Pulmonary surfactant impacts in vitro activity of selected antifungal drugs against Candida krusei and Candida albicans.

PURPOSE: This study investigates how surfactants affect the in-vitro anti-infective efficacy of micafungin, caspofungin, anidulafungin, and amphotericin B in treating pulmonary mycoses. METHODS: MIC values for antifungal agents were determined against Candida krusei (now Pichia kudriavzevii) ATCC 6258, Candida albicans ATCC 90028, and 18 clinical isolates using the broth microdilution method in RPMI medium, following EUCAST recommendations. MIC assays included testing with and without Curosurf® surfactant at 1 mg/mL for C. krusei ATCC 6258 and all C. krusei isolates. Subsequent Time-kill studies in Sabouraud broth involved testing both C. albicans ATCC 90028 and C. krusei ATCC 6258 strains at concentrations equal their respective MIC values, with and without surfactant, using all four antifungals. CFU/mL were assessed at multiple time points up to 24 h. TKCs with different surfactant concentrations for C. krusei ATCC 6258 and mini-TKCs at various concentrations relative to the MIC of C. krusei isolates and the reference strain were conducted with micafungin, anidulafungin, and caspofungin. RESULTS: MIC results showed that 1 µg/mL surfactant reduced killing of micafungin and anidulafungin against C. krusei, while caspofungin was unaffected. Amphotericin B's MIC decreased by half. TKCs demonstrated significant effects of surfactant on micafungin and anidulafungin against C. krusei, with complete abolition of anidulafungin's activity against C. albicans. CONCLUSION: This in-vitro study highlights the concentration-dependent inhibitory effect of surfactant on antifungal activity against C. krusei and, to some extent, C. albicans, necessitating further clinical validation for invasive lung mycoses treatment.

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment.

BACKGROUND AND OBJECTIVE: Ceftaroline fosamil is a ß-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, 'standard dosing') or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2-4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility. METHODS: A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment (ƒT>MIC = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032-8 mg/L). RESULTS: A two-compartment model with linear elimination adequately described ceftaroline concentrations (n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒT>MIC systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒT>MIC the most. CONCLUSION: The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility.

Equated hospitalization rate of patients with inflammatory rheumatic diseases as compared to normal population in 2°wave SARSCoV2 infection.

OBJECTIVE: To investigate the clinical manifestations and outcome of COVID-19 in patients with inflammatory rheumatic and musculoskeletal disease (iRMD) as compared with the general population. METHODS: This is a case-control study of patients selected from the South-Tyrol public health service-Italy with and without iRMD affected by COVID-19. We included patients ≥18 years and with a positive SARS-CoV-2 PCR test between 1.10.2020 and 01.03.2021. Cases were identified by linking the diagnosis of a rheumatic disease with PCR test positivity; these were matched in a 1:1.8 (planned 1:2) ratio for age, sex, and date of COVID-19 diagnosis with people from the general population. The outcomes of primary interest were hospitalization and severe course (intensive care unit, mechanical ventilation/extracorporeal membrane oxygenation, death). RESULTS: The study population consisted of 561 COVID-19 patients, of which 201 (mean age 60.4 years; 65.2% female) were patients with iRMD and 360 were controls from the general population (59.8 years; 64.7% female). The majority of iRMD patients (88.6%) received an immunosuppressive drug at time of COVID-19 diagnosis, 36.3% were under glucocorticoids. COVID-19 related hospitalization (12.4% vs 10.6%, p= 0.49), severe course (5.0% vs 5.3%, p= 1.00), and mortality (3.5% vs 4.4%, p= 0.66) were similar between groups. Among hospitalized patients, mechanic ventilation was more common in iRMD patients than in controls [n = 5 (20.0%) vs n = 1 (2.6%), p= 0.035]. CONCLUSIONS: Our study indicates similar rates for admission, severe course and mortality between patients with iRMD and controls affected by COVID-19. Among hospitalized patients, mechanical ventilation was more frequently required in the iRMD group.

Plasma and intraperitoneal pharmacokinetics of ceftazidime/avibactam in peritoneal dialysis patients.

