Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19-Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT).

Background: To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19. Methods: In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavir (LPV/RTV). The primary endpoint was time to sustained clinical improvement (≥48 h) of at least one point on the 7-category WHO scale. Secondary endpoints included length of stay (LOS), need for mechanical ventilation (MV) or death, and 29-day mortality. Results: 201 patients were included in the study (101 CM and 100 LPV/RTV) between 20 April 2020 and 14 May 2021. Mean age was 58.7 years, and 67% were male. The median time from symptom onset to randomization was 7 days (IQR 5-9). Patients in the CM group had a significantly shorter time to sustained clinical improvement (HR = 0.67, 95%-CI 0.49-0.90; 9 vs. 11 days, p = 0.008) and demonstrated less progression to MV or death [6/101 (5.9%) vs. 15/100 (15%), p = 0.036] and a shorter LOS (12 vs. 14 days, p = 0.023). A statistically nonsignificant trend toward a lower 29-day mortality in the CM group than the LPV/RTV group [2/101 (2%) vs. 7/100 (7%), p = 0.089] was observed. Conclusion: In patients hospitalized for COVID-19, the use of CM was associated with shorter time to clinical improvement, reduced need for MV or death, and shorter LOS than the use of LPV/RTV. Furthermore, research is needed to confirm the efficacy of CM in larger placebo-controlled trials. Systematic Review Registration: [https://clinicaltrials.gov/ct2/show/NCT04351724, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001302-30/AT], identifier [NCT04351724, EUDRACT-NR: 2020-001302-30].

A pharmacokinetic-pharmacodynamic (PKPD) model-based analysis of tedizolid against enterococci using the hollow-fibre infection model.

BACKGROUND: Tedizolid is a novel oxazolidinone antibiotic. Considering the higher antibacterial effect in immunocompetent compared with immunosuppressed animals, it is not recommended in immunocompromised patients. OBJECTIVES: In this study, we assessed the 'pure' pharmacokinetic-pharmacodynamic (PKPD) relationship for tedizolid against Enterococcus in the hollow-fibre infection model (HFIM). METHODS: Unbound plasma concentration time profiles (200-5000 mg/day IV) were simulated in the HFIM over 120 h against an Enterococcus faecalis strain and two clinical isolates of Enterococcus faecium (VRE-vanB and VRE-vanA). Next, a PKPD model describing tedizolid efficacy against bacterial isolates was developed. A population PK model was linked to the developed PKPD model and utilized to predict the bacterial kinetics in plasma and in target tissues [adipose, muscle, epithelial lining fluid (ELF) and sputum] over 120 h of therapy. RESULTS: The PKPD model adequately described the bacterial kill kinetics for all bacterial populations. At the human recommended dose of 200 mg/day, bacterial growth was predicted in plasma and all tissues, except for ELF. Bacteriostasis was observed only at a higher dose of 1200 mg/day over 120 h. An fAUC/MIC of 80 related to stasis over 120 h. Subpopulations resistant to 3 × MIC were amplified in plasma and target tissues, except for ELF, at doses of 200-800 mg/day. CONCLUSIONS: The human dose of 200 mg/day was insufficient to suppress bacterial growth in the HFIM, indicating that further components contribute to the clinical effect of tedizolid. This study supports the warning/precaution for tedizolid to limit its use in immunocompromised patients.

High-Dosage Fosfomycin Results in Adequate Plasma and Target-Site Exposure in Morbidly Obese and Nonobese Nonhyperfiltration Patients.

The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT>MIC (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC0-24h/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m2) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC ≤ 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of <130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement ß-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status. (This study has been registered in the EU Clinical Trials Register under EudraCT no. 2012-004383-22.).

Challenging T > MIC Using Meropenem vs. Escherichia coli and Pseudomonas aeruginosa.

