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

Santos-Borges, Karolina Torres; Henz, Pricilla; Araújo, Bibiana Verlindo de

doi:10.1590/s2175-97902023e22982

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 59 • 2023 • https://doi.org/10.1590/s2175-97902023e22982 copy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Keywords:
Sepsis; Antimicrobials; Microdialysis; Tissue penetration; Pharmacokinetics; Pharmacodynamics.

Antimicrobial	Study group	Tissue of ISF	PK parameters	fT	References
Piperacilin	Shock septic patients (n=7)	Muscle and adipose subcutaneous tissue	V_sepsis= 40.7 ± 8.69 L*	Muscle	*Joukhadar et al. 2001*Joukhadar C, Derendorf H, Muller M. Microdialysis a novel tool for clinical studies of anti-infective agents. Eur J Pharmacol. 2001b;57:211-219.
	Volunteers (n=6)		V_healthy= 9.61 ± 1.79 L	fT_sepsis = 0.19 ± 0.03*
			CL_sepsis= 8.16 ± 1.98 L.h^-1	fT_healthy= 0.55 ± 0.09
			CL_healthy= 7.86 ± 0.9 L.h^-1	Subcutis
				fT_sepsis = 0.10 ± 0.02*
				fT_healthy= 0.31 ± 0.07
Cefpirome	Sepsis patients (n=12)	Skeletal muscle	V_sepsis= 25.9 ± 7.1 L*	fT_sepsis = 0.63 ± 0.04	*Joukhadar et al. 2002*Joukhadar C, Klein N, Mayer BX, Kreischitz N, Delle-Karth G, Palkovits P, et al. Plasma and tissue pharmacokinetics of cefpirome in patients with sepsis. Crit Care Med . 2002;30(7):1478-82.
	Volunteers (n=6)		V_healthy= 14.6 ± 1.3 L	fT_healthy = 0.83 ± 0.08
			CL_sepsis= 4.5 ± 0.66 L.h^-1
			Cl_healthy = 4.68 ± 0.48 L.h^-1
Cefpirome	Sepsis patients (n=11)	Adipose subcutaneous tissue	V_sepsis= 21.9 ± 4.5 L*	fT_sepsis = 0.42 *	*Sauermann et al. 2005*Sauermann R, Delle-Karth G, Marsik C, Steiner I, Zeirlinger M, Mayer-Helm BX, et al. Pharmacokinetics and pharmacodynamics of cefpirome in subcutaneous adipose tissue of septic patients. Antimicrob Agents Chemother . 2005;49(2):650-655.
	Volunteers (n=7)		V_healthy= 15.8 ± 5.6 L	fT_healthy = 0.80
			CL_sepsis= 4.8 ± 1.56 L.h^-1
			Cl_healthy = 6.3 ± 1.86 L.h^-1
Aztreonam	Rats with cecal ligation and puncture (CLP) surgery (n=9)	Skeletal muscle and intraperitoneal fluid	V_sepsis= 0.503 ± 0.328 L	Muscle	Chauzi et al. 2018
	Control of health rats (n=5)		V_healthy= 0.473 ± 0.075 L	fT_sepsis = 1.00 ± 0.30
			CL_sepsis= 0.702 ± 0.474 L.h^-1.kg^-1	fT_healthy= 0.95 ± 0.12
			CL_healthy= 0.768 ± 0.108 L.h^-1.kg^-1	Intraperitoneal fluid
				fT_sepsis = 0.92 ± 0.41
				fT_healthy= 0.89 ± 0.14
Avibactam	Rats with cecal ligation and puncture (CLP) surgery (n=9)	Skeletal muscle and intraperitoneal fluid	V_sepsis= 0.312 ± 0.040 L	Muscle	Chauzi et al. 2018
	Control of health rats (n=5)		V_healthy= 0.285 ± 0.043 L	fT_sepsis = 1.01 ± 0.14
			CL_sepsis= 0.612 ± 0.072 L.h^-1.kg^-1	fT_healthy= 0.91 ± 0.11
			CL_healthy= 0.636 ± 0086 L.h^-1.kg^-1	Intraperitoneal fluid
				fT_sepsis = 0.94 ± 0.21
				fT_healthy= 0.88 ± 0.11
Imipenem	Rats with cecal ligation and puncture (CLP) surgery	Intraperitoneal fluid	V_sepsis= 0.310 ± 0.049 L	fT_sepsis = 0.89 ± 0.28	*Lefeuvre et al.* 2006**Lefeuvre S, Marchand S, Lamarche I, Mimoz O, Couet W. Microdialysis Study of Imipenem Distribution in the Intraperitoneal Fluid of Rats with or without Experimental Peritonitis. Antimicrob Agents Chemother . 2006;50(1):34- 37.
