Table 1.

Summary of studies pertaining to ARC.

Author, Year	Study Type	Age (Years) Median (IQR)	Population	N	Sex (% Male)	Measured CrCl (mL/min)—Otherwise Specified	Intervention	Main Results
Barletta et al. [4], 2017	Retrospective observational	48 ± 19	ICU trauma patients where measured SCr available and SCr < 115 µmol/L	133	76	168 ± 65	ARCTIC (Augmented Renal Clearance in Trauma Intensive Care) Scoring system suggested	67% of patients identified to have ARC (CrCl > 130 mL/min) ARC risk factors identified: from multivariate analysis were age < 56 years, age = 56–75 years, SCr < 62 µmol/L, male sex ARCTIC score > 6 had sensitivity 84% and specificity 68%
Naeem et al. [5], 2017	Prospective observational	ARC: 37 ± 16 Non-ARC: 34 ± 14	ICU patients with SCr < 115 µmol/L	50	ARC: 70 Non-ARC: 60	ARC: 214 ± 46 Non-ARC: 112 ± 11	The effects of ARC on enoxaparin determined; Patients received enoxaparin 40 mg SC daily; Anti-Xa activity measured and compared among patients with and without ARC; measured 24 h CrCl	40% of patients identified to have ARC (CrCl > 130 mL/min) Anti-Xa activity did not differ in both groups at baseline and 4 h after administration ARC patients had significantly lower anti-Xa activity 12 and 24 h post enoxaparin administration; this implies short duration of action of enoxaparin in patients with ARC.
Udy et al. [6], 2017	Prospective observational (sub-study of BLING II RCT)	ARC: 52 (33–60) Non-ARC: 65 (55–73)	ICU patients with severe sepsis	254	ARC: 73 Non-ARC: 57	ARC: 165 (144–198) Non-ARC: 56 (27–83)	Conducted to determine the effect of ARC on patient outcome; patients randomized to receive beta lactam antibiotics (piperacillin/tazobactam, ticarcillin/clavulanic acid or meropenem) by intermittent or continuous infusion; measured 8 h CrCl	18% of patients identified to have ARC (CrCl > 130 mL/min); mainly younger, male and with less organ dysfunction No outcome differences (ICU-free days or mortality) between ARC and non-ARC No outcome differences were identified between continuous or intermittent infusion strategy
Udy et al. [7], 2017	Prospective observational	37 (24–49)	ICU (TBI patients with SCr < 120 µmol/L)	11	82	Median (day 1): 201 (76–289)	Measured 8-h CrCl, cardiac output and ANP were determined and correlated	ARC complicates TBI patients (Measured CrCl generally > 150 mL/min); mainly males and with young age CrCl was not significantly associated with changes in ANP or cardiac output
Barletta et al. [8], 2016	Retrospective observational	48 ± 18	ICU (trauma)	65	74	169 ± 70	Measured 12-h CrCl compared with CG method, CKD-EPI, and MDRD-4	69% of patients identified to have ARC (CrCl > 130 mL/min)—more common in younger patients and patients with SCr < 71 µmol/L Measured CrCl was significantly higher (p < 0.001) than all estimates of CrCl CG demonstrated lowest amount of bias (38 ± 56 mL/min) compared to CKD-EPI and MDRD-4
Chu et al. [9], 2016	Retrospective observational	Group A: 63 ± 15 Group B: 59 ± 14 Group C: 44 ± 16	Patients treated with vancomycin	148	66	Estimated by CG Group A: 54 ± 17 Group B: 106 ± 15 Group C: 188 ± 50	Vancomycin 1000 mg IV Q12H regimen given; vancomycin levels drawn pre 4th or 5th dose; levels compared across three groups: A (CrCl < 80), B (CrCl 80–129), C (CrCl ≥ 130; ARC)	Patients with ARC (Group C) had higher percentage of subtherapeutic vancomycin Vancomycin trough concentrations at steady state: Group A = 25 ± 10, Group B = 15 ± 8, Group C = 9 ± 5 mg/L Vancomycin trough concentration below 10 mcg/mL: Group A = 0%, Group B = 28%, Group C = 63%
