International Journal of Clinical Practice

Review Article

Are Antibiotics Appropriately Dosed in Critically Ill Patients with Augmented Renal Clearance? A Narrative Review

Table 1

A summary of recommendations of studies that have been done to compare different dosing regimens for antibiotics in patients with augmented renal clearance.


Author	Year	Type of the study	Population	Number of patients	CrCl measurement method	ARC definition	Main result	Evaluated and/or recommended regimens	Quality grading

Beta-lactams
Agyeman [22]	2021	Randomized clinical trial	In vitro study	6 P. aeruginosa isolates		130 ml/min/1.73	72-hour static concentration-time-kill study	Meropenem 2 g q8hr as intermittent or continuous infusion plus ciprofloxacin 400 mg q8hr	P
Carrie [23]	2019	Retrospective study	Critically ill patients with HAP/VAP	177	CrCl_24h	150 ml/min/1.73	Efficacy and safety	Recommended: PTZ: 20 + 2.5 g daily CI after 4 + 0.5 g LD Meropenem: 6 g daily CI or 2 g q8hr EI over 4 hr Cefepime: 6 g daily CI after 2 g LD over 30 min Ceftazidime: 6 g daily CI after 2 g LD over 30 min	G
Gerlach [24]	2019	Retrospective study	Hospitalized patients with bacteremia or/and pneumonia due to P. aeruginosa	102	CrCl_CG	130 ml/min	fT > MIC (>60% for cefepime and >50% for PTZ) (MIC = 8 mg/L for cefepime and 16 mg/L for PTZ) clinical cure	PTZ: 4.5 g q8hr as the EI over 4 hr Cefepime: 2 g q8hr as the EI over 4 hr Both groups received an LD over 30 min	F
Besnard [25]	2019	Prospective study	Critically ill patients	35 (36 serum concentrations)	CrCl_24h	150 ml/min	Piperacillin unbound concentration < MIC (= 16 mg/L for P. aeruginosa) toxic cutoff of PTZ (≥150 mg/L)	PTZ: 20 + 2.5 g/day over 10 hr infusion (160 mg/ml) after 4 + 0.5 g LD over 60 min	P
Jacobs [17]	2018	Retrospective study	Critically ill patients who received TDM	215 (512 drug concentrations)	CrCl_24h	120 ml/min	fT > 4×MIC (70% for FEP/CAZ, 50% for PIP, and 40% for MEM)	Meropenem (MEM) Cefepime (FEP) Ceftazidime (CAZ) Piperacillin (PIP)	F
Carrie [6]	2018	Prospective observational study	Critically ill patients	79 (235 drug concentrations)	CrCl_24h	≥170 ml/min	Rate of underdosing (<4 MIC) clinical failure	PTZ: 16 + 2 g daily CI as a 12 hr infusion after an LD of 4 + 0.5 g over 60 min Cefepime, ceftazidime, cefotaxime, meropenem: 6 g daily CI as an 8 hr infusion after an LD of 2 g over 60 min	F
Burger [10]	2018	Prospective observational study	ICU-admitted patients	101	CrCl_CG	≥130 ml/min/1.73	100% fT > MIC in 90% of patients	Recommended: Meropenem: 6 g daily with increased frequency of administration or duration of infusion	F
Andersen [9]	2018	Prospective study	Septic patients who were treated empirically with PTZ	22	CrCl_CG	130 ml/min/1.73	100% and 50% fT > MIC (breakpoint MIC for P. aeruginosa: 16 mg/L)	IA of 4 g piperacillin q6hr, q8hr, and q12hr, over 3 min EI of 4 g piperacillin q6hr (over 3 hr), q8hr (over 4 hr), and q12hr (over 6 hr) CI of 20 g, 16 g, and 12 g piperacillin daily after a bolus LD of 4 g	F
Carrie [26]	2018	Prospective study	Critically ill patients	59	CrCl_24h	130 ml/min/1.73	100% fT > MIC	PTZ: comparison of two dosing regimens (20 + 2.5 g/day vs. 16 + 2 g/day) that are both 12 hr CI	F
Dhaese [27]	2018	Prospective study	Critically ill patients	110 (270 plasma samples)	CrCl_8h	130 ml/min/1.73	100% fT > 4×MIC (MIC ≤16 mg/L for susceptible P. aeruginosa)	Piperacillin: 24 g daily as CI immediately after 4 g LD	F
Mahmoud [15]	2017	Systemic review				≥130 ml/min		Recommended: Meropenem: 2 g q8hr PTZ: 4 + 0.5 g q6hr as an EI over 4 hr
Hobbs [8]	2015	Review article	Critically ill patients with ARC		CrCl_8h	130 ml/min/1.73	fT > MIC (60% for FEP, 50% for PTZ, and 40% for MEM)	Recommended: Meropenem (MEM): 2 g q8hr as a 3 hr infusion PTZ: 4.5 g q6hr as a 4 hr infusion Cefepime (FEP): 2 g q6-8hr as a 3 hr infusion
Huttner [7]	2015	Observational prospective cohort study	Critically ill patients	100	CrCl_CG	130 ml/min/1.73	Clinical response 28 days after inclusion	Imipenem/cilastatin: 500 mg q6hr Meropenem: 2 g q8hr PTZ: 4 + 0.5 g q8hr Cefepime: 2 g q12hr	F
Udy [28]	2015	Prospective study	Critically ill patients with sepsis	48	CrCl_6h	120 to 300 ml/min	Clinical response	PTZ: 4.5 g q6hr as an IA over 20 min	F
Carlier [1]	2013	Prospective study	Critically ill patients	61	CrCl_24h	130 ml/min/1.73	100% and 50% fT > MIC	3 hr infusion immediately after an LD over 30 min of the following: Meropenem: 1 g q8hr PTZ: 4 + 0.5 g q6hr	F
Udy [29]	2012	Observational study	Critically ill patients who received empirical B-lactam therapy	52 trough concentrations collected for TDM	CrCl_8h	130 ml/min/1.73	Trough concentrations less than MIC and 4 MIC	Ampicillin, dicloxacillin, penicillin, flucloxacillin, piperacillin, cephalothin, cefazolin, ceftriaxone, ceftazidime, cefepime, meropenem, ertapenem	F
Taccone [30]	2012	Case report	A patient with septic shock due to XDR P. aeruginosa	1	CrCl_24h	>200 ml/min	fT > 4×MIC	Meropenem: 12 g daily (3 g q6hr as a 3 hr EI)
Tröger [12]	2012	Case reports	Septic patients	2	CrCl_CG and CrCl_CKD-EPI	≥120 ml/min	Trough concentration >4×MIC	Meropenem: 1 g q8hr

