Acta Anaesthesiol Scand. 2020;00:1–10. wileyonlinelibrary.com/journal/aas
|
1 Received: 13 January 2020|
Revised: 28 May 2020|
Accepted: 9 June 2020DOI: 10.1111/aas.13658
O R I G I N A L A R T I C L E
Factors increasing the risk of inappropriate vancomycin therapy in ICU patients: A prospective observational study
Elin Helset
1| Ingvild Nordøy
2,3| Hilde Sporsem
4| Victoria D. Bakke
5|
Jan F. Bugge
1* | Karianne W. Gammelsrud
6| Manuela Zucknick
7| Elisabeth von der Lippe
8This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2020 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation
*Post mortem
1Division of Critical care and Emergency Medicine, Oslo University Hospital, Oslo, Norway
2Section for Clinical Immunology and Infectious diseases, Oslo University Hospital, Oslo, Norway
3Research Institute for Internal Medicine, University of Oslo, Oslo, Norway
4Oslo Hospital Pharmacy, Oslo, Norway
5Department of Anesthesiology, Nordland Hospital, Bodø, Norway
6Department of Microbiology, Oslo University Hospital, Oslo, Norway
7Oslo Center for Biostatistics and Epidemiology, Department of Biostatistics, Faculty of Medicine, University of Oslo, Oslo, Norway
8Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway Correspondence
Elin Helset, Department of Anesthesiology, Oslo University Hospital, Kirkevn. 166, 0450 Oslo, Norway.
Email: [email protected] or ehj@ous-hf.
no
Funding information
Financial support was solely from institutional sources.
Background: Vancomycin trough levels are frequently subtherapeutic in intensive care unit (ICU) patients. The aim of this study was to identify patients at risk of therapeutic failure defined as vancomycin area-under-the-curve0-24/minimum inhibitory concentration (AUC0-24/MIC) <400, and to examine possible effects of different MICs, the variability in renal clearance and continuous renal replacement therapy (CRRT), and the relevance of vancomycin therapy.
Methods: A prospective observational study of ICU patients ≥18 years at initiation of vancomycin therapy was conducted from May 2013 to October 2015. The patients were divided into four groups according to renal function and CRRT-mode as follows:
normal- or augmented renal clearance and continuous venovenous hemodialysis or -hemofiltration. Vancomycin peak and trough levels were measured at 24, 48, and 72 hours after therapy initiation. Relevance of vancomycin therapy was retrospec- tively evaluated based on microbiological results.
Results: Eighty-three patients were included, median age 54.5 years, 74.5% male, SAPS II score 46, and 90 day mortality 28%. Vancomycin therapy was initiated on ICU-day 8 (IQR, 5-12), with a median treatment time of 7.5 (IQR, 5-12) days. AUC0-24/ MIC > 400 was reached in 81% and 8% with MIC = 1 and 2 mg/L respectively. The CRRT groups had higher AUC0-24/MIC-ratios than the non-CRRT groups (P < .001).
Augmented renal clearance increased the risk of AUC0-24/MIC < 400, independent of MIC-value. Initiation of vancomycin therapy was retrospectively considered relevant in 28 patients (34%).
Conclusion: A MIC-value >1 mg/L and augmented renal clearance, were factors increasing the risk of therapeutic failure. Vancomycin treatments could have been omitted or shortened in most of these patients.
1 | INTRODUCTION
The high incidence of empiric initiation and variability in drug phar- macokinetics in a population with multiorgan failure and increasing pathogen susceptibility problems, have increased the focus on when and how antibiotics are used in the intensive care units (ICU).1-5
Empiric initiation may lead to inappropriate use of antibiotics, especially in surgical ICU patients where differentiation between inflammation and infection is particularly challenging.3,6 The glyco- peptide vancomycin is one of the antibiotics subjected to frequent empiric use when life-threatening Gram-positive infections are sus- pected.5,7,8 In Norway, the main indication for vancomycin therapy is suspected hospital-acquired infections by coagulase-negative staphyolococci and Enterococcus faecium. MRSA infections are rare.