Declercq et al. [10], 2016	Prospective observational	Abdominal Surgery: 63 (51–71) Trauma Surgery: 62 (46–75)	Non-critically ill surgery patients	232	Abdo. Surgery: 74 Trauma Surgery: 58	Abdominal Surgery: 109 (82–135) Trauma Surgery: 109 (85–142)	Aim to assess the prevalence of ARC in non-critically ill surgical patients; Measured 8-h CrCl	Abdominal surgery patients: 30% of patients identified to have ARC (CrCl > 130 mL/min) Trauma surgery patients: 35% of patients identified to have ARC (CrCl > 130 mL/min) The study identified presence of ARC in non-ICU surgery patients especially in younger male patients and undergoing trauma surgery
Hirai et al. [11], 2016	Retrospective observational	4.4 (range 1–15)	Pediatric ICU patients with normal renal function (Japan)	109	59	eGFR estimated by Schwartz formula 160 ( range 90–323) mL/min/1.73 m2	Vancomycin 40–60 mg/kg per day given in 2–4 divided doses; vancomycin clearance estimated	ARC defined as eGFR ≥ 160 mL/min/1.73 m2 Febrile neutropenia is an independent risk factor for ARC Age and eGFR significantly associated with vancomycin clearance (p < 0.0001)
Kawano et al. [12], 2016	Prospective observational	67 (53–77)	ICU (Japan)	111	56	Not reported	Measured 8-h CrCl	39% of patients identified to have ARC (CrCl > 130 mL/min/1.73 m2) Age < 63 years was identified as a risk factor for ARC
Roberts et al. [13], 2016	Prospective PK study	61 ± 17	Patients treated with levofloxacin	18	67	Estimated using CG 70 ± 67	Doses of levofloxacin 500 and 750 mg daily have been used; Monte-Carlo simulation conducted to determine PTA in ICU cohort compared to non ICU ones	For CrCl > 130 and CrCl > 200, levofloxacin 1000 mg Q24H provided the highest target attainment for S. pneumoniae, P. aeruginosa and S. aureus. For H. influenza, all levofloxacin doses/regimens analyzed were able to achieve >99% attainment
De Cock et al. [14], 2015	Prospective PK study	2.6 (range 0.08–15)	Pediatric ICU	50	60	Not reported	Population PK of amoxicillin/clavulanate in pediatric ICU population; Conventional dosing of 25–35 mg/kg every 6 h was tested.	In ARC patients; the best dosing is 25 mg/kg over 1 h every 4 h; it produced the best median target attainment by Monte-Carlo Simulation
De Waele et al. [15], 2015	Retrospective observational	62 (50–72)	ICU	1081	63	ARC: 178 (140–243) Non-ARC: 54 (32–82)	Measured 24-h CrCl and ARC risk factors determined	56% of patients identified to have ARC (CrCl > 130 mL/min): mainly younger and less likely to be treated with vasopressors Continuous ARC was present in 33% of patients ARC incidence 37 per 100 ICU patient-days
Dias et al. [16], 2015	Retrospective observational	Mean 42 (range 20–66)	ICU (TBI patients)	18	89	CG method 199 (Range 62–471)	Cerebrovascular pressure reactivity index (PRx) correlated with CrCl	A strong negative correlation between CG CrCl and PRX (r = −0.82, p = 0.001) have been reported This correlation suggests that reduction in cerebral autoregulation (i.e., after TBI) is associated with an increase in creatinine clearance.
