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.

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

INTRODUCTION

Sepsis has been recently defined as a life-threatening organ dysfunction caused by a response of the host to the infection, leading to a misbalance of body homeostasis (Angus, Poll, 2013; Singer et al., 2016). This disease is one of the major causes of death in developed countries (Nguyen et al., 2000) and this topic has emerging importance in medicine due to increasing incidence in hospitals, caused by bacteria resistance and inefficiency in antimicrobial treatment (Hotchkiss, Karl, 2003; Micek, Hampton, Kollefc, 2018). At a global level, 48.9 million sepsis cases were registered in 2017 and 19.7% of global deaths had sepsis as the cause (Rudd et al., 2020). One of clinicians’ challenges is the choice of antimicrobial therapy regimen to cover up the larger range of microorganisms, who are spread all over blood and tissue, mostly at the site of infection (Micek, Hampton, Kollefc, 2018). For that reason, the antimicrobial treatment of choice will depend on the spectrum of action and the pharmacokinetics properties of the drug, aiming broad blood and tissue distribution.

Considering that in critically ill patients, as those with sepsis, the concentration in plasma does not necessarily reflect tissue concentration (Liu et al., 2011), in the last years, researchers showed the relevance of studying what happens within tissues (Venkatesh, Morgan, Cohen, 2010). That is why many studies were conducted to evaluate drug tissue distribution in a sepsis scenario, but a great part of those used biopsy (Condon et al., 1997; Wagenlehner et al., 2006) to determine drug concentration at the site of infection. The disadvantage of these studies was not being able to define free drug concentration, which are the fraction of action of the drug. Therefore, microdialysis (MD) became very popular in the last years for being an advanced technique of semi-invasive sampling, that can be use in any tissue for free interstitial concentration measuring, being applied to many pre-clinic and clinic studies (Nandi, Lunte, 2009). This technique allows the distinction of interstitial space fluid (ISF) and the others compartments (Joukhadar et al., 2001a), allowing the determination of free drugs level in ISF. The ratio of antimicrobial exposition in tissue and free drug exposition in plasma give the penetration factor (fT). This factor, combined with evaluation of plasma and tissue concentration profiles and other pharmacokinetic parameters, can help to define antimicrobial treatment for each patient. Considering the pathophysiology of the disease and variability between patients, selection of best antimicrobial drug for sepsis situation and the individualization of the regimen for each patient, can contribute to reduction of sepsis mortality.

For the reasons mentioned above, this article review was conducted after a research in Pubmed, Scielo and Web of Science databases, using the same follower 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)). No time intervals were applied or any other filters. In Pubmed, Scielo and Web of Science, 119, 2 and 162 articles published between 1993 and 2021 were extracted, respectively, and, after authors reading of titles and abstracts, 24 articles were finally selected for complete reading. Four of the 24 articles were excluded for not fulfilling the prerequisites to be used in this review. In the end, 18 articles were in fact selected for writing this systematic review.

Microdialysis as a technique for tissue penetration evaluation

MD technique is done through a probe with a dialysis membrane, that is semipermeable to small molecules (molecular weight < 20,000 Da) (Shippenberg, Thompson, 2001). Through this probe, an isotonic solution relative to the body fluid, is perfused during the experiment time interval. By the osmolar difference between the perfusate and the fluid around the membrane, some molecules pass through the membrane, then, they dilute in perfusate solution. Perfusate containing the analyte of interest flows through the output tube, where it can be collected for posterior quantification. The main advantage of MD is that it allows for multiple determinations of pharmacologically active drug, that is the free fraction (or the fraction not bound to plasma proteins), at the target site in the same patient (Joukhadar, Derendorf, Muller, 2001b). However, tissue biopsies only can provide the total drug concentration in a tissue portion at a single moment (Mouton et al., 2008).

The membrane probe is able to sample a fraction of the drug in the ISF, so is necessary to perform a probe calibration procedure to quantify how much is possible to harvest the drug in the microdialysate by classic approaches such no netflux and retrodialysis. The majority of the articles selected for this review used the retrodialysis technique. In retrodialysis, before the drug administration, a solution containing a certain concentration of the drug, or another internal standard, is perfused through the probe and then the analyte in dialysate is quantified. This percentage of recovery is used for calculation of microdialysis concentration of the drug in ISF. Also, the high-performance liquid chromatography, with tandem mass spectrometry detector, was the most used method to quantification. Still, other detectors were used, like UV spectroscopy and fluorescence, depending on molecules and matrix characteristics.

Pathophysiology of sepsis and diagnosis criteria

Sepsis is a highly heterogeneous syndrome that is defined as a systemic inflammatory response syndrome (SIRS) caused by an infection. Sepsis complicated by organ dysfunction was termed severe sepsis, which could progress to septic shock, (defined as sepsis and refractory hypotension). In the most recent ‘Sepsis-3’ consensus definition, sepsis is defined as a life-threatening organ dysfunction that is caused by a deregulated host response to infection, and the term severe sepsis has been avoided (Singer et al., 2016). In sepsis, a host response is trigger in the presence of an infectious agent, causing a misbalance in homeostasis due to an extremely inflammatory phenomenon, as activation of cytokines (Ilias et al., 2018), nitric oxide production and expression of adhesion molecules to endothelium, where important alterations in coagulation and fibrinolysis process can happen (Michie, 1996; Schouten et al., 2008). At the same time, the body regulates against this response, triggering an anti-inflammatory response, which is fundamental to patient recovery (Hotchkiss, Karl, 2003). However, the imbalance between these two forces, inflammatory and anti-inflammatory, is responsible for organ dysfunction (Nedeva, Menassa, Puthalakath, 2019).

High levels of serum lactate is an indication of cardiovascular compromise. Circulatory alterations, like vasodilatation and increase of capillary permeability, contribute to relative hypovolemia and hypotension, being a good predictor of sepsis worsening, as septic shock (Seymour, Rosengart, 2015). Edema will occur with reduction of plasma oncotic pressure, due to increase of glucose and albumin or metabolic changes, leading to leakage of liquid to ISF, causing distribution volume (V) increment (Venkatesh, Morgan, Cohen, 2010). This larger V, together with albumin increase, will elevate antimicrobial bound to protein and, consequently, reduce the active free fraction of the drug (Fly, 1996; Power et al., 1998). This fluid retention could also be due to renal dysfunction and may cause V increase, but mostly, renal dysfunction can cause clearance (CL) reduction and this delay of depuration increase time of half-life (t1/2) of drugs in septic patients. Renal dysfunction in sepsis is multifactorial, so the cause may be hypovolemia nd hypotension, which leads to poor organ oxygenation (Silva Júnior et al., 2006). In this situation, acute tubular necrosis and lesion through cellular apoptosis happens, prompting a urinary deficit and increase of serum urea and creatinine levels (Michie, 1996).

