A Systematic Review of Vancomycin Dosing in Patients with Hematologic Malignancies or Neutropenia

Figures & data

Figure 1 Flow chart of study selection.

Table 1 Studies with Clinical Audit of Vancomycin Dosing

Author (Year)	Country	Study Design	Characteristics of Patients Included	Patients with Neutropenia (%)	Sample Size	Age (Years)	Gender (M/F)	Weight (kg)	Renal Function	Vancomycin Dosing Regimen	Timing of Serum Vancomycin	Summary of Results
Hochart 2011^Citation21	France	Single-center retrospective study	Acute myeloid leukemia patients with febrile neutropenia	100%	54 (67 vancomycin treatment courses, VTCs)	50 ± 13.6	27/27	73 ± 18.1	107.5 ± 35.4 mL/min	Continuous infusion; loading dose: 15.5 ± 3.3 mg/kg; maintenance dose: 35.4 ± 6.9 mg/kg/d	At 24 hours for patients with a loading dose and 48 hours for patients without any loading dose.	▪ the target serum level for continuous infusion was greater than 20 mg/L, and only 6 (12%) cases achieved the target
O’Donnell 2011^Citation16 (conference abstract)	UK	Single-center retrospective study	Bone marrow transplant patients who experienced an episode of febrile neutropenia	100%	12	NR	NR	NR	NR	NR	At 24 hours, then twice weekly.	▪ 32% of trough levels were subtherapeutic (< 5 mg/L).
Donovan 2012^Citation18 (conference abstract)	United states	Retrospective study	Neutropenic adult patients	100%	198	NR	NR	NR	NR	Intermittent infusion; 15 – 20 mg/kg/dose and administration times are determined by renal function	NR	▪ 25.3% of patients achieved therapeutic trough concentrations (15 – 20 mg/L)
Vazin 2012^Citation22	Iran	Prospective study	Patients in a hematology-oncology ward who received at least 3 successive doses of vancomycin and had serum vancomycin concentrations at steady state	88%	58	36.58 ± 14.33	44/14	68.05 ± 12.61	57/58 (98.2%) ^a	Intermittent infusion; Correcting dosage based on creatinine clearance was given to 10 (17.23%) of the patients	Blood samples were taken from the patients who received vancomycin for 3 consecutive days, and just before the administration of the next dose.	▪ vancomycin trough serum concentration range was 15.59 ± 13.02 mg/L ▪ subtherapeutic trough level (< 10 mg/L) was detected in 3.6% of patients ▪ 53.3% had a level above the maximum therapeutic concentration
Ghehi 2013^Citation20	Iran	Single-center prospective study	Adults receiving vancomycin for neutropenic fever after HSCT	100%	46	32.9 ± 12.45	30/16	74.8 ± 16.6	102.5 ± 35.33 mL/min	Intermittent infusion; 31.9 (±10.5) mg/kg/d	Within 30 minutes prior to the fourth dose	▪ 25 (54.3%) patients had trough concentrations of <10 mg/L ▪ 6 patients (13%) had trough levels of < 5 mg/L
Luo 2014^Citation17	Canada	Single-center prospective study	Leukemia/bone marrow transplant outpatients (at least two doses of vancomycin)	42%	48	54.5^b	24/24	NR	77 μmol/L^b	Intermittent infusion; once-daily (2073 ± 338 mg/d)	NR	▪ 10 (21%) patients had therapeutic vancomycin trough concentrations (i.e., greater than 10 mg/L)
Vermis 2014^Citation19 (conference abstract)	Belgium	Single-center retrospective study	Patients with hematologic malignancies	72%	96 (112 VTCs)	NR	NR	NR	NR	Continuous infusion; loading dose: 15 mg/kg, maintenance dose: 30 mg/kg/d	NR	▪ ARC^c was observed in 73 VTC with an average renal clearance of 147.0 mL/min versus 79.0 mL/min. ▪ Therapeutic vancomycin levels (20 mg/L) were obtained on day 5 (median) with an average vancomycin maintenance dose of 41.7 mg/kg/day when ARC was present versus 32.7 mg/kg/day on day 3.

Notes: ^aProportion of patients with normal renal function; ^bmedian; ^cARC was defined as calculated creatinine clearance exceeding 120 mL/min (Cockcroft–Gault formula).

Abbreviations: NR, not reported; HSCT, hematopoietic stem cell transplantation; VTC, vancomycin treatment course; ARC, augmented renal clearance.

