Dataset Information

Population Pharmacokinetics of Cefazolin in Serum and Tissue for Patients with Complicated Skin and Soft Tissue Infections (cSSTI).

ABSTRACT:

Introduction

Cefazolin is commonly used to treat complicated skin and soft tissue infections (cSSTI) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacteriaceae. We aimed to determine the variability of cefazolin exposure in interstitial fluid (ISF) of tissue and evaluate its dosing recommendations.

Methods

Population pharmacokinetics were performed to co-model serum and ISF concentration data from six patients enrolled in a previous in vivo microdialysis study. A 5,000 patient Monte Carlo simulation was then conducted for 1 and 2 g every 8 h (q8h) regimens to calculate the penetration ratio and probability of target attainment (PTA) at 30% and 50% of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT > MIC) in ISF of tissue.

Results

A three-compartment model, with one of the compartments representing ISF concentrations, fits the data best. The final model resulted in the mean ± SD parameter values: Clearance = 3.8 ± 2.1 L/h, volume of distribution in central compartment = 8.6 ± 6.4 L and volume of distribution in ISF = 36.6 ± 17.9 L. The mean ± SD and median penetration ratios were 1.36 ± 4.57 and 0.80, respectively. At the MIC90 for MSSA of 1 mg/L, PTAs for the 1 g q8h dose in ISF were 96% and 91% for 30% and 50% fT > MIC targets, respectively, which decreased to 87% and 71% at 2 mg/L. For the same respective targets, a 2 g q8h dosing regimen increased PTA to 96% and 91% at 2 mg/L.

Conclusion

Cefazolin penetration into the ISF of a lower limb infection varied across this simulated patient population. Based on these data, a 1 g q8h regimen should be sufficient to obtain 30% fT > MIC exposure against most MSSA causing cSSTI. However, a 2 g q8h dose is required to obtain 50% fT > MIC pharmacodynamic targets at the current breakpoint for Enterobacteriaceae (2 mg/L).

SUBMITTER: So W

PROVIDER: S-EPMC4269627 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Publications

Population Pharmacokinetics of Cefazolin in Serum and Tissue for Patients with Complicated Skin and Soft Tissue Infections (cSSTI).

So Wonhee W Kuti Joseph L JL Nicolau David P DP

Infectious diseases and therapy 20141120 2

<h4>Introduction</h4>Cefazolin is commonly used to treat complicated skin and soft tissue infections (cSSTI) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacteriaceae. We aimed to determine the variability of cefazolin exposure in interstitial fluid (ISF) of tissue and evaluate its dosing recommendations.<h4>Methods</h4>Population pharmacokinetics were performed to co-model serum and ISF concentration data from six patients enrolled in a previous in vivo microdialysis ...[more]

PMID: 25410773

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Project description:BackgroundThe treatment of complicated skin and soft tissue infections (cSSTI) is challenging and many patients do not receive adequate first-line therapy. REACH (REtrospective Study to Assess the Clinical Management of Patients With Moderate-to-Severe cSSTI or Community-Acquired Pneumonia in the Hospital Setting) was a retrospective observational study of cSSTI patients in real-life settings in European hospitals. In this analysis, we review characteristics and outcomes of patients with an early response (≤72 hours) compared with those without an early response to treatment. We also compare the results according to two differing definitions of early response, one of which (Definition 1) requires resolution of fever within 72 hours, in line with previous US FDA guidelines.MethodsPatients were adults hospitalized with cSSTIs 2010-2011 and requiring treatment with intravenous antibiotics. Clinical management, clinical outcomes and healthcare resource use were assessed using a descriptive analysis approach.ResultsThe analysis set included 600 patients, of which 363 showed early response with Definition 1 and 417 with Definition 2. Initial treatment modification was frequent, and highest in patients without early response (48.1% with Definition 1). Patients without early response were more likely to have diabetes than those with early response (31.6% vs. 22.9%, respectively) and to suffer from more severe disease (e.g. skin necrosis: 14.8% and 7.7%, respectively), to be infected with difficult-to-treat microorganisms and to have recurrent infections. Furthermore, patients without early response had a higher rate of adverse clinical outcomes (e.g. septic shock) and higher use of healthcare resources. The results obtained with the two definitions for early response were largely similar.ConclusionsThis study highlights the significance of early evaluation of patients in hospitals, in potentially preventing prolonged use of inappropriate or ineffective antibacterial therapy.Trial registrationNCT01293435 .