This particular physiopathological situation of critically ill septic patients makes infection disease management difficult with standard antimicrobial protocols of treatment (Roberts et al., 2010). Impairment on tissue penetration can lead to alterations in the achievement of concentration levels in the site of infection and in drug exposition in plasma and tissue, given by area under the curve (AUC_0-t). This can shift expected treatment outcomes, prompting failure and patient’s death.

Sepsis diagnosis is usually made using the criteria of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee. They define that a sepsis situation, must include at least the manifestations of: low or high temperature, less than 36 °C and more than 38°C; heart rate more than 90 beats per minute; respiratory rate over 20 breaths per minute or hyperventilation (CO₂ pressure less than 32 mm Hg); alterations in white blood cells count, with elevated presence of immature neutrophils (Bone et al., 1992). Prognosis are predicted using different criteria, as Acute Physiology And Chronic Health Evaluation (APACHE) (Knaus et al., 1985), especially version II, Simplified Acute Physiology Score (SAPS) (Gall, Lemeshow, Saulnier, 1993), and, specifically for sepsis, Sequential Organ Failure Assessment (SOFA) (Vincent et al., 1996) and Sepsis Severity Score (SSS) (Osborn et al., 2014). All those are models who score the disease using different variables (Osborn et al., 2014 [30]) for evaluation of severity, risk of death and for patients monitoring during treatment (Khwannimit, Bhurayanontachai, Vattanavanit, 2017).

Sepsis initial site of infection and main pathogens

Sepsis could be related to any kind of infection. A 2017 study made with data collected around the world, showed that diarrheal diseases and lower respiratory infections were the main causes of sepsis through patients of any age (Rudd, 2020 [6]). However, sepsis is also related to pneumonia, intra-abdominal infection and urinary infection (Kaukonen et al., 2014). Also, there are highly frequent infections related to catheters, soft tissue abscess, meningitis and endocarditis (Ilias et al., 2018). For these reasons, the World Health Organization defines that, cases of severe infection, such as diarrhea, lower respiratory tract infection, bacteremia, fungus infection, malaria, dengue and any communicable disease have sepsis as the fate and death as a common prognosis (WHO, 2020).

Severe infections are commonly caused by resistant pathogens, who are more difficult to treat with conventional antimicrobial therapy (WHO, 2020). Microorganisms as Escherichia coli, Klebsiella pneumoniae, Acinetobacter spp. and Staphylococcus aureus are frequently resistant to third generation of cephalosporins, as carbapenems, to aminoglycosides and to methicillin (MRSA) (WHO, 2017). In cases of intra-abdominal infections, more than one microorganism could be isolated from the infection and, among them, are Gram-positive and Gram-negative bacteria (Nord, 1994; Ilias et al., 2018). In a Turkey study, Gram-negative (65.9%) bacteria, like Klebsiella spp. And E. coli, were the most isolated in sepsis cases compared to Gram-positive, still, Staphylococcus spp. were one of the main pathogen isolated (21.9%) (Tanriover et al., 2006). However, in another European study, S. aureus (30%), each 14% were methicillin-resistant, Pseudomonas spp. (14%), and E. coli (13%) were the main pathogens isolated from septic patients (Vincent et al., 2006). In Brazil, the largest South American country, also Gram-negative bacteria were predominant in isolates from pediatric patients with sepsis (37.5%), while S. aureus were about 27.5% of the cases, followed by Neisseria meningitides (12.5%) (São Pedro, Morcillo, Baracat, 2015). In cases of fungus infections, Candida spp. is prevalent as an agent in immunosuppressed patients, leading to sepsis (Eggimann, Garbino, Pittet, 2003; Sekyere, 2018; Tanriover et al., 2006).

ANTIMICROBIALS IN SEPSIS: PHARMACOKINETICS AND PHARMACODYNAMICS

In this systematic review, organized in subtopics, the most important groups of antimicrobials used in the sepsis treatment were evaluated in terms of their pharmacokinetics and pharmacodynamics properties, comparing the PK differences observed in healthy volunteers and septic patients. The pharmacokinetic parameters were organized by respective study in Table I.

TABLE I
Pharmacokinetic parameters and penetration factor of antimicrobials in sepsis

