Relationship between vancomycin trough concentration and 24-h area under the curve concentration in Tunisian patients

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INTRODUCTION
Vancomycin is a tricyclic glycopeptide antibiotic (Hale et al., 2017) widely used in clinical care units.It is the drug of choice for serious Gram positive infections (Ghosh et al., 2014).A serum trough concentration between 10 and 20 mg/mL was associated with a successful treatment of methicillin-resistant Staphylococcus aureus (MRSA) (Thompson et al., 1993;Meng et al., 2019).In fact, serum vancomycin trough concentrations are suggested as a surrogate for achieving a ratio of the area under the concentration curve (AUC) to minimum inhibitory concentration (MIC) of ≥400 for an organism with MIC ≤1 mg/mL (Liu et al., 2011).
Numerous studies have found that maintaining an AUC/MIC ≥ 400 predicted time-related clinical and bacteriogical success for patients with infections caused by MRSA (Thompson et al., 1993;Liu et al., 2011).Because of the emergence of bacterial resistance, consensus guidelines issued by the infectious diseases society of America in 2009, recommend maintaining trough concentrations between 15 and 20 mg/mL as a convenient target to reach an AUC/MIC≥400 (Thompson et al., 1993;Fowler et al., 2005) in severe infections.However, recently, it was reported that vancomycin trough concentration does not accurately predict AUC.Additionally, AUC was underestimated by 23%, and this may lead to over exposure and subsequent nephrotoxicity (Neely et al., 2014).So, this study aimed to determine the correlation between measured vancomycin trough concentration and a calculated AUC/MIC ratio in Tunisian patients treated by vancomycin.

Population and samples
This study was conducted among patients treated with vancomycin for a suspected or proven Gram-positive infection and addressed to the department of Clinical Pharmacology of the National Pharmacovigilance Centre for therapeutic drug monitoring (TDM) of vancomycin during the period from 24 January 2010 to 13 April 2021.It included 161 samples from 161 patients receiving a slow intravenous infusion of vancomycin.
Blood samples were taken just before the next drug intake (trough concentration C 0 ).The samples were collected in EDTA tubes and monitored by the chemiluminescent microparticle immunoassay method (CMIA) on Architect 8000.The CMIA method is linear from 7.69 to 96.97 μg/mL range (r= 0.99).Detection (LOD) and quantification limits (LOQ) were 0.42 and 3 μg/mL, respectively.

Data acquisition
A standardized form was used to collect data including age, sex, indication and dose of vancomycin, weight, creatinine clearance, medication administration data and serum concentration data.
We excluded all insufficient data (lack of dose, weight or creatinine) and data with non-valid concentrations (C 0 under the limit of detection, samples taken after the vancomycin administration).

Calculations and definitions
AUC over 24 h was calculated using the Rodvold method (Biagi et al., 2019).The formula was based on a relationship between total body clearance of vancomycin, patient specific creatinine clearance and total daily dose of vancomycin: AUC = dose/[(CrCl × 0.79) + 15.7] • 0.06 Creatinine clearance was estimated with Cockcroft-Gault equation (mL/min).

Statistical analysis
The correlation between through vancomycin concentrations and AUC 24 h was analyzed through a Pearson correlation coefficient and a regression model.Statistical analyses were performed by using GraphPad ® and Microsoft Excel ® .

RESULTS
One hundred sixty-one trough vancomycin concentrations derived from 161 patients were included in the study.The samples were analyzed with CMIA method.The linear range was from 7.69 to 96.97 μg/mL (r= 0.99) and the detection (LOD) and quantification limits (LOQ) were 0.42 and 3 μg/mL, respectively.Demographic data and vancomycin dosing characteristics for the population are shown in Table 1.

DISCUSSION
In this retrospective study, we sought a limited correlation between plasma vancomycin trough concentration and achieving a calculated AUC/MIC ratio ≥400 when trough concentrations are above 15 mg/mL.Current published data indicate that dosing based on vancomycin trough concentrations underestimate AUC by 23%(7).
In the present study, we found that 89% (25 of 28) of patients with vancomycin trough concentration between 15 and 20 mg/mL did not achieve the pharmacodynamic target of AUC/MIC ≥400.Otherwise, 9 patients of 12 with vancomycin trough concentration above 20 mg/L achieve the pharmacodynamic target of AUC/MIC ≥400.Previously, in a study of Hale et al. (2017), 53.4% of patients with vancomycin trough concentrations between 15 and 20 mg/mL did not reach an AUC/MIC ≥400(1).Similar results were reported by a retrospective cohort study of Ghosh et al. (2014).This seems contradict consensus recommendations for therapeutic drug monitoring of vancomycin which suggest a minimum trough concentration of 15 mg/mL to reach target AUC/MIC (Thompson al., 1993;Meng et al., 2019).
It is clear from the present study that optimizing individual patient vancomycin exposure requires monitoring of both AUC 24 h and MIC values.So, it seems that using trough concentration to adjust vancomycin dose does not allow achieving the recommended targets and has a consequence the possible emergence of vancomycin resistance with subtherapeutic concentration and increased the risk of nephrotoxicity with increasing drug exposure.
However, the present study has some limitations.First, this was a retrospective design that did not assess clinical outcomes.Additionally, we calculated AUC using the Rodvold method which relates patient specific creatinine clearance to total body clearance of vancomycin (Biagi et al., 2019).This method may slightly underestimate the true AUC.In another hand, this method is characterized by its rapidity and practicality.It can be especially used to optimize empiric dosing in patients with suspected S. aureus infections.
Another potential limitation was that we supposed that MIC values of all cases were 1 mg/L because of insufficient information accompanying the prescriptions.Clinicians should be mindful of the importance of MIC results on the final AUC 24 /MIC (Meng et al., 2019;Liu et al., 2011;Sakoulas et al., 2004).For example, double the AUC might have been achieved in those with staphylococcus aureus with a MIC of 0.5 mg/L compared to 1 mg/L, such as MICs of 2 mg/L requires seeking an alternative therapy with less renal toxicity (Biagi et al., 2019).
In conclusion, vancomycin steady state trough concentrations correlated poorly with AUC 24 /MIC targets.In order to improve therapeutic drug monitoring of vancomycin, a patient specific AUC 24 /MIC may serve to predict efficacy while serum trough concentrations can be used as indicators of possible nephrotoxicity and development of resistance.

Figure 1 .
Figure 1.Fit plot for AUC and trough vancomycin concentrations of all 161 participants.Each black dot represents 1 participant.The black line is on the fit line.Source: Authors 2023

Table 1 .
Patient and therapy characteristics.