Huttner et al. [17], 2015	Prospective observational	ARC: 41 ± 12 Non-ARC: 51:10	ICU with CrCl ≥ 60 mL/min	100	75	Estimated with CG ARC: 166 (145–200) Non-ARC: 103 (87–113)	They determined the influence of ARC on patient outcome; Standard dose antibiotic regimens given (imipenem/cilastatin 500 mg IV QID; meropenem 2 g IV TID; piperacillin/tazobactam 4.5 g IV TID; cefepime 2 g IV BID)	64% of patients identified to have ARC (CrCl > 130 mL/min); mainly younger ARC predicted undetectable antimicrobials concentrations but was not correlated with clinical failure
Morbitzer et al. [18], 2015	Retrospective observational	CN: 44 (29–52) TH/PI: 48 (40–62)	ICU (TBI)	27	63	Estimated using CG CN: 119 (91–166) TH/PI: 129 (100–156)	Vancomycin pharmacokinetics compared in patients with CN (T = 36–37 C), TH (T=33–34 C) or pentobarbital infusion	Vancomycin clearance was higher in controlled normothermic patients compared to predicted values based on population parameters
Ruiz et al. [19], 2015	Prospective observational	ARC: 39 ± 16 No ARC: 55 ± 19	ICU (patients with normal SCr)	360	ARC: 75 No ARC: 65	ARC: 173 ± 44 No ARC: 79 ± 30	Measured 24-h CrCl compared with 4 formulas to estimate CrCl/GFR (CG, Robert, MDRD and CKD-EPI methods)	33% of patients identified to have ARC (CrCl > 130 mL/min/1.73 m2): mainly trauma patients; younger Different formulas tended to overestimate CrCl for low eGFR values and underestimate CrCl for normal and high eGFRs Three factors suggested to identify ARC: Age ≤ 58 years, trauma and eGFR > 108.1 mL/min/1.73 m2 as calculated by CKD-EPI
Spadaro et al. [20], 2015	Retrospective observational	Group A: 63 ± 11 Group B: 71 ± 10	ICU	348	Group A: 73 Group B: 69	Group A: 106 ± 41 Group B: 37 ± 16	Vancomycin administration protocol based on measured 24 h CrCl and vancomycin serum measurements; levels compared between two groups: A (CrCl > 50) and B (CrCl ≤ 50) Vancomycin serum trough target: 15–25 mg/L	66% of patients had subtherapeutic vancomycin on second determination ARC and increased to 80% on third determination Patients who had a subtherapeutic vancomycin levels at the first determination had a significant correlation with in-hospital mortality (OR = 2, p = 0.003)
Steinke et al. [21], 2015	Prospective observational	66 (57–74)	ICU	100	61	73 (47–107)	Measured CrCl compared with estimated CrCl using serum cystatin C Hoek formula, CG, and CKD-EPI	16% of patients identified to have ARC (CrCl > 130 mL/min/1.73 m2): mainly trauma patients; TBI or SAH The Hoek formula’s precision was higher than CG and CKD-EPI Authors suggested more studies are needed to identify the rule of Hoek’s formula in drug dosing.
Adnan et al. [22], 2014	Prospective observational	34 (24–47)	ICU patients with SCr < 120 µmol/L)	49	76	ARC: 173 (141–223) Non-ARC: 91 (64–112)	Measured 24-h CrCl compared with CG method	39% of patients identified to have ARC (CrCl > 130 mL/min) CG method significantly underestimated CrCl in ARC patients
Akers et al. [23], 2014	Prospective observational	45 ± 19	ICU	13	62	Not reported	They determined the ability of the ARC score to predict piperacillin/tazobactam clearance; Piperacillin/tazobactam doses given were (3.375 g IV Q6H or 4.5 g Q6H)	ARC score had sensitivity 100%, specificity 71% in detecting enhanced clearance of piperacillin/tazobactam
Baptista et al. [24], 2014	Prospective observational	ARC: 49 ± 15 No ARC: 60 ± 18	ICU patients with normal SCr	54	ARC: 64 No ARC: 36	ARC Patients: 161 ± 28 Non-ARC Patients: 105 ± 16	Measured 8-h CrCl compared with CG method, CKD-EPI, and MDRD	56% of patients identified to have ARC (CrCl > 130 mL/min) All formulas underestimated 8h-CrCl for values >120 mL/min/1.73 m2 and a overestimated for values <120 mL/min/1.73 m2
Baptista et al. [25], 2014	Prospective observational (Group 1 data were retrospectively collected)	Group 1: 58 ± 16 Group 2: 60 ± 17	ICU	G 1: 79 G 2: 25	Group 1: 66 Group 2: 68	Group 1: 125 ± 67 mL/min/1.73 m2 Group 2: 121 ± 54 mL/min/1.73 m2	Continuous infusion Vancomycin dosing nomogram based on 8h measured CrCl was suggested Group 1: retrospective data Group 2: prospective assessment of the nomogram Target vancomycin level: 20–30 mg/L	36% and 40% of patients identified to have ARC in groups 1 and 2, respectively (CrCl > 130 mL/min/1.73 m2) Vancomycin clearance was significantly proportional to measured CrCl
