Table 5.

Selected biomarkers for predicting antibiotic pharmacokinetics

Biomarkers	Pathogenesis	Value	MW (kDa)	Peak (h)	t½a	Affected drug PK	References
Inflammation biomarkers
Cytokines/chemokines
IL-1β	Proinflammatory cytokine	Px	18–25	4	2	D	[227]
IL-6	Proinflammatory cytokine	Dx, Px	21	6	2–4	D	[228, 229]
IL-8	Neutrophilic inflammation cytokine	Dx, Px	8.4	4–8	4	D	[230, 231]
IL-10	Regulatory cytokine	Dx, Px	18	12–24	2–4	D	[232]
TNFα	Proinflammatory cytokine, neutrophilic activation	Px	17.3	6	1–2	D	[233]
IFNγ	Th1 immune response	–	17	6	2	D	[234, 235]
MIP-1, -2	Neutrophil, leukocyte activation	Px	440	2	2.5	D	[236, 237]
MCP-1	Monocyte chemoattractant protein	Px					[238]
Cell markers/soluble receptors
Presepsin	N-terminal fragment of sCD14 (LPS receptor)	Dx, Px, Tx	13	3	4–5	D	[239–241]
CD64	Binds Fc fraction of IgG, induces phagocytosis	Dx, Tx	43	4–6	5–17	D	[242–244]
mHLA-DR	Expressed on APC, activation of T-cells	Px	–	24	3–22	D	[245, 246]
TLR2, TLR4	Recognition of bacterial peptidoglycan (TLR2) or LPS (TLR4)	Dx	–	–	3	D	[247–249]
sTREM-1	TREM-1 secreted by phagocytes	Dx, Px	23.8	6	1.5	D	[250–252]
SuPAR	Recruitment of neutrophils and monocytes	Dx, Px	–	4 (d)	10 (d)	D	[253–255]
Acute-phase reactants
CRP	Complement activation, proinflammatory effects	Px	20–25	24–48	19	D	[256, 257]
PCT	Prohormone stimulated by IL-1, IL-6, TNFα	Dx, Px, Tx	14.5	6–24	20–36	D	[258, 259]
LBP	Connects CD14 to bacteria LPS	Dx, Px	50	12	12–24	D	[260]
Pro-ADM	Precursor of adrenomedullin, induces vasodilatation	Px	4–5.5	4	2	D	[261–263]
Pentraxin 3	Pathogen recognition and removal	Dx, Px	35	–	4	D	[264–266]
C5a, C3a	Neutrophil migration, coagulopathy	Dx, Px	190	–	4	D	[267, 268]
Albumin	Increased vascular permeability	Px	66.5	NA	21 (d)	D, M	[269–271]
Endotheliopathy biomarkers
Syndecans	Glycocalyx component indicates damage	Px	30	NA	0.06	D	[272]
Heparan sulfate	Polysaccharide	Px	30	NA	3–4	D	[273]
Endocan	Soluble endothelial peptidoglycan, increases microvascular permeability	Px	50	NA	–	D	[94, 274, 275]
Ang-2/Ang-1	Vascular integrity, Ang-2 is Ang-1 antagonist	Px	1	NA	30 (s)	D	[99, 254, 276, 277]
sVCAM-1	Adhesion protein expressed by endothelial cells, which binds to lymphocytes	Px	102	NA	4	D	[278, 279]
sICAM-1	Intercellular adhesion molecules	Dx, Px	76–114	NA	–	D	[278–281]
E-selectin	Glycoprotein expressed in activated endothelial cells	Px	115	NA	1.9	D	[279, 281, 282]
P-selectin	Adhesion receptor expressed in platelets and endothelial cell	Px	140	NA	2.3	D	[283]
VEGF	Endothelial cells proliferation factor	Px	23	NA	0.5–1	D	[284]
Blood flow biomarkers
SO2 %	Oxygen saturation	Px	NA	NA	NA	D	[285]
MAP	Main global perfusion index	Px	NA	NA	NA	D	[286, 287]
CO	Cardiac output	Px	NA	NA	NA	D	[288]
HR	Heart rate	Px	NA	NA	NA	D	[289]
ScvO2	Central venous oxygen saturation	Px	NA	NA	NA	D	[290]
StO2	Tissue oxygen saturation	Px	NA	NA	NA	D	[291]
Lactate	Anaerobic glycolysis end product	Px	0.08	–	20 (m)	D	[286]
Coagulation biomarkers
vWf Ag	Platelet adhesion and accumulation	Px	5000–10,000	NA	4–26	D, M	[292]
ADAMTS-13 activity	vWf cleaving protease	Px	154	NA	48–72	D, M	[293–295]
F ibrinogen	Low activation of secondary fibrinolysis	Px	340	NA	100	D, M	[296, 297]
PT	Consumption, depletion of endogenous haemostasis factors	Px	NA	NA	–	D, M	[298, 299]
aPPT	Indicative of CRP activity	Dx	NA	NA	–	D, M	[300–303]
AT activity	Coagulation inhibition and anti-inflammation	Px	58	NA	72	D, M	[296]
PF-4	Protein secreted by activated platelets	Px	29	NA		D	[304–306]
D-Dimer	Fibrinogen, fibrin breakdown, excessive coagulation	Px	180	NA	8	D, M	[304]
PAI-1	Fibrinolysis inhibition	Px	43	NA	2	D	[304, 307]
Protein C	Antithrombotic action	Dx, Px	62	NA	8	D, M	[308–310]
Thrombomodulin	Endothelial cells glycoprotein, protein C pathway	Px	74	NA	20	D, M	[311–313]
Hepatic function biomarkers
Bilirubin	Product of heme catabolism	Px	548.67	NA	2–4	M	[314–316]
ALT	Transaminase enzyme, indicates liver function	–	110	NA	8	M	[316, 317]
AST	Transaminase enzyme, indicates liver function	–	90	NA	16	M	[316, 317]
Ceruloplasmin	Increases as part of acute-phase response	Px	115	-	15	M	[318]
Hyaluronic acid	Indicates liver dysfunction	Px	1000–8000	NA	4 (m)	D, M	[319]
Renal function biomarkers
Creatinine	Estimate GFR	Px	0.113	NA	3.85	E	[320]
Cystatin C	Estimate GFR	Px	13.3	NA	2	E	[320]
BUN	Urea nitrogen in blood, indicative of renal function	Px	NA	NA	NA	M, E	[321–323]
NGAL	Indicative of kidney injury	Px	25	6–12	15	E	[320, 324]
KIM-1	Injured kidney epithelial cells	Px	60–90	12–24	6	E	[320]