Project description:Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally (n = 77) or intravenously (n = 50), and 139 patients with cUTI received finafloxacin intravenously. Plasma (2,824 samples from volunteers and 414 samples from patients) and urine (496 samples from volunteers and 135 samples patients) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). NONMEM was used to build a population pharmacokinetic model, and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression. A two-compartment model with first-order elimination described the data best (central volume of distribution [Vc] and peripheral volume of distribution [Vp] of 47 liters [20%] and 43 liters [67%], respectively, and elimination clearance and intercompartmental clearance of 21 liters/h [54%] and 2.8 liters/h [57%], respectively [median bootstrap estimates {coefficients of variation}]). Vc increased with body surface area, and clearance was reduced in patients (-29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability of 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens. Despite the interindividual variability, the present data set does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.).

Project description:OBJECTIVES:Skin and soft tissue infections (SSTIs) carry significant economic burden, as well as morbidity and mortality, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Several new MRSA-active antibiotics have been developed, including semisynthetic glycopeptides (telavancin, dalbavancin and oritavancin). Of these, dalbavancin and oritavancin offer extended dosing intervals. METHODS:We performed a systematic review, network meta-analysis and cost analysis to compare the newer glycopeptides to standard care and to each other for the treatment of complicated SSTIs (cSSTI). A search for randomized controlled trials (RCTs) was conducted in Medline, Embase and the Cochrane Central Register of Controlled Trials. We also developed a model to evaluate the costs associated with dalbavancin and oritavancin from the third-party payer perspective. RESULTS:Seven RCTs met the inclusion criteria. Network meta-analyses suggested that the clinical response to telavancin, dalbavancin and oritavancin was similar to standard care (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.90-1.33; OR 0.78, 95% CI 0.52-1.18; and OR 1.06, 95% CI 0.85-1.33, respectively). Head-to-head comparisons showed no difference in clinical response between oritavancin and dalbavancin (OR 1.36; 95% CI 0.85-2.18), oritavancin and telavancin (OR 0.98; 95% CI 0.72-1.31) or dalbavancin and telavancin (OR 0.72; 95% CI 0.45-1.13). Telavancin had a higher incidence of overall adverse events compared to standard care (OR 1.33; 95% CI 1.10-1.61). Compared to telavancin, there were fewer overall adverse events with dalbavancin (OR 0.58; 95% CI 0.45-0.76) and oritavancin (OR 0.71; 95% CI 0.55-0.92). Studies were of high quality overall. Our cost analyses demonstrated that dalbavancin and oritavancin were less costly compared to standard care under baseline assumptions and many scenarios evaluated. The use of dalbavancin could save third-party payers $1442 to $4803 per cSSTI, while the use of oritavancin could save $3571 to $6932 per cSSTI. CONCLUSIONS:Dalbavancin and oritavancin demonstrate efficacy and safety comparable to standard care in well-designed RCTs and result in cost savings when standard care is treatment that covers MRSA.

Dataset Information

Population Pharmacokinetics of Cefazolin in Serum and Tissue for Patients with Complicated Skin and Soft Tissue Infections (cSSTI).

Introduction

Methods

Results

Conclusion

Publications

Population Pharmacokinetics of Cefazolin in Serum and Tissue for Patients with Complicated Skin and Soft Tissue Infections (cSSTI).

Similar Datasets

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