Campassi et al. [26], 2014	Prospective observational	ARC: 48 ± 15 Non-ARC: 65 ± 17	ICU patients with SCr < 115 µmol/L	363	ARC: 48 Non-ARC: 47	ARC: 155 ± 33 Non-ARC: 78 ± 25	CrCl measured by 24 h urine collection; Vancomycin loading dose 15 mg/kg followed by continuous infusion 30 mg/kg/day was given Target trough 15–25 mg/L	28% of patients identified to have ARC (CrCl > 120 mL/min/1.73 m2); generally younger; more trauma and obstetric admissions; lower APACHE II scores 27% of patients who received vancomycin were identified to have ARC and had significantly lower vancomycin levels (p < 0.05) than non-ARC patients at 3 days; none of the ARC patients reached target trough despite being administered significantly higher vancomycin doses
Hites et al. [27], 2014	Prospective observational	61 (18–84)	Non-ICU obese (BMI ≥ 30 kg/m2) patients treated with antibiotics	56	50	107 (6–389.0)	They assessed the adequacy of serum concentrations of antimicrobials when given to obese individuals; Standard doses of antibiotics given (Cefepime 2 g TID, Piperacillin/tazobactam 4 g QID, Meropenem 1 g TID); Measured 24-h CrCl determined	Low levels of antimicrobials were detected following standard doses. Elevated CrCl was the only predictor of those low concentrations underlining the role of ARC in under-dosing obese individuals.
Udy et al. [28], 2014	Prospective observational	Mean 37 (95% CI 29 –44)	ICU patients with SCr < 120 µmol/L and age ≤ 60	20	60	Mean: 168 (95% CI 139–197)	Measured 24-h CrCl determined; various exogenous markers given to detect changes in nephron physiology	ARC involves increased glomerular filtration, renal tubular secretion of anions and renal tubular reabsorption using various exogenous markers, suggesting that ARC affects many components of the nephron physiology
Udy et al. [29], 2014	Prospective observational	Mean 54 (95% CI 53–56)	ICU patients with SCr < 120 µmol/L	281	63.3	Mean: 108 (95% CI 102–115)	Measured 8-h CrCl determined daily	65% of patients identified to have ARC (CrCl > 120 mL/min/1.73 m2); mainly younger, men, multi-trauma victims, and receiving mechanical ventilation Presence of ICU admission day 1 ARC predicted sustained ARC during ICU stay
Carlier et al. [30], 2013	Prospective observational	56 (48–67)	ICU	61	85	125 (93–175)	Meropenem or piperacillin/tazobactam were given as extended IV infusions; antibiotics concentrations measured; measured 24 h CrCl determined; Meropenem dose: an IV loading of 1 g over 30 min then 1 g Q8H as extended infusion over 3 h; Piperacillin/tazobactam dose: an IV loading of 4.5 g over 30 min then 4.5 g Q6H extended infusion over 3 h.	80% of patients identified to have ARC (CrCl > 130 mL/min) Elevated creatinine clearance is an independent predictor for not achieving meropenem and piperacillin/tazobactam target levels
Claus et al. [31], 2013	Prospective observational	ARC: 54 (44–61) Non-ARC: 66 (57–77)	ICU patients receiving antimicrobial therapies	128	ARC: 73 Non-ARC: 61	98 (57–164) mL/min/1.73 m2	Measured 8 h-CrCl determined; measuring the effect of ARC on antimicrobial therapy failure	52% of patients identified to have ARC (CrCl > 130 mL/min/1.73 m2); mainly younger and male 27% of ARC patients had therapeutic failure (poor clinical response to antimicrobial therapy), more often than non-ARC patients (13%) (p = 0.04)
Minkute et al. [32], 2013	Retrospective observational	ARC: 46 (21–66) Non-ARC: 54 (22–86)	Patients treated with vancomycin	36	80	Estimated CG ARC: 151 (131–324) Non-ARC: 103 (90–127)	Vancomycin level comparison between ARC and non-ARC groups	50% of patients identified to have ARC (CrCl > 130 mL/min, using CG) Vancomycin concentrations were lower in ARC group compared to Non-ARC Vancomycin doses up to 44 mg/kg/day were needed in the ARC group to achieve target trough levels.