OBJECTIVES: Peritonitis is a serious complication in patients undergoing automated peritoneal dialysis (APD) that increases morbidity and frequently disqualifies patients from the peritoneal dialysis programme. Ceftazidime/avibactam (CAZ/AVI) is a potential treatment option for APD patients with peritonitis caused by resistant Gram-negative bacteria, but limited data exist on systemic and target-site pharmacokinetics (PK) in patients undergoing APD. This study set out to investigate the PK of CAZ/AVI in plasma and peritoneal dialysate (PDS) of patients undergoing APD. METHODS: A prospective, open-label PK study was conducted on eight patients undergoing APD. CAZ/AVI was administered as a single intravenous dose of 2 g/0.5 g over 120 minutes. APD cycles were initiated 15 hours after the study drug administration. Dense PDS and plasma sampling was performed for 24 hours after the start of administration. PK parameters were analysed with population PK modelling. Probability of target attainment (PTA) was simulated for different CAZ/AVI doses. RESULTS: PK profiles of both drugs in plasma and PDS were similar, indicating that the two drugs are well suited for a fixed-dose combination. A two-compartment model best described the PK of both drugs. A single dose of 2 g/0.5 g CAZ/AVI led to concentrations that far exceeded the PK/PD targets of both drugs. In the Monte Carlo simulations, even the lowest dose (750/190 mg CAZ/AVI) achieved a PTA of >90% for MICs up to 8 mg/L (The European Committee on Antimicrobial Susceptibility Testing epidemiological cut-off value for Pseudomonas aeruginosa) in plasma and PDS. DISCUSSION: On the basis of PTA simulations, a dose of 750/190 mg CAZ/AVI would be sufficient to treat plasma and peritoneal fluid infections in patients undergoing APD.

Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers.

PURPOSE: A population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets. METHODS: Eight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC24h/MIC of 83 and 75%T>MIC) and bacteriostatic (AUC24h/MIC of 25) plasma targets and bacteriostatic (AUC24h/MIC of 3994) urine target. RESULTS: A total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L. CONCLUSION: For the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T>MIC target than intermittent infusion.

Effect of the human endotoxin challenge on tedizolid tissue penetration.

The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6 days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2 ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75-1.15] vs. 1.14 [1.11-1.43] mg × h/L, P = .0078) and muscle tissue fCmax (0.15 [0.14-0.19] vs. 0.19 [0.18-0.24] mg/L, P = .0078) were significantly increased by 38% and 24%, respectively. The human endotoxin challenge was associated with increased tissue concentrations of tedizolid, without affecting its plasma concentration-time profile. The human endotoxin challenge combined with microdialysis may be used to investigate the influence of systemic inflammation on tissue pharmacokinetics.

Binding of temocillin to plasma proteins in vitro and in vivo: the importance of plasma protein levels in different populations and of co-medications.

BACKGROUND: Temocillin plasma protein binding (PPB) in healthy individuals is reported to be ∼85% but had not been studied in patients. OBJECTIVES: To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU. METHODS: Plasma was obtained from healthy individuals (Group #1), non-ICU patients with UTI (Group #2), ICU patients with suspected/confirmed ventriculitis (Group #3) or with sepsis/septic shock (Group #4). Total and unbound temocillin concentrations were measured in spiked samples from temocillin-naive donors (in vitro) or in plasma from temocillin-treated subjects (in vivo). The impact of diluting plasma, using pharmaceutical albumin, or adding drugs potentially competing for PPB was tested in spiked samples. Data were analysed using a modified Hill-Langmuir equation taking ligand depletion into account. RESULTS: Temocillin PPB was saturable in all groups, both in vitro and in vivo. Maximal binding capacity (Bmax) was 1.2-2-fold lower in patients. At 20 and 200 mg/L (total concentrations), the unbound fraction reached 12%-29%, 23%-42% and 32%-52% in Groups #2, #3, #4. The unbound fraction was inversely correlated with albumin and C-reactive protein concentrations. Binding to albumin was 2-3-fold lower than in plasma and non-saturable. Drugs with high PPB but active at lower molar concentrations than temocillin caused minimal displacement, while fluconazole (low PPB but similar plasma concentrations to temocillin) increased up to 2-fold its unbound fraction. CONCLUSIONS: Temocillin PPB is saturable, 2-4-fold lowered in infected patients in relation to disease severity (ICU admission, hypoalbuminaemia, inflammation) and only partially reproducible with albumin. Competition with other drugs must be considered for therapeutic concentrations to be meaningful.

