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01-08-2014 | Review Article

A Comprehensive Review on the Pharmacokinetics of Antibiotics in Interstitial Fluid Spaces in Humans: Implications on Dosing and Clinical Pharmacokinetic Monitoring

Authors: Tony K. L. Kiang, Urs O. Häfeli, Mary H. H. Ensom

Published in: Clinical Pharmacokinetics | Issue 8/2014

Abstract

The objective of the current review was to provide an updated and comprehensive summary on pharmacokinetic data describing the distribution of antimicrobials into interstitial fluid (ISF) by comparing drug concentration versus time profiles between ISF and blood/plasma in healthy individuals and/or diseased populations. An extensive literature search identified 55 studies detailing 87 individual comparisons. For each antibiotic (antibacterial) (or antibiotic class), we comment on dosing implications based on tissue ISF distribution characteristics and determine the suitability of conducting clinical pharmacokinetic monitoring (CPM) using a previously published scoring algorithm. Using piperacillin as an example, there is evidence supporting different degrees of drug penetration into the ISF of different tissues. A higher dose of piperacillin may be required to achieve an adequate ISF concentration in soft tissue infections. To achieve these higher doses, alternative administration regimens such as intravenous infusions may be utilized. Data also suggest that piperacillin can be categorized as a ‘likely suitable’ agent for CPM in ISF. Regression analyses of data from the published studies, including protein binding, molecular weight, and predicted partition coefficient (using XlogP3) as dependent variables, indicated that protein binding was the only significant predictor for the extent of drug distribution as determined by ratios of the area under the concentration–time curve between muscle ISF/total plasma (R ² = 0.65, p < 0.001) and adipose ISF/total plasma (R ² = 0.48, p < 0.004). Although recurrent limitations (i.e., small sample size, lack of statistical comparisons, lack of steady-state conditions, high individual variability) were identified in many studies, these data are still valuable and allowed us to generate general dosing guidelines and assess the suitability of using ISF for CPM.

Liu P, Muller M, Derendorf H. Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations. Int J Antimicrob Agents. 2002;19:285–90.PubMedCrossRef

Pichini S, Altieri L, Zuccaro P, et al. Drug monitoring in nonconventional biological fluids and matrices. Clin Pharmacokinet. 1996;30:211–28.PubMedCrossRef

Muller M, de la Pena A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: distribution in tissue. Antimicrob Agents Chemother. 2004;48:1441–53.

Joukhadar C, Derendorf H, Muller M. Microdialysis. A novel tool for clinical studies of anti-infective agents. Eur J Clin Pharmacol. 2001;57:211–9.PubMedCrossRef

Joukhadar C, Muller M. Microdialysis: current applications in clinical pharmacokinetic studies and its potential role in the future. Clin Pharmacokinet. 2005;44:895–913.PubMedCrossRef

Häfeli UO, Ensom MH, Kiang TK, et al. Comparison of vancomycin concentrations in blood and interstitial fluid: a possible model for less invasive therapeutic drug monitoring. Clin Chem Lab Med. 2011;21:2123–5.

Kiang TK, Schmitt V, Ensom MH, et al. Therapeutic drug monitoring in interstitial fluid: a feasibility study using a comprehensive panel of drugs. J Pharm Sci. 2012;101:4642–52.PubMedCrossRef

Barbour A, Scaglione F, Derendorf H. Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices. Int J Antimicrob Agents. 2010;35:431–8.PubMedCrossRef

Brunner M, Derendorf H, Muller M. Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs. Curr Opin Pharmacol. 2005;5:495–9.PubMedCrossRef

10.

Liu P, Derendorf H. Antimicrobial tissue concentrations. Infect Dis Clin N Am. 2003;17:599–613.CrossRef

11.

Islinger F, Bouw R, Stahl M, et al. Concentrations of gemifloxacin at the target site in healthy volunteers after a single oral dose. Antimicrob Agents Chemother. 2004;48:4246–9.PubMedCentralPubMedCrossRef

12.

Cheng T, Zhao Y, Li X, et al. Computation of octanol-water partition coefficients by guiding an additive model with knowledge. J Chem Inf Model. 2007;47:2140–8.PubMedCrossRef

13.

Brunner M, Pernerstorfer T, Mayer BX, et al. Surgery and intensive care procedures affect the target site distribution of piperacillin. Crit Care Med. 2000;28:1754–9.PubMedCrossRef

14.

Joukhadar C, Frossard M, Mayer BX, et al. Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med. 2001;29:385–91.PubMedCrossRef

15.

