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ABSTRACT: Daptomycin is bactericidal against Gram-positive bacteria, with peak-dependent effect but trough-dependent toxicity. This study was performed to develop dosing recommendations in continuous venovenous haemodiafiltration (CVVHDF).
Nine critically ill patients in intensive care units of the Medical University Hospital of Vienna, requiring CVVHDF due to acute renal failure and antimicrobial treatment, were included. Blood and effluent samples were collected over 72 h to determine daptomycin concentrations by HPLC. Pharmacokinetic parameters were based on 10 sampling timepoints during the first 24 h, and peak and trough samples thereafter. An open two-compartment model was fitted to each subject's plasma concentration-time data. Simulations of serum concentration-time profiles after different doses and intervals were performed using ADAPT 5.
Peak plasma concentrations with 6 mg/kg daptomycin were 62.2 ± 16.2, 66.1 ± 17.3 and 78.5 ± 22.1 mg/L on days 1, 2 and 3, respectively. The total clearance was 6.1 ± 4.9 mL/min, and the elimination half-life was 17.8 ± 9.7 h. Daptomycin was filtrated and could therefore be measured in the effluent. Protein binding was lower than that seen in healthy volunteers. The unbound fraction was 16 ± 4.5%. All subjects maintained trough serum concentrations above 4 mg/L, at which relevant pathogens are considered daptomycin-susceptible. Accumulation resulted when daptomycin was given every 24 h. Simulation of 8 mg/kg daptomycin given every 48 h resulted in adequate levels without accumulation.
We recommend 8 mg/kg daptomycin every 48 h in patients on CVVHDF and therapeutic drug monitoring, if possible.
Journal of Antimicrobial Chemotherapy 12/2011; 67(4):977-83. · 5.07 Impact Factor
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ABSTRACT: the objective of the present investigation was to measure the extracellular concentrations of cefpirome in unaffected and infected lung tissue of septic patients.
a single intravenous dose of 30 mg/kg total body weight of cefpirome was administered to eight patients every 12 h prior to insertion of microdialysis probes into lung tissue.
the median (minimum, maximum) peak concentration (C(max)), time to C(max) (T(max)), area under the concentration-time curve from 0 to 4 h (AUC(0-4)) and AUC(0-∞) of unbound cefpirome for unaffected lung were 48 (32, 107) mg/L, 0.83 (0.17, 3.17) h, 117 (60, 177) mg · h/L and 182 (80, 382) mg · h/L, respectively. The corresponding values for infected lung tissue were 45 (6, 122) mg/L, 1.17 (0.83, 2.83) h, 92 (17, 253) mg · h/L and 206 (49, 379) mg · h/L, respectively. The median apparent terminal elimination half-lives (t(½z)) of cefpirome were 2.61, 3.05 and 3.39 h for plasma, unaffected lung and infected lung, respectively. The median ratios of the AUC(0)(-∞) for lung to the AUC(0)(-∞) for plasma were 0.63 (0.19, 1.55) and 0.46 (0.32, 0.98) for unaffected and infected lung, respectively.
we provide strong evidence that cefpirome penetrates effectively into the extracellular space fluid of lung tissue. Under steady-state conditions, the median concentrations of cefpirome in plasma, unaffected lung and infected lung exceeded the MICs of the majority of relevant bacteria over the entire dosing interval of up to 12 h after intravenous administration of a dose of 30 mg/kg total body weight.
Journal of Antimicrobial Chemotherapy 11/2010; 66(1):160-4. · 5.07 Impact Factor
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ABSTRACT: The present investigation explored the ability of fosfomycin to penetrate lung tissue of septic patients by utilizing the microdialysis technique.
After microdialysis probe insertion into healthy and infected lung tissue, a single intravenous dose of 4 g of fosfomycin was administered.
The mean C(max), T(max), AUC(0-4) and AUC(0-infinity) for healthy lung were 131.6 +/- 110.6 mg/L, 1.1 +/- 0.4 h, 242.4 +/- 101.6 mgxh/L and 367.6 +/- 111.9 mgxh/L, respectively. The corresponding values for infected lung were 107.5 +/- 60.2 mg/L, 1.4 +/- 0.5 h, 203.5 +/- 118.4 mgxh/L and 315.1 +/- 151.2 mgxh/L. The half-life of fosfomycin ranged from 2.2 to 2.7 h between compartments. The magnitude of lung tissue penetration, as determined by the ratios of the AUC(0-infinity) for lung to the AUC(0-infinity) for plasma, was 0.63 +/- 0.31 and 0.53 +/- 0.31 for healthy and infected lung, respectively.
We conclude that fosfomycin achieves antimicrobially effective concentrations in infected lung tissue.
Journal of Antimicrobial Chemotherapy 03/2010; 65(5):995-8. · 5.07 Impact Factor
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ABSTRACT: Dosage recommendations for fosfomycin are available for haemodialysed patients but there are no data for patients undergoing continuous renal replacement therapy. Therefore, the present study was designed to determine the concentration-versus-time profile of fosfomycin in continuous venovenous haemofiltration (CVVH).
A total of 12 anuric intensive care patients (10 males and 2 females) with suspected or proven infection requiring parenteral antibiotic therapy were included in the study. All patients underwent CVVH. Blood samples were drawn from the arterial (input) and venous (output) line of the extracorporeal circuit after application of a single dose of 8 g of fosfomycin. Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the haemofilter. Fosfomycin in the samples was quantified by gas chromatography.