Perception of clinical research among patients and healthy volunteers of clinical trials.

PURPOSE: Clinical research relies on data from patients and volunteers, yet the target sample size is often not achieved. Here, we assessed the perception of clinical research among clinical trial participants to improve the recruitment process for future studies. METHODS: We conducted a single-center descriptive and exploratory study of 300 current or former participants in various phase I-III clinical trials. Questionnaires were either distributed to current clinical trial participants or emailed to former subjects. RESULTS: Subjects strongly agreed or agreed that contributing to improving medical care (> 81%), contributing to scientific research (> 79%), and trusting their treating physicians (> 77%) were motives for study participation. Among healthy volunteers, financial motives positively correlated with the number of clinical trials they had participated in (p < 0.05). Higher age positively correlated with expectation of best available treatment during study participation among patients (p < 0.05). Less than 8% of all subjects expressed "great concern" about the potential risks of sharing their personal information as part of the study. Subjects displayed "great trust" or "trust" in medical staff (86.6%) and in government research institutions (76.4%), and "very little trust" or "little trust" in pharmaceutical companies (35.4%) and health insurance companies (16.9%). CONCLUSION: Altruistic motives and trust in treating physicians were predominant motives for clinical trial participation. Older patients expected to receive the best available treatment during participation. Healthy volunteers who reported financial motives had participated in more clinical trials. Consistent with great trust in medical staff and government research institutions, little concern was expressed about the misuse of personal data during the trial.

Topical niclosamide (ATx201) reduces Staphylococcus aureus colonization and increases Shannon diversity of the skin microbiome in atopic dermatitis patients in a randomized, double-blind, placebo-controlled Phase 2 trial.

BACKGROUND: In patients with atopic dermatitis (AD), Staphylococcus aureus frequently colonizes lesions and is hypothesized to be linked to disease severity and progression. Treatments that reduce S. aureus colonization without significantly affecting the skin commensal microbiota are needed. METHODS AND FINDINGS: In this study, we tested ATx201 (niclosamide), a small molecule, on its efficacy to reduce S. aureus and propensity to evolve resistance in vitro. Various cutaneous formulations were then tested in a superficial skin infection model. Finally, a Phase 2 randomized, double-blind and placebo-controlled trial was performed to investigate the impact of ATx201 OINTMENT 2% on S. aureus colonization and skin microbiome composition in patients with mild-to-severe AD (EudraCT:2016-003501-33). ATx201 has a narrow minimal inhibitory concentration distribution (.125-.5 µg/ml) consistent with its mode of action - targeting the proton motive force effectively stopping cell growth. In murine models, ATx201 can effectively treat superficial skin infections of methicillin-resistant S. aureus. In a Phase 2 trial in patients with mild-to-severe AD (N = 36), twice-daily treatment with ATx201 OINTMENT 2% effectively reduces S. aureus colonization in quantitative colony forming unit (CFU) analysis (primary endpoint: 94.4% active vs. 38.9% vehicle success rate, p = .0016) and increases the Shannon diversity of the skin microbiome at day 7 significantly compared to vehicle. CONCLUSION: These results suggest that ATx201 could become a new treatment modality as a decolonizing agent.

Influence of tedizolid on the cytokine response to the endotoxin challenge in healthy volunteers: a cross-over trial.

BACKGROUND: Preclinical data suggested anti-inflammatory properties of tedizolid. OBJECTIVES: To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid. METHODS: In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid. RESULTS: Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155-502] versus 287 [132-541]  pg/mL; P = 0.875) and AUC0-24 (979 [676-1319] versus 1000 [647-1632]  pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0-24 of TNF-α remained also unchanged with and without tedizolid (47 [31-61] versus 54 [27-69]  pg/mL; P = 0.73 and 197 [163-268] versus 234 [146-280]  pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0-24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge. CONCLUSIONS: Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid.

Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin.

BACKGROUND AND OBJECTIVE: In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid. METHODS: Healthy subjects received a single intravenous bolus injection of a microdose of [14C]ciprofloxacin (1.1 µg, 7 kBq) with (cohort A, n = 9) or without (cohort B, n = 9) a prior intravenous infusion of a therapeutic dose of unlabeled ciprofloxacin (400 mg). Microdialysis and bronchoalveolar lavage were applied for determination of subcutaneous and intrapulmonary drug concentrations. Microdose [14C]ciprofloxacin was quantified by accelerator mass spectrometry and therapeutic-dose ciprofloxacin by liquid chromatography-tandem mass spectrometry. RESULTS: The pharmacokinetics of therapeutic-dose ciprofloxacin (cohort A) in plasma, subcutaneous tissue, and epithelial lining fluid was in accordance with previous data. In plasma and subcutaneous tissue, the dose-adjusted area under the concentration-time curve of microdose ciprofloxacin was similar in cohorts A and B and within an 0.8-fold to 1.1-fold range of the area under the concentration-time curve of therapeutic-dose ciprofloxacin. Penetration of microdose ciprofloxacin into subcutaneous tissue was similar in cohorts A and B and comparable to that of therapeutic-dose ciprofloxacin with subcutaneous tissue-to-plasma area under the concentration-time curve ratios of 0.44, 0.44, and 0.38, respectively. Penetration of microdose ciprofloxacin into epithelial lining fluid was highly variable and failed to predict the epithelial lining fluid penetration of therapeutic-dose ciprofloxacin. CONCLUSIONS: Our study confirms the feasibility of microdosing for pharmacokinetic measurements in plasma and subcutaneous tissue. Microdosing combined with microdialysis is a potentially useful tool in clinical antimicrobial drug development, but its applicability for the assessment of pulmonary pharmacokinetics with bronchoalveolar lavage requires further studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03177720 (registered 6 June, 2017).

Phase I Study to Assess Safety of Laser-Assisted Topical Administration of an Anti-TNF Biologic in Patients With Chronic Plaque-Type Psoriasis.

Ablative fractional laser treatment facilitates epidermal drug delivery, which might be an interesting option to increase the topical efficacy of biological drugs in a variety of dermatological diseases. This work aims at investigating safety and tolerability of this new treatment approach in patients with plaque-type psoriasis. Eight patients with plaque-type psoriasis were enrolled in this study. All patients received (i) ablative fractional laser microporation (AFL) of a psoriatic lesion with an Er:YAG laser + etanercept (ETA; Enbrel® solution for injection) (AFL-ETA), (ii) ETA alone on another lesion, and, if feasible, (iii) AFL alone on an additional lesion. Overall, all treatment arms showed a favorable safety profile. AFL-ETA improved the lesion-specific TPSS score by 1.75 vs. baseline, whereas ETA or AFL alone showed a TPSS score improvement of 0.75 points, a difference that was not statistically significant and might be attributable to differences in baseline scores. Topical administration of ETA to psoriatic plaques via AFL-generated micropores was generally well-tolerated. No special precautions seem necessary in future studies. Clinical benefit will need assessment in sufficiently powered follow-up studies.

Microdialysis as a potential tool for comparative assessment of tissue pharmacokinetics of two different patches containing lidocaine: A crossover pilot study.

OBJECTIVE: Lidocaine 5% patches are approved for the treatment of post-herpetic neuralgia in adults. Little information is available on the penetration of lidocaine into skin and skin-related soft tissue, which are thought to be closer to the site where lidocaine exerts its pharmacological action on neuronal structures. This pilot study investigated subcutaneous and systemic pharmacokinetics of lidocaine during topical application of two different lidocaine 5% patches. MATERIALS AND METHODS: This randomized two-way, two-period crossover study assessed lidocaine concentrations in subcutaneous tissue (by microdialysis) and plasma of n = 5 healthy subjects during 12-hour-long applications of a recently developed lidocaine 5% patch (Laboratorios Gebro Pharma, SA, Barcelona, Spain) and a marketed reference patch (Versatis 5% lidocaine patch, Grünenthal, Brunn am Gebirge, Austria), respectively. RESULTS: Lidocaine was detectable in subcutaneous tissue within 60 minutes from start of patch application, and in plasma only after a marked delay. The test formulation led to increased exposure to lidocaine in both subcutaneous tissue and plasma. CONCLUSION: This study has underscored the potential of microdialysis to comparatively assess the pharmacokinetics of two different drug formulations and encourages its further use in this area.