Tomaselli F, Dittrich P, Maier A, et al. Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis. Br J Clin Pharmacol. 2003;55:620–4.PubMedCentralPubMedCrossRef

16.

Roberts JA, Roberts MS, Robertson TA, et al. Piperacillin penetration into tissue of critically ill patients with sepsis–bolus versus continuous administration? Crit Care Med. 2009;37:926–33.PubMedCrossRef

17.

Legat FJ, Krause R, Zenahlik P, et al. Penetration of piperacillin and tazobactam into inflamed soft tissue of patients with diabetic foot infection. Antimicrob Agents Chemother. 2005;49:4368–71.PubMedCentralPubMedCrossRef

18.

Ensom MH, Davis GA, Cropp CD, et al. Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes? Clin Pharmacokinet. 1998;34:265–79.PubMedCrossRef

19.

de la Pena A, Brunner M, Eichler HG, et al. Comparative target site pharmacokinetics of immediate- and modified-release formulations of cefaclor in humans. J Clin Pharmacol. 2002;42:403–11.CrossRef

20.

Liu P, Muller M, Grant M, et al. Tissue penetration of cefpodoxime and cefixime in healthy subjects. J Clin Pharmacol. 2005;45:564–9.PubMedCrossRef

21.

Barbour A, Schmidt S, Sabarinath SN, et al. Soft-tissue penetration of ceftobiprole in healthy volunteers determined by in vivo microdialysis. Antimicrob Agents Chemother. 2009;53:2773–6.PubMedCentralPubMedCrossRef

22.

Muller M, Haag O, Burgdorff T, et al. Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis in humans. Antimicrob Agents Chemother. 1996;40:2703–9.PubMedCentralPubMed

23.

Muller M, Rohde B, Kovar A, et al. Relationship between serum and free interstitial concentrations of cefodizime and cefpirome in muscle and subcutaneous adipose tissue of healthy volunteers measured by microdialysis. J Clin Pharmacol. 1997;37:1108–13.PubMedCrossRef

24.

Hollenstein U, Brunner M, Mayer BX, et al. Relationship between serum and free interstitial concentrations of cefodizime and cefpirome in muscle and subcutaneous adipose tissue of healthy volunteers measured by microdialysis. Clin Pharmacol Ther. 2000;67:229–36.PubMedCrossRef

25.

Steiner M, Langenberger H, Marsik C, et al. Effect of norepinephrine on cefpirome tissue concentrations in healthy subjects. J Antimicrob Chemother. 2004;53:506–11.PubMedCrossRef

26.

Sauermann R, Delle-Karth G, Marsik C, et al. Pharmacokinetics and pharmacodynamics of cefpirome in subcutaneous adipose tissue of septic patients. Antimicrob Agents Chemother. 2005;49:650–5.PubMedCentralPubMedCrossRef

27.

Joukhadar C, Klein C, Mayer BX, et al. Plasma and tissue pharmacokinetics of cefpirome in patients with sepsis. Crit Care Med. 2002;30:1478–82.PubMedCrossRef

28.

Barbour A, Schmidt S, Rout WR, et al. Soft tissue penetration of cefuroxime determined by clinical microdialysis in morbidly obese patients undergoing abdominal surgery. Int J Antimicrob Agents. 2009;34:231–5.PubMedCrossRef

29.

Brunner M, Hollenstein U, Delacher S, et al. Distribution and antimicrobial activity of ciprofloxacin in human soft tissues. Antimicrob Agents Chemother. 1999;43:1307–9.PubMedCentralPubMed

30.

Bielecka-Grzela S, Klimowicz A. Penetration of ciprofloxacin and its desethylenemetabolite into skin in humans after a single oral dose of the parent drug assessed by cutaneous microdialysis. J Clin Pharm Ther. 2005;30:383–90.PubMedCrossRef

31.

Hollenstein U, Brunner M, Schmid R, et al. Soft tissue concentrations of ciprofloxacin in obese and lean subjects following weight-adjusted dosing. Int J Obes Relat Metab Disord. 2001;25:354–8.PubMedCrossRef

32.

Joukhadar C, Dehghanyar P, Traunmuller F, et al. Increase of microcirculatory blood flow enhances penetration of ciprofloxacin into soft tissue. Antimicrob Agents Chemother. 2005;49:4149–53.PubMedCentralPubMedCrossRef

33.

Brunner M, Stabeta H, Moller JG, et al. Target site concentrations of ciprofloxacin after single intravenous and oral doses. Antimicrob Agents Chemother. 2002;46:3724–30.PubMedCentralPubMedCrossRef

34.