Table 2 The Characteristic of Comparative Studies

Author (Year)	Country	Study Design	Characteristics of Patients Included	Sample Size	Grouping		Gender (M/F)	Age (Years)		Weight (kg)		Patients with Hematologic Malignancies/Neutropenia n(%)		Renal Function		Vancomycin Dosing Regimen	Timing of Serum Vancomycin	Determination of Pharmacokinetic Parameters	Outcomes
					Study Group	Control Group		Study Group	Control Group	Study Group	Control Group	Study Group	Control Group	Study Group	Control Group
Neutropenic patients vs non-neutropenic patients
Haeseker 2014^Citation25	Netherlands	Single-center prospective study	Adults received vancomycin intravenously and had at least two plasma samples	171	Neutropenia (< 500/mm^Citation3): n=56	Non-neutropenia: n=115	104/67	55 ± 13	61 ± 14	NR	NR	55/56 (98.2%)^a	13/115 (11.3%)^a	113 ± 57 mL/min	107 ± 78 mL/min	Intermittent infusion; an initial loading dose of 15 mg/kg + dose individualization based on TDM and renal function.	Two plasma samples (peak and trough concentration)	Maximum a posterior (MAP) Bayesian estimation (MW/Pharm 3.60, Mediware, the Netherlands)	CLva, V
				68 (a subset of patients with hematologic malignancies)	Neutropenia (< 500/mm^Citation3): n=55	Non-neutropenia: n=13	NR	NR	NR	NR	NR	55 (100%)^a	13 (100%)^a	114 ± 57 mL/min	111 ± 58 mL/min
Choi 2017^Citation23	Korea	Single-center retrospective study	Adults receiving routine TDM of vancomycin (trough and peak).	1307	Neutropenia (< 500/mm^Citation3) n=162	Non-neutropenia: n=1145	728/579	54 (37–65)^#	56 (45–64)^#	62.0 (56.0–70.0)^#	60.0 (53.0–68.7)^#	135 (83.3%)^a	184 (16.1%)^a	0.6 (0.5–0.8) ^#mg/dL	0.7 (0.5–0.9) ^#mg/dL	Intermittent infusion; 1000 mg vancomycin every 12 h	Steady-state serum vancomycin concentration (after at least the fourth dose)	Posterior Bayesian estimation (Abbott’s PKS software)	Serum trough vancomycin concentration at steady state, t1/2
Patients with hematologic malignancies vs non-cancer patients
Al-Kofide 2009^Citation24	Saudi Arabia	Single-center retrospective study	Adults receiving vancomycin therapy	31	Cancer patients (proportion of patients with hematologic malignancies was 88.9%): n=18	Patients without cancer: n=13	NR	48.5 ± 20.2	43.4 ± 22.1	66.7 ± 17.1	68.9 ± 14	NR^b	NR^b	105.4 ± 62.3 mL/min	87.2 ± 27.5 mL/min	Intermittent infusion; Initial vancomycin dosing regimens were chosen by attending physicians	Peak and trough vancomycin serum concentration (after the third dose or at steady state)	Pharmacokinetic equations	CLva, V, t1/2
Izumisawa 2019^Citation37	Japan	Retrospective cohort study	Adults receiving > 3 days of vancomycin therapy	522	Hematologic malignancy patients: n=261	Non-malignancy patients: n=261	321/201	65.6 ± 13.6	67.2 ± 16.9	55.0 ± 10.3	56.2 ± 13.1	1.47 ± 2.46 × 10^3/μL^c	7.80 ± 4.66 × 10^3/μL^c	77.0 ± 29.2 mL/min	74.1 ± 35.6 mL/min	Intermittent infusion; Initial dosing was not pre-specified	After ≧ 3 days following the start of administration	Bayesian estimation using TDM software Ver 3.3	Trough concentration, CLva, Vss, t1/2

Notes: ^#Median (interquartile range); ^aproportion of patients with hematologic malignancy; ^bproportion of patients with neutropenia; ^cthe absolute count of neutrophils.

Abbreviations: NR, not reported; V, volume of distribution; Vss, volume of distribution at steady state; CLva, vancomycin clearance; t_1/2, half-life; TDM, therapeutic drug monitoring.

Table 3 The Pharmacokinetic Parameters in Comparative Studies

Author (Year)	Sample Size	Vancomycin Clearance (mL/min)			T1/2 of Vancomycin (h)			V (L)
		Hematologic Malignancies or Neutropenia	Control Group	P value	Hematologic Malignancies or Neutropenia	Control Group	P value	Hematologic Malignancies or Neutropenia	Control Group	P value
Neutropenic patients vs. non-neutropenic patients
Haeseker 2014^Citation25	171	67 ± 26	50 ± 22	<0.001	–	–	–	62 ± 32	56 ± 29	0.304
	68 (subset of patients with hematologic malignancies)	68 ± 26	53 ± 16	0.024	–	–	–	62 ± 32	59 ± 18	0.691
Choi 2017^Citation23	1307	–	–	–	7.4 h (5.9–10.7 h) ^#	8.9 h (6.9 −12.0 h)^#	<0.0001	–	–	–
Patients with hematologic malignancies vs. non-cancer patients
Al-Kofide 2009^Citation24	31	110.1 ± 42	71.2 ± 22.2	0.005	8.6 ± 7.1	5.4 ± 1.9	0.111	70 ± 45	31.1 ± 8.3	0.002
Izumisawa 2019^Citation37	522	0.055 ± 0.017 L/h/kg	0.051 ± 0.019 L/h/kg	<0.05	32.7 ± 13.0	37.1 ± 18.8	<0.05	1.81 ± 0.57 L/kg	1.84 ± 0.62 L/kg	>0.05

Notes: –, not reported; #, median (interquartile range).