Protein binding of clindamycin in vivo by means of intravascular microdialysis in healthy volunteers.

OBJECTIVES: The efficacy of an anti-infective drug is influenced by its protein binding (PB), since only the free fraction is active. We hypothesized that PB may vary in vitro and in vivo, and used clindamycin, a drug with high and concentration-dependent PB to investigate this hypothesis. METHODS: Six healthy volunteers received a single intravenous infusion of clindamycin 900 mg. Antibiotic plasma concentrations were obtained by blood sampling and unbound drug concentrations were determined by means of in vivo intravascular microdialysis (MD) or in vitro ultrafiltration (UF) for up to 8 h post dosing. Clindamycin was assayed in plasma and MD fluid using a validated HPLC-UV (ultraviolet) method. Non-linear mixed effects modelling in NONMEM® was used to quantify the PB in vivo and in vitro. RESULTS: C max was 14.95, 3.39 and 2.32 mg/L and AUC0-8h was 41.78, 5.80 and 6.14 mg·h/L for plasma, ultrafiltrate and microdialysate, respectively. Calculated ratio of AUCunbound/AUCtotal showed values of 13.9%±1.8% and 14.7%±3.1% for UF and microdialysate, respectively. Modelling confirmed non-linear, saturable PB for clindamycin with slightly different median (95% CI) dissociation constants (Kd) for the alpha-1 acid glycoprotein (AAG)-clindamycin complex of 1.16 mg/L (0.91-1.37) in vitro versus 0.85 mg/L (0.58-1.01) in vivo. Moreover, the estimated number of binding sites per AAG molecule was 2.07 (1.79-2.25) in vitro versus 1.66 in vivo (1.41-1.79). CONCLUSIONS: Concentration-dependent PB was observed for both investigated methods with slightly lower levels of unbound drug fractions in vitro as compared with in vivo.

Recent Advances in Imaging for Diagnosis, Monitoring, and Prognosis of Psoriatic Arthritis.

Psoriatic arthritis (PsA) is an inflammatory condition characterized by a strong heterogeneity and multifaceted behavior. PsA manifests in two types-axial and peripheral-which may be present at the same time. Peripheral manifestations can be further divided into the articular (arthritis) and extra-articular (i.e., enthesitis and dactylitis) subgroups. In such a complex disease, imaging is often required to characterize the type of involvement and to evaluate the radiological damage and progression of PsA. In addition, imaging plays a pivotal role in clinical practice; that is, for axial involvement. Conventional radiology has been the main standard of reference for many years. However, in recent years, there has been growing interest in different imaging modalities, such as ultrasonography (US) and magnetic resonance imaging (MRI). All these techniques play a role in the diagnosis and follow-up of patients with PsA and cover all the types of the disease. US and MRI have good sensitivities and specificities for detecting synovitis, and this may be helpful for differential diagnosis with other musculoskeletal diseases and useful in the early or preclinical phases of the disease. However, US is not useful in the diagnosis of axial PsA. In addition, other modalities have been investigated in the field of PsA imaging. Computed tomography (CT), in particular, dual energy-CT and high-resolution peripheral CT (HRpQ-CT) might play an important role in the assessment of bone damage, erosions, and new bone formation. Regarding advanced functional imaging, FDG PET/CT is another interesting technique for exploring disease activity.

Clinical Pharmacokinetics of Fosfomycin after Continuous Infusion Compared with Intermittent Infusion: a Randomized Crossover Study in Healthy Volunteers.