Antimicrobial	Study group	Tissue of ISF	PK parameters	fT	References
Piperacilin	Shock septic patients (n=7)	Muscle and adipose subcutaneous tissue	Vsepsis= 40.7 ± 8.69 L*	Muscle	Joukhadar et al. 2001
	Volunteers (n=6)		Vhealthy= 9.61 ± 1.79 L	fTsepsis = 0.19 ± 0.03*
			CLsepsis= 8.16 ± 1.98 L.h-1	fThealthy= 0.55 ± 0.09
			CLhealthy= 7.86 ± 0.9 L.h-1	Subcutis
				fTsepsis = 0.10 ± 0.02*
				fThealthy= 0.31 ± 0.07
Cefpirome	Sepsis patients (n=12)	Skeletal muscle	Vsepsis= 25.9 ± 7.1 L*	fTsepsis = 0.63 ± 0.04	Joukhadar et al. 2002
	Volunteers (n=6)		Vhealthy= 14.6 ± 1.3 L	fThealthy = 0.83 ± 0.08
			CLsepsis= 4.5 ± 0.66 L.h-1
			Clhealthy = 4.68 ± 0.48 L.h-1
Cefpirome	Sepsis patients (n=11)	Adipose subcutaneous tissue	Vsepsis= 21.9 ± 4.5 L*	fTsepsis = 0.42 *	Sauermann et al. 2005
	Volunteers (n=7)		Vhealthy= 15.8 ± 5.6 L	fThealthy = 0.80
			CLsepsis= 4.8 ± 1.56 L.h-1
			Clhealthy = 6.3 ± 1.86 L.h-1
Aztreonam	Rats with cecal ligation and puncture (CLP) surgery (n=9)	Skeletal muscle and intraperitoneal fluid	Vsepsis= 0.503 ± 0.328 L	Muscle	Chauzi et al. 2018
	Control of health rats (n=5)		Vhealthy= 0.473 ± 0.075 L	fTsepsis = 1.00 ± 0.30
			CLsepsis= 0.702 ± 0.474 L.h-1.kg-1	fThealthy= 0.95 ± 0.12
			CLhealthy= 0.768 ± 0.108 L.h-1.kg-1	Intraperitoneal fluid
				fTsepsis = 0.92 ± 0.41
				fThealthy= 0.89 ± 0.14
Avibactam	Rats with cecal ligation and puncture (CLP) surgery (n=9)	Skeletal muscle and intraperitoneal fluid	Vsepsis= 0.312 ± 0.040 L	Muscle	Chauzi et al. 2018
	Control of health rats (n=5)		Vhealthy= 0.285 ± 0.043 L	fTsepsis = 1.01 ± 0.14
			CLsepsis= 0.612 ± 0.072 L.h-1.kg-1	fThealthy= 0.91 ± 0.11
			CLhealthy= 0.636 ± 0086 L.h-1.kg-1	Intraperitoneal fluid
				fTsepsis = 0.94 ± 0.21
				fThealthy= 0.88 ± 0.11
Imipenem	Rats with cecal ligation and puncture (CLP) surgery	Intraperitoneal fluid	Vsepsis= 0.310 ± 0.049 L	fTsepsis = 0.89 ± 0.28	Lefeuvre et al. 2006
	Control of health rats		Vhealthy= 0.289 ± 0.047 L	fThealthy= 1.01 ± 0.19
			CLsepsis = 0.654 ± 0.126 L.h-1 .kg-1
			CLhealthy= 0.714 ± 0.138 L.h-1.kg-1
Meropenem	Shock septic patients (n=6)	Intraperitoneal fluid	Vsepsis= 7.11 ± 2.36 L	fTsepsis = 0.73 ± 0.15	Karjagin et al. 2007
			CLsepsis= 6.72 ± 4.2 L.h-1
Meropenem	Sepsis patients (n=10)	Adipose subcutaneous tissue	For intermittent infusion and continuous infusion	Intermittent infusion	Roberts et al. 2009b
			V = 7.9 L	fTday1= 0.73
			CL = 13.6 (CV 95%: 12.2-14.9) L.h-1	fTday3= 0.45
				Continuous infusion
				fTday1= 0.15
				fTday3= 0.67
Levofloxacin	Sepsis patients (n=7)	Skeletal muscle	Vsepsis= 124.6 ± 39 L	fTsepsis = 0.85	Zeitlinger et al. 2003
			CLsepsis= 8.79 ± 5.50 L.h-1
Moxifloxacin	Shock septic patients (n=10)	Muscle and adipose subcutaneous tissue	Vday1= 131.1 ± 28.7 L	Muscle	Nowak et al. 2019.
			Vday3= 121.2 ± 23.2 L	fTday1= 0.90
			Vday5= 118.6 ± 39.8 L	fTday3= 0.95
			CLday1 = 16.2 ± 5.9 L.h-1	fTday5 = 1.14
			CLday3 = 15.7 ± 7.4 L.h-1	Subcutis
			CLday5 = 14.9 ± 4.2 L.h-1	fTday = 1.05
				fTday3 = 0.91
				fTday5 = 0.93
Linezolid	Sepsis patients (n=12)	Adipose subcutaneous tissue	IV single	Muscle	Buerger et al. 2006
			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	fTmuscle= 1.0
	Volunteers (n=10)		CL = 14.83 ± 7.55 L.h-1	fTsubcutanous = 1.35
			Shock septic	Shock septic
			V = 60.37 ± 13.92 L	fTmuscle= 1.0
			CL = 9.81 ± 4.32 L.h-1	fTsubcutanous = 0.9
			Volunteers	Volunteers
			V = 51.47 ± 9.51 L	fTmuscle= 1.22
			CL = 8.59 ± 3.38 L.h-1	fTsubcutanous = 1.71
Fosfomycin	Sepsis patients(n=9)	Skeletal muscle	Vsepsis= 31.5 ± 4.5 L	fTsepsis = 0.7 (0.4-1.0)	Joukhadar et al. 2003
			Clsepsis = 7.2 ± 1.33 L.h-1
Fosfomycin	Shock septic patients (n=5)	Lung	Vhealthy= 18.1 L	fTsepsis = 0.63 ± 0.31	Matzi et al. 2010
	Volunteers (n=7)		Clhealthy = 5.24L.h-1	fThealthy = 0.53 ± 0.31
Vancomycin	Sepsis patients (n=7)	Adipose subcutaneous tissue	Vsepsis= 10.87 ± 3.73 5 L	fTsepsis = 0.37 (0.3-0.53)	Abraham et al. 2018
			CLsepsis= 3.33 ± 1.19 L.h-1
Metronidazole	Shock septic patients (n=6)	Skeletal muscle	Vsepsis= 53.5 ± 4.0 L	fTsepsis = 0.87	Karjagin et al. 2005
			CLsepsis= 3.37 ± 1.61 L.h-1
Fluconazole	LPS-induced sepsis model (n=12)	Skeletal muscle and Lung	Vsepsis= 0.17 L	Muscle	Mauric et al. 2011
	Control of health rats (n=16)		CLsepsis= 0.0118L.h	fTsepsis = 1.18
				fThealthy= 1.12
				Lung
				fTsepsis = 1.32 ± 0.04
				fThealthy= 1.38 ± 0.39
Metronidazole	Shock septic patients (n=6)	Adipose subcutaneous tissue	Vsepsis= 20.4 (15.5-26.7) L	fTsepsis = 0.53 ± 0.30	Sinnollareddy et al. 2015
			CLsepsis= 0.5 (0.2-0.6) L.h-1

• CL= clearance; V = volume of distribution; fT = penetration factor given by ƒAUC_tissue/ƒAUC_plasma
• *Significant statistical difference between groups.
• ^# Significant statistical difference between IV bolus and continuous infusion.

The Figure 1 shows the mechanism of action of the drugs revised in the current study.

FIGURE 1
Mechanism of action of antimicrobials used in sepsis treatment.

Piperacillin, Cefpirome and Aztreonam

Piperacillin is a largely prescribed antimicrobial in ICUs, as are many other β-lactams (Rello et al., 2011). This class presents hydrophilic characteristics, (Tjandramaga et al., 1978) which is why it is expected to distribute well in ISF. Joukhadar et al. (2001a), compared 7 septic shock patients with 6 healthy volunteers after a single intravenous (IV) administration of 4g of piperacillin. Plasma and ISF (microdialysis) samples from skeletal muscle and subcutaneous tissue were collected and concentration-time profiles analyzed. The main findings were the surprising lower concentrations of piperacillin in both tissues, compared to plasma concentrations, in septic patients. This could be due to great V of septic patients compared to volunteers (40.72 ± 8.69 vs. 9.61 ± 1.79 L, respectively). More astonishing was the difference in tissue penetration of septic patients: almost three times lower than in controls. Also, it was observed that the half- life of the elimination phase (t_1/2β) was higher in septic patients due to slower clearance. The extreme conditions present in shock septic patients explain all these findings, especially the use of vasopressors that are very needed in shock situations. In 2009a, Roberts et al. in a prospective randomized trial, with 13 septic patients compared the administration of piperacillin associated with tazobactam, a β-lactam inhibitor, in constant infusion with IV bolus. Plasma and ISF (microdialysis) samples of subcutaneous tissue were collected and concentration-time profiles showed a mean plasma concentration higher with continuous infusion when compared to IV bolus (16.6 the therapeutic target of 100% T > MIC, that means time above minimum inhibitory concentration (MIC), PK/PD index usually applied to -lactams, for bacteria with MIC’s over 2 - 4 mg.L^-1.