Despite a long tradition of therapeutic drug monitoring (TDM) of vancomycin, reports from ICU populations find achieving therapeu- tic target trough values of 15-20 mg/L difficult.7,9 Furthermore, most clinicians are not aware that the prerequisite for the trough values is a pathogen MIC ≤ 1.10 The vancomycin trough level of 15-20 mg/L is a surrogate marker for the vancomycin area under the curve0-24/ minimum inhibitory concentration (AUC0-24/MIC)>400, which has so far been less attainable for everyday use.7,10-12 To use the vanco- mycin AUC0-24/MIC ratio is important, because it also includes the pathogen`s susceptibility to the drug. A vancomycin MIC ≥ 1.5 mg/L, has been associated with a poorer clinical outcome in patients in- fected with MRSA.13
Sepsis and septic shock may change the distribution, metabolism, and elimination of antimicrobial drugs, especially hydrophilic drugs such as vancomycin, due to changes in volume of distribution (Vd) and renal clearance.4 In an ICU population, there is a wide variability in renal function as well as continuous renal replacement therapies (CRRT). Patients with systemic inflammatory response syndrome (SIRS) in need of vasopressors, may have a hyperdynamic circulation with augmented renal clearance (ARC) or rapidly developing acute renal failure requiring CRRT.4,11,14 Recent prospective studies have demonstrated early inadequate serum concentrations of vancomy- cin in patients with ARC.9,15,16 However, only few reports with lim- ited data exist on vancomycin AUC0-24/MIC endpoint in this group.17 The effect of different CRRT-techniques, convection vs dif- fusion, modes and settings on pharmacokinetics of antibiotics in- cluding vancomycin is not finally established.18-20 Although several population pharmacokinetic-pharmacodynamic (PK-PD) models for vancomycin exist, many are based on smaller, often retrospec- tive studies, and are not updated regarding CRRT-filters, mode and CRRT-dose, with few and not consecutively collected vancomycin levels.17,21,22 In the present study, we wanted to compare the effect of CVVHD and CVVHF on CRRT-clearance of vancomycin.
In a previous publication from the same cohort of patients with focus on adherence to dosing guidelines and TDM, we demonstrated that vancomycin trough levels were frequently subtherapeutic.9 The aim of the present study was to identify ICU patients at risk of therapeutic failure defined by a vancomycin AUC0-24/MIC < 400, assuming MICs of 1, 2, or 4 mg/L. Furthermore, the aim also includes
the study of the effect of variability in renal clearance and CRRT- clearance with CVVHD and CVVHF, on vancomycin AUC0-24/MIC.
Finally, we examined retrospectively the indications for vancomycin therapy, in order to find the proportion of patients where vancomy- cin treatment was appropriate.
2 | METHODS
This study was carried out as a part of the PharmacoCRRT2012 study (NCT01582360 at clinicaltrials.gov). The study protocol was approved by the Regional Committee for Medical and Research Ethics and the institutional Data Inspectorate Health Authority in November 2012.
This prospective observational study was performed at four ICUs at Oslo University Hospital (OUS), a 1200 beds tertiary hos- pital, including the major trauma and the national organ transplant center in Norway. Patients were included from a neurosurgical-, a cardiovascular-, and two general ICUs. The patients were enrolled from May 1st 2013 until October 31st 2015, with a final follow-up in January 31st 2016. The inclusion criteria were initiation of vanco- mycin therapy within the last 24 hours, age ≥18 years, and expected treatment-time with vancomycin >72 hours. Written informed con- sent from the patient or next of kin was obtained prior to inclusion.
The patients were included into two main groups as follows: the non-CRRT groups and CRRT groups, and four subgroups. The non- CRRT group was divided according to creatinine clearance—nor- mal renal clearance >60 <129 mL/min (NRC), and augmented renal clearance ≥130 mL/min (ARC); the CRRT group according to CRRT mode—CVVHF and CVVHD.
The ICUs consistently used CVVHF-mode (Prismaflex®
Gambro) or CVVHD-mode (Multifiltrate® Fresenius). For CVVHF, the Prismaflex M-150® filter with an AN69 membrane was used.
For CVVHD, the Ultraflux®AV1000S filter with the Fresenius Polysulfone® membrane was used. The settings for the CRRT treat- ments are described in Table 2.
The following information was gathered from the electronic medical records (DIPS® and MetaVision® IMD-soft): Simplified Acute Physiology Score (SAPS) II at admission, the SIRS and the Sequential Organ Failure Assessment score (SOFA) the day before inclusion, and at 24, 48, and 72 hours thereafter, and a 90-day
Editorial Comment
It has been reported that vancomycin levels frequently be sub-therapeutic in critically ill patients. This prospec- tive observational study of adult ICU patients assesses risk factors associated with therapeutic failure of vancomy- cin therapy. The authors found that, in retrospect, many patient-vancomycin treatment events could have been avoided.
mortality follow up. Furthermore, indications for vancomycin therapy, and clinical- and microbiological laboratory data results.
Change in SOFA-score was calculated at start of the vancomycin therapy and across time for the first 72 hours. For calculation of creatinine clearance, urine was collected from initiation of van- comycin therapy until the next morning, and thereafter every 24 hours. The data were entered into a Medinsight® database (OUS).