Objective: For meropenem 40%T > MIC is associated with optimal killing of P. aeruginosa and E. coli. However, it is unknown how the distribution of %T > MIC through a treatment day impacts the antimicrobial effect in vitro. Therefore, we investigated the in vitro antibiotic activity of meropenem, precisely if 40%T > MIC is achieved in one single long period (single dose), 2 × 20% periods (dosing-bid), or 3 × 13.3% (dosing t.i.d.) thereby keeping the overall period of T > MIC constant. Material/Methods: Time kill curves (TKC) with P. aeruginosa-ATCC-27853 and E. coli-ATCC-25922 and five clinical isolates each were implemented over 24 h in CAMHB with concentrations from 0.25×MIC-32×MIC. Periods over and under MIC were simulated by centrifugation steps (discarding supernatant and refilling with fresh CAMHB). Double and triple dosing involved further addition and removal of antibiotic. Complementary growth controls (GC) with and without centrifugation steps were done and the emergence of phenotypical resistance was evaluated (repeated MIC-testing after antibiotic administration). Results: No impact of centrifugation on bacterial growth was seen. TKC with P. aeruginosa showed the best killing in the triple dosage, followed by the double and single dose. In multiple regimens at least a concentration of 4×MIC was needed to achieve a recommended 2-3 log10 killing. Likewise, a reduction of E. coli was best within the three short periods. Contrary to the TKCs with P. aeruginosa we could observe that after the inoculum reached a certain CFU/mL (≥10^8), no further addition of antibiotic could achieve bacterial killing (identified as the inoculum effect). For P. aeruginosa isolates resistance appeared within all regimens, the most pronounced was found in the 40%T > MIC experiments indicating that a single long period might accelerate the emergence of resistance. Contrary, for E. coli no emergence of resistance was found. Conclusion/Outlook: We could show that not solely the %T > MIC is decisive for an efficient bacterial eradication in vitro, but also the distribution of the selected %T > MIC. Thus, dividing the 40%T > MIC in three short periods requested lowers antibiotic concentrations to achieve efficient bacterial killing and reduces the emergence of resistance in P. aeruginosa isolates. The distribution of the %T > MIC did impact the bacterial eradication of susceptible pathogens in vitro and might play an even bigger role in infections with intermediate or resistant pathogens.

In vivo / in vitro Correlation of Pharmacokinetics of Gentamicin, Vancomycin, Teicoplanin and Doripenem in a Bovine Blood Hemodialysis Model.

Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy. Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma. Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min. Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

Plasma and Lung Tissue Pharmacokinetics of Ceftaroline Fosamil in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass: an In Vivo Microdialysis Study.

Ceftaroline fosamil, a fifth-generation cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), is currently approved for the treatment of pneumonia and complicated skin and soft tissue infections. However, pharmacokinetics data on free lung tissue concentrations in critical patient populations are lacking. The aim of this study was to evaluate the pharmacokinetics of the high-dose regimen of ceftaroline in plasma and lung tissue in cardiac surgery patients during intermittent and continuous administration. Nine patients undergoing elective cardiac surgery on cardiopulmonary bypass were included in this study and randomly assigned to intermittent or continuous administration. Eighteen hundred milligrams of ceftaroline fosamil was administered intravenously as either 600 mg over 2 h every 8 h (q8h) (intermittent group) or 600 mg over 2 h (loading dose) plus 1,200 mg over 22 h (continuous group). Interstitial lung tissue concentrations were measured by in vivo microdialysis. Relevant pharmacokinetics parameters were calculated for each group. Plasma exposure levels during intermittent and continuous administration were comparable to those of previously published studies and did not differ significantly between the two groups. In vivo microdialysis demonstrated reliable and adequate penetration of ceftaroline into lung tissue during intermittent and continuous administration. The steady-state area under the concentration-time curve from 0 to 8 h (AUCss 0-8) and the ratio of AUCSS 0-8 in lung tissue and AUC in plasma (AUClung/plasma) were descriptively higher in the continuous group. Continuous administration of ceftaroline fosamil achieved a significantly higher proportion of time for which the free drug concentration remained above 4 times the minimal inhibitory concentration (MIC) during the dosing interval (% fT>4xMIC) than intermittent administration for pathogens with a MIC of 1 mg/liter. Ceftaroline showed adequate penetration into interstitial lung tissue of critically ill patients undergoing major cardiothoracic surgery, supporting its use for pneumonia caused by susceptible pathogens.

Plasma and soft tissue pharmacokinetics of ceftolozane/tazobactam in healthy volunteers after single and multiple intravenous infusion: a microdialysis study.