Continuous infusion (CON) of fosfomycin has been proposed as potentially advantageous in certain clinical scenarios. However, no clinical data on the pharmacokinetics (PK) of fosfomycin after CON are available to date. This study aimed to investigate the PK of fosfomycin after CON and compare it with intermittent infusion (INT) of fosfomycin. A randomized two-way crossover study including 8 healthy male volunteers was performed. Each subject received fosfomycin as INT of 8 g over 30 min every 8 h and, separated by a washout period, as CON of 1 g/h preceded by a loading dose of 8 g over 30 min. PK sampling was performed for 18 and 24 h in the CON and INT groups, respectively. Fosfomycin was generally well tolerated. However, 2 out of 8 subjects (25%) developed thrombophlebitis at the infusion site following CON, which was prevented in the following subjects with a simultaneous coinfusion of Ringer's lactate. The steady-state maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h at steady state (AUCSS,0-24) of fosfomycin after INT were 551.5 ± 67.8 mg/liter and 3,678.5 ± 601.9 h · mg/liter, respectively. CON led to an average steady-state concentration of 183.8 ± 35.9 mg/liter, resulting in a calculated AUCSS,0-24 of 4,411.2 ± 862.4 h · mg/liter, which was 1.2-fold higher than that with INT. CON resulted in a 100% T>MIC (time during which the drug concentration exceeds the MIC) for MICs of ≤128 mg/liter, whereas the %T>MIC for INT was only 44% for an MIC of 128 mg/liter. CON of fosfomycin led to improved PK and PK/pharmacodynamic (PD) determinants in plasma of healthy volunteers. The clinical relevance of these findings remains to be investigated in patients.

Human diamine oxidase is readily released from activated neutrophils ex vivo and in vivo but is rarely elevated in bacteremic patients.

During human diamine oxidase (DAO) ELISA development we noticed that in serum DAO concentrations appear to be higher when compared to plasma. Neutrophils contain DAO in the specific granules and we hypothesized that DAO is released from neutrophils during serum coagulation. If activation of neutrophils can release DAO, its concentrations might be elevated in vivo after lipopolysaccharide (LPS) administration and in bacteremic patients. Using blood from healthy volunteers DAO concentrations were measured ex vivo in serum, citrate, EDTA and heparin plasma over several hours and after activation of neutrophils. Lipopolysaccharide and granulocyte-colony stimulating factor (G-CSF) were administered to 15 and 8 healthy volunteers, respectively and DAO concentrations were measured at different timepoints. DAO antigen levels were also determined in three different subcohorts of patients with culture-proven bacteremia and high C-reactive protein (CRP) levels. DAO concentrations were elevated in a time-dependent manner in serum but not in EDTA or citrate plasma (P < 0.01). Neutrophil activation using phorbol myristate acetate (PMA) and zymosan dose-dependently caused DAO concentrations to be elevated more than 10-fold at both 22°C and 37°C (both P-values <0.001). Administration of LPS to healthy volunteers released DAO from neutrophils (P < 0.001). Of the 55 different bacteremic patients selected from three independent cohorts only 3 (5.4%) showed highly elevated DAO concentrations. Serum DAO concentrations do not accurately reflect circulating enzyme levels but coagulation-induced neutrophil activation and consequently DAO release. Only a few bacteremic patients show high DAO concentrations able to degrade histamine rapidly.

Single-dose pharmacokinetics of temocillin in plasma and soft tissues of healthy volunteers after intravenous and subcutaneous administration: a randomized crossover microdialysis trial.