Vancomycin was administered as an intermittent intravenous infusion at a maximum rate of 1 g/h with a frequency of median 2 times/day (range 1-6).9 Blood samples for vancomycin trough con- centrations were drawn immediately prior to the vancomycin doses at 24, 48, and 72 hours. Vancomycin peak concentrations were sampled 1 hour after the end of the vancomycin infusion. For CRRT- patients, parallel ultrafiltrate samples were obtained for calculation of the sieving (Sc)- or saturation (Sd) coefficients and CRRT-clearance.
Vancomycin concentrations were determined using a commercial assay (Cobas C Systems®, Roche).
Bacterial isolates were identified to species level by using Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (Bruker Daltonics). All Gram-positive isolates were susceptibility tested for vancomycin using the current methods at the time of the study which include the following: MIC gradi- ent strips, Etests® (bioMeriéux) or VITEK® 2 automated system (bioMeriéux).
A retrospective evaluation of empiric and targeted vancomycin therapy was performed by three specialists in infectious diseases and microbiology. Vancomycin therapy was considered not relevant when no vancomycin susceptible pathogen was detected, or the positive isolate was considered to be a colonizer.
Calculations of vancomycin PK and AUC0-24/MIC, were per- formed for each patient using a PK/PD calculator. Traditional phar- macokinetic equations modified after the Sawchuk-Zaske method were used.23 The formulas used for the calculations are shown in Data S1.
TA B L E 1 Baseline characteristics of 83 Intensive Care Unit patients started on vancomycin therapy
Clinical characteristics Total (n = 83) Missing
Age (year) 54.5 (38-63) 0
Sex female No. (%) 22 (26.5) 0
SAPS II score 46 (34-56) 7
90-day mortality No. (%) 23 (28) 0
Body weight (kg) 80 (70-92) 1
CRRT groups No. (%) 40 (48)
CVVHF-group No. 19
CVVHD-group No. 21
Non-CRRT groups No. (%) 43 (52)
ARC-group No. 21
NRC-group No. 22
Diagnosis at admission to ICU No. (%)a
Cardiovascular 7 (5.8)
Hematological malignancy 7 (5.8)
Neurological disease 8 (6.6)
Pneumonia 10 (8.3)
Septicemia 20 (16.5)
Postoperative complications 29 (24)
Trauma 19 (15.7)
Other 21 (17.4)
Sepsis criteria, increase in SOFA > 2p No. (%)
14 (16.9) 6
SIRS criteria ≥ 2 No. (%) 46 (55.5) 0
CRP 185 (84-293) 0
Leukocytosis No. (%) 45 (54.2) 0
Vancomycin therapy initiation, ICU day
8 (3-16) 0
Patients using other antibiotics No.
(%):
79 (95) 0
Patients using antimycotics No. (%): 38 (46) 0 Note: Data are presented as medians with interquartile range (IQR), unless stated otherwise.
aThe number of diagnoses adds up to a greater total than 83, because many patients were admitted to the Intensive Care Unit (ICU) with more than one diagnosis. SAPS II, simplified acute physiology score II; SOFA, sequential organ failure assessment; SIRS, systemic inflammatory response syndrome; ARC, augmented renal clearance ≥130 mL/min;
NRC, normal renal clearance, 60-129 mL/min; CRRT, continuous renal replacement therapy; CVVHF, continuous venovenous hemofiltration;
CVVHD continuous venovenous hemodialysis.