Vancomycin
Fransson [31]	2021	Case report		1	CrCl_12h	130 ml/min/1.73	Trough concentrations between 10 and 20 mg/L	Despite using doses from 1.5 g q8hr to 2 g q6hr, a stable vancomycin target level was not achieved until 1.5 g q6hr
Molina [32]	2020	Retrospective study	Traumatic ICU-admitted patients	119	CrCl_CG	>105 ml/min	Subtherapeutic trough concentration (<10 mg/L)	Mean daily dose: 44 9 mg/kg/day	F
Mahmoud [15]	2017	Systemic review			CrCl_24h	130 ml/min/1.73		LD: 25–30 mg/kg MD: 45 mg/kg/day q8hr
Chu [33]	2016	Retrospective study	Patients who received empirical vancomycin therapy	148	CrCl_CG	130 ml/min	Subtherapeutic trough concentration (<10 mg/L)	1000 mg q12hr	F
Hirai [34]	2016	Retrospective observational study	Patients who were treated with vancomycin	292 (48 patients with ARC)	CrCl_CG	130 ml/min/1.73	Subtherapeutic trough concentrations (10 mcg/mL)	TDM is used for optimizing the dose of vancomycin	F
Hobbs [8]	2015	Review article	Critically ill patients with ARC		CrCl_8h	130 ml/min/1.73	Trough concentration between 15 and 20 mg/L AUC/MIC >400	LD: 25–30 mg/kg MD: 15–20 mg/kg q8-12hr
Robert [35]	2011	Retrospective data collection	Critically ill septic patients	206	CrCl_24h	ml/min/1.73	Trough concentrations between 20 and 30 mg/L	LD: 35 mg/kg over 180 min MD: at least 35 mg/kg/day as CI	F
Baptista [36]	2014	Two-step study (first retrospective and then prospective)	Critically ill patients	104 patients in total (79 and 25 patients, respectively)	CrCl_8h	130 ml/min/1.73	Trough concentrations between 20 and 30 mg/L	Dosing nomogram for different CrCls: LD: 1000 mg for patients with TBW 70 kg and 1500 mg for TBW >70 kg MD: 3 to 5.8 g/day as CI for a CrCl of 125 to 350 mg/ml	G