BACKGROUND: The antibiotic temocillin has recently been rediscovered as a promising therapeutic option against MDR Gram-negative bacteria. However, some aspects of the pharmacokinetic (PK) profile of the drug are still to be elucidated: subcutaneous administration of temocillin might be of interest as an alternative to the intravenous route in selected patients. Similarly, information on the penetration of temocillin into human soft tissues is lacking. OBJECTIVES: To investigate the feasibility and plasma PK of subcutaneous dosing as well as soft tissue PK of temocillin after intravenous administration to healthy volunteers. METHODS: Eight healthy volunteers received 2 g of temocillin both as intravenous and subcutaneous infusion in a randomized two-period crossover study. Concentration-time profiles of total temocillin in plasma (after both routes) and of unbound temocillin in plasma, muscle and subcutis (only after intravenous dosing) were determined up to 12 h post-dose. RESULTS: Subcutaneous dosing caused some infusion site discomfort but resulted in sustained drug concentrations over time with only slightly decreased overall exposure compared with intravenous dosing. Plasma protein binding of temocillin showed concentration-dependent behaviour and was higher than previously reported. Still, unbound drug concentrations in muscle and subcutis determined by microdialysis markedly exceeded those in plasma, suggesting good tissue penetration of temocillin. CONCLUSIONS: The subcutaneous administration of temocillin is a valid and feasible alternative to intravenous dosing. With the description of plasma protein binding and soft tissue PK of temocillin in healthy volunteers, this study provides important information that adds to the ongoing characterization of the PK profile of temocillin and might serve as input for PK/PD considerations.

A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure.

Non-compartmental analysis of telavancin microdialysis data indicated a sustained exposure in soft tissues and that unbound plasma concentrations were underestimated in vitro. The objective of the present evaluation was to develop a population pharmacokinetic model of telavancin to describe its plasma protein binding, its distribution into muscle, and subcutaneous tissue and to predict pharmacokinetic/-dynamic target attainment (PTA). Total plasma concentrations and microdialysate concentrations (plasma, subcutaneous, and muscle tissue) were available up to 24 h (plasma microdialysate, up to 8 h) post-dose from eight healthy subjects after a single intravenous infusion of 10 mg/kg telavancin. Population pharmacokinetic modeling and simulations were performed using NONMEM. A two-compartment model with saturable protein binding best described plasma concentrations. Plasma unbound fractions at steady state were 23, 15, and 11% at 100, 50, and 10% of the maximum predicted concentrations respectively. Distribution into muscle and subcutaneous tissue was non-linear and described appropriately by one additional compartment each. Based on total plasma concentrations, predicted median (95% confidence interval) values of AUC/MIC (MIC 0.125 mg/L, clinical breakpoint for MRSA) at steady state were 4009 [3421-4619] with a PTA of 96 [78-100] %. The fAUC/MIC in muscle was 496 [227-1232] with a PTA of 100 [98-100] %. The %fT>MIC was approximately 100% in plasma and interstitial space fluid of muscle and subcutaneous tissues up to an MIC of 0.25 mg/L. The model provided a new hypothesis on telavancin plasma protein binding in vivo. Proposed pharmacodynamic targets in plasma and muscle are achieved with currently approved doses of 10 mg/kg daily.

High voriconazole target-site exposure after approved sequence dosing due to nonlinear pharmacokinetics assessed by long-term microdialysis.

Voriconazole, a broad-spectrum antifungal drug used to prevent and treat invasive fungal infections, shows complex pharmacokinetics and is primarily metabolised by various CYP enzymes. An adequate unbound antibiotic concentration-time profile at the target-site of an infection is crucial for effective prophylaxis or therapy success. Therefore, the aim was to evaluate the pharmacokinetics of voriconazole after the approved sequence dosing in healthy volunteers in interstitial space fluid, assessed by microdialysis, and in plasma. Moreover, potential pharmacogenetic influences of CYP2C19 polymorphisms on pharmacokinetics were investigated. The prospective, open-labelled, uncontrolled long-term microdialysis study included 9 healthy male individuals receiving the approved sequence dosing regimen for voriconazole. Unbound voriconazole concentrations were sampled over 84 h in interstitial space fluid of subcutaneous adipose tissue and in plasma and subsequently quantified via high-performance liquid chromatography. For pharmacokinetic data analysis, non-compartmental analysis was used. High interindividual variability in voriconazole concentration-time profiles was detected although dosing was adapted to body weight for the first intravenous administrations. Due to nonlinear pharmacokinetics, target-site exposure of voriconazole in healthy volunteers was found to be highly comparable to plasma exposure, particularly after multiple dosing. Regarding the CYP2C19 genotype-predicted phenotype, the individuals revealed a broad spectrum, ranging from poor to rapid metaboliser status. A strong relation between CYP2C19 genotype-predicted phenotype and voriconazole clearance was identified.