Area under the Concentration-Time Curve-Guided Dosing of Vancomycin: History
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Subjects: Infectious Diseases
Contributor:
Yoshio Takesue

The area under the concentration-time curve (AUC)-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 μg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom vancomycin (VCM) was administered with q12h. To increase the concentration on days 1–2, the routine use of a loading dose is required. Therapeutic drug monitoring (TDM) on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. 

  • model-informed precision dosing
  • vancomycin
  • therapeutic drug monitoring
  • area under the concentration-time curve

1. Introduction

Vancomycin has been widely used to treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA) [1][2][3][4][5]. Vancomycin treatment is associated with several adverse effects such as acute kidney injury (AKI) [6][7][8] and ototoxicity [9][10]. Because of the narrow therapeutic range of vancomycin, therapeutic drug monitoring (TDM) is mandatory for maximizing efficacy while preventing these adverse effects.
At that time, trough concentrations of 15–20 μg/mL were recommended as the surrogate of area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) > 400 excluding MIC = 2 μg/mL for the treatment of complicated infections [11]. By contrast, because of the insufficient data supporting the safety of sustained trough concentrations of 15–20 μg/mL, the previous Japanese guideline recommended that initial therapy should be started at a dosage sufficient to achieve trough concentrations of 10–15 μg/mL even in patients with complicated infections, and the dose can be adjusted after TDM to achieve trough concentrations of 15–20 μg/mL according to the treatment response [12]. A committee consisting of the Japanese Society of Chemotherapy (JSC) and the Japanese Society of Therapeutic Drug Monitoring (JSTDM) developed Japanese practice guidelines for TDM of vancomycin in 2013 [12]. Ye et al. conducted a systematic review of 12 guidelines for vancomycin TDM using the Appraisal of Guidelines for Research & Evaluation II [13], and a consensus guideline developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists [11] and the Japanese guideline had the highest scores in this domain, and only these two guidelines were recommended.
In the era in which model-informed precision dosing (MIPD) became a possible tool in clinical practice, two guidelines for TDM of vancomycin have been recently published [3][14]. The revised American guideline reported by Rybak et al. recommended AUC-guided dosing, and trough-guided dosing targeting 15–20 μg/mL was no longer recommended for serious MRSA infections [3]. Conversely, the updated Chinese guideline recommended trough-guided dosing and AUC-guided dosing at the same strength, considering institutions in which Bayesian software is not available and the possibility of poor feasibility of measuring two-point samples in a first-order pharmacokinetic (PK) equation [11]. In contrast, updated Japanese guidelines aimed to provide recommendations emphasising the importance of the MIPD approach to TDM practice for vancomycin.

2. Area under the Concentration-Time Curve-Guided Dosing of Vancomycin 

2.1. Using MIPD Software to Increase the Accuracy of Dose Individualization

Approximately 90 population PK models have been reported in the last two decades for vancomycin [15][16][17]. Neely et al. reported an internal evaluation study in which the ratio of Bayesian posterior AUC using peak–trough sampling combined with a population PK model developed using peak–trough sampling (AUCPT-PT) to that using rich sampling combined with a population PK model developed using richly sampling (AUCF-F) was 0.86 (95% confidence interval [CI] = 0.81–0.93) [18].

Blouin et al. [19] showed a significant difference in weight-indexed volume of distribution (Vd) between obese and non-obese patients. Ducharme et al. [20] found that mean weight-indexed vancomycin Vd decreased with increasing body size. Hence, Bayesian posterior AUC for obese patients is required [21].

2.2. Recommended Pharmacokinetic (PK)/Pharmacodynamic (PD) Parameters for TDM

Pharmacokinetic (PK)/pharmacodynamic (PD) analysis using a neutropaenic mouse thigh infection model demonstrated that the AUC/MIC ratio most strongly correlated with bactericidal effects against methicillin-susceptible Staphylococcus aureus and MRSA [22]. A meta-analysis in the actual clinical setting revealed that higher AUC/MIC was significantly correlated with lower mortality and treatment failure rates [23]. Therefore, AUC/MIC should be employed to predict clinical and bacteriological efficacy [3][12]. In vitro studies with low-susceptibility strains demonstrated the correlation between AUC and the incidence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hetero VISA) [24][25][26].
The occurrence of AKI was investigated in rats, suggesting that urinary KIM-1 levels can be used for the early detection of VCM-induced AKI [27]. Increased urinary KIM-1 levels were more strongly correlated with AUC than with trough levels [28]. Aljefri et al. conducted a meta-analysis of clinical studies, demonstrating that higher AUC was significantly correlated with a higher incidence of AKI [29]. Therefore, AUC should be employed to predict the risk of AKI [3]. Basic and clinical studies suggested that AUC is the most appropriate PK/PD parameter indicating the efficacy and safety of vancomycin. In the actual clinical setting, trough levels have been substituted for AUC [12][30].