Muller M, Stass H, Brunner M, et al. Penetration of moxifloxacin into peripheral compartments in humans. Antimicrob Agents Chemother. 1999;43:2345–9.PubMedCentralPubMed

35.

Zeitlinger M, Traunmuller F, Abrahim A, et al. A pilot study testing whether concentrations of levofloxacin in interstitial space fluid of soft tissues may serve as a surrogate for predicting its pharmacokinetics in lung. Int J Antimicrob Agents. 2007;29:44–50.PubMedCrossRef

36.

Bielecka-Grzela S, Klimowicz A. Evaluation of ofloxacin penetration into the skin after a single oral dose assessed by cutaneous microdialysis. Pol J Pharmacol. 2003;55:613–8.PubMed

37.

Muller M, Brunner M, Hollenstein U, et al. Penetration of ciprofloxacin into the interstitial space of inflamed foot lesions in non-insulin-dependent diabetes mellitus patients. Antimicrob Agents Chemother. 1999;43:2056–8.PubMedCentralPubMed

38.

Joukhadar C, Klein N, Frossard M, et al. Angioplasty increases target site concentrations of ciprofloxacin in patients with peripheral arterial occlusive disease. Clin Pharmacol Ther. 2001;70:532–9.PubMedCrossRef

39.

Zeitlinger M, Dehghanyar P, Mayer BX, et al. Relevance of soft-tissue penetration by levofloxacin for target site bacterial killing in patients with sepsis. Antimicrob Agents Chemother. 2003;47:3548–53.PubMedCentralPubMedCrossRef

40.

Bellmann R, Kuchling G, Dehghanyar P, et al. Tissue pharmacokinetics of levofloxacin in human soft tissue infections. Br J Clin Pharmacol. 2004;57:563–8.PubMedCentralPubMedCrossRef

41.

Joukhadar C, Stass H, Muller-Zellenberg U, et al. Penetration of moxifloxacin into healthy and inflamed subcutaneous adipose tissues in humans. Antimicrob Agents Chemother. 2003;47:3099–103.PubMedCentralPubMedCrossRef

42.

Burian B, Zeitlinger M, Donath O, et al. Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers. Antimicrob Agents Chemother. 2012;56:532–5.PubMedCentralPubMedCrossRef

43.

Burkhardt O, Brunner M, Schmidt S, et al. Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis. J Antimicrob Chemother. 2006;58:632–6.PubMedCrossRef

44.

Tegeder I, Schmidtko A, Brautigam L, et al. Tissue distribution of imipenem in critically ill patients. Clin Pharmacol Ther. 2002;71:325–33.PubMedCrossRef

45.

Dahyot C, Marchand S, Bodin M, et al. Application of basic pharmacokinetic concepts to analysis of microdialysis data: illustration with imipenem muscle distribution. Clin Pharmacokinet. 2008;47:181–9.PubMedCrossRef

46.

Roberts JA, Kirkpatrick CM, Roberts MS, et al. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64:142–50.PubMedCrossRef

47.

Sahre M, Sabarinath SN, Grant M, et al. Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers. Int J Antimicrob Agents. 2012;40:51–4.PubMedCentralPubMedCrossRef

48.

Dehghanyar P, Burger C, Zeitlinger M, et al. Penetration of linezolid into soft tissues of healthy volunteers after single and multiple doses. Antimicrob Agents Chemother. 2005;49:2367–71.PubMedCentralPubMedCrossRef

49.

Islinger F, Dehghanyar P, Sauermann R, et al. The effect of food on plasma and tissue concentrations of linezolid after multiple doses. Int J Antimicrob Agents. 2006;27:108–12.PubMedCrossRef

50.

Thallinger C, Buerger C, Plock N, et al. Effect of severity of sepsis on tissue concentrations of linezolid. J Antimicrob Chemother. 2008;61:173–6.PubMedCrossRef

51.

Traunmuller F, Schintler MV, Spendel S, et al. Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections. Int J Antimicrob Agents. 2010;36:84–6.PubMedCrossRef

52.

Matzneller P, Krasniqi S, Kinzig M, et al. Blood, tissue, and intracellular concentrations of azithromycin during and after end of therapy. Antimicrob Agents Chemotherapy. 2013;57:1736–42.CrossRef

53.

