Pharmacokinetics and Pharmacodynamics of Levofloxacin against<i>Streptococcus pneumoniae</i>and<i>Staphylococcus aureus</i>in Human Skin Blister Fluid

Trampuž, Andrej; Wenk, Markus R.; Rajacic, Zarko; Zimmerli, Werner

doi:10.1128/aac.44.5.1352-1355.2000

Cited by 24 publications

(17 citation statements)

References 24 publications

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“…In the case of levofloxacin, the great majority of PK-PD human studies have been performed with a dose of 500 mg/day (19,32,40); our experimental group for levofloxacin 50 showed TCF levels consistent with this human dose. However, high doses of levofloxacin (750 to 1,000 mg/day) have been approved for treatment of nosocomial pneumonia and complicated skin structure infections and have recently been recommended for orthopedic prosthetic infections (47), given the inherent difficulties in curing them.…”

Section: Discussionmentioning

confidence: 96%

“…Based on previous experimental studies (13,33,43,40), the definitive antibiotic doses were those achieving PD parameters in TCF that were similar to human ones in serum with conventional doses. For all drugs except cloxacillin, we adjusted AUC values to obtain similar AUC/MIC ratios in animals and in humans (7,8,24,25,32,34).…”

Section: Microorganism Used and Determination Of Mics And Minimum Bacmentioning

confidence: 99%

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Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

Murillo¹,

Domènech²,

García

et al. 2006

Antimicrob Agents Chemother

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Antimicrobial efficacy in orthopedic device infections is diminished because of bacterial biofilms which express tolerance to antibiotics. Recently, the use of high doses of levofloxacin with rifampin has been recommended for staphylococcal infections. In the present study, we evaluated the efficacy of levofloxacin at doses of 50 mg/kg/day and 100 mg/kg/day (mimicking the usual and high human doses of 500 mg/day and 750 to 1,000 mg/day, respectively) and compared it to that of to linezolid, cloxacillin, vancomycin, and rifampin in a rat tissue cage model of experimental foreign-body infection by Staphylococcus aureus. The antimicrobial efficacy in vitro (by MIC, minimum bactericidal concentration, and kill curves) for logarithmic-and stationary-phase bacteria was compared with the in vivo efficacy. In vitro bactericidal activity at clinically relevant concentrations was reached by all drugs except rifampin and linezolid in the log-phase studies but only by levofloxacin in the stationary-phase studies. The bacterial count decreases from in vivo tissue cage fluids (means) for levofloxacin at 50 and 100 mg/kg/day, rifampin, cloxacillin, vancomycin, linezolid, and controls, respectively, were: ؊1.24, ؊2.26, ؊2.1, ؊1.56, ؊1.47, ؊1.15, and 0.33 (all groups versus controls, P < 0.05). Levofloxacin at 100 mg/kg/day (area under the concentration-time curve/MIC ratio, 234) was the most active therapy (P ‫؍‬ 0.03 versus linezolid). Overall, in vivo efficacy was better predicted by stationary-phase studies, in which it reached a high correlation coefficient even if the rifampin group was excluded (r ‫؍‬ 0.96; P < 0.05). Our results, including in vitro studies with nongrowing bacteria, pharmacodynamic parameters, and antimicrobial efficacy in experimental infection, provide good evidence to support the use of levofloxacin at high doses (750 to 1,000 mg/day), as recently recommended for treating patients with orthopedic prosthesis infections.Patients suffering from orthopedic device infections will have usually undergone surgical interventions and received antibiotic therapies over a long period of time, these being major clinical issues. It is very difficult to eradicate such infections using antibiotics because of the formation of biofilm, a protein matrix including bacteria with reduced metabolism and with tolerance to antimicrobials (2,9,11,38).These infections are frequently caused by Staphylococcus aureus, and rifampin has been shown to be the most effective antimicrobial agent in such cases, in in vitro and experimental studies (26, 48) and in clinical practice (14,15,46). Since this drug should not be given alone due to the development of early bacterial resistance, antibiotic combinations are required. The combination of rifampin and fluoroquinolones has been found to be particularly efficacious and is thus usually recommended (10,14,44).In recent years, the experimental foreign-body infection model developed by Lucet et al. (26) has provided relevant data regarding the antimicrobial efficacy of several antibiotics ...

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Section: Discussionmentioning

confidence: 96%

Section: Microorganism Used and Determination Of Mics And Minimum Bacmentioning

confidence: 99%

Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

Murillo¹,

Domènech²,

García

et al. 2006

Antimicrob Agents Chemother

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“…Microdialysis technique has been used for determination glucose concentration (1,2), percutaneous absorption (3) of drugs and histamine release in the cutaneous tissue (4). Microdialysis has the advantage of sampling only the free drug (5,6). ETS is a noninvasive method of reversible permeabilization of stratum corneum and sampling of drugs from the ECF by diffusion.…”