Roberts and Lipman [33], 2013	PK study (analysis of Phase III trial data)	58 ± 15	ICU patients with pneumonia	31	93	Estimated by CG 137 ± 71	Population PK of doripenem in critically ill.	Doripenem clearance correlated with CrCl and was increased compared to non-ICU patients
Shimamoto et al. [34], 2013	Retrospective observational	Non-SIRS: 64 SIRS-2: 54 SIRS-3: 49 SIRS-4: 42	ICU (Septic patients on vancomycin)	105	66	Using CG No-SIRS: 121 ± 51 SIRS-2: 160 ± 65 SIRS-3: 195 ± 70 SIRS-4: 191 ± 77	Identified patients who had SIRS and categorized based on the number of SIRS criteria they had (non-SIRS, SIRS-2, 3 and 4); vancomycin CL and CrCL (CG) determined	In patients age < 50: higher SIRS score predicted higher vancomycin clearance In patients age > 50: higher SIRS does not reliably predict higher vancomycin clearance
Udy et al. [35], 2013	Prospective observational	42 ± 17	ICU (trauma, septic, SCr < 110 µmol/L)	71	63	Mean: 135 ± 52	They determined the prevalence and risk factors of ARC	58% of patients identified to have ARC; more in trauma patients; generally younger, males, with lower APACHE II , SOFA and higher cardiac index Three risk factors suggested to predict ARC: age < 50 years, trauma, and SOFA score ≤ 4 (ARC score)
Udy et al. [36], 2013	Prospective observational	51 ± 17	ICU patients with SCr < 121 µmol/L	110	64	Mean: 125 ± 45 mL/min/1.73 m2	Measured 8 h CrCl compared to estimated CrCl (CG and CKD-EPI)	CKD-EPI and CG underestimated CrCl in patients with ARC In patients with CKD-EPI eGFR = 60–119 mL/min/1.73 m2, 42% had ARC
Baptista et al. [37], 2012	Prospective observational	Non-ARC: 70 (52–79) ARC: 41 (32–56)	ICU septic patients on vancomycin	93	Non-ARC: 71 ARC: 79	Non-ARC: 70 (58–104) ARC: 159 (141–194)	The effect of ARC on vancomycin PK: ARC patients compared to non-ARC patients; measured 24 h CrCl Vancomycin dosing: A loading dose of 1000 mg if wt. < 70 kg or 1500 mg if wt. > 70 kg then 30 mg/kg/day continuous infusion	Serum vancomycin concentrations in ARC were significantly lower than control group for the 3 days of study
Grootaert et al. [38], 2012	Retrospective observational	59 (48–67)	ICU patients with measured CrCl > 120 mL/min (24-h method)	390	63	148 (132–172) mL/min/1.73 m2	Measured 24-h CrCl compared with CG method (CrCl) and 4-variable MDRD method (eGFR)	CG and MDRD underestimated measured CrCl in ARC patients
Udy et al. [39], 2012	Prospective observational	53 ± 21	ICU	48	71	134 ± 90	Measured 8 h CrCl; beta lactam antibiotic concentrations measured	For patients with trough less than MIC and less than 4× MIC: 82 and 72% had CrCl > 130 mL/min/1.73 m2, respectively A 25 mL/min/1.73 m2 increase in CrCl is associated with a 60% reduction in the probability of obtaining a trough concentration ≥ 4×MIC
Baptista et al. [40], 2011	Retrospective observational (post hoc analysis)	35 (25–51)	ICU patients with ARC	86	77	162 (145–190) mL/min/1.73 m2	Measured 8-h (Australia) or 24 h (Portugal) CrCl compared with CG, modified CG, 4-variable MDRD and 6-variable MDRD	All CrCl estimates underestimated measured CrCl CG estimates had the greatest sensitivity→identified 62% of cohort with ARC; lower sensitivity observed with 4-variable MDRD (47%) and 6-variable MDRD (29%) formulae