As well as piperacillin, cefpirome belongs to the class of β-lactam; it is a four-generation cephalosporin, which has a wide spectrum, being indicated for the treatment of seriously ill patients. Joukhadar et al. (2002), performed microdialysis on the skeletal muscle of 12 septic patients compared with 6 healthy volunteers after a single IV administration of 2g of cefpirome. The C_máx and AUC_{0-4 h} in skeletal muscle were significantly lower and T_máx were significantly higher in patients with sepsis compared with the control group (62 ± 4* vs. 127 ± 15 mg.L^-1, 0.16 ± 0.012* vs. 0.259 ± 0.024 g.h.L^-1and 1.45 ± 0.18 vs. 0.72 ± 0.1 h, respectively). In septic patients, mean AUC_{0-4 h} values for free cefpirome in plasma and skeletal muscle were consistently lower than those in healthy volunteers, however, the fT, was not significantly different between both groups. Yet, the fluid overload, as expressed by a higher volume of distribution in patients with sepsis when compared with healthy controls (25.9* ± 7.1 and 14.6 ± 1.3 L), decreases directly drug concentrations in plasma and interstitial space. The authors conclude that after an equilibration period of 2 hours, the concentration- time profile of cefpirome in skeletal muscle is identical to plasma concentrations in patients and volunteers.

Another study of cefpirome was made by Sauermann et al. (2005). They performed microdialysis of subcutaneous adipose tissue in 11 patients with sepsis and compared against 7 healthy individuals after administration of 2 g of vs. 4.9 mg.L^-1, respectively), even the continuous infusion cefpirome. The t_1/2β of cefpirome was significantly longer dose was 25% less than IV bolus dose. Therefore, for an adequate regimen of treatment, a dose increase may not be necessary. Equilibration times between tissue and plasma concentrations, for 50% and 90%, were extremely high (173 and 570 h, respectively) for continuous infusion, so the equilibrium was not achieved during the experiment, maybe because of vascular alterations compromising drug distribution. Tissue penetration was almost three times higher for continuous infusion than IV bolus. Those differences between these two regimens could impact the effect, as can be seen by pharmacodynamics simulation results: continuous infusion more frequently achieved for patients than for healthy controls (3.05 ± 0.9 and 1.58 ± 0.5 h*) in plasma and subcutaneous adipose tissue (5.16 ± 2.41 and 1.55 ± 0.37 h*). For tissue, the C_máx was lower in patients than in the healthy subjects (41 ± 17* and 116 ± 48 mg.L^-1, respectively) and showed reduction in AUC _{4 h} of septic patients (0.115 ± 0.043* and 0.219 ± 0.087 g.h.L^-1, respectively), further the patients exhibit increasing in the distribution volume (21.9 ± 4.5* and 15.8 ± 5.6 L, respectively). Plasma to tissue balance was considerably delayed in patients with sepsis compared to healthy patients. Thus, the penetration of cefpirome into subcutaneous adipose tissue occurs quickly in healthy subjects, and it was strongly delayed in septic patients. In PD, the lowest and the highest tissue concentrations of cefpirome were tested by dynamic time-kill curves experiments against S. aureus and P. aeruginosa. T>MIC appeared to be slightly higher in septic patients, due their slower clearance, though, no statistical difference was found.

Chauzy et al. (2018) studied the combination of Aztreonam and Avibactam, β-lactam/β-lactamase inhibitors for the treatment of serious infections (Sy, 2016 [48]). Aztreonam (100 mg.kg^-1) and Avibactam (25 mg.kg^-1) were administered to rats that underwent cecal ligation and puncture (CLP) surgery to mimic a model of animal sepsis. Skeletal muscle and intraperitoneal fluid MD were performed. The AUC, of plasma, muscle and intraperitoneal fluid for control rats (131.8 ± 16.8, 123.7 ± 7.5, 116.2 ± 18.7 mg.h.L^-1, respectively) showed no significant difference when compared to the CLP group (180.6 ± 74.6, 169.9 ± 64.4, 150.6 ± 65.7 mg.h.L^-1). The peritonitis group showed similar values of penetration factors when compared to the control group, both closed to unit, indicating great distribution. There were no differences in the pharmacokinetic parameters analyzed, demonstrating that this combination of drugs presents good tissue penetration and can be used as an alternative in critically ill patients.

Meropenem and Imipenem

In 2006, Lefeuvre et al. investigated imipenem tissue distribution in peritoneal ISF, using an experimental model of induced peritonitis by cecal ligation and punctures in rats. Through plasma and tissue MD, after a 30 mg.kg^-1 dose of imipenem infused over 30 min, they evaluated the pharmacokinetics. No statistical differences were found in clearance (CL) (0.714 ± 0.138 vs. 0.654 ± 0.126 L.h^-1.kg^-1) or volume of distribution (V) (0.296 ± 0.047 vs. 0.310 ± 0.049 L.kg^-1) for the control group and peritonitis group. In septic rats, ISF concentrations in tissue were slightly less than plasma concentrations, however, tissue and plasma drug expositions had no differences and, consequently, fT is close to one. These findings showed that imipenem is fully distributed to peritoneal ISF in both groups, indicating that infection have no influence in imipenem penetration in this fluid, in a sepsis model of rats. Nonetheless, posterior clinical studies with meropenem, - another broad-spectrum carbapenem widely prescribed for patients with sepsis (Baldwin, Lyseng-Williamson, Keam, 2008), especially in case of infections in peritoneal cavity, like peritonitis (Wiesholzer et al., 2016) - observed impact of sepsis in tissue concentrations.

Karjagin et al. (2008) studied meropenem penetration into peritoneal fluid (PF) in patients affected by peritonitis and septic shock and the concentrations in plasma and in PF were analyzed using compartmental approach. Based on the PK parameters estimated, they simulated exposition by different dosing regimens of meropenem. For the usual dose of 1 g every 8 hours, AUC_{0-24 h} in plasma and PF was 0.625 and 0.491 mg.h.L^-1. Moreover, C for plasma and PF was 98.2 and 32.3 mg.L^-1 and C was 12.5 and 11.9 mg.L^-1.. Effect was evaluated for different regimens through the percentage of time interval between doses that concentration in plasma and PF stayed over MIC. For MIC of 4 mg.L^-1, the mean of 87% of interval between doses was achieved for any regimen, in plasma and PF. Yet, for MIC of 16 mg.L^-1, the treatment using the usual dose was not that successful, since the mean of 55% in plasma and 43% in PF were achieved.