Teicoplanin
Li [37]	2020	Retrospective study	Critically ill patients	55	CrCl_CG		Trough concentration ≥10 mg/L on days 2 and 4 Clinical response Adverse effects (nephrotoxicity and hepatotoxicity)	LD: 400 mg or 800 mg q12hr for three doses MD: 400 mg or 800 mg q24hr, q48hr, or q72hr according to renal adjustment	F
Ueda [38]	2020	Retrospective study	Patients who were treated with teicoplanin	512 (for safety), 76 (for efficacy)	Estimated GFR by a formula that is developed by the Japanese Society of Nephrology		Clinical response Adverse effects (nephrotoxicity and hepatotoxicity) On day 4 and the end of teicoplanin therapy	LD: 12 mg/kg q12hr for four consequent doses and then 12 mg/kg once daily on day 3 MD: 6.7 mg/kg once daily	F
Kim [39]	2019	Retrospective study	Patients who were treated with teicoplanin ≥72 hr	65 (124 serum concentrations)			Trough concentration ≥10 mg/L and ≥20 mg/L within 10 days	No LD, low LD (<9 mg/kg), and high LD ( 9 mg/kg) q12hr for three consequent doses The MD is calculated according to TDM and renal adjustment (q24hr, q48hr, or q72hr)	F
Byrne [40]	2018	Prospective study	Patients with haematologic malignancy	30	CrCl_24h		Trough concentrations: Total 20 mg/L Unbound 1.5 mg/L On days 3 and 7	Recommended: 18–25 mg/kg for both LD (five doses with 12 hr interval) and MD (q24hr) for CrCl 130 ml/min	F
Cazaubon [41]	2017	Retrospective study	Infected patients with Gram-positive cocci	98	CrCl_CGCrCl_MDRD		Trough concentration 15 mg/L AUC0–24/MIC 900 AUC0–24/MIC 1800	Monte Carlo simulation	F
Richards et al. [11]	2015	Review article	Critically ill patients			≥130 ml/min		LD: 800 mg teicoplanin twice a day for four consequent doses MD: 400 mg q12hr
Byrne [42]	2015	Retrospective cohort study	Patients with haematologic malignancy	104	CrCl_CG		Total trough concentration Treatment outcomes: nephrotoxicity (according to RIFLE criteria)	LD: intravenous bolus injection of 600 mg (800 mg if TBW >80 kg) q12hr for three consequent doses MD: 600 mg (800 mg) once daily Recommended: LD: 12 mg/kg q12hr for 3–5 consequent doses MD: 12 mg/kg daily	F
Nakamura [43]	2015	Prospective study	Critically ill patients	106	CrCl_24h		Trough concentration between 15 and 30 mg/L on day 3 Clinical response Adverse effects (nephrotoxicity and hepatotoxicity)	LD: 12 mg/kg q12hr for five consequent doses MD: 12 mg/kg according to TDM and renal adjustment	P
Matsumoto [44]	2013	Retrospective study	Critically ill patients	20			Correlation between teicoplanin LD and trough concentration on day 3 Adverse effects (nephrotoxicity and hepatotoxicity)	11–15 mg/kg q12hr for three consequent doses	P
Mimoz [45]	2006	Prospective study	Critically ill patients	13			Trough concentration ≥20 mg/L	LD: 12 mg/kg q12hr for four consecutive doses MD: 12 mg/kg once daily	F

Linezolid
Barrasa [46]	2020	PK modeling study	ICU-admitted patients	43 (136 plasma samples)	CrCl_10h	130 ml/min/1.73	AUC0–24/MIC > 80 fT > MIC > 85% (target MIC = 2 mg/L)	600 mg q12hr as IA (over 30 min) or CI (50 mg/hr) Recommended: 600 mg q8hr as CI (75 mg/hr)	F
Wang [47]	2020	Prospective multicenter observational study	ICU-admitted patients	117	CrCl_CG	120 ml/min/1.73	AUC0–24/MIC >80 Trough concentration <10 mg/L (for MIC 0.5 to 4)	600 mg q12hr	F
Dou [48]	2020	PK modeling study	Critically ill septic patients	52	CrCl_CG		AUC0–24/MIC of 100 (to provide a bacterial eradication rate of 80% in septic patients) Safety (thrombocytopenia)	Recommended: 800 mg q12hr	F
Morata [49]	2013	Retrospective study	Patients who received linezolid	78	CrCl_MDRD	80 ml/min	Trough concentration <2 mg/L	600 mg q12hr	P