Minville et al. [41], 2011	Retrospective observational	NPT: 58 ± 17 PT: 42 ± 18	ICU	284	NPT: 63 PT: 75	NPT: 85 ± 5 PT: 131 ± 5 mL/min/1.73 m2	Measured 24-h CrCl; compared among patients with (NPT) and without polytrauma (PT)	37% of patients identified to have ARC (CrCl > 120 mL/min; significantly more trauma patients; younger; had lower SAPS II score; males Age and trauma independently correlated to CrCl
Spencer et al. [42], 2011	Prospective PK study	54 ± 14	Neuro ICU	12	42	96 ± 32 (estimated, method not reported)	Patients received levetiracetam 500 mg iv every 12 h; levetiracetam levels measured	Levetiracetam clearance was higher in neurocritical care population compared to healthy volunteers (drug clearance directly proportional to estimated CrCl r2 = 0.5, p = 0.01); Higher doses of levetiracetam are recommended in neurocritical care population
Goboova et al. [43], 2015	Case Report	16	ICU (Polytrauma and sepsis)	1	100	Method not reported Day 29: 138 Days 41–51: 340 mL/min/1.73 m2	Vancomycin initiated at doses of 1 g IV every 12 h then titrated up	A trauma patient who developed ARC later during hospital stay Vancomycin needed to be increased to up to 6 g per day to achieve therapeutic target trough level Vancomycin increased to 2 g Q12H, which produced troughs of 15 mg/L and 10 mg/L Increase in CrCl observed on day 46, vancomycin trough decreased to 5 mg/L, then dose increased to 2 g Q8H (67 mg/kg/day); trough: 19 mg/L
Abdul-Aziz et al. [44], 2014	Case Report	36	ICU (CNS infection)	1	100	234	Days 1–3: Flucloxacillin 2 g IV Q4H Days 4–16: Flucloxacillin 20 g/day via continuous infusion	A case report of an ICU patient with CNS infection Presence of ARC (Measured 8 h) lead to difficulty achieving therapeutic flucloxacillin concentration above MIC with conventional dosing (IV 2 g Q4H) A continuous infusion of high dose flucloxaciilin (20 g/day) was required to achieve clinical cure
Cook et al. [45], 2013	Case Report	22	Neuro ICU (TBI)	1	0	Method not reported 153	They described a case of ARC leading to subtherapeutic vancomycin and levetiracetam levels	A conventional vancomycin dose 750 mg IV Q12H (17.5 mg/kg/dose) yielded a trough level of 2.2 mg/L (subtherapeutic); dose had to be increased to 1.25 g iv Q8H (29 mg/kg/dose) to achieve a trough of 11 mg/L Levetiracetam dose was increased from 1000 mg IV BID to 1000 mg Q8H to maintain a trough within reference range (usual dose 0.5–1 g iv Q12H)
Lonsdale et al. [46], 2013	Case Report	44	Neuro ICU (SAH with ventriculitis)	1	100	375 mL/min/1.73 m2	They described a case of ARC leading to subtherapeutic vancomycin and meropenem levels	The patient required dose escalation of vancomycin up to 6 g/day (Vancomycin 63 mg/kg/day) in order to achieve therapeutic trough levels (usual dose 45 mg/kg/d for CNS infections) The patient required dose escalation of meropenem up to 2 g every 6 h in order to achieve therapeutic levels (usual dose 2 g iv Q8H for CNS infections)