Roberts et al. (2009b) provides information on the concentrations of meropenem in subcutaneous tissue, where two groups receive different meropenem regimens: one was intermittent bolus and other was continuous infusion, where the dose was 3.5 g at day one, when was given a loading dose, and followed by 3 g/day. Statistical difference was found between parameters at day 1 - where for plasma AUC was 97.2 and 99.0 mg.h.L^-1 and for subcutaneous tissue AUC_{40 - 48 h} was 71.5 and 8.8 mg.h.L^-1 - and at day 2 - where for plasma AUC was 69.1 and 67.55 mg.h.L^-1 and for subcutaneous tissue AUC was 30.3 and 38.8 mg.h.L^-1 - for intermittent bolus infusion and continuous infusion, respectively. The administration of meropenem by continuous infusion maintains statistically significant higher concentrations at steady state (mean 7.5 mg.L^-1 between day 1 and 2), in subcutaneous tissue and plasma, when compared with trough concentrations of intermittent bolus dosing, where C_min was almost zero for this regimen. Tissue penetration was good in both regimens, however, after day 1 continuous infusion was very low compared with the first day of intermittent infusion, that may be because of the lower loading dose administered in this regimen. Through PK results, PD analysis was made by Monte Carlo simulations to evaluate probability of target attainment (PTA) using 40% ƒT > MIC as therapeutic target for those regimens and others. Continuous infusion was more efficiently against pathogens with higher values of MIC (4-16 mg.L^-1). Cumulative fraction of response (CFR), that is the success of treatment probability when PTA against the MIC breakpoints of frequent pathogens, was 100% achieved for more susceptible microorganisms, though for P. aeruginosa and Acinetobacter spp. showed a significant reduction in values of PTA to intermittent infusion. Another interesting simulation finding was that people with lower renal function have higher PTA, due to higher time of drug exposition.

Levofloxacin and Moxifloxacin

Levofloxacin is a synthetic broad-spectrum antimicrobial, belonging to the class of fluoroquinolones (Zhanel et al., 2002). Zeitlinger et al. (2003), performed muscle microdialysis in 7 patients with sepsis after a single 500 mg levofloxacin intravenous dose. High variability was found in concentration-time profiles in tissue, but not for plasma. The means of AUC_{0-8 h} (22.1 ± 13.1 and 24.9 ± 6.7 mg.h.L^-1) and C (3.6 ± 2.0 and 7.3 ± 1.5 mg.L^-1) were lower in muscle tissue than the means of total plasma (p = 0.018). Despite the high variability, the mean penetration factor was almost close to unit, indicating that levofloxacin is able to penetrate well into the tissues of patients with sepsis. PD analysis was made with dynamic time-kill curves, using the concentrations found in plasma and tissue. A Spearman rank order correlations between the decrease of P. aeruginosa colonies count and individual tissue parameters as C_max/ MIC (R = 0.96), AUC_{0-8 h}/MIC (R = 0.96) and fT (R = 0.93) were significant.

Another f luoroquinolone investigated was moxifloxacin, which belongs to the fourth generation of this class. Nowak et al. (2019), monitored concentrations in plasma and ISF of muscle and subcutaneous tissue, in 10 patients with sepsis, after 400 mg of moxifloxacin one time per day, through 2 hours infusion. Plasma samples collection and microdialysis were performed for a long period of time, at 1, 2 and 3 days after beginning of treatment. As a result, a rapid balance between free concentrations in plasma and tissue was observed, where no significant difference was found in the parameters between plasma and tissue through the study days. Maximum tissue concentrations were reached 1 hour behind plasma, however, values of C_max were very close. Like for levofloxacin, a high variability was observed in concentrations measured by microdialysis in tissue, more than in plasma. Using concentration-time profile of each patient, ƒAUC_{0-24 h}/MIC was calculated employing European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Staphylococcus spp. All the values of ratio were over 30 hours for each patient, at muscle, at subcutaneous tissue and plasma, through all study days, reaching the target if it was considered concentrations between 30-100 for maximum effect. However, for day 5, muscle showed a higher mean of ƒAUC_{0-24 h}/MIC than plasma, due to moxifloxacin accumulation in this tissue after multiple doses.

Linezolid

Linezolid belongs to a class of synthetic antibacterial agents called oxazolidinones and has been approved for the reserve treatment of serious infections caused by resistant aerobic and gram-positive anaerobic pathogens (Ford, Zurenko, Barbachyn, 2001). Also, is often administered to patients who have sepsis and septic shock (De Gascun et al., 2006).

Buerger et al. (2006) performed MD on subcutaneous adipose tissue and skeletal muscle in 12 patients with sepsis. Two studies were carried out, where patients received 600 mg of linezolid through 30 min infusion every 12 hours. At day one, after administration of the first dose, plasma samples were collected and microdialysis was performed. Three days after the first dose, the same procedure was made, for single dose and multidose comparison. Free fraction of linezolid was calculated individually for all patients and an average of 86.6% (CV=7.9%) was obtained. Although high variability, the penetration factor of linezolid found was almost close to the unit in both adipose and muscular tissue, meaning that sepsis cannot affect linezolid tissue distribution. The pharmacokinetic parameters estimated for single and multiple doses was distribution volume at steady state (V_ss) = 61.4 vs. 79.8 L, CL = 9.91 vs. 8.44 L/h, respectively, showed no significant differences. In the same way that the AUC was not different between groups.

With those findings, it is possible to conclude that this dosing regimen presents a larger interval between doses, so cannot produce linezolid accumulation, so every dose function as a single dose and steady state is in fact never reached.

In PK/PD analysis, 70% of patients achieved the therapeutic target of 40% ƒT>MIC. Though, for more rigorous targets like >80% ƒT>MIC, only 40% of patients could achieved. Still, if the index of ƒAUC/MIC is considered for bacteriostatic effect (ratio of 48-147) and bactericidal effect (ratio >51), almost every patient stay above this target. So, for effectiveness, a reduction in this time of interval is necessary to avoid subtherapeutic dose.