Traunmuller F, Zeitlinger M, Zeleny P, et al. Pharmacokinetics of single- and multiple-dose oral clarithromycin in soft tissues determined by microdialysis. Antimicrob Agents Chemother. 2007;51:3185–9.PubMedCentralPubMedCrossRef

54.

Krasniqi S, Matzneller P, Kinzig M, et al. Blood, tissue, and intracellular concentrations of erythromycin and its metabolite anhydroerythromycin during and after therapy. Antimicrob Agents Chemotherapy. 2012;56:1059–64.CrossRef

55.

Gattringer R, Urbauer E, Traunmuller F, et al. Pharmacokinetics of telithromycin in plasma and soft tissues after single-dose administration to healthy volunteers. Antimicrob Agents Chemother. 2004;48:4650–3.PubMedCentralPubMedCrossRef

56.

Traunmuller F, Fille M, Thallinger C, et al. Multiple-dose pharmacokinetics of telithromycin in peripheral soft tissues. Int J Antimicrob Agents. 2009;34:72–5.PubMedCrossRef

57.

Kim A, Suecof LA, Sutherland CA, et al. In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers. Antimicrob Agents Chemother. 2008;52:3941–6.PubMedCentralPubMedCrossRef

58.

Traunmuller F, Schintler MV, Metzler J, et al. Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections. J Antimicrob Chemother. 2010;65:1252–7.PubMedCrossRef

59.

Bulik CC, Wiskirchen DE, Shepard A, et al. Tissue penetration and pharmacokinetics of tigecycline in diabetic patients with chronic wound infections described by using in vivo microdialysis. Antimicrob Agents Chemother. 2010;54:5209–13.PubMedCentralPubMedCrossRef

60.

Skhirtladze K, Hutschala D, Fleck T, et al. Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents Chemother. 2006;50:1372–5.PubMedCentralPubMedCrossRef

61.

Frossard M, Joukhadar C, Erovic BM, et al. Distribution and antimicrobial activity of fosfomycin in the interstitial fluid of human soft tissues. Antimicrob Agents Chemother. 2000;44:2728–32.PubMedCentralPubMedCrossRef

62.

Legat FJ, Maier A, Dittrich P, et al. Penetration of fosfomycin into inflammatory lesions in patients with cellulitis or diabetic foot syndrome. Antimicrob Agents Chemother. 2003;47:371–4.PubMedCentralPubMedCrossRef

63.

Joukhadar C, Klein C, Dittrich P, et al. Target site bacterial killing of cefpirome and fosfomycin in critically ill patients. J Antimicrob Chemother. 2003;51:1247–52.PubMedCrossRef

64.

Lorentzen H, Kallehave F, Kolmos HJ, et al. Gentamicin concentrations in human subcutaneous tissue. Antimicrob Agents Chemother. 1996;40:1785–9.PubMedCentralPubMed

65.

Lorentzen H, Kallehave F, Kolmos HJ, et al. Gentamicin concentrations in human subcutaneous tissue. Antimicrob Agents Chemother. 1996;40:1785–9.PubMedCentralPubMed

66.

Bielecka-Grzela S, Klimowicz A. Application of cutaneous microdialysis to evaluate metronidazole and its main metabolite concentrations in the skin after a single oral dose. J Clin Pharm Ther. 2003;28:465–9.PubMedCrossRef

67.

Karjagin J, Pahkla R, Starkopf J. Perioperative penetration of metronidazole into muscle tissue: a microdialysis study. Eur J Clin Pharmacol. 2004;59:809–13.PubMedCrossRef

68.

Karjagin J, Pahkla R, Karki T, et al. Distribution of metronidazole in muscle tissue of patients with septic shock and its efficacy against Bacteroides fragilis in vitro. J Antimicrob Chemother. 2005;55:341–6.PubMedCrossRef

69.

Chua B, Desai S, Tierney M, et al. Effect of microneedles shape on skin penetration and minimally invasive continuous glucose monitoring in vivo. Sens Actuators A. 2013;203:373–81.CrossRef

Title: A Comprehensive Review on the Pharmacokinetics of Antibiotics in Interstitial Fluid Spaces in Humans: Implications on Dosing and Clinical Pharmacokinetic Monitoring
Authors: Tony K. L. Kiang
Urs O. Häfeli
Mary H. H. Ensom
Publication date: 01-08-2014
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 8/2014
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-014-0152-3

At a glance: The STEP trials

Springer Medicine

A Comprehensive Review on the Pharmacokinetics of Antibiotics in Interstitial Fluid Spaces in Humans: Implications on Dosing and Clinical Pharmacokinetic Monitoring

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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