The influence of sepsis on antimicrobials tissue penetration: The use of microdialysis technique to access free drug distribution

Abstract Sepsis is described as a life-threatening organ dysfunction caused by a host's response to infection, leading to an unbalance in body homeostasis. It is one of the leading causes of death in developed countries. Considering that in critically ill patients, such as those with sepsis, plasma concentrations do not necessarily reflect tissue concentrations, one way to assess tissue concentrations is through the microdialysis technique, which allows direct measurements of free drug at the site of action. This review was carried out after searching the Pubmed, Scielo and Web of Science databases, using the following descriptors: (microdialysis AND (sepsis OR septic shock OR severe sepsis OR septicemia)) OR (microdialysis AND (sepsis OR septic shock OR severe sepsis) OR septicemia) AND (antimicrobial OR antibiotic OR antifungal)). The physiological changes generated by sepsis may imply changes in pharmacokinetic parameters, such as in clearance, which may be reduced in these patients and in volume of distribution, which presents an expansion, mainly due to edema. Both events contribute to a high inter- individual variability in tissue penetration of antimicrobials which is generally observed in patients with sepsis.

Population Pharmacokinetic Modeling and Probability of Target Attainment of Ceftaroline in Brain and Soft Tissues.

Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investigate the probability of target attainment (PTA) of the percentage of the dosing interval that the unbound drug concentration exceeded the MIC (%fT>MIC) to treat MRSA infections. Healthy subjects' plasma and microdialysate concentrations from muscle and subcutaneous tissue following 600 mg every 12 h (q12h) and q8h and neurosurgical patients' plasma and CSF concentrations following single 600-mg dosing were used. Plasma concentrations were described by a two-compartment model, and tissue concentrations were incorporated as three independent compartments linked to the central compartment by bidirectional transport (clearance in [CLin] and CLout). Apparent volumes were fixed to physiological interstitial values. Healthy status and body weight were identified as covariates for the volume of the central compartment, and creatinine clearance was identified for clearance. The CSF glucose concentration (GLUC) was inversely correlated with CLin,CSF. Simulations showed a PTA of >90% in plasma and soft tissues for both regimens assuming an MIC of 1 mg/L and a %fT>MIC of 28.8%. Using the same target, patients with inflamed meninges (0.5 < GLUC ≤ 2 mmol/L) would reach PTAs of 99.8% and 97.2% for 600 mg q8h and q12h, respectively. For brain infection with mild inflammation (2 < GLUC ≤ 3.5 mmol/L), the PTAs would be reduced to 34.3% and 9.1%, respectively. Ceftaroline's penetration enhanced by meningeal inflammation suggests that the drug could be a candidate to treat MRSA CNS infections.

Is the penetration of clindamycin into the masseter muscle really enough to treat odontogenic infections?

OBJECTIVES: This study aims to determine the penetration of clindamycin into the masseter muscle of rats by microdialysis and correlate with the main microorganisms involved in odontogenic infections. MATERIALS AND METHODS: Tissue concentrations of clindamycin in healthy muscle tissue were measured by microdialysis after administration of a single intravenous dose of 51 mg/kg and multiple doses of 17 mg/kg (8/8 h). It was quantified in plasma after a single administration of 51 mg/kg. Microdialysis samples were collected at 30-min intervals and clindamycin was assayed by LC-MS. Pharmacokinetic parameters and tissue penetration were determined. Pharmacokinetic/pharmacodynamic index (ƒ%T > minimum inhibitory concentration (MIC)) was considered to assess dosing regimens. RESULTS: The pharmacokinetic parameters determined by non-compartmental plasma analysis for the dose of 51 mg/kg were similar to that determined by compartmental analysis. The maximum free interstitial concentration (Cmax) of clindamycin in muscle tissue was 14.20 (10.63-14.89) and 4.82 (3.35-6.66) mg/L for 51 mg/kg and 17 mg/kg 8/8 h, respectively. In addition, the area under the curve (AUC0-inf) for plasma and tissue of clindamycin were 44.78 (28.82-65.65) and 16.54 (13.83-18.35) h.mg/L for 51 mg/kg, respectively, and the tissue penetration factor determined was 1.10. Considering that the main bacteria that cause odontogenic infections generally present MIC ≤ 0.5 mg/L, the ƒ%T > MIC index is reached when the dose regimen of 17 mg/kg 8/8 h is employed. CONCLUSIONS: This investigation showed that clindamycin excellently penetrates muscle tissue of rats. It provides effective antibacterial concentrations at the target site when 17 mg/kg 8/8 h is employed and can be applied to treat the main bacteria causing odontogenic infections. CLINICAL RELEVANCE: It reinforces the use of clindamycin in odontogenic infections with significant tissue penetration.

