Vancomycin loading dose is associated with increased early clinical responses without attainment of initial target trough concentration at a steady state in patients with normal renal function

Background Vancomycin therapeutic guidelines suggest a loading dose of 25–30 mg/kg for seriously ill patients. However, high-quality data to guide the use of loading dose are lacking. Evaluate whether a loading dose 1) achieves a target trough concentration (Cmin) at steady state and 2) improves early clinical responses. Methods Patients with an estimated glomerular filtration rate ≥90 mL/min/1.73 m2 were included. A loading dose of 25 mg/kg vancomycin followed by 15 mg/kg twice daily was compared with traditional dosing. A Cmin sample was obtained before the fifth dose. An early clinical response 48–72 h after the start of therapy and clinical success at end of therapy (EOT) was evaluated in patients with methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci, or Enterococcus faecium. This study was conducted between April 2011 and May 2018. Adult patients with an estimated glomerular filtration rate (eGFR) of ≥ 90 mL/min/1.73 m 2 who were treated with vancomycin, and in whom therapeutic drug monitoring (TDM) was performed, were included in the study. Exclusion criteria were patients with known hypersensitivity to vancomycin, pregnancy, below the age of 18 years, and body weight of ≥ 100 kg. Retrospective evaluation of the regimen without a loading dose was conducted between April 2011 and December 2015, and the evaluation of the regimen with a loading dose of 25 mg/kg was conducted between January 2016 and May 2018. A maintenance dose of 15 mg/kg every 12 h was administered to both regimens. An initial C min sample was obtained before the fifth dose. Vancomycin concentration was measured using a commercial reagent kit (Vanc Flex; Siemens Healthcare Diagnostics, Tokyo, Japan). function


KEYWORDS
vancomycin, a loading dose, trough concentration, clinical efficacy, therapeutic drug monitoring decreased over the past decade [1,2], MRSA remains one of the most prevalent resistant organisms in health care associated infections [3]. Vancomycin is a commonly used antibiotic for the treatment of MRSA infections. The optimization of vancomycin dosing is important and a target trough concentration (C min ) of 10-20 μg/mL has been proposed [4,5]. The C min should be maintained above 10 μg/mL to avoid the development of resistance [6]. A C min of 15-20 μg/mL improved outcomes in patients with complicated MRSA bacteremia [7].
Vancomycin is commonly initiated at a standard dose of 15 mg/kg every 12 h with dosage adjustment based on creatinine clearance (CL cr ) [4,5]. However, with the same dosage regimen, the median C min remained 9.4 μg/mL (62% of patients were < 10 μg/mL) on day 3 of a study for the treatment of complicated skin and soft tissue infections caused by MRSA [8]. In a randomized trial for the treatment of nosocomial pneumonia caused by MRSA, the median C min on day 3 was 12.3 μg/mL, and 25% of patients had a C min < 7.9 μg/mL [9]. The standard dosing regimen was inadequate at achieving the target C min [10]. In patients with sepsis, fluid extravasation causes an increase in interstitial volume. For hydrophilic antibiotics such as vancomycin, these pathophysiological changes might increase the volume of distribution and cause low antibiotic serum concentration [11].
Therefore, initial loading is important to avoid the risk of underexposure.
Vancomycin therapeutic guidelines [4,5] suggest a loading dose of 25-30 mg/kg for seriously ill patients. However, high-quality data to guide the use of loading dose are lacking. In a systematic review, Reardon et al. [12] suggested that a loading dose may attain target C min of 15-20 μg/mL. Accessed November 10, 2018.). Infections with at least one of the following signs were analyzed: core temperature >37.8°C, total peripheral white blood cell (WBC) count >10,000 /mm 3 , or C-reactive protein (CRP) >3.0 mg/dL. Diagnosis of pneumonia was defined as chest X-rays or CT scans consistent with pneumonia and at least two of the following signs or symptoms: (new onset or worsening cough; purulent sputum or increased suctioning requirements; auscultatory findings of pneumonia; dyspnea, tachypnea, or respiratory rate ³ 30 min; hypoxemia; worsening gas exchange, and at least one of the inflammatory signs described above [9]. The MIC of vancomycin was measured by microdilution methods in accordance with the Clinical and Laboratory Standards Institute testing guidelines (M02 and M07, 2018) [14].