Thallinger et al. (2008), employing data from Buerger et al. (2006) patients and increasing this number for statistical purposes, compared the concentration-time profiles and pharmacokinetics to health individuals from a previously study (Dehghanyar et al., 2005) to evaluate the influence of sepsis severity in tissue penetration. AUC_{0 - 24 h} was calculated for both groups and, in the same way of AUC_{0 - 8 h}, no significant difference were found. The free fraction of linezolid in plasma was completely balanced with the tissue interstitial fluid. The penetration factors found were approximately 1 in all groups, however, in healthy individuals was observed a tendency of linezolid deposit in adipose tissue. Linezolid is a lipophilic molecule and it volume of distribution varied between 50 and 60 liters, so the authors suggest that this drug does not distribute exclusively to the fluid in the extracellular space, also penetrates into the cells, making it less susceptible to major changes in the volume of the extracellular fluid, which can be found in patients with sepsis.

Fosfomycin

Fosfomycin is a broad-spectrum bactericidal antimicrobial that is not structurally related to otherclasses of antimicrobials. It has high in vitro activity against gram-positive bacteria such as S. aureus and Staphylococcus pyogenes and gram-negative bacteria such as P. aeruginosa (Grif et al., 2001). The tissue penetration capacity of fosfomycin may be partially related to its high hydrophilicity, small molecular weight and low protein binding. (Popovic et al., 2009).

Joukhadar et al. (2003) studied the concentrations of fosfomycin in ISF of muscle and showed that it was fully balanced with plasma at 1.3 hours after drug administration. When analyzing 9 patients with sepsis who underwent muscle microdialysis, after a single intravenous dose of 8.0 g of fosfomycin, the results of AUC_{0-4 h} and C_max for muscle and plasma (501 ± 69 vs. 721 ± 66 mg.h.L^-1, and 247 ± 38 vs. 357 ± 28 mg.L^-1, respectively) were significantly lower. Although the exposition in tissue is smaller than in plasma, S. pyogenes time-kill curves showed an almost 2 log₁₀/ mL decrease when exposed to the concentrations found in plasma and ISF. In addition, the fT of muscle was very good, even better than in lungs, studied by Matzi and collaborators (2010), where, after microdialysis probe insertion into healthy and infected lung tissue, a single intravenous dose of 4 g of fosfomycin was administered in a cohort of septic patients and healthy volunteers. Observed mean values of C_max, T_max and AUC_{0-4 h}, showed no significant difference between groups. The fT of infected lung tissue was also very similar to the healthy ones. The main find was that equilibration is fully obtained among free fosfomycin in plasma and in extracellular space fluid of tissues, in either healthy volunteers or septic patients. There was considerable variability in tissue and plasma pharmacokinetic profiles, exposing individuals to the potential risk of sub-therapeutic exposure, but severe inflammation in septic patients seems not be clinically relevant on fosfomycin ability to penetrate infected lung tissue.

Vancomycin

Vancomycin is a bacteriostatic glycopeptide antibiotic widely used in the ICU (Tenover, Biddle, Lancaster, 2001), especially against resistant microorganisms (Liu et al., 2011 [7]). However, there is only one study, of Abraham et al. (2018), who performed microdialysis of vancomycin in a sepsis situation. Subcutaneous tissue microdialysis was performed after vancomycin infusion in 6 patients with sepsis. A high variability was observed in the concentration-time profiles and the median AUC_0- in total plasma was 346 (328-373) mg.h.L^-1 and in subcutaneous tissue was 123 (90-148) mg.h.L^-1, showing a low tissue penetration, demonstrating that vancomycin can not be completely distribute in tissue.

Fluconazole and Metronidazole

Metronidazole can be used for anaerobic infections which lead to sepsis (Eykyn, Phillips, 1976) and fluconazole is another triazole often used in ICUs for the treatment of critically ill patients (Colombo et al., 2013). Metronidazole penetration properties were studied by Karjagin et al. (2005). Patients with sepsis were treated with 500 mg of metronidazole in a single IV dose and muscle microdialysis was performed. AUC_{0-10 h} for plasma was 66 ± 8.3 mg.h.mL^-1 and for muscle tissue of 57.9 ± 29.9 mg.h.L^-1, where no significant differences were found, so a high muscle penetration factor of metronidazole was observed, indicating that septic shock has no major influence in metronidazole distribution. However, high variability was found in tissue concentrations of these patients. Mean concentrations found in tissue after this 500 mg dose were used to calculate tissue concentrations for 250 and 1000 mg doses, considering linear pharmacokinetics. These profiles were simulated in time-kill curves experiments against Bacteroides fragilis strains. As a result, bactericidal effect was observed through significant log decrease for each dose until 10 hours after inoculum exposition to metronidazole.

Mauric et al. (2011) suggests that fluconazole has great tissue penetration into the lung and muscle in healthy rats and in LPS-induced sepsis model. A LPS (lipopolysaccharide) model was used to induce systemic inflammation in rats after peritoneum administration. Later to administration of a single intravenous dose of 6 mg.kg^-1 of fluconazole, MD of pulmonary tissue and skeletal muscle was performed. Over the unit penetration factors for health, inflamed lungs and muscles were observed, as results of the similar values of AUC_{0-6 h} of plasma and lungs in this two groups: the AUC of healthy rats was 35.5 ± 5.8 mg.h.L^-1 for plasma, 47.4 ± 8.6 mg.h.L^-1 for lungs and 39.1 ± 6.4 mg.h.L^-1 for muscle; sepsis rats had an AUC of 35.3 ± 7.3 mg.h.L^-1 for plasma, 52.9 ± 6.2 mg.h.L^-1 for lungs and 41.5 ± 6.7 mg.h.L^-1, for muscle. No changes were found in any of the PK parameters analyzed, when animals with sepsis were compared with healthy animals, indicating that severe inflammation did not affect the ability of fluconazole to penetrate tissues. However, the LPS model used in the study does not mimic all forms of inflammation found in sepsis and this can explain why fluconazole penetration in tissues was so good.

In a study done by Sinnollareddy et al. (2015), 12 septic patients received 400 mg (5.1 mg/kg) dose of fluconazole, through intravenous infusion. When compared the median AUC of plasma (340.4 mg.h.L^-1) to subcutaneous tissue (141.1 mg.h.L^-1), the AUC of free plasma was significantly higher, still reflecting in adequate fluconazole tissue penetration. Lag distribution to tissue from plasma was observed through the t_max of ISF, almost 3 times higher than t_max of plasma. Therefore, the fluconazole was incompletely distributed from plasma to subcutaneous tissue, with high variability among patients. The PK/PD index used for effect analysis was ƒAUC_{0-24 h}/MIC ≥100 and, for the majority of patients (33- 92%), this target was reached for breakpoints established by EUCAST and Clinical and Laboratory Standards Institute (CLSI) to Candida albicans, Candida tropicalis, and Candida parapsilosis. However, with values of MIC’s of 4-8 mg.L^-1, the percentage of patients who achieved this target decreased considerably (0-42%). Although this PK/PD results showed the efficiency of fluconazol, only one patient of twelve responded well to the treatment.