Troger et al. [47], 2012	Case Reports	Pt 1: 37 Pt 2: 66	ICU patients with sepsis	2	100	Estimated with CG Pt 1: Initially: 138 Day 5: 276 Pt 2: Initially: 185 Later: 219	Described 2 cases of sepsis patients who required high doses of meropenem secondary to ARC Pt 1: meropenem 1 g IV Q8H then increased to meropenem 2 g IV Q4H Pt 2: meropenem 1 g Q8H then dose increased to1 g Q6H then to 2 g Q6H Meropenem trough target 4–10 mg/L	Pt 1: meropenem dose was increased to 2 g IV Q4H × 1 week, trough was still <4 mg/L but procalcitonin decreased and clinical improvement was observed Pt 2: meropenem dose was increased to 2 g Q6H, producing a trough concentration of 8.4 mg/L
Udy et al. [3], 2010	Case Series	Pt 1: 19 Pt 2: 41 Pt 3: 32	ICU Pt 1 TBI Pt 2 Surgery Pt 3 Burn	3	100	Pt 1: 224 Pt 2: 206 Pt 3: 151 Measured 8 h CrCl	Three case reports of patients with ARC Pt. 1: meropenem Pt 2: vancomycin + meropenem Pt 3: amikacin + ciprofloxacin	Pt 1: meropenem 1 g Q8H, increased to 2 g Q8H due to undetectable trough serum concentration; pt. still did not have detectable concentration Pt 2: vancomycin doses were increased up to 4 g (44 mg/kg) continuous infusion over 24-h for clinical cure; Meropenem increased to 1 g Q4H to reach target trough Pt 3: Amikacin 1 g daily was increased up to 1.2 g Q12H due to undetectable trough levels
Caro et al. [48], 2016 Abstract	Phase I PK study	Range 29–50	ICU patients with ARC (CrCl ≥ 180 mL/min estimated by CG)	5	40	Estimated using CG 282 (207–417)	Determined the PK of ceftolozane/tazobactam in patients with ARC	Study identified higher clearance of ceftolozane/tazobactam in ARC patients compared to non-ARC patients
Goboova et al. [49], 2016 Abstract	Retrospective observational	Mean 42 ± 14	Patients treated with gentamicin	204	78	Method not reported ARC Patients: 166 ± 28 mL/min/1.73 m2	Identification of the influence of ARC on gentamicin dosing	14% of patients identified to have ARC (CrCl > 130 mL/min/1.73 m2; 93% of ARC patients were under-dosed (low peak levels) with standard gentamicin regimens
Morbitzer et al. [50], 2016 Abstract	Prospective observational	63 (56–71)	Neuro ICU (Hemorrhagic stroke)	17	27	131 (108–216) mL/min/1.73 m2	Measured 8-h CrCl compared with CG method; vancomycin trough concentration determined	CG method underestimated CrCl in ARC patients Measured vancomycin trough was lower than predicted
Morimoto and Ishikura [51], 2016 Abstract	Prospective observational	Not reported	ICU (Japan)	33	Not reported	Not reported	CrCl measured (method not reported)	39% of patients identified to have ARC (CrCl > 130 mL/min/1.73 m2); mainly younger, less males, had lower APACHE II score and not septic
Dunning and Roberts [52], 2015 Abstract	A survey	N/A	N/A	123	N/A	N/A	A survey of 123 ICU physicians about antibiotic prescribing and renal function assessment	15% responded that they would consider modifying the dosage regimen of beta-lactams and vancomycin antimicrobials in patients with ARC This highlights the need for dosing guidance in patients with ARC.