Colistin
Fujii [50]	2020	Review article	Critically ill patients					Recommended: combination therapy with following high-dose colistin in patients with CrCl >80 ml/min/1.73 LD: 9 mIU MD: 360 mg (11 mIU) daily q12hr, 12 hr after the LD
Aitullina [51]	2019	Retrospective study	ICU-admitted patients with MDR Gram-negative bacterial infection and at least 72 hr colistin therapy	100	CrCl_CKD-EPI	108 ml/min/1.73	Efficacy Nephrotoxicity	LD: 9 mIU LD MD: 3 mIU q8hr	F
Nation [52]	2017	Four-center observational study	Adult critically ill patients	214	CrCl_CG	90 ml/min/1.73	PTA >80% and <30% for average steady-state concentration of colistin ≥2 and ≥4 mg/L, respectively.	An algorithm for colistin dosing in different CrCls: 360 mg (11 mIU) daily for patients with CrCl >90 ml/min/1.73 q12hr	F
Dalfino [53]	2015	Prospective observational study	Patients with severe sepsis or septic shock who received colistin >72 hr	70	CrCl_CKD-EPI	130 ml/min/1.73	Nephrotoxicity Steady-state concentration (target = 2.5 mg/L)	Recommended: LD: 9 mIU MD: 9 mIU/day for CrCl 60–130 ml/min/1.73 and 12 mIU/day for CrCl 130 ml/min/1.73 q12hr, 12 hr after an LD	F

Aminoglycosides
Carrie [54]	2020	Retrospective study	Critically ill patients who received amikacin and underwent TDM	70 (179 serum concentrations(	CrCl_CG	130 ml/min/1.73	Cmax/MIC 8 AUC0–24/MIC ≥75 Trough concentration <2.5 mg/L (toxic cutoff)	Monte Carlo simulations	F
Fujii [50]	2020	Review article	Critically ill patients				Cmax/MIC 8–10	Amikacin: 30 mg/kg/day q24hr Gentamycin: 8 mg/kg/day q24hr Tobramycin: 10 mg/kg/day q24hr
Tängdén [20]	2017	Review article	Critically ill patients with severe infections				Amikacin: Cmax/MIC ≥ 8–10, AUC/MIC >70, Cmin <2 mg/L Gentamycin and tobramycin: Cmax/MIC ≥10, AUC/MIC >70, Cmin <0.5 mg/L	Initial empirical dosage: Amikacin: 30 mg/kg q24hr Gentamycin and tobramycin: 7–10 mg/kg q24hr MD: adjusted doses according to TDM
Hobbs [8]	2015	Review article	Critically ill patients with ARC		CrCl_8h	>130 ml/min	Cmax/MIC = 8–10	7 mg/kg/day for gentamycin and tobramycin
Najmeddi [55]	2014	Randomized clinical trial	Septic patients who received empirical treatment, including amikacin, against Gram-negative bacteria	40			Cmax >40 and fT > MIC >60% Nephrotoxicity	Amikacin: 12.5 mg/kg q12hr instead of 25 mg/kg q24hr	G

Fluoroquinolones
Mahmoud [15]	2017	Review article				≥130 ml/min		Recommended: Levofloxacin: 750–1000 mg/day
Tängdén [20]	2017	Review article	Critically ill patients with severe infections				Ciprofloxacin: AUC/MIC ≥125 and Cmax/MIC ≥ 8 Levofloxacin: AUC/MIC ≥80	Recommended: Levofloxacin: 750 mg daily or 500 mg q12hr Ciprofloxacin: 400 mg q8hr or 600 mg q12hr Given as initial empirical dosage
Robert [56]	2016	Observational pharmacokinetic study		35	CrCl_CG		AUC/MIC 80	Monte Carlo simulations	F
Hobbs [8]	2015	Review article	Critically ill patients with ARC		CrCl_8h	>130 ml/min	AUC/MIC ≥125	Recommended: Ciprofloxacin: 400 mg q8hr Levofloxacin: 750 mg daily

ARC: augmented renal clearance; CrCl: creatinine clearance; CrCl_24h: measuring urinary creatinine clearance in the 24-hour urinary collection; CrCl_CG: estimated creatinine clearance using the Cockcroft–Gault equation; CrCl_CKD-EPI: estimated creatinine clearance using the CKD-EPI equation; % fT > MIC: duration of time that the free drug plasma concentration remains above the minimum inhibitory concentration (MIC) of each pathogen; Cmax/MIC ratio: maximum concentration of antibiotic relative to the pathogen MIC; AUC0–24/MIC ratio: area under the plasma concentration-time curve over 24 hr relative to the pathogen MIC; Cmin: minimum concentration of antibiotic; hr: hours; min: minutes; q: every; IA: intermittent administration; EI: extended infusion; CI: continuous infusion; LD: loading dose; MD: maintenance dose; TBW: total body weight; TDM: therapeutic dose monitoring; XDR: extensively drug-resistant; MDR: multidrug-resistant; PTZ: piperacillin-tazobactam; HAP/VAP: hospital-acquired pneumonia/ventilator-associated pneumonia; G: good; F: fair; P: poor.