F I G U R E 1 Individual vancomycin dose, trough, and peak concentrations, at 24, 48, and 72 hours after start of therapy in an Intensive Care Population. The ICU population of 83 patients was divided into four groups according to renal clearance and continuous renal replacement therapy (CRRT) mode. Groups: NRC, normal renal clearance 60-129 mL/min, n = 22; ARC, augmented renal clearance >130 mL/min, n = 21; CVVHD, continuous venovenous hemodialysis, n = 21; CVVHF, continuous venovenous hemofiltration, n = 19. The individual vancomycin dose in mg/kg is depicted on the right panel (x); vancomycin concentration in mg/L on the left panel (o). Ctrough, vancomycin trough concentration;
Cpeak, vancomycin peak concentration
TABLE 2 Continuous renal replacement therapy settings for 40 ICU patients started on vancomycin therapy; comparing continuous venovenous hemodialysis and continuous venovenous hemofiltration Sampling hours (h)
CVVHD (n = 21)CVVHF (n = 19)P value between groups*P value across time24 h48 h72 h24 h48 h72 h Blood-flow mL/min Median (IQR)100 (85-120)100 (95-120)100 (100-112)267*(200-300)250*(200-300)250*(200-300)<.001.45 Missing000202 Effluent flow rate, mL//h Median (IQR)2000 (1900-2500)2000 (2000-2500)2000 (2000-2450)3000*(2250-3000)2950*(2000-3000)3000*(2000-3000)<.001.90 Missing000420 Sc or Sd Median (IQR)0.72 (0.63-0.80)0.72 (0.66-0.76)0.68 (0.57-0.73)0.78*(0.75-0.82)0.76*(0.74-0.82)0.81*(0.74-0.84)<.001.61 Missing333433 CRRT (h/day) Median (IQR)23 (21-24)22 (20-24)23 (21-24)21 (19-22)22 (20-24)23 (22-24).93.12 Missing012424 CRRT clearance (mL/min) Median (IQR)24 (18-28)22 (18-28)21 (19-24)27*(19-31)27*(23-35)33*(27-39)<.001.55 Missing122423 Fluid-withdrawal, (mL/day) Median (IQR)2370 (638-3808)2725 (2043-3365)2600 (2348-3900)1556*(459-3153)1792*(833-2363)1529*(536-2867).002.98 Missing101404 Urine production (mL/day) Median (IQR)110 (45-334)70 (33-455)118 (1-299)240*(23-698)185*(25-715)320*(0-1092).02.80 Missing221652 S-urea (mmol/L) Median (IQR)14 (9-18)10 (7-17)11 (8-18)12 (8-18)9 (7-14)9 (8-13).16.38 Missing000000 (Continues)
To study the effect of MIC, the MICs of 1, 2, and 4 mg/L were used to calculate vancomycin AUC0-24/MIC (https://www.eucast.
org/clini cal_break point s/). In addition, measured MIC-values were used for calculation of AUC0-24/MIC in cases where a pathogen was identified and the infection was considered relevant.
Calculations of the Sc, Sd,and the CRRT-clearance are previously described by Li et al and shown in Data S2.18
2.1 | Endpoints 2.1.1 | Primary
To identify patients at risk of therapeutic failure as assessed by the vancomycin AUC0-24/MIC > 400 endpoint assuming MICs of 1, 2, and 4 mg/L, and to study the effect of variability in renal clearance, and the different CRRT-modes, CVVHF and CVVHD, on vancomycin AUC0-24/MIC.
2.1.2 | Secondary
To retrospectively examine the indications for vancomycin therapy in order to find the proportion of patients where vancomycin treat- ment was appropriate.
2.2 | Statistical analysis 2.2.1 | Study size
A sample size of 20 patients per group ensured that the propor- tion of patients at risk of treatment failure could be estimated with a standard error lower than 0.1 using the Wilson score interval method, a method shown to have superior performance for small sample sizes.24,25
2.2.2 | Statistical methods
Continuous data are presented as medians with interquartile range (IQR), and categorical data as numbers and percentages.
Independent samples t-tests or one- or two-way analysis of vari- ance (ANOVA) was used when comparing mean values of normally distributed data, and Mann-Whitney U or Kruskall-Wallis tests were used when comparing non-normal continuous data. Chi- square test was used when comparing categorical data. Linear mixed model for repeated measurements across time was used to compare changes within and between groups. To study the cor- relation between SAPS II, SOFA, and SIRS scores, Spearman rank correlations was used. Multiple testing adjustment was performed by controlling the family-wise error rate at 0.05 according to the method of Bonferroni.
Sampling hours (h)
CVVHD (n = 21)CVVHF (n = 19)P value between groups*P value across time24 h48 h72 h24 h48 h72 h S-creatinine (μmol/L) Median (IQR)138 (112-183)132 (81-160)126 (84-151)106 (85-178)96 (82-172)122 (81-150).22.14 Missing000000 Note: Data are presented as medians with interquartile range (IQR). Abbreviations: CRRT, continuous renal replacement therapy; CVVHF, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; BF, blood flow-rate; Sc-sieving coefficient; Sd-saturation coefficient. *indicates statistically significant differences between groups, P < .05.
TABLE 2 (Continued)
Data were analyzed using IBM SPSS statistics version 25 and R version 3.5.
3 | RESULTS
3.1 | Patient characteristics
The baseline characteristics of the patient population and the group distributions are presented in Table 1. Eighty-three patients were included in the study. Two patients in the non-CRRT group changed to the CVVHF-group after 24 hours. One patient in the CVVHD- group and three from the CVVHF-group ended CRRT after 48 hours.