OBJECTIVES: To investigate ceftolozane/tazobactam pharmacokinetics (PK) in plasma and interstitial space fluid (ISF) of muscle and subcutaneous tissue and establish a population PK model. METHODS: Eight healthy volunteers received four IV doses of 1000/500 mg ceftolozane/tazobactam q8h in a prospective, open-labelled PK study. ISF concentration-time profiles were determined via in vivo microdialysis up to 8 h post-dose and efficacy of unbound ceftolozane and tazobactam was estimated using the time above MIC (%ƒT>MIC) and time above threshold concentration (%T>CT), respectively. A population PK model was established by merging derived plasma and soft tissue PK data. RESULTS: Ceftolozane reached %ƒT>MIC values of 100% in plasma, muscle and subcutaneous ISF for Enterobacteriaceae and 87%, 89% and 87%, respectively, for Pseudomonas aeruginosa. Tazobactam %T>CT was 21%, 22% and 21% in plasma, muscle and subcutaneous ISF, respectively. Plasma protein binding was 6.3% for ceftolozane and 8.0% for tazobactam. Multiple-dose ceftolozane AUC0-8 ISF/plasma ratios were 0.92 ±â€Š0.17 in muscle and 0.88 ±â€Š0.18 in subcutis, and tazobactam ratios were 0.89 ±â€Š0.25 in muscle and 0.87 ±â€Š0.21 in subcutis, suggesting substantial soft tissue penetration. CONCLUSIONS: Tazobactam %T>CT values were distinctly below proposed target values, indicating that tazobactam might be underdosed in the investigated drug combination. However, ISF/unbound plasma ratios of ceftolozane and tazobactam support their use in soft tissue infections. A plasma and soft tissue PK model adds important information on the PK profile of ceftolozane/tazobactam. Further investigations in patients suffering from wound infections are needed to confirm these findings.

Risk of target non-attainment in obese compared to non-obese patients in calculated linezolid therapy.

OBJECTIVES: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. METHODS: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600-1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices. RESULTS: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0-44.9%). Both factors caused lower area under the concentration-time curve in typical obese patients in plasma (-20.4%, 95% CI -22.0% to -15.9%) and at target-site (-37.7%, 95% CI -47.1% to -24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900- and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) ≤2 mg/L (probability of target attainment 62.5-100%) but could not be reached for MIC = 4 mg/L (probability of target attainment ≤82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. DISCUSSION: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC ≤2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

A pharmacometric approach to define target site-specific breakpoints for bacterial killing and resistance suppression integrating microdialysis, time-kill curves and heteroresistance data: a case study with moxifloxacin.

OBJECTIVES: Pharmacokinetic-pharmacodynamic (PK-PD) considerations are at the heart of defining susceptibility breakpoints for antibiotic therapy. However, current approaches follow a fragmented workflow. The aim of this study was to develop an integrative pharmacometric approach to define MIC-based breakpoints for killing and suppression of resistance development for plasma and tissue sites, integrating clinical microdialysis data as well as in vitro time-kill curves and heteroresistance information, exemplified by moxifloxacin against Staphylococcus aureus and Escherichia coli. METHODS: Plasma and target site samples were collected from ten patients receiving 400 mg moxifloxacin/day. In vitro time-kill studies with three S. aureus and two E. coli strains were performed and resistant subpopulations were quantified. Using these data, a hybrid physiologically based (PB) PK model and a PK-PD model were developed, and utilized to predict site-specific breakpoints. RESULTS: For both bacterial species, the predicted MIC breakpoint for stasis at 400 mg/day was 0.25 mg/L. Less reliable killing was predicted for E. coli in subcutaneous tissues where the breakpoint was 0.125 mg/L. The breakpoint for resistance suppression was 0.06 mg/L. Notably, amplification of resistant subpopulations was highest at the clinical breakpoint of 0.25 mg/L. High-dose moxifloxacin (800 mg/day) increased all breakpoints by one MIC tier. CONCLUSIONS: An efficient pharmacometric approach to define susceptibility breakpoints was developed; this has the potential to streamline the process of breakpoint determination. Thereby, the approach provided additional insight into target site PK-PD and resistance development for moxifloxacin. Application of the approach to further drugs is warranted.

Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients - A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial.

BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. METHODS: We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m2 for obese or between 18.5 and 30 kg/m2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0-8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC0-8) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. DISCUSSION: Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. TRIAL REGISTRATION: EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776).

Impact of different pathophysiological conditions on antimicrobial activity of glycopeptides in vitro.

OBJECTIVES: Susceptibility testing is usually performed under standardized conditions for comparison of the activity of antimicrobial agents and the susceptibility of strains, but this does not reflect potential pathophysiological alterations at the infection site. While some impact factors have been studied already, there is a lack of knowledge about how different factors interact pharmacodynamically. We investigated the impact of albumin, pH and temperature in various combinations on the antimicrobial activity of glycopeptides. METHODS: Determination of minimal inhibitory concentrations (MICs) and time-kill curves were performed for telavancin, vancomycin and teicoplanin using 20 clinical isolates of Staphylococcus aureus and ATCC29213. The impact of the addition of 12% albumin, pH reduction to pH6, and temperature ranging from 32°C to 42°C was studied and compared to the standard setting in the reference medium Mueller Hinton broth (MHB). RESULTS: At pH7 and 37°C the addition of albumin increased median MICs four-fold, eight-fold and two-fold for telavancin, teicoplanin and vancomycin, respectively. While changing temperature or pH alone had a moderate impact, the combination of albumin addition, pH decrease and temperature increase led to the maximum reduction of activity of 16-fold for teicoplanin compared to the standard setting. Temperature increase to 42°C increased the effect of albumin for teicoplanin and telavancin, resulting in ratios of 15.9 and 8. In contrast, reducing pH with concomitant albumin addition reduced the effect of albumin addition alone for telavancin, resulting in a ratio of 2 instead of 4. CONCLUSION: Combining different impact factors showed a highly heterogeneous impact on the activity of glycopeptides. It might be misleading to take only protein binding into consideration in pharmacokinetic/pharmacodynamic (PK/PD) models.

Cutaneous innervation of the hand: clinical testing in volunteers shows high intra- and inter-individual variability.

BACKGROUND: Many clinicians require a solid understanding of the anatomical areas supplied by specific peripheral nerves. Virtually all pertinent medical textbooks claim that the entire (palmar and dorsal) surface of the hand is supplied by three (median, radial, and ulnar) nerves and that each of these covers a well-defined area. This study was designed to evaluate the sensory-distribution pattern of peripheral nerves in the hand. METHODS: Twelve volunteers were enrolled and randomly allocated to have median, ulnar, or radial nerve blocks to each hand on three successive days. All blocks were performed using ultrasound guidance. A neurologist carried out pinprick testing to define the sensory-distribution area of each procedure. The hand surface was then scanned, and the sensory-distribution area of the blocked nerve was traced, measured, and quantified in relation to the entire hand surface for descriptive and comparative statistical analyses. RESULTS: The sensory-distribution areas of the three nerves revealed a high degree of inter-individual and intra-individual variabilities. Sizeable areas were not covered by any of the three nerves, again involving great variability. Conversely, 15 of the 24 hands showed areas of overlapping supply from more than one nerve. CONCLUSIONS: Our findings suggest that the anatomical areas supplied by peripheral nerves are characterised by much greater variability than is routinely claimed. CLINICAL TRIAL REGISTRATION: DRKS00010707.

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Concentrations of Cefuroxime in Brain Tissue of Neurointensive Care Patients.