	Control of health rats		V_healthy= 0.289 ± 0.047 L	fT_healthy= 1.01 ± 0.19
			CL_sepsis = 0.654 ± 0.126 L.h^-1 .kg^-1
			CL_healthy= 0.714 ± 0.138 L.h^-1.kg^-1
Meropenem	Shock septic patients (n=6)	Intraperitoneal fluid	V_sepsis= 7.11 ± 2.36 L	fT_sepsis = 0.73 ± 0.15	Karjagin et al. 2007
Meropenem	Shock septic patients (n=6)	Intraperitoneal fluid	CL_sepsis= 6.72 ± 4.2 L.h^-1	fT_sepsis = 0.73 ± 0.15	Karjagin et al. 2007
Meropenem	Sepsis patients (n=10)	Adipose subcutaneous tissue	For intermittent infusion and continuous infusion	Intermittent infusion	*Roberts et al. 2009b*Roberts JA, Kirkpatrick CMJ, Roberts MS, Robertson TA, Dalley AJ, Lipman J. 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. Journal of Antimicrobial Chemotherapy, 2009b;64(1):142-50.
			V = 7.9 L	fT_day1= 0.73
			CL = 13.6 (CV 95%: 12.2-14.9) L.h^-1	fT_day3= 0.45
				Continuous infusion
				fT_day1= 0.15
				fT_day3= 0.67
Levofloxacin	Sepsis patients (n=7)	Skeletal muscle	V_sepsis= 124.6 ± 39 L	fT_sepsis = 0.85	*Zeitlinger et al. 2003*Zeitlinger MA, Dehghanyar P, Mayer BX, Schenk BS, Neckel U, Heinz G, et al. Relevance of Soft-Tissue Penetration by Levofloxacin for Target Site Bacterial Killing in Patients with Sepsis. Antimicrob Agents Chemother . 2003;47(11):3548- 3553.
Levofloxacin	Sepsis patients (n=7)	Skeletal muscle	CL_sepsis= 8.79 ± 5.50 L.h^-1	fT_sepsis = 0.85
Moxifloxacin	Shock septic patients (n=10)	Muscle and adipose subcutaneous tissue	V_day1= 131.1 ± 28.7 L	Muscle	*Nowak et al. 2019*Nowak H, Weidemann C, Martini S, Oesterreicher ZA, Dorn C, Adamzik M, et al. Repeated determination of moxifloxacin concentrations in interstitial space fluid of muscle and subcutis in septic patients. J Antimicrob Chemother . 2019;74(9):2681-2689..
			V_day3= 121.2 ± 23.2 L	fT_day1= 0.90
			V_day5= 118.6 ± 39.8 L	fT_day3= 0.95
			CL_day1 = 16.2 ± 5.9 L.h^-1	fT_day5 = 1.14
			CL_day3 = 15.7 ± 7.4 L.h^-1	Subcutis
			CL_day5 = 14.9 ± 4.2 L.h^-1	fT_day = 1.05
				fT_day3 = 0.91
				fT_day5 = 0.93
Linezolid	Sepsis patients (n=12)	Adipose subcutaneous tissue	IV single	Muscle	*Buerger et al. 2006*Buerger C, Plock N, Dehghanyar P, Joukhadar C, Kloft C. Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing usingmicrodialysis. Antimicrob Agents Chemother. 2006;50(7):2455-63.
			V = 61.4 L	fT= 0.99
			CL = 9.91 L.h^-1	Subcutis
			IV multiple	fT= 0.89
			V = 79.8 L
			CL = 8.44 L.h^-1
Linezolid	Severe Sepsis patients (n=8)	Muscle and adipose subcutaneous tissue	Severe sepsis	Severe sepsis	Thallinger et al. 2007
	Shock septic patients (n=16)		V = 57.15 ± 17.8 L	fT_muscle= 1.0
	Volunteers (n=10)		CL = 14.83 ± 7.55 L.h^-1	fT_subcutanous = 1.35
			Shock septic	Shock septic
			V = 60.37 ± 13.92 L	fT_muscle= 1.0
			CL = 9.81 ± 4.32 L.h^-1	fT_subcutanous = 0.9
			Volunteers	Volunteers
			V = 51.47 ± 9.51 L	fT_muscle= 1.22
			CL = 8.59 ± 3.38 L.h^-1	fT_subcutanous = 1.71