These patients were analyzed in the group they belonged to longest.
In the NRC-group, six patients had creatinine clearance <60 mL/min at 24 hours. The median creatinine clearance in the NRC-group was 69 (IQR, 53-97) mL/min and in the ARC-group 156 (IQR, 132-180) mL/min. Baseline clinical laboratory results reflecting organ function are presented in Table S1.
The SAPS II score at ICU admittance was statistically signifi- cantly higher in the CRRT-group with median 52 (IQR, 42-62) compared to the non-CRRT group with median 40 (IQR, 30-50) (P < .01). In the proportion of patients (n = 28) where vancomy- cin therapy retrospectively was considered relevant, the last 24-h change in SOFA-score before the start of vancomycin therapy, was median 0 (IQR, 0-1), not statistically significantly different from the rest of the cohort. There were statistically significant correlations between SAPS II score at ICU admission and SOFA-score at 24, 48, and 72 hours (rs = 0.44, P < .05). The SOFA-score for the total pop- ulation at 24 hours was 9 (IQR, 6-13), and no statistically significant changes were observed within 72 hours, 8 (IQR, 5-11) (P = .75).
3.2 | Vancomycin pharmacokinetics and AUC
0-24/ MIC
A total of 249 maintenance doses were registered at 24, 48, and 72 hours. In total 492 trough and peak samples were collected, and six were missing. In the CRRT group, 105 ultrafiltrate samples were collected, and 18 were missing.
3.2.1 | Dose-concentration relationships of vancomycin
Figure 1 shows the vancomycin dose (mg/kg) and the measured trough-and peak levels (mg/L) for each patient during the first 72 hours after initiation of vancomycin therapy.
3.2.2 | Loading dose
The first dose of vancomycin was not statistically significantly dif- ferent between groups: NRC 14.9 (IQR, 4.5-28.9) mg/kg, ARC 23.6 (IQR, 9.4-37.8) mg/kg, CVVHF 14.8 (IQR, 7.8-21.8) mg/kg, CVVHD 16.7 (IQR, 6.6-26.8) mg/kg, (P = .06).
3.2.3 | Maintenance doses
Patients in the ARC-group were given statistically significantly higher daily doses of 44.4 (IQR, 28.7-60.1) mg/kg compared to the other groups: NRC 29.6 (IQR, 21.3-38.0) mg/kg, CVVHF 24.0 (IQR, 5.1-28.7) mg/kg, and CVVHD 20.3 (IQR, 13.7-26.9) mg/kg, (P < .001).
TA B L E 3 Vancomycin pharmacokinetics in an Intensive Care Unit population the first 72 hours after therapy initiation
Sampling hours (h)
NRC (n = 22) ARC (n = 21) CVVHF (n = 19) CVVHD (n = 21)
P value between groups
P value across time
24 h 48 h 72 h 24 h 48 h 72 h 24 h 48 h 72 h 24 h 48 h 72 h
Vd (L/kg)
Median (IQR) 0.6 (0.5-0.8) 0.7 (0.5-0.9) 0.7 (0.6-0.8) 0.6 (0.5-0.7) 0.6 (0.5-0.7) 0.6 (0.5-0.8) 0.7 (0.6-0.8) 0.7 (0.6-0.9) 0.7 (0.6-0.8) 0.6 (0.5-0.8) 0.6 (0.5-0.8) 0.7 (0.6-0.8) .21 .37
Missing 1 0 2 2 0 3 4 3 2 3 5 1
Tot.Cl (mL/min)
Median (IQR) 77 (56-98) 58 (34-82) 59 (37-81) 109* (89-129) 104* (88-120) 102* (90-114) 73 (58-88) 56‡ (41-71) 49‡ (42-56) 52† (35-69) 49† (38-60) 32† ,‡ (18-46) <.001 .02
Missing 1 0 2 2 0 3 4 3 1 2 5 2
T1/2, (h)
Median (IQR) 7.1‡ (5.9-8.3) 9.5 (6.0-13.0) 9.4 (5.4-13.5) 4.4* (3.7-5.1) 4.6* (3.5-5.8) 6.2* (4.8-7.6) 10.1 (7.7-12.6) 11.4 (8.9-14.0) 12.1‡ (8.6-15.6) 11.2 (8.3-14.1) 15.4 (11.0-19.8) 14.7
(10.7-18.7) <.001 .02
Missing 1 1 2 2 0 3 3 3 2 2 6 3
Note: Data are presented as medians with interquartile range (IQR).
Abbreviations: NRC, normal renal clearance 60-129 mL/min; ARC, augmented renal clearance >130 mL/min; CVVHF, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; Vd, volume of distribution; Tot.Cl, total clearance of vancomycin; T1/2, half-life of vancomycin.