Baptista et al. [53], 2014 Abstract	Retrospective observational	Not reported	ICU	477	Not reported	Not reported	CrCl measured by 8 h urine collection	33% of patients identified to have ARC (CrCl > 130 mL/min/1.73 m2) Urinary creatinine > 45 mg/mL and age < 65 are identified as best predictors of ARC (sensitivity 60%, specificity = 88%); specificity increased to 95% by adding BUN < 7 mmol/L
May et al. [54], 2014 Abstract	Prospective observational	Not reported	Neuro ICU (SAH)	20	Not reported	326 ± 135 mL/min/1.73 m2	Measured 24-h CrCl determined; Monte-Carlo Simulation for levetiracetam doses to achieve trough levels ≥ 6 mg/L	Estimated CrCl (method not reported) significantly underestimated CrCl Monte Carlo Simulation suggested that levetiracetam dosing poorly achieved target attainment unless TID was used (as opposed to standard regimen)
Vermis et al. [55], 2014 Abstract	Retrospective observational	Not reported	Patients with hematological malignancies	96	Not reported	CrCl estimated using CG ARC pts: 147 Non-ARC pts: 79	Aimed to determine the prevalence of ARC in a hematological population; Vancomycin continuous infusion: loading 15 mg/kg, maintenance 30 mg/kg given and titrated based on levels Vancomycin trough target: 20 mg/L	Therapeutic vancomycin trough targets were achieved with dose of 42 mg/kg/day in ARC patients (day 5 post initiation) and with 33 mg/kg/day in non-ARC (day 3 post initiation).
Weigel et al. [56], 2014 Abstract	Retrospective observational	55	ICU patients without renal replacement and receiving vancomycin infusion	287	69	ARC: MDRD eGFR > 130 Non ARC: MDRD eGFR < 130	A vancomycin loading dose of 20 mg/kg was given then adjusted by Therapeutic drug monitoring to target 20–25 mg/L; Vancomycin levels compared in patients with various degrees of eGFR using MDRD	Subtherapeutic vancomycin levels were more frequent in patients with MDRD > 130 mL/min (55%) i.e., ARC vs. patients with MDRD < 130 mL/min (29%) p < 0.001 Higher than conventional vancomycin dosing is recommended in patients with ARC
Neves et al. [57], 2013 Abstract	Prospective observational	55 ± 13	ICU	54	72	Mean: 138	Measured 8-h CrCl compared with CG method	ARC identified in 50% of samples Per subgroup analyses: CrCl > 120 mL/min/1.73 m2, CG underestimated measured CrCl; CrCl < 120 mL/min/1.73 m2, CG overestimated measured CrCl
Grootaert et al. [58], 2012 Abstract	Retrospective observational	66 (56–75)	ICU patients with measured CrCl available	1317	63	Not reported	Measured 24-h CrCl	16% of patients identified to have ARC (CrCl > 120 mL/min): mainly younger, taller, have lower BMI and had longer ICU stay 30% patients had at least 1 episode of ARC Relative duration of ARC per patient was 5 days in all pts, and 7 days in antimicrobial group
Drust et al. [59], 2011 Abstract	Retrospective observational	Not reported	ICU patients with CrCl > 120 mL/min	15	Not reported	>120	Meropenem plasma concentrations measured	27% of patients had appropriate meropenem plasma levels 67% of patients required higher doses of meropenem (up to 8 g/day) than recommended

ANP = atrial natriuretic peptide; APACHE II = Acute Physiology and Chronic Health Evaluation; ARC = Augmented Renal Clearance; CG = Cockcroft Gault equation; CKD-EPI = Chronic Kidney Disease Epidemiology; CN = controlled normothermia; CrCl = creatinine clearance; GFR = glomerular filtration rate; ICU = intensive care unit; IQR = interquartile range; MDRD = modification of diet in renal disease method; MIC = minimum inhibitory concentration; PK = pharmacokinetic; PT = patient; PTA = probability of target attainment; SAH = subarachnoid hemorrhage; SAPS II = Simplified Acute Physiology Score SCr = serum creatinine; SIRS = systemic inflammatory response syndrome; SOFA = sequential organ failure assessment score; TBI = traumatic brain injury; TH = therapeutic hypothermia. Age and CrCl reported in median (IQR) or mean ± SD.