Pharmacokinetic/pharmacodynamic modeling of etoposide tumor growth inhibitory effect in Walker-256 tumor-bearing rat model using free intratumoral drug concentrations.

The purpose of this study was to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model linking etoposide free tumor and total plasma concentrations to the inhibition of solid tumor growth in rats. Walker-256 tumor cells were inoculated subcutaneously in the right flank of Wistar rats, which were randomly divided in control and two treated groups that received etoposide 5 or 10mg/kg i.v. bolus every day for 8 and 4days, respectively, and tumor volume was monitored daily for 30days. The plasma and intratumoral concentrations-time profiles were obtained from a previous study and were modeled by a four-compartment population pharmacokinetic (popPK) model. PK/PD analysis was conducted using MONOLIX v.4.3.3 on average data and by mean of a nonlinear mixed-effect model. PK/PD data were analyzed using a modification of Simeoni Tumor Growth Inhibition (TGI) model by introduction of an Emax function to take into account the concentration dependency of k2variable parameter (variable potency). The Simeoni TGI-Emax model was capable to fit schedule-dependent antitumor effects using the tumor growth curves from the control and two different administered schedules. The PK/PD model was capable of describing the tumor growth inhibition using total plasma or free tumor concentrations, resulting in higher k2max (maximal potency) for free concentrations (25.8mL·µg-1·day-1 - intratumoral vs. 12.6mL·µg-1·day-1 total plasma). These findings indicate that the plasma concentration may not be a good surrogate for pharmacologically active free tumor concentrations, emphasizing the importance of knowing drug tumor penetration to choose the best antitumor therapy.

Application of a LC-MS/MS method for evaluating lung penetration of tobramycin in rats by microdialysis.

A bioanalytical LC-MS/MS method was developed and validated to determine tobramycin in plasma and lung microdialysate samples. Tobramycin was separated using a C18 column and a mobile phase consisting of water and acetonitrile, both with 10mM of heptafluorobutyric acid, eluted as gradient. Apramycin was used as internal standard (IS) for plasma samples. Drugs were monitored using electrospray ionization operating on positive mode (ESI+) monitoring the transitions 468.2>163.3 m/z for tobramycin and 540.3>217.2 m/z for IS. The method showed linearity in the concentration range of 0.1-50µgmL-1 for microdialysate and 0.5-100µgmL-1 for plasma with coefficients of determination ≥0.991. The inter- and intra-day precision, the accuracy and the stability of the drug in different conditions were in accordance with the limits established by US Food and Drug Administration guideline. The concentrations of tobramycin in plasma and lung microdialysate, determined using CMA/20 probes and a Ringer solution at a flow rate of 1µLmin-1, were evaluated in healthy Wistar rats after a 10mgkg-1 i.v. bolus dose. Samples were harvested up to 12h post-dose. Before animal's experiments, probe recovery was determined by dialysis and retrodialysis in vitro and by retrodialysis in vivo. Probes recovery was independent of drug concentration and method of determination. In vivo recovery was 27.74±7.70%. Pharmacokinetic parameters were estimated by non-compartmental analysis using the software Phoenix®. The estimated area under the curve (AUC0-∞) was 128±19µghmL-1 and 105±12µghmL-1 for plasma and lung, respectively. Tobramycin plasma clearance was 0.07±0.01L/h/kg and the volume of distribution was 0.49±0.09L/kg. Elimination half-life in plasma was 4.4±0.7h and in lung, 4.2±0.56h. The free tissue/free plasma AUC0-∞ ratio was 0.94. This is the first study showing a validated method to quantify tobramycin in microdialysate samples and to evaluate the lung interstitial concentration of the drug.