*indicates a statistically significant difference between the ARC group and the other groups, P < .05.
†indicates a statistically significant difference between the CVVHD group and the other groups, P < .05.
‡indicates statistically significant differences across time within a group, P < .05.
3.2.4 | CRRT
In Table 2, CVVHD and CVVHF settings are compared, along with the resulting Sc, Sd, and CRRT-clearance for vancomycin.
Thirty (76%) CRRT-patients had their filters changed within 6 hours before the first dose of vancomycin was given. Within the 72 hours observation time, the filters were changed in 10 (48%) of the CVVHD-patients, and in 8 (52%) of the CVVHF-patients (P = .11). The ultrafiltration rate for the CVVHF treatments were 30 (IQR, 28-38) mL/kg/h and for the CVVHD 25 (IQR, 23-27) mL/kg/h, (P < .001). There were statistically significant correla- tions between CRRT-clearance and ultrafiltration flow-rate in both groups—CVVHF (rs = 0.81, P < .001) and CVVHD (rs = 0.61, P < .001).
3.2.5 | Vancomycin volume of distribution (Vd), total-clearance, and half-life
Vd, total-clearance, and half-life during the first 3 days of therapy are shown in Table 3.
3.2.6 | Vancomycin AUC
0-24/MIC
Vancomycin AUC0-24/MIC, with assumed MICs of 1, 2, and 4 mg/L are shown in Figure 2. Within the first 72 hours, AUC0-
24/MIC > 400 was achieved in 81%, 8%, and 0% of the observa- tions with MICs of 1, 2 and 4 mg/L, respectively. There were statistically significant differences between the CRRT and non-CRRT groups, 612 (IQR, 495-729) vs 548 (IQR, 419-677)
(P = .02), representing the data for MIC = 1 mg/L . In the ARC- group, 29% did not reach vancomycin AUC0-24/MIC > 400 with MIC = 1 mg/L.
TA B L E 3 Vancomycin pharmacokinetics in an Intensive Care Unit population the first 72 hours after therapy initiation
Sampling hours (h)
NRC (n = 22) ARC (n = 21) CVVHF (n = 19) CVVHD (n = 21)
P value between groups
P value across time
24 h 48 h 72 h 24 h 48 h 72 h 24 h 48 h 72 h 24 h 48 h 72 h
Vd (L/kg)
Median (IQR) 0.6 (0.5-0.8) 0.7 (0.5-0.9) 0.7 (0.6-0.8) 0.6 (0.5-0.7) 0.6 (0.5-0.7) 0.6 (0.5-0.8) 0.7 (0.6-0.8) 0.7 (0.6-0.9) 0.7 (0.6-0.8) 0.6 (0.5-0.8) 0.6 (0.5-0.8) 0.7 (0.6-0.8) .21 .37
Missing 1 0 2 2 0 3 4 3 2 3 5 1
Tot.Cl (mL/min)
Median (IQR) 77 (56-98) 58 (34-82) 59 (37-81) 109* (89-129) 104* (88-120) 102* (90-114) 73 (58-88) 56‡ (41-71) 49‡ (42-56) 52† (35-69) 49† (38-60) 32† ,‡ (18-46) <.001 .02
Missing 1 0 2 2 0 3 4 3 1 2 5 2
T1/2, (h)
Median (IQR) 7.1‡ (5.9-8.3) 9.5 (6.0-13.0) 9.4 (5.4-13.5) 4.4* (3.7-5.1) 4.6* (3.5-5.8) 6.2* (4.8-7.6) 10.1 (7.7-12.6) 11.4 (8.9-14.0) 12.1‡ (8.6-15.6) 11.2 (8.3-14.1) 15.4 (11.0-19.8) 14.7
(10.7-18.7) <.001 .02
Missing 1 1 2 2 0 3 3 3 2 2 6 3
Note: Data are presented as medians with interquartile range (IQR).
Abbreviations: NRC, normal renal clearance 60-129 mL/min; ARC, augmented renal clearance >130 mL/min; CVVHF, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; Vd, volume of distribution; Tot.Cl, total clearance of vancomycin; T1/2, half-life of vancomycin.
*indicates a statistically significant difference between the ARC group and the other groups, P < .05.
†indicates a statistically significant difference between the CVVHD group and the other groups, P < .05.
‡indicates statistically significant differences across time within a group, P < .05.