Clinical efficacy
The primary endpoint was set as an early clinical response at 48-72 h after the start of therapy. We defined patients as responders if they had a 30% or greater decrease in total peripheral WBC count or CRP, decline of fever (defined as a daily maximum temperature decrease of > 0.3°C for at least two consecutive days in febrile patients), without worsening of clinical features, and did not die within 96 h. Secondary efficacy end points were clinical success at the end of vancomycin therapy (EOT), which was defined as survival with resolution or improvement in all core symptoms and signs of infection in each infection to the extent that further antibacterial therapy with anti-MRSA activity was unnecessary. Microbiological assessments were conducted using cultures taken before the start of vancomycin administration and at the completion of treatment, and microbiological success was defined as "eradication" (admission pathogen absent in culture) or "presumed eradication" (no material available for culture because of the infection site being cured or attenuated).

Adverse effects
Adverse effects of nephrotoxicity and hepatotoxicity were evaluated on the third day of therapy and at the end of vancomycin therapy. Nephrotoxicity was defined as a serum creatinine (Cre) increase > 0.5 mg/L or 50% increase from the baseline. Hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels at or above three times the upper limit of normal. If the AST or ALT baseline was abnormal, hepatotoxicity was defined as AST or ALT at or above three times the baseline.

Discussion
Recent guidelines [4,5] suggest a loading dose of 25-30 mg/kg to achieve the targeted range for treatment with vancomycin. In our study, however, the proportions of patients achieving 10-20 µg/mL and 15-20 µg/mL at 48 h after the first dose were 56.9% and 5.6%, respectively, in patients with an eGFR ≥ 90 mL/min/1.73 m 2 who received a regimen with a loading dose of 25 mg/kg. There was no significant difference in the C min between the regimen with and without a loading dose. Rosini et al. [15] reported that the 12-h C min allowed a significantly greater proportion of patients to achieve 15 μg/mL among patients with a loading dose of 30 mg/kg followed by 15 mg/kg twice daily compared with those without a loading dose. However, the effect of the loading dose was attenuated at the steady state, and only 20% of patients with a loading dose attained the target C min at steady state.
Most of their study patients also had a high CL cr (mean 93 mL/min). However, in a study including patients with deteriorated renal function, a loading dose resulted in a higher concentration at steady state [16,17]. In patients with deteriorated renal function, not only a loading dose but also a maintenance dose had a significant impact on the C min .
Why the C min was low in our study might be explained by only three obese patients being included.
Pharmacokinetic (PK) data indicated a larger volume of distribution and accelerated renal clearance of vancomycin in obese patients [18], which might justify a weight-based dosing regimen. However, a study using weight-based regimens by Reynolds et al. [19] reported a C min > 20 μg/mL in approximately 50% of obese patients. Richardson et al. [20] reported that increasing BMI categories were associated with a C min >20 μg/mL. Leong et al. [21] demonstrated that an adjusted body weight was more accurate at predicting vancomycin clearance in obese individuals.
A loading dose alone may not be sufficient to increase the C min measured 48 h after the initial dose in patients without decreased vancomycin clearance. However, the main purpose of a loading dose is not to obtain the target C min at steady state, but the rapid achievement of a therapeutic concentration within 12-24 h [15]. To maintain a high concentration thereafter, an increase in the maintenance dose from 15 mg/kg to 20 mg/kg might be required [22]. Many studies reported a higher achievement of a C min >15 μg/mL after the first dose in patients with a loading dose compared with patients without a loading dose [10,15,23,24]. Clinical response beyond 72 h of treatment can be affected by changes in the vancomycin dose later in therapy, based on the initial TDM conducted. Indeed, the achievement rate of target C min of 10-20 μg/mL was increased from 7.4% to 74.1% of patients in whom the dosage was increased after initial TDM in our study.
PK analysis indicated that a loading dose of 25-30 mg/kg could be applied irrespective of renal function [28]. Clinicians, however, tend to be reluctant to use a loading dose, especially in patients with decreased renal function, for fear of causing renal injury. Alvarez et al. [10] demonstrated that all patients with a loading dose who presented with decreased vancomycin clearance before the administration of vancomycin had an elevated serum concentration (>28 μg/mL) in the first 24 h of treatment. These patients, however, did not have nephrotoxicity. Although prolonged exposure to elevated C min causes nephrotoxicity, a temporary increase in the C min with an initial loading dose might not cause nephrotoxicity. Marvin et al. [29] reported that a loading dose > 20 mg/kg was not associated with increased nephrotoxicity in patients with a CL cr < 30 mL/min compared with a standard dosing regimen.

Limitations
This study had some limitations. First, we did not measure the C min 24 h after the first dose, and the

Consent for publication
Not applicable.

Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

1.
Takesue has received grant support from Shionogi & Co., Ltd., and payment for lectures from Astellas Pharma Inc., and MSD Japan. Other authors have no conflict of interest to declare.

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors' contributions
TU was involved in the conception of the study, collection, analysis andinterpretation of data, the creation of new software used in the work, draft the work and substantively revised of the manuscript.
YT was involved in the design of the study and draft the work. KN