Fosfomycin	Sepsis patients(n=9)	Skeletal muscle	V_sepsis= 31.5 ± 4.5 L	fT_sepsis = 0.7 (0.4-1.0)	*Joukhadar et al. 2003*Joukhadar C, Klein N, Dittrich P, Zeitlinger M, Geppert A, Skhirladze K, et al. Target site penetration of fosfomycin in critically ill patients. J Antimicrob Chemother . 2003;51(5):1247-52.
Fosfomycin	Sepsis patients(n=9)	Skeletal muscle	Cl_sepsis = 7.2 ± 1.33 L.h^-1	fT_sepsis = 0.7 (0.4-1.0)
Fosfomycin	Shock septic patients (n=5)	Lung	V_healthy= 18.1 L	fT_sepsis = 0.63 ± 0.31	*Matzi et al. 2010*Matzi V, Lindenmann J, Porubsky C, Kugler SA, Maier A, Dittrich P, et al. Extracellular concentrations of fosfomycin in lung tissue of septic patients. J Antimicrob Chemother . 2010;65(5):995-998.
Fosfomycin	Volunteers (n=7)	Lung	Cl_healthy = 5.24L.h^-1	fT_healthy = 0.53 ± 0.31
Vancomycin	Sepsis patients (n=7)	Adipose subcutaneous tissue	V_sepsis= 10.87 ± 3.73 5 L	fT_sepsis = 0.37 (0.3-0.53)	*Abraham et al. 2018*Abraham J, Sinollareddy M, Roberts MS, Willians P, Peake SL, Lipman J, et al. Plasma and interstitial ßuid population pharmacokinetics of vancomycin in critically patients with sepsis. Int J Antimicrob Agents. 2018.
Vancomycin	Sepsis patients (n=7)	Adipose subcutaneous tissue	CL_sepsis= 3.33 ± 1.19 L.h^-1	fT_sepsis = 0.37 (0.3-0.53)
Metronidazole	Shock septic patients (n=6)	Skeletal muscle	V_sepsis= 53.5 ± 4.0 L	fT_sepsis = 0.87	*Karjagin et al. 2005*Karjagin J, Pahkla JR, Karki T, Starkopf J. Distribution of metronidazole in muscle tissue of patients with septic shock and its efficacy against Bacteroides fragilis in vitro. J Antimicrob Chemother . 2005;55(3):341-346.
Metronidazole	Shock septic patients (n=6)	Skeletal muscle	CL_sepsis= 3.37 ± 1.61 L.h^-1	fT_sepsis = 0.87
Fluconazole	LPS-induced sepsis model (n=12)	Skeletal muscle and Lung	V_sepsis= 0.17 L	Muscle	*Mauric et al. 2011*Mauric O, Thallinger C, Kugler SA, Joukhadar SM, Kovar FM, Konz KH, et al. The Ability of Fluconazole to Penetrate into Ventilated, Healthy and Inflamed Lung Tissue in a Model of Severe Sepsis in Rats. Pharmacology. 2011;87(3- 4):130-134.
	Control of health rats (n=16)		CL_sepsis= 0.0118L.h	fT_sepsis = 1.18
				fT_healthy= 1.12
				Lung
				fT_sepsis = 1.32 ± 0.04
				fT_healthy= 1.38 ± 0.39
Metronidazole	Shock septic patients (n=6)	Adipose subcutaneous tissue	V_sepsis= 20.4 (15.5-26.7) L	fT_sepsis = 0.53 ± 0.30	*Sinnollareddy et al. 2015*Sinnollareddy MG, Roberts MS, Lipman J, Lassing-Smith M, Starr T, Robertson T, et al. Determination of Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis Using In Vivo Microdialysis. Antimicrob Agents Chemother . 2015;60(2):827-832.
Metronidazole	Shock septic patients (n=6)	Adipose subcutaneous tissue	CL_sepsis= 0.5 (0.2-0.6) L.h^-1	fT_sepsis = 0.53 ± 0.30

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[1] *Correspondence: B. V. de Araujo. Programa de Pós-Graduação em Ciências Farmacêuticas. Faculdade de Farmácia. Universidade Federal do Rio Grande do Sul. Av. Ipiranga, 2752 - CEP: 90610-000, Porto Alegre, Rio Grande do Sul, Brazil. Phone: +555133085418. E-mail: bibiana.araujo@ufrgs.br.