F I G U R E 2 The effect of the minimum inhibitory concentration of 1, 2, and 4 mg/L on the vancomycin area-under-the-curve0-24/ minimum inhibitory concentration in an Intensive Care Unit population. The effect of assumed MICs of 1, 2, and 4 mg/L on vancomycin AUC0-24/MIC ratio was calculated. The ICU population of 83 patients was divided into four groups according to renal clearance and continuous renal replacement therapy (CRRT) mode.
AUC0-24/MIC, Area-under-the-curve0-24/minimum inhibitory concentration. Groups: NRC, normal renal clearance 60-129 mL/
min, n = 22; ARC, augmented renal clearance >130 mL/min, n = 21;
CVVHD, continuous venovenous hemodialysis, n = 21; CVVHF, continuous venovenous hemofiltration, n = 19. Data are presented as mean ± SEM. ⋆ indicates statistically significant differences between the CVVHD-group and the other groups, P < .01. ⋆⋆
indicates statistically significant differences between the ARC- group and the other groups, P < .05
In the proportion of patients where vancomycin therapy was considered relevant, the median AUC0-24/MICs were 501 (IQR, 298- 670), 470 (IQR, 352-737), and 509 (IQR, 345-720) at 24, 48, and 72 hours, respectively, with median MIC = 1.0 (IQR, 0.5-2.0) mg/L.
Sixty-one percent of these patients belonged to the CRRT-groups.
3.2.7 | Nephrotoxicity
There was no statistically significant reduction in creatinine clear- ance across the 72 hours observation time in the two non-CRRT groups—24 hours compared to 72 hours—NRC 68 (IQR, 42-94) mL/
min vs 75 (IQR, 53-97) mL/min, (P = .63); ARC 154 (IQR, 122-186) mL/min vs 151 (IQR, 125-177) mL/min, (P = .93).
3.3 | Indications for the use of vancomycin
Table 4 shows the identified vancomycin-susceptible bacteria from 40 patients. Vancomycin therapy was considered relevant in only 28 of these patients. Vancomycin was initiated at a median of 8 (IQR, 3-16) days after ICU admission. The median treatment time with vancomycin in the proportion of patients with relevant infection was 8 (IQR, 5-14) days, in the rest of the cohort, 7 (IQR, 4-12) days.
Among the 83 patients included, an infection related to indwelling catheters was suspected in 42% of the patients. An intravascular catheter-related infection was verified in 12 patients (14%), and a catheter-related bloodstream infection (CRBSI) in 4 patients (5%). In 55 patients (66%), vancomycin therapy was considered not relevant:
no vancomycin-sensitive pathogens were detected, or the positive isolates were considered colonizers.
4 | DISCUSSION
The present study documents the risk of therapeutic failure of van- comycin therapy in an ICU-population assessed by the target of van- comycin AUC0-24/MIC > 400. This is particularly relevant for patients infected with pathogens with MIC > 1 mg/L, and in patients with augmented renal clearance. Furthermore, in a large proportion of our patients, vancomycin treatment was, in retrospect, unwarranted.
Assuming MIC = 1 mg/L, our results show comparable target achievement with 81% of the AUC0-24/MIC > 400, compared to the DALI study with 50%-88% assuming MIC ≤ 1 and the patients receiv- ing vancomycin as continuous infusion.17 The daily dose of vancomy- cin was in the same or even higher range as compared to the DALI study. The MIC, being the denominator in the AUC0-24/MIC fraction, has crucial impact on the final AUC0-24/MIC value. In the present study, when calculating AUC0-24/MIC with an MIC = 2, only 10%
reached target >400, and none with MIC = 4. As opposed to the DALI study, we found significant differences in the AUC0-24/MIC between the groups, depending on renal clearance and CRRT.17 The high clearance of vancomycin in the ARC-group resulted in low vancomy- cin AUC0-24/MIC ratios. Continuous infusion of vancomycin may be easier to implement and a safer way to achieve appropriate serum concentrations.17,26 However, continuous infusion requires an extra intravenous line and is no guarantee for target achievement.26,27
The patients considered to have an infection relevant for vanco- mycin therapy, had a median AUC0-24/MIC > 400 at all time-points, and a median MIC = 1 mg/L, with the majority of patients being from the CRRT groups. In the CRRT groups, we observed a reduced vancomycin clearance as compared to the non-CRRT groups. The CVVHF-clearance and the sieving-coefficient of vancomycin in the present study, were in accordance with previous reports.27-29 The TA B L E 4 Identified vancomycin-susceptible pathogens in positive isolates from 40 Intensive Care Unit patients started with vancomycin therapy
Pathogen identified
No of positive
isolates Blood BAL Catheter* Ascites Wound
MIC, mg/L
S epidermidis 28 10 14 2 2 0.5-2
S hominis 2 2 0.5-2
S haemolyticus 2 1 1 2
S lugdunensis 1 1 0.5
MSSA 5 2 3 0.5-1
MRSA 2 1 1 0.5-2
Streptococcus oralis 1 1 0.5
Corynebacterium sp 1 1 0.5
E faecium 12 2 3 5 2 0.5-2
E faecalis 3 2 1 2
Total no. of positive isolates
57 20 1 19 7 10
Abbreviations: MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; MIC, the minimum inhibitory concentration; BAL, bronchoalveolar lavage.
