Stefania Fallani

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection

Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program.

Valganciclovir for congenital CMV infection : A pilot study on plasma concentration in newborns and infants

The pharmacokinetics of valganciclovir were studied in 8 infants ranging in age from 4 to 90 days (mean 20 days). We suggest that doses of 15 mg/kg given twice daily may be suitable for neonates and young infants.

Regional and systemic prophylaxis with teicoplanin in monolateral and bilateral total knee replacement procedures: study of pharmacokinetics and tissue penetration.

Twenty-four patients undergoing monolateral or bilateral total knee replacement (TKR) procedures were randomized to receive teicoplanin (T) either systemically or regionally. Subjects scheduled for systemic prophylaxis and undergoing monolateral (six patients) or bilateral (five patients) TKR received a single 800-mg dose of T in 100 ml of saline as a 5-min infusion into a forearm vein 2.5 h before surgery. For regional prophylaxis, patients undergoing monolateral surgery (eight subjects) received 400 mg of T in 100 ml of saline as a 5-min infusion into a foot vein of the leg to be operated on immediately after the tourniquet was inflated. For the five patients scheduled for bilateral operation and regional prophylaxis, the administration of T was also repeated for the second knee operation. The tourniquet, as the standard TKR surgical technique, was inflated to 400 mm Hg (c. 50 kPa) in all 24 patients immediately before the beginning of surgery and kept in place for the duration of the operation. Samples of serum, bone, skin, synovia, and subcutaneous tissue were collected at timed intervals during surgery. They were microbiologically assayed for T by using Bacillus subtilis as the test organism. Overall, the mean T concentrations obtained with regional route prophylaxis were found to be 2 to 10 times higher than those achieved following systemic prophylaxis. Moreover, peak levels in different tissues after regional prophylaxis were significantly higher (P < 0.05). None of the patients experienced adverse effects due to regional or systemic T administration; no prosthetic or wound infections were observed in the follow-up period (from 12 to 26 months).

Rapid and sensitive LC-MS/MS method for the analysis of antibiotic linezolid on dried blood spot.

Linezolid is a new drug from the oxazolidinone class of antibiotics used against mycobacteria and multi-drug resistant (MDR) Gram-positive bacterial infections, which may are also glycopeptide-resistant. The drug usage in pediatric age needs an accurate drug monitoring for effective patient management. The aim of this study was to evaluate the use of dried blood spot (DBS) specimens to determinate linezolid levels during treatment. Advantages of DBS include short collection time, low invasiveness, ease and low cost of sample collection, transport and storage. The analysis was performed in LC-MS/MS operating in positive ion mode and multiple reaction monitoring (MRM) mode. The calibration curve in matrix was linear in the concentration range of 1-100 mg/L with correlation coefficient value of 0.9987. Intraday and interday coefficients of variation were within 3.6% and 13.0%, respectively. We also tested the thermal and temporal drug stability in dried blood spots at four different temperatures to evaluate the risks of sample delivery in different conditions. The short term stability studies showed that linezolid concentration remained stable for at least one month under all the conditions tested. This new assay has favorable characteristics being highly precise and accurate and allows a fast linezolid analysis with a total run time 22 min long, in gradient analysis. Concentration data for plasma and DBS samples from patients after treatment were compared showing a good correlation. Correlation between DBS data and serum samples measured by HPLC-UV was satisfactory. The benefit for patients is the ability to monitor the treatment with a simple and convenient sample collection at home.

Drug repositioning: auranofin as a prospective antimicrobial agent for the treatment of severe staphylococcal infections

Auranofin, (AF), a gold(I) complex in clinical use for the therapy of rheumatoid arthritis, is reported here to produce remarkable bactericidal effects in vitro against Staphylococcus sp. Noticeably, a similar antimicrobial action and potency are also noticed toward a few methicillin-resistant Staphylococcus aureus strains but not toward Escherichia coli. The time and concentration dependencies of the antimicrobial actions of AF have been characterized through recording time kill curves, and a concentration dependent profile highlighted. Overall, the present results point out that auranofin might be quickly and successfully repurposed for the treatment of severe bacterial infections due to resistant Staphylococci.

Prospective Phase II Single-Center Study of the Safety of a Single Very High Dose of Liposomal Amphotericin B for Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia

ABSTRACT Some preclinical and pharmacokinetic studies suggested the variable safety and the potential efficacy of an antifungal prophylaxis with a single high dose of liposomal amphotericin B (L-AmB) in high-risk patients. An open-label, prospective study was conducted with 48 adults receiving induction chemotherapy for acute myeloid leukemia (AML). Patients received a single infusion of 15 mg/kg of body weight L-AmB and, eventually, a second dose after 15 days of persistent neutropenia. The primary objective was tolerability and safety. Efficacy was also evaluated as a secondary endpoint. A pharmacokinetic study was performed with 34 patients in order to evaluate any association of plasma L-AmB levels with toxicity and efficacy. Overall, only 6 patients (12.5%) reported Common Toxicity Criteria (CTC) grade 3 hypokalemia, which was corrected with potassium supplementation in all cases, and no patient developed clinically relevant nephrotoxicity. Mild infusion-related adverse events occurred after 6 of 53 (11.3%) total infusions, with permanent drug discontinuation in only one case. Proven invasive fungal disease (IFD) was diagnosed in 4 (8.3%) patients. The mean AmB plasma levels at 6 h, 24 h, and 7 days after L-AmB administration were 160, 49.5, and 1 mg/liter, respectively. The plasma AmB levels were higher than the mean values of the overall population in 3 patients who developed CTC grade 3 hypokalemia and did not significantly differ from the mean values of the overall population in 3 patients who developed IFD. Our experience demonstrates the feasibility and safety of a single 15-mg/kg L-AmB dose as antifungal prophylaxis in AML patients undergoing induction chemotherapy.

In Vivo Pharmacodynamic Evaluation of Clarithromycin in Comparison to Erythromycin

Abstract The efficacy of various dosing regimens of clarithromycin and erythromycin against recently isolated Streptococcus pneumoniae strains was determined In Vivo using two animal infection models (mouse peritonitis and thigh infection). For the thigh infection model, mice received a total dose of 4 mg/Kg of either clarithromycin or erythromycin, as a single total dose or divided into 2, 4 or 8 doses/24h. After 24h of therapy S. pneumoniae organisms were killed at 2.06 to 4.03 log10 CFU/thigh by clarithromycin and the one- or two-dose regimens were significantly more effective than the four- or eight-dose regimens. Organism killing following 24h of therapy with erythromycin ranged from 1.13 to 2.31 log10 CFU/thigh, with the one- or two-dose regimens significantly less effective than the four- or eight-dose regimens. In the mouse survival study, the same dose of either clarithromycin or erythromycin was given as a single total dose or divided into two or four doses with dosing intervals of 4 and 2-times the t1/2 respectively. The results obtained in this model show that there is a significant difference in survival when clarithromycin is administered less frequently (4% deaths for the one-dose regimen in comparison to 40% deaths with the four-dose regimen, P<0.01, Chisquare test). With erythromycin there was a trend for increased survival with the multiple-dose regimen, with significantly higher survival when concentrations exceeding the MIC were maintained for a longer time period. These results indicate that the time during which serum concentrations exceeding the MIC value of the pathogen is an important parameter for efficacy for erythromycin. On the contrary, results with both animal models demonstrate that bacterial killing and survival are significantly higher among clarithromycin-treated mice when the antibiotic is administered less frequently and the highest Cmax/MIC ratio is achieved.

Azithromycin Concentrations in Serum and Bronchial Secretions of Patients with Cystic Fibrosis

AbstractObjective: To measure azithromycin (AZM) concentrations in serum and bronchial secretions in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa pulmonary infection. Patients and Methods: 10 CF patients (four male, six female; mean age 29 ± 10 years) with chronic P. aeruginosa pulmonary infection were randomised to receive either 500 or 1000mg of AZM (five patients per group) orally once daily for 5 days. Concentrations of AZM in serum and bronchial secretions (obtained after physiotherapy) were evaluated every 24 hours for the 5 days of administration and the following 6 days. Main Outcome Measures and Results: High AZM concentrations were found in bronchial secretions, persisting after drug administration had ended. Mean concentrations were ≥4 mg/L for the 1000 mg/day dose from day 2 to 11 and >2 mg/L for the 500 mg/day dose from day 2 to day 10. Serum AZM concentrations were much lower (<0.4 mg/L for the 1000 mg/day, and <0.2 mg/L for the 500 mg/day, dosage). Conclusions: These data appear to indicate the possibility of obtaining in vivo AZM concentrations previously shown to inhibit production of virulence factors in P. aeruginosa in vitro. We consider that clinical trials evaluating prolonged administration of AZM to CF patients would be both useful and justifiable.

Efficacy of Caspofungin against Aspergillus terreus

ABSTRACT We investigated the in vitro and in vivo activities of caspofungin against Aspergillus terreus. The drug increased survival and reduced tissue fungal burden in neutropenic mice. Therefore, our data support the role of caspofungin in treating systemic infections due to this emerging pathogen.

Daptomycin serum levels in critical patients undergoing continuous renal replacement

Abstract Background: Daptomycin pharmacokinetics has not been extensively studied in patients undergoing continuous renal replacement therapy (CRRT). Methods: The aim of the study was to collect pharmacokinetics and clinical data of patients undergoing CRRT and receiving daptomycin therapy. Daptomycin was measured using an isocratic high-performance liquid chromatography technique. Results: Three patients with bloodstream infection underwent CVVHD and three CVVHDF. CVVHDF patients had significantly lower mean AUC0−24 and Cmax values. A significant decrease in plasma levels was observed in a CVVHDF patient using ‘high cut-off’ hemofilters. Conclusion: Increasing doses of daptomycin should be considered in critical patients, especially those undergoing CVVHDF.