpoint present on all canine X chromosomes—the pseudoautosomal breakpoint (PAB). In so doing we have further characterized the canine pseudoautosomal region (PAR) to extend approximately 6.6 Mb from the telomeric end of CFA Xp and established that the canine PAB is contained within a 2 kb region. Our characterization of the canine PAR allowed for the comparative study of gene content across previously defined mammalian PARs and indicates that the canine PAB is contained with the gene Shroom2. The future application of the approach demonstrated in this study will prove useful when seeking to identify the genomic sequences surrounding recurrent chromosome breakpoints present in canine cancers.     

Pharmacokinetic/pharmacodynamic profiling of imipenem in patients admitted to an intensive care unit in India: A nonrandomized,cross-sectional,analytical, open-labeled study

Results:The difference in the plasma imipenem concentration between the gastrointestinal and the nongastrointestinal groups was significant at 2 h (P = 0.015) following drug dosing; while the difference was significant between the skin/cellulitis and nonskin/cellulitus groups at 2 h (P = 0.008), after drug dosing. The imipenem levels were above the MIC and 5 times the MIC for the isolated organism in 96.67% and 50% of the patients, respectively.Conclusions:The pharmacokinetic profile of imipenem does not vary according to the locus of an infection in critically ill patients. Imipenem, 3 g/day intermittent dosing, maintains a plasma concentration which is adequate to treat most infections encountered in patients admitted to an ICU. However, a change in the dosing regimen is suggested for patients infected with organisms having MIC values above 4 mg/L.     

Safety,efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma

Interleukin-2 receptor α chain (CD25) is overexpressed in human T-cell leukemia virus 1 associated adult T-cell leukemia/lymphoma (ATL). Daclizumab a humanized monoclonal antibody blocks IL-2 binding by recognizing the interleukin-2 receptor α chain (CD25). We conducted a phase I/II trial of daclizumab in 34 patients with ATL. Saturation of surface CD25 on circulating ATL cells was achieved at all doses; however saturation on ATL cells in lymph nodes required 8 mg/kg. Up to 8 mg/kg of daclizumab administered every 3 weeks was well tolerated. No responses were observed in 18 patients with acute or lymphoma ATL; however, 6 partial responses were observed in 16 chronic and smoldering ATL patients. The pharmacokinetics/pharmacodynamics of daclizumab suggest that high-dose daclizumab would be more effective than low-dose daclizumab in treatment of lymphoid malignancies and autoimmune diseases (e.g., multiple sclerosis) since high-dose daclizumab is required to saturate IL-2R alpha in extravascular sites.