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confidence: 99%

Electroporation and transcutaneous sampling (ETS) of acyclovir

Murthy¹,

Zhang²

2008

Journal of Dermatological Science

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Dermatokinetics determine the efficacy and toxicity of drugs used to treat skin disorders. The time course of drug in the dermal extracellular fluid (ECF) could be used as a tool for assessing the concentration dependent activity/toxicity of the drugs in the skin tissue. Currently dermatokinetic studies of drugs are carried out by tissue biopsy or skin blister sampling or by microdialysis. However, all these methods are invasive and causes significant discomfort to the patients. Microdialysis technique has been used for determination glucose concentration (1,2), percutaneous absorption (3) of drugs and histamine release in the cutaneous tissue (4). Microdialysis has the advantage of sampling only the free drug (5,6). ETS is a noninvasive method of reversible permeabilization of stratum corneum and sampling of drugs from the ECF by diffusion. The diffusion flux of drug is governed by the unbound drug concentration gradient between the dermal tissue fluid and the sampling medium. Similar to microdialysis, the ETS samples are from the interstitial space, which is a defined, anatomical compartment and there is no net loss of body fluid (7). The hypothesis is that the transcutaneous flux of drugs is proportional to the concentration of unbound drug in the dermal ECF. Knowing the "reciprocal of Permeability coefficient (1/P in vivo )" of skin, the unbound drug concentration in the dermal ECF could be determined. The objective of this project was to assess the feasibility of using ETS technique for studying dermatokinetics of acyclovir. Acyclovir, an antiviral agent used in the treatment of herpes simplex infection that occurs at the lowest epidermis. The time course of acyclovir in the dermal ECF is critical in determining the efficacy of acyclovir therapy of herpes simplex. In the present work, Acyclovir was administered to hairless rats and the time course of drug concentration in the dermal ECF was determined by ETS and microdialysis sampling.The experiment was carried out in hairless rats (∼300 g) under ketamine (80 mg/kg) and xylazine (20 mg/kg) anesthesia. For ETS sampling, the shaved portion of the back skin was folded and clamped on to a custom made in vivo electroporation cell. The cell contains a sample collection chamber with platinum wire electrode. A stainless steel plate clamped across the skin fold served as the counter electrode (7,8). The collection chamber was filled with 200 μl of 0.05% w/v SDS solution prepared in phosphate buffered saline (PBS, pH 7.1) and 15 pulses each of 1 ms duration at 120 V and 1 Hz were applied. The SDS solution in the collection chamber was immediately replaced with 500 μl of PBS, which remained in the collection * Corresponding Author, 113 Faser Hall, The University of Mississippi, University, MS 38677, Tel: 662-915-5164, Fax: 662-915-1177, Email: Murthy@olemiss.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript ...

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“…Before the therapeutic experiments, the antibiotic dosages were selected according to pharmacokinetic and pharmacodynamic parameters by using the methodology described in detail in our previous work (34). On the basis of previous data, we selected the dose whose pharmacodynamic parameters in TCF were close to those in human serum (12,43); area under the concentration-time curve (AUC) values were adjusted for each antibiotic to allow similar ratios of AUC/MIC in both animals and humans (7,27,37). Peak and trough levels in TCF were determined on day 4 for each drug to check the equilibrium test concentrations during treatment.…”

Section: In Vitro Studies (I) Determination Of Mics and Mbcsmentioning

confidence: 99%

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

Murillo¹,

Pachón²,

Euba³

et al. 2008

Antimicrob Agents Chemother

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Since levofloxacin at high doses was more active than levofloxacin at conventional doses and was the best therapy alone in a rat model of staphylococcal foreign-body infection, in this study we tested how these differences affect the activities of their respective combinations with rifampin in vitro and in vivo. In vitro studies were performed in the log and stationary phases. By using this model, rifampin at 25 mg/kg of body weight/12 h, levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, levofloxacin at 50 mg/kg/day, levofloxacin at 50 mg/kg/day plus rifampin, or a control treatment was administered for 7 days; and therapy with for levofloxacin at 100 mg/kg/day alone and rifampin alone was prolonged to 14 days. We screened for the appearance of resistant strains. Killing curves in the log phase showed a clear antagonism with levofloxacin at concentrations >2؋ MIC and rifampin and tended to occur in the stationary phase. At the end of 7 days of therapy, levofloxacin at 100 mg/kg/day was the best treatment and decreased the bacterial counts from tissue cage fluid (P < 0.05 compared with the results for groups except those receiving rifampin alone). At the end of 14 days of therapy with levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, and the control treatment, the bacterial counts on the coverslips were 2.24 (P < 0.05 compared with the results with the combined therapy), 3.36, and 5.4 log CFU/ml, respectively. No rifampin or levofloxacin resistance was detected in any group except that receiving rifampin alone. In conclusion, high-dose levofloxacin was the best treatment and no resistant strains appeared; the addition of rifampin showed an antagonistic effect. The efficacy of the rifampin-levofloxacin combination is not significantly improved by the dosage of levofloxacin.Orthopedic prosthetic infections are difficult to treat because of the presence of bacterial biofilms. The definitive therapy for such infections requires a combination of surgical and medical approaches and the use of selected antibiotics active against the microorganisms involved (11, 40, 48).On the basis of previous experimental and clinical studies, rifampin plays a main role in the treatment of staphylococcal foreign-body infections (4,45,47,49), while fluoroquinolones are considered the best drugs for use in combination with rifampin (14,15,46). Recent work recommended the use of a combination of high doses of levofloxacin (750 to 1,000 mg/ day) plus rifampin for the treatment of staphylococcal prosthetic infections (48), even though the information available from this setting is limited (3, 34, 39).The rat model of staphylococcal tissue cage infection is a well-standardized model of chronic foreign-body infection that has provided relevant information in this regard (8,9,32,44). Using this model, we previously reported that high-dose levofloxacin (equivalent to 750 to 1,000 mg/day) was more active than the conventional levofloxacin dose (500 mg/day) and that it was the best therapy for u...

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Pharmacokinetics and Pharmacodynamics of Levofloxacin againstStreptococcus pneumoniaeandStaphylococcus aureusin Human Skin Blister Fluid

Cited by 24 publications

References 24 publications

Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus

Electroporation and transcutaneous sampling (ETS) of acyclovir

Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection

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