2.3. Candidates for AUC-Guided Dosing

AUC-guided dosing is recommended for patients with risk factors for AKI during vancomycin treatment such as prolonged treatment [31][32], impaired kidney function [31][32][33], the concomitant use of nephrotoxic drugs (aminoglycosides, amphotericin B, contrast medium, and frequent use of non-steroidal anti-inflammatory drug [NSAIDs]) and PIPC/TAZ [6][32][34][35][36][37], the use of hypertensive drugs [31], dehydration [31][33], and severe illness [32].
Patients with altered Vd might be candidates for AUC-guided dosing to increase the prediction accuracy [38][39][31][32][33][40]. Vd was 0.4 L/kg [19] in healthy adults, 0.7 L/kg [41] in patients with infectious diseases, and 1.3 L/kg [42] in patients with septic shock. Augmented renal clearance [43] is experienced by patients with sepsis [44][45][46]. Enhanced clearance is also observed in patients with hematopoietic tumours or febrile neutropaenia [47]. Furthermore, patients with heart failure [48][49], oedema [48][50], dehydration [31][33], burns [51][52], obesity [40][53][54][55], or emaciation [55] have different Vd and clearance from individuals in the normal population.

2.4. Is the Trough Concentration Alone Sufficient to Estimate AUC Using Bayesian Software?

Although it is preferred to obtain two PK samples to accurately estimate AUC using the Bayesian approach, updated TDM for vancomycin guidelines suggested that the trough level alone may be sufficient to estimate AUC in some patients [3]. Utilizing only the trough concentration, accuracy (range 0.79–1.03) and bias (range 5.1–21.2%) were reported using Bayesian dose-optimising software [56]. Although variation was present, the achievement of therapeutic PK targets was substantially higher for the AUC estimated using the Bayesian method with trough-only measurements than using traditional trough monitoring without the Bayesian approach. Neely et al. reported that AUC ≥ 400 µg·h/mL indicated trough concentrations of <15 μg/mL in 68% of cases [57]. Using data from the trough-only measurement, Ueda et al. reported that the median trough level was only 11.0 μg/mL for AUC = 400–600 µg·h/mL [58].

2.5. When Should TDM Be Performed?

Previously, it was recommended to perform initial TDM immediately prior to the fourth or fifth dose including the loading dose on day 3 when steady state was reached. Takahashi et al. reported that steady-state VCM serum concentrations were not achieved on day 3 in patients with impaired kidney function, and underestimation of the trough level on day 3 should be considered in those patients [59]. To improve clinical outcomes, early achievement of the target vancomycin concentration is preferable. Because Bayesian estimation does not require steady-state serum vancomycin concentrations, it enables the early assessment of AUC target attainment. Casapao et al. reported that higher day 1 exposure resulted in lower rates of clinical failure and persistent bacteraemia in patients with MRSA bacteraemia [60]. However, in a prospective, multicentre study of adult patients with MRSA bacteraemia, a higher day 2 AUC/MIC ratio was not associated with a lower rate of failure, but it was associated with the risk of AKI [61]. The authors concluded that day 2 AUCs should be maintained at less than approximately 515 µg·h/mL to minimize the likelihood of AKI.

2.6. the Target AUC in TDM

The MIC of VCM is generally 1 μg/mL [62][63][64]. The MIC distribution of MRSA strains obtained from the European Committee on Antimicrobial Susceptibility Testing MIC distribution website (https://mic.eucast.org/Eucast2/; accessed on 12 February 2022) was 12.7% in MIC at 2 μg/mL, 83.1% in MIC at 1 μg/mL, and 4.1% in MIC at 0.5 μg/mL. The target AUC for treatment success to achieve AUC/MIC ≥400 is ≥800 µg·h/mL, ≥400 µg·h/mL, and ≥200 µg·h/mL, respectively. For an MIC of 2 μg/mL, the conventional dosing regimens failed to achieve the targeted AUC/MIC ratio. In the treatment of MRSA infections with vancomycin MIC at 2 μg/mL, determination of the dose producing AUC/MIC ≥ 400 is impractical and might cause adverse effects [65][66][67][68][69][70][71][72]. For an MIC of 0.5 μg/mL, there are no data supporting dose reductions to achieve an AUC/MIC ≥ 400 (AUC ≥ 200 µg·h/mL) and the emergence of hetero VISA was associated with an AUC of <400 μg·h/mL [24][25][26].