Table 4 Characteristics and Results of Studies for Developing PK/PPK Models

Author (Year)	Country	Study Design	Characteristics of Patients Included	Patients with Neutropenia (%)	Sample Size	Number of serum Concentrations	Age	Gender (M/F)	Weight (kg)	Renal Function	Vancomycin Dosing	Timing of Vancomycin Sampling	Pharmacokinetic Modeling Method	Model	Pharmacokinetic Parameters
															V	CL	Ke (h−^Citation1)	t1/2 (h)
Pharmacokinetic analysis
Kureishi 1990^Citation26	Canada	Single-center prospective study	Patients with acute leukemia and had absolute granulocyte below 500/mm^3	100%	25	NR	NR	NR	NR	NR	Intermittent infusion; 15 mg/kg q12h	Prior to infusion and at 1 and 3 h post-infusion daily during the first 3 days and every 3 to 7 days thereafter	Equations with two steady-state samples	One-compartment model	0.61 ± 0.21 L/kg	NR	NR	5.6 ± 1.8
Le Normand 1994^Citation28	France	Single-center prospective study	Patients with hematologic malignancies who were neutropenic (100/mm^3)	100%	10	130	36.2 (range: 18–50)	4/6	64.6 ± 10.4	141.2 ± 36.2 mL/min	Intermittent infusion; 1000 mg every 12 h	The first dose: prior to injection, at the end of the infusion, and 11 samples collected until 11 h after the end of the infusion	G-Pharm computer program	Two-compartment model	Vc: 22.9 ± 11.4 L	158 ± 51 mL/min	NR	2.94 ± 0.84
Jarkowski 2011^Citation27	United states	Single-center prospective study	Acute myeloid leukemia patients receiving vancomycin	NR	25	NR	59.12 ± 16.26	17/8	86.05 ± 19.42	85.72 ± 37.28 mL/min/1.73m^2	Intermittent infusion; 1970.00 ± 605.19 mg/d	Three samples: 1 h, 3–8 h, and 8–24 h post-infusion	Maximum a priori Bayesian estimation using Adapt 5	Two-compartment model	Vc: 0.23 L/kg Vss: 0.60 L/kg	0.14 L/h/kg	NR	NR
Ghehi 2013^Citation20	Iran	Single-center prospective study	Patients with neutropenic fever after HSCT	100%	20	40	29.9 ± 9.5	NR	72.5 ± 15.2 (ABW)	104.7 ± 37.0 mL/min	Intermittent infusion; 31.9 (±10.5) mg/kg/d (69.6%:1g q12h; 17.4%:1g q8h)	First steady-state trough (within 30 minutes prior to the fourth dose), peak concentration, random sample	Equations with two steady-state samples	One-compartment model	0.60 (0.44–0.76) L/kg	0.090 (0.071–0.109) L/h/kg 109.7 (82.7–136) mL/min	0.16 (0.13–0.19)	4.9 (3.8–6.0)
Population pharmacokinetic model
Buelga 2005^Citation29	Spain	Single-center retrospective study	Adult inpatients with an underlying hematologic malignancy	43.7%	215	1004	51.5 ± 15.9	119/96	64.7 ± 11.3	89.4 ± 39.2 mL/min	Intermittent infusion	Blood sampling was ordered as required clinically	Nonlinear mixed-effect modeling approach (NONMEM)	One-compartment model	CL (L/h): 1.08 × CLCR (Cockcroft and Gault) (L/h); CVCL: 28.16% V (L) =0.98 ×TBW; CVV:37.15%.
Okada 2018^Citation38	Japan	Single-center retrospective study	Patients undergoing allo-HSCT who received preventive treatment with vancomycin	NR	75	227	49 (range: 17–69)	49/26	59.4 (range: 39.4–104.5)	113 (range: 47–253) mL/min	Intermittent infusion initial dosage of 1 g/12 hours (if the CLCR was >75 mL/min/1.73 m2).	Immediately before ad-ministering vancomycin,1 hour after drug administration and at some other points as necessary	Nonlinear mixed-effect modeling approach (NONMEM)	Two-compartment model	Vc (L)= 39.2 × (TBW/59.4)^0.78; CVVc=14.2% CL (L/h) =4.25 × (CLCR/113)^0.70; CVCL=25.2% Vp (L) =56.1; CVVp=66.9%
Bury 2019^Citation36	The Netherlands	Retrospective matched cohort study	Intravenous vancomycin therapy for ≥ 2 days and at least one available vancomycin concentration	26.7%	116	742	61.4 ± 13.4	67/49	NR	Median 92.7 mL/min	Intermittent infusion The specific dosing was not pre-specified	NR	Nonlinear mixed-effect modeling (NONMEM)	Two-compartment model	CL(L/h) = 3.22+(1+0.00834 × (CLCR −104)) × 1.277^NEUTROPENIA; CVCL=33.0%

Abbreviations: V, volume of distribution; CL, clearance; Ke, elimination rate constant; t_1/2, half-life; NR, not reported; ABW, adjusted body weight; TBW, total body weight; CL_CR, creatinine clearance; Vc, volume of central compartment; Vss, steady-state volume of distribution; Vp, distribution volume of peripheral compartment.

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