Effective concentrations of antibiotics in brain tissue are essential for antimicrobial therapy of brain infections. However, data concerning cerebral penetration properties of antibiotics for treatment or prophylaxis of central nervous system infections are rare. Six patients suffering subarachnoid hemorrhage and requiring cerebral microdialysis for neurochemical monitoring were included in this study. Free interstitial concentrations of cefuroxime after intravenous application of 1,500 mg were measured by microdialysis in brain tissue, as well as in plasma at steady-state (n = 6) or after single-dose administration (n = 1). At steady state, free area under the concentration-time curve from 0 to 24 h (AUC0-24) values of 389.0 ± 210.3 mg/liter·h and 131.4 ± 72.8 mg/liter·h were achieved for plasma and brain, respectively, resulting in a brain tissue penetration ratio (AUC0-24 brain/AUC0-24 free plasma) of 0.33 ± 0.1. Plasma and brain tissue concentrations at individual time points correlated well (R = 0.59, P = 0.001). At steady-state time over MIC (t>MIC) values of >40% of dosing interval were achieved up to an MIC of 16 mg/liter for plasma and 4 mg/liter for brain tissue. Although MIC90 values could not be achieved in brain tissue for relevant bacteria, current dosing strategies of cefuroxime might be sufficient to treat pathogens with MIC values up to 4 mg/liter. The activity of cefuroxime in brain tissue might be overestimated when relying exclusively on plasma levels. Although currently insufficient data after single dose administration exist, lower brain-plasma ratios observed after the first dose might warrant a loading dose for treatment and perioperative prophylaxis.

Penetration of linezolid into synovial fluid and muscle tissue after elective arthroscopy.

Objectives: Penetration of antibiotics into synovial fluid is crucial to combat septic arthritis efficiently. Since linezolid may be used for treatment of septic arthritis when methicillin-resistant bacterial strains are suspected, we investigated its target-site concentrations in synovial fluid. Patients and methods: Ten patients undergoing elective knee arthroscopy were included in this study. Subjects received a single dose of 600 mg of linezolid intravenously and linezolid concentrations were measured in plasma and by using microdialysis in muscle tissue and synovial fluid. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing ability were performed using CLSI breakpoints and MIC90 for clinical isolates. Results: All 10 subjects tolerated linezolid well. As indicated by AUCtissue/AUCfree plasma ratios of 0.76 ±âŸ0.34 (synovial fluid) and 0.98 ±âŸ0.62 (muscle tissue) linezolid penetrated well into the knee gap and tissue. In synovial fluid AUC0-24/MIC ratios for bacteria with an MIC of 1, 2 and 4 mg/L were 86.8 ±âŸ47.0, 43.4 ±âŸ23.5 and 21.7 ±âŸ11.8, respectively. Conclusions: Linezolid may be used to treat septic arthritis caused by bacterial strains with an MIC ≤1 mg/L. Assuming a pharmacokinetic/pharmacodynamic target of > 50 for AUC0-24/MIC, when treating strains with an MIC >1 mg/L treatment surveillance is warranted. However, pharmacokinetic/pharmacodynamic targets for tissue are poorly understood and clinical data are needed to verify our assumptions.

Pharmacokinetics of Cefuroxime in Synovial Fluid.

Cefuroxime is frequently used as preoperative antibiotic prophylaxis and may be used for the treatment of septic arthritis. A prerequisite for successful treatment of septic arthritis is the ability of an antibiotic agent to penetrate into the target site. Therefore, the concentration of cefuroxime in synovial fluid was evaluated. Ten patients who underwent elective knee arthroscopy were included in this study. Patients were treated with a single dose of 1,500 mg cefuroxime intravenously, and subsequently, the concentrations in plasma, the interstitial fluid of muscle tissue, and synovial fluid were measured by using microdialysis. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing were performed using the epidemiologically defined MIC90 for clinical isolates and CLSI breakpoints. Cefuroxime penetrated excellently into muscle tissue (ratio of the area under the concentration-time curve [AUC] for muscle tissue/AUC for free plasma, 1.79) and synovial fluid (ratio of the AUC for synovial fluid/AUC for free plasma, 1.94). The cefuroxime concentration was greater than the MIC90 for Staphylococcus aureus and S. epidermidis strains (≤2 mg/liter) over the complete dosing interval (the percentage of the dosing interval during which the free cefuroxime concentration exceeded the MIC for the pathogen [fTMIC]). CLSI defines staphylococci with MICs of ≤8 mg/liter to be susceptible to cefuroxime. For staphylococci with MICs of ≤8 mg/liter, the fTMIC in plasma was 52.5%, while the fTMIC in muscle tissue and synovial fluid was 93.6% and 96.3%, respectively. Cefuroxime may be used to treat septic arthritis caused by susceptible bacterial strains (MIC ≤ 8 mg/liter). The activity of cefuroxime in septic arthritis might be underestimated when relying exclusively on plasma concentrations.