The proposed biomarkers are classified according to the pathophysiological processes. We provide some important characteristics: pathogenesis, proved value, MW, biology (peak concentration, half-life), and the proposed pharmacokinetic process affected

ADAMTS-13 a disintegrin-like and metalloprotease with thrombospondin type 1 motif no, 13, ALT alanine transaminase, Ang angiotensin, APC activated protein C, aPPT activated partial thromboplastin time, AST aspartate transaminase, AT antithrombin, BUN blood urea nitrogen, CO cardiac output, CRP C-reactive protein, d days, D distribution, Dx diagnostic, E excretion, GFR glomerular filtration rate, HR heart rate, ICAM intercellular adhesion molecule 1, IFN interferon, IgG immunoglobulin, IL interleukin , KIM-1 kidney injury molecule-1, LBP lipopolysaccharide-binding protein, LPS lipopolysaccharide, M metabolism, m minutes, MAP mean arterial pressure, MCP monocyte chemoattractant protein, mHLA monocytic human leukocyte antigen, MIP macrophage inflammatory protein, MW molecular weight, NA not applicable, NGAL Neutrophil Gelatinase-Associated Lipocalin, PAI-1 plasminogen activator inhibitor-1, PCT procalcitonin, PF-4 platelet factor 4, PK pharmacokinetics, Pro-ADM proadrenomedullin, PT prothrombin time, Px prognostic, s seconds, sCD14 soluble cluster of differentiation 14, ScvO₂ central venous oxygen saturation, sICAM soluble ICAM, SO₂% oxygen saturation, StO₂ tissue oxygen saturation, sTREM soluble triggering receptor expressed on myeloid cells 1, suPAR soluble urokinase-type plasminogen activator receptor, sVCAM soluble VCAM, t_½ elimination half-life, Th₁ T helper type 1, TLR toll-like receptor, TNF tumor necrosis factor, Tx therapeutic, VCAM vascular cell adhesion molecule, VEGF vascular endothelial growth factor, vWf von Willebrand factor

^at_½ presented in h unless otherwise indicated