2.7. Continuous Infusion Administration Strategy and Intermittent Infusion

Bissell et al. reported that the continuously infused vancomycin had a shorter time to target achievement with a higher incidence of target attainment than intermittently infused vancomycin in critically ill patients, which resulted in a lower average number of blood samples per patient and shorter duration of therapy [73]. A recent meta-analysis of RCTs and observational studies for critically ill adult patients reported by Flannery et al. demonstrated that continuous infusion was associated with a lower AKI risk (OR = 0.47, 95% CI = 0.34–0.65) and a higher PK target attainment rate (OR = 2.63, 95% CI = 1.52–4.57) than intermittent infusion [74]. The meta-analysis conducted by Chu et al. [75] also demonstrated a low AKI risk for continuous infusion. Although most continuous infusion studies did not report vasculitis, Vuagnat et al. reported two cases of catheter-associated phlebitis among 23 patients who underwent continuous infusion therapy [76].
The evaluated PK variable was the trough level for intermittent infusion and the plateau level (i.e., steady-state concentration) for continuous infusion [75][74]. As the most common practice, the maintenance dose (e.g., 30 mg/kg) was administered continuously over 24 h after a loading dose (15–20 mg/kg), and the plateau concentration was sustained after reaching steady state with continuous infusion [77]. Therefore, the PK target is not the trough concentration, but instead, it is the plateau concentration in an continuous infusion strategy. The target plateau concentration was 20–25 μg/mL for continuous infusion and trough-guided dosing (15–20 mg/L) was conducted for intermittent dosing. The average time to achieve a vancomycin trough level of 15 μg/mL with intermittent infusion was 50 ± 21 h, versus 16 ± 8 h to reach a serum plateau level of 20 μg/mL with continuous infusion (p < 0.001).
Continuous administration simplifies TDM through easier AUC estimation than intermittent administration, in which AUC was estimated using Bayesian software. Compared to trough concentrations in intermittent administration, the plateau concentration with continuous infusion is a more trustworthy surrogate of AUC. Plateau concentrations of 17.5–22.5 μg/mL correspond to AUCs of 420–540 μg·h/mL [78]. Once the infusion is started, a serum concentration at one point is measured after 24–48 h, which is likely to represent the steady-state value in patients with normal renal function. The daily dose or hourly dosing rate can then be optimised proportionately to achieve the desired plateau concentration.

2.8. Is a Loading Dose Required to Achieve the Target Concentration and Improve Treatment Efficacy?

Starting doses commonly recommended for patients with sepsis/septic shock frequently fail to achieve the desired target exposures because of the change of Vd caused by extravasation. In general, a vancomycin loading dose of 20–35 mg/kg is suggested to rapidly attain the target concentration in critically ill patients [3]. However, if a loading dose increases treatment efficacy without increasing the risk for AKI, routine loading should be considered even in clinically stable patients.
Rosini et al. reported that the trough level 12 h after the start of vancomycin therapy allowed a significantly greater proportion of patients to achieve the target of 15 μg/mL using a loading dose of 30 mg/kg compared to the findings for patients who did not receive a loading dose [79]. However, the effect of the loading dose was attenuated gradually, and only 20% of patients with a loading dose attained the target trough level at steady state. A loading dose alone may not be sufficient to increase the trough level measured 48 h after the initial dose in patients with normal vancomycin clearance. The main purpose of the loading dose is not to obtain the target concentration at steady state, but instead, the goal is the rapid achievement of a therapeutic concentration within 12–24 h [80][81][82][83].

2.9.  How Can the Dosage Regimen Be Optimised to Achieve the Target AUC?

The revised IDSA guidelines recommended doses of 15–20 mg/kg every 8–12 h and suggested a loading dose of 20–35 mg/kg to rapidly achieve the target concentration in critically ill patients. The recommended vancomycin dosing regimens to achieve AUC/MIC > 400 were evaluated using PK/PD modelling and Monte Carlo simulations. All evaluated regimens resulted in target attainment probabilities (PTAs) of >90% only for MICs of 0.5 and 0.75 mg/L, and daily doses exceeding 3 g (i.e., 1.5 g q12h) were required for an MIC of 1 μg/mL in patients with cancer and an average body weight of 72.7 kg [84].

2.10. How Can the Dosage Regimen Be Optimised to Achieve the AUC Targets in Patients with Impaired Kidney Function?

Most nomograms for vancomycin dosing in patients with impaired kidney function were generated to achieve the targeted trough level [85][86][87][88][89]. Thomson et al. reported that the trough level of 10–20 μg/mL was achieved in 71% of patients using their nomogram [85]. Kullar et al. developed a nomogram for a target trough concentration of 15–20 μg/mL [87]. In total, 58% of patients achieved the initial target trough concentration, and only 4.5% of patients developed AKI.

3. Conclusions

The guideline provided recommendations for AUC-guided dosing for vancomycin. To expand the use of AUC-guided dosing, the availability of verified open and free Bayesian dose-optimizing software programs is required. In addition, the development of user-friendly programs that are adaptive for special patient populations is the next issue to be resolved in clinical practice. Although physicians should be fully responsible for their prescriptions, education and support by academia via the use of software are mandatory.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14030489

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