These findings of Mauric et al. (2011) and Sinnollareddy et al. (2015) are examples of how important is to study antimicrobial tissue penetration in different populations, also, not always a pre-clinic study could be extrapolated to humans. Simulation tools need to be improved and apply before translation of pre-clinic to clinic studies, because the results of one may not reflect in the other.

CONCLUSION

Sepsis is a life-threatening disease where impaired tissue penetration can occur and this will reflect in treatment outcome. Clearance seems to be slower in septic patients, which can lead to toxic implications and aggravation of patient state. Also, expansion of ISF volume of distribution due to edema, can result in a decrease of osmotic gradient and fluid overload, with an increase of circulating proteins, which can bind to drugs, cause reduction of free concentrations of the antimicrobials in ISF, as can be seen through lower AUC and, consequently, lower fT. Another important fact is the elevated variability in tissue penetration of antimicrobials (Karjagin et al., 2005; Thallinger et al., 2008; Matzi et al., 2010), once hemodynamic and other manifestations vary through the employment of different strategies of treatment, is the use of vasopressors, like norepinephrine, that delays drug distribution to ISF, by restriction of perfusion capillaries (Zeitlinger et al., 2007).

Considering the complexity of this subject matter and the variety of antimicrobials for this treatment purpose, highlights the necessity for further investigation about tissue penetration and pharmacokinetics of antimicrobials in sepsis scenarios, especially employing MD technique, that can access free drug interstitium concentrations per time. There is a lack of information about some drugs, for example vancomycin, a widely use antimicrobial for critically ill patients, which has only one microdialysis study in septic patients. Pre-clinic studies employing animal sepsis model are also restricted in number, which can result in difficulties to perform clinic studies with previous evidence.

In conclusion, is possible to say that sepsis will implicate in imbalance plasma/tissue concentrations and impact in drug distribution, resulting in pharmacokinetic and, consequently, pharmacodynamics alterations of antimicrobials.

ACKNOWLEDGMENTS

This work was financed by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES, Código 001), by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS - 19/2551- 0001700-6) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - 423260/2021-9). K.S.T.B received a doctoral scholarship from CNPq. Authors declare no conflict of interest.