The peak serum concentration was 442.7+/-124 mg/L at the arterial port. The trough serum level was 103.1+/-36.6 mg/L at the arterial port after 720 min. The mean value of the area under the concentration-versus-time curve from 0 to 12 h (AUC0-12) was 2159.4+/-609.8 mg.h/L. Mean total removal of the drug was 76.7+/-6.2%. The mean calculated clearance was 1.1+/-0.2 L/h for CLHF. Mean CLtot was 6.4+/-7.7 L/h.
A regimen of 8.0 g of fosfomycin every 12 h, which is usually used in patients with intact renal function, should be an appropriate antimicrobial treatment for patients undergoing CVVH.
Journal of Antimicrobial Chemotherapy 09/2006; 58(2):367-71. · 5.07 Impact Factor
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ABSTRACT: Until recently, information on antibiotic pharmacokinetic properties in infected human lung tissue was limited. We therefore studied a microdialysis-based approach for measurement of the penetration of meropenem into the extracellular space fluid of human pneumonic lung parenchyma. The lung penetration of meropenem was determined for seven patients with pneumonia and metapneumonic pleural empyema treated by decortication. Intraoperatively, two microdialysis probes were inserted into pneumonic lung tissue and one was inserted into healthy skeletal muscle for reference values. Serum and microdialysis samples were collected at 20-min intervals for at least 8 h following a single intravenous dose of 1 g of meropenem. The maximum free interstitial concentration (mean and standard deviation) of meropenem in infected lung tissue was 11.4 +/- 10.9 mg/liter, and that in serum was 47.3 +/- 21.0 mg/liter. The areas under the curve for infected lung tissue (36.2 +/- 17.9 mg. h/liter) and serum (95.4 +/- 46.6 mg. h/liter) revealed a significant difference. This technique enabled quasi-continuous tissue pharmacokinetic measurements of free, unbound antibiotic in pneumonic lung tissue of patients with pneumonia. The present data corroborate the use of meropenem in the treatment of lung infections caused by extracellular bacteria, demonstrating the excellent distribution profile for meropenem in the interstitial space of human pneumonic lung tissue.
Antimicrobial Agents and Chemotherapy 07/2004; 48(6):2228-32. · 4.84 Impact Factor
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ABSTRACT: The present study was performed to test the ability of fosfomycin to penetrate into the CSF of neurointensive care patients with ventriculostomy-associated ventriculitis.
Six patients requiring neurointensive care monitoring, including extraventricular drainage due to secondary obstructive hydrocephalus, were enrolled into the study. All patients received 8 g of fosfomycin intravenously three times a day over a period of at least 5 days. Concentrations of fosfomycin in the CSF and plasma were measured after single-dose administration and at steady state.
Mean values of the fosfomycin area under the time-concentration curves for the dosing interval of 8 h (AUC(8)) were 929 +/- 280 and 225 +/- 131 mg.h/L for plasma and CSF after single-dose administration, respectively (P < 0.03). The ratios of the AUC(8) for CSF to the AUC(8) for plasma were 0.23 +/- 0.07 after a single dose and 0.27 +/- 0.08 following multiple doses (P > 0.05, not significant). Additional in vitro experiments have shown that fosfomycin exerts non-concentration-dependent microbial growth inhibition. At steady state, the time above MIC (t > MIC) values were 98%, 92% and 61% for pathogens with MIC values of 8, 16 and 32 mg/L, respectively.
The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. Thus, the co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible pathogens.
Journal of Antimicrobial Chemotherapy 05/2004; 53(5):848-52. · 5.07 Impact Factor
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ABSTRACT: The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma.
The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam.
The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed.
This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.
British Journal of Clinical Pharmacology 07/2003; 55(6):620-4. · 2.96 Impact Factor
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ABSTRACT: The present study was undertaken to investigate the target site penetration properties of fosfomycin, an antibiotic particularly suitable for treatment of soft tissue infections (STIs) in critically ill patients.
The study population included nine patients with sepsis. Penetration of fosfomycin into the interstitial space fluid of skeletal muscle was measured using the microdialysis technique, following a single intravenous administration of 8.0 g of fosfomycin to patients. The median (range) fosfomycin area under the concentration versus time profile for plasma and skeletal muscle were 673 (459-1108) and 477 (226-860) mg x h/L (P < 0.011), respectively. Interstitial maximum concentrations were lower than plasma values (P < 0.029). Median fosfomycin concentrations in the interstitium and plasma exceeded 70 mg/L throughout the observation period of 4 h and covered MICs for Streptococcus pyogenes, Staphylococcus aureus and Pseudomonas aeruginosa. Simulation of bacterial growth inhibition of S. pyogenes, based on tissue concentration data, confirmed the bactericidal properties of fosfomycin described in previous studies.
Fosfomycin concentrations in muscle interstitium and plasma exceeded the MICs for a range of clinically relevant pathogens in critically ill patients. Thus, fosfomycin exhibits a tissue pharmacokinetic profile, which appears to offer an alternative to other broad-spectrum antibiotics in intensive care patients suffering from STI.
Journal of Antimicrobial Chemotherapy 06/2003; 51(5):1247-52. · 5.07 Impact Factor
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ABSTRACT: Objectives The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma.Patients and methods The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam.Results The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 ± 105.0 mg l−1 and 326.0 ± 60.6 mg l−1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 ± 167.0 mg.h l−1 and for serum 470.0 ± 142.0 mg.h l−1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4–6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed.Conclusion This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.
British Journal of Clinical Pharmacology 05/2003; 55(6):620 - 624. · 2.96 Impact Factor
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British Journal of Clinical Pharmacology 12/2002; 54(5):548-50. · 2.96 Impact Factor