aCatheter: central venous lines, dialysis catheters, arterial lines, external cerebral ventricular drainage lines.
higher clearance of vancomycin in the CVVHF-group compared to the CVVHD-group, was related to a higher effluent flow-rate in the CVVHF-group. This is in line with previous publications on effluent flow intensity and vancomycin clearance.27,28
The observed vancomycin Vd of 0.7 in the present study has previously been reported in critically ill patients.27 Furthermore, we found that the connection to a CRRT machine did not influence van- comycin Vd.
Drug-induced nephrotoxicity is a dreaded complication in the ICU, and the original reason for vancomycin TDM.10 Although not frequently reported, longer treatment course, older age, and higher doses may be associated with vancomycin nephrotoxicity.10 In the present study, no change in renal function was observed within the 72-hours observation time with the present dosing regimen.
In two-thirds of the patients in this study, vancomycin therapy was not well-founded when evaluated retrospectively. In 42%, a nos- ocomial infection related to an indwelling catheter was suspected.
Retrospectively, the empiric diagnose of CRBSI was confirmed in only 5%. Despite negative blood cultures and lack of significant bac- terial growth on catheter tips, vancomycin therapy was continued for a median of 7 days. More focus on antibiotic stewardship may have shortened vancomycin treatments in the present study.30
There was a significant correlation between SAPS II score at admittance to ICU, and the SOFA score at initiation of vancomycin treatment. This probably reflected that the organ failures present at admission still prevailed when signs of a new infection appeared.
Before the start of the vancomycin therapy, no significant changes in SOFA-score were observed, indicating lack of septic shock devel- opment. The Surviving Sepsis guidelines advocates for early antibi- otics within an hour of sepsis identification to reduce mortality.31 However, a conservative approach awaiting microbiological analysis results before treatment start, did not increase mortality as demon- strated in a study of an ICU population with suspected ICU acquired infection but without septic shock.32
4.1 | Limitations
We were not able to gather precise weights of all the patients.
Where precise weights could not be obtained, estimated weight was used. This might influence the calculations of dose/kg and vol- ume of distribution. Secondly, we chose to take only two samples for pharmacokinetic analysis every 24 hours. This allowed us to do the calculations of vancomycin pharmacokinetics, but with the as- sumption of a first-order reaction in a one-compartment model.
The serum vancomycin concentration-time profile is complex, and has been characterized as one-, two-, and three compartment mod- els.10,33 Lastly, ideally MIC-testing of all the isolates should have been performed using broth microdilution, which is considered the gold standard. Unfortunately, this method was not available at the time of the study. Also, as summarized by Mouton et al, an exact MIC determination is in general not possible to obtain due to natural
and assay variation, and MIC-measurement variation must therefore always be taken into account.34
4.2 | Conclusion
In this prospective observational study on the use of vancomycin in an ICU-population, we demonstrate that the target of AUC0-24/ MIC > 400 was only reached for the majority of patients when as- suming a pathogen with a vancomycin MIC = 1 mg/L. Furthermore, patients with augmented renal clearance need customized dos- ing regimens, even with MIC = 1 mg/L to avoid therapeutic failure.
Regular monitoring of creatinine clearance in non-CRRT patients, and daily TDM, should be mandatory.
With CRRT, standardization of effluent flow rate is important for predictability of vancomycin levels.
With a more conservative approach awaiting microbiological anal- ysis results as part of the antibiotic stewardship program, the number of vancomycin treatments could have been reduced or shortened.
ACKNOWLEDGEMENTS
We thank MSc Sigbjørn Helset for help with development of the PK/
PD calculator.
CONFLIC TS OF INTEREST None.
ORCID
Elin Helset https://orcid.org/0000-0002-9465-7673
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section.
How to cite this article: Helset E, Nordøy I, Sporsem H, et al.
Factors increasing the risk of inappropriate vancomycin therapy in ICU patients: A prospective observational study.
Acta Anaesthesiol Scand. 2020;00:1–10. https://doi.
org/10.1111/aas.13658