REFERENCES

• 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.
• Angus DC, Poll TVD. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-51.
• Baldwin CM, Lyseng-Williamson KA, Keam SJ. Meropenem A Review of its Use in the Treatment of Serious Bacterial Infections. Drugs. 2008;68(6):803-838.
• Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644-1655.
• 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.
• Chauzy A, Lamarche I, Adiera C, Couet W, Marchand S. Microdialysis Study of Aztreonam-Avibactam Distribution in Peritoneal Fluid and Muscle of Rats with or without Experimental Peritonitis. Antimicrob Agents Chemother . 2018;62(10):e01228-18.
• Colombo AL, Guimarães T, Camargo LFA, Ritchtmann R, Queiroz-Telles F, Salles MJC, et al. Brazilian guidelines for the management of candidiasis - a joint meeting report of three medical societies: Sociedade Brasileira de Infectologia, Sociedade Paulista de Infectologia and Sociedade Brasileira de Medicina Tropical. Braz J Infect Dis. 2013;17(3):283-312.
• Condon RE, Walker AP, Hanna CB, Greenberg RN, Broom A, Pitkin D. Penetration of meropenem in plasma and abdominal tissues from patients undergoing intraabdominal surgery. Clin Infect Dis. 1997;24 Suppl 2:181-183.
• De Gascun C, Rajan L, O’Neill E, Smyth EG. Linezolid use in sepsis due to methicillin-susceptible Staphylococcus aureus. J Antimicrob Chemother. 2006;57(1):150-1.
• Dehghanyar P, Buerger C, Zeitlinger M, Isinger F, Kovan F, Muller M, et al. Penetration of linezolid into soft tissues of healthy volunteers after single and multiple doses. Antimicrob Agents Chemother . 2005;49(6):2367-71.
• Eggimann P, Garbino J, Pittet D. Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. Lancet Infec Dis. 2003;3(11):685-702.
• Eykyn S, Phillips Y. Metronidazole and anaerobic sepsis. Br Med J. 1976;2(6049):1418-1421.
• Fly DE. The Importance of Antibiotic Pharmacokinetics in Critical Illness. Excerpta Med. 1996;172(6A):20S-25S.
• Ford CW, Zurenko GE, Barbachyn MR. The Discovery of Linezolid, the First Oxazolidinone Antibacterial Agent. Curr Drug Targets Infect Disord. 2001;1(2):181-199.
• Gall JR, Lemeshow S, Saulnier F. A New Simplified Acute Physiology Score (SAPS II) Based on a European/North American Multicenter Study. Jama. 1993;270(24):2957-2963.
• Grif K, Dierich MP, Pfaller K, Miglioli PA, Allerberger F. In vitro activity of fosfomycin in combination with various antistaphylococcal substances. J Antimicrob Chemother . 2001;48(2):209-17.
• Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med . 2003;348(2):138-50.
• Ilias L, Apollonatou S, Nikitas N, Theodorakopoulou M, Vassiliou AG, Kotanidou A, et al. Microdialysis-Assessed Adipose Tissue Metabolism, Circulating Cytokines and Outcome in Critical Illness. Metabolites. 2018;8(4):62.
• Joukhadar C, Derendorf H, Muller M. Microdialysis a novel tool for clinical studies of anti-infective agents. Eur J Pharmacol. 2001b;57:211-219.
• Joukhadar C, Frossard M, Mayer BX, Klein N, Siostrzonek P, Eichler HG, et al. Impaired target site penetration of β-lactam s may account for therapeutic failure in patients with septic shock. Crit Care Med. 2001a;29(2):385-91.
• 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.
• 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.
• Karjagin J, Lefeuvre S, Oselin K, Kipper K, Marchand S, Tikkerberi A, et al. Pharmacokinetics of Meropenem Determined by Microdialysis in the Peritoneal Fluid of Patients With Severe Peritonitis Associated With Septic Shock. Clin Pharmacol Ther. 2008;83(3):452-459.
• 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.
• Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000- 2012. JAMA. 2014;311(13):1308-16.
• Khwannimit B, Bhurayanontachai R, Vattanavanit V. Validation of the sepsis severity score compared with updated severity score in predicting hospital mortality in sepsis patients. Shock. 2017;47(6):720-725.
• Knaus AW, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med . 1985;13(10):818-829.
• 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.
• Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Infectious Diseases Society of America. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of Methicillin-Resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis . 2011;52(3):e18-55.
• 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.
• 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.
• Micek ST, Hampton N, Kollefc M. Risk Factors and Outcomes for Ineffective Empiric Treatment of Sepsis Caused by Gram- Negative Pathogens: Stratification by Onset of Infection. Antimicrob Agents Chemother . 2018;62(1):e0157 7-17.
• Michie HR. Metabolism of Sepsis and Multiple Organ Failure. World J Surg. 1996;20(4):460-4.
• Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O. Tissue concentrations: do we ever learn? J Antimicrob Chemother . 2008;61(2):235-237.
• Nandi P, Lunte SM. Recent trends in microdialysis sampling integrated with conventional and microanalytical systems for monitoring biological events: A review. Anal Chim Acta. 2009;651(1):1-14
• Nedeva C, Menassa J, Puthalakath H. Sepsis: Inflammation Is a Necessary Evil. Front Cell Dev Biol. 2019;7:108.
• Nguyen HB, Rivers EP, Havstad S, Knoblich B, Resser JA, Muzzin AM, et al. Critical Care in the Emergency Department: a physiologic assessment and outcome evaluation. Acad Emerg Med. 2000;7(12):1354-61.
• Nord CE. The treatment of severe intra-abdominal infections: the role of piperacillin/tazobactam. Intensive Care Med. 1994;20 Suppl 3:S35-38.
• 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.
• Osborn TM, Phillips G, Lemeshow S, Townsend S, Schorr CA, Levy MM, et al. Sepsis Severity Score: an internationally derived scoring system from the surviving sepsis campaign database. Crit Care Med . 2014;42(9):1969-76.
• Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis. 2009;29(2):127-142.
• Power BM, Forbes AM, Van Heerden PV, Llett KF. Pharmacokinetics of Drugs Used in Critically Ill Adults. Clin Pharmacokinet. 1998;34(1):25-56.
• Rello J, Ulldemolins M, Lisboa T, Koulenti D, Mãnez R, Martin-Loeches, et al. Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia. Eur Respir J. 2011;37(6):1332-1339.
• Roberts JA, Kirkapatrick CM, Roberts MS, Dalley AD, Lipman J. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents . 2010;35(2):156-63.
• 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.
• Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Piperacillin penetration into tissue of critically ill patients with sepsis-Bolus versus continuous administration? Crit Care Med . 2009a;37(3):926-933.
• Rudd KE, Johnson SC, Agesa KM, Shackelford K, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200-11.
• São Pedro TC, Morcillo AM, Baracat ECE. Etiology and prognostic factors of sepsis among children and adolescents admitted to the intensive care unit. Rev Bras Ter Intensiva. 2015;27(3):240-246.
• 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.
• Schouten M, Wiersinga WJ, Levi M, Van Der Pol T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008;83(3):536-45.
• Sekyere JO. Candida auris: A systematic review and meta- analysis of current updates on an emerging multidrug-resistant pathogen. Microbiol Open. 2018;7: 57-8.
• Seymour CW, Rosengart MR. Septic Shock Advances in Diagnosis and Treatment. Clinical Review & Education. 2015;314(7):708-17.
• Shippenberg TS, Thompson AC. Overview of Microdialysis. Curr Protoc Neurosci. 2001;Chapter 7:Unit7.1.
• Silva Júnior GB, Daher EF, Mota RMS, Menezes FA. Risk factors for death among critically ill patients with acute renal failure. Sao Paulo Med J. 2006;124(5):257-63.
• Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA . 2016; 315(8):801-810.
• 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.
• Sy SKB, Beaudoin ME, Zhuang L, Loblein KI, Lux C, Kissek M, et al. In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms. J Antimicrob Chemother . 2016;71(7):1866-1880.
• Tanriover MD, Guven GS, Sen D, Unal S, Uzun O. Epidemiology and outcome of sepsis in a tertiary-care hospital in a developing country. Epidemiol Infect. 2006;134(2):315-322.
• Tenover FC, Biddle JW, Lancaster MV. Increasing Resistance to Vancomycin and Other Glycopeptides in Staphylococcus aureus. Emerg Infec Dis. 2001;7(2):327-332.
• Thallinger C, Buerger C, Plock N, Kljucar S, Wuenscher S, Sauermaan R, et al. Effect of severity of sepsis on tissue concentrations of linezolid. J Antimicrob Chemother. 2008;61(1):173-176.
• Tjandramaga TB, Mullie A, Verbesselt R, De Schepper PJ, Verbist L. Piperacillin: Human Pharmacokinetics After Intravenous and Intramuscular Administration. Antimicrob Agents Chemother . 1978;14(6):829-837.
• Venkatesh B, Morgan TM, Cohen J. Interstitium: The next diagnostic and therapeutic platform in critical illness. Crit Care Med . 2010;38(10 Suppl):S630-6.
• Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis.related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med . 1996;22(7):707-710.
• Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: Results of the SOAP study*.Crit Care Med . 2006;34(2):344- 53.
• Wagenlehner FME, Lunz JC, Kees F,Wieland W, Nsber KG. Serum and Prostatic Tissue Concentrations of Moxifloxacin in Patients Undergoing Transurethral Resection of the Prostate. J Chemother. 2006;18(5):485-489.
• Wiesholzer M, Pichler P, Reznicek G, Wimmer M, Kussmann M, Balcke P, et al. An Open, Randomized, Single-Center, Crossover Pharmacokinetic Study of Meropenem after Intraperitoneal and Intravenous Administration in Patients Receiving Automated Peritoneal Dialysis. Antimicrob Agents Chemother . 2016;60(5):2790-2797.
• World Health Organization, WHO. 2017. https://apps.who.int/iris/bitstream/handle/10665/332081/9789240005587- eng.pdf
  » https://apps.who.int/iris/bitstream/handle/10665/332081/9789240005587- eng.pdf
• World Health Organization. WHO. 2020. https://apps.who.int/iris/bitstream/handle/10665/334216/9789240010789-eng. pdf?sequence=1&isAllowed=y
  » https://apps.who.int/iris/bitstream/handle/10665/334216/9789240010789-eng. pdf?sequence=1&isAllowed=y
• Zeitlinger BS, Zeitlinger M, Leitner I, Muller M, Joukhadar C. Clinical Scoring System for the Prediction of Target Site Penetration of Antimicrobials in Patients with Sepsis. Clin Pharmacokinet . 2007;46(1):75-83.
• 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.
• Zhanel GG, Ennis K, Vercaigne L, Walkty A, Gin AS, Embil J, et al. A Critical Review of the Fluoroquinolones Focus on Respiratory Tract Infection. Drugs . 2002;62(1):13-59.

Publication Dates

• Publication in this collection
  03 Nov 2023
• Date of issue
  2023

History

• Received
  22 Feb 2023
• Accepted
  03 Aug 2023