Comparison between conventional dosing versus personalized pharmacokinetic dosing of vancomycin: a pilot study from a Malaysian private hospital

Pharmacist led vancomycin dosing is not a common practice in private hospital settings of the Malaysian healthcare system. The lack of this pharmacist led system has led to conventional vancomycin dosing without considering the differences in patients pharmacokinetic parameters. This study aims to compare the differences in vancomycin doses between conventional dosing and pharmacist-led personalized pharmacokinetic dosing. A retrospective pilot study was conducted on inpatient adults who were prescribed with intravenous vancomycin in a private hospital. Personalized vancomycin doses were retrospectively calculated by using the pharmacokinetic parameters and was then compared with the actual conventional doses used in the patients. The area under concentration curve over 24 hours/minimum inhibitory concentration (AUC24/MIC) ratio achieved by the doses was also compared. The targeted AUC24/MIC ratio was 400-600 to ensure ef icacy and safety of the therapy. A total of 24 patients with a median age of 55.50 years were conveniently sampled. The patients were mostly male (58.3%) and were admitted to the neurosurgical ward (33.3%). Vancomycin wasmainly prescribed as empirical treatment (58.3%) for a median treatment period of 5.00 days (IQR 4.00 – 7.00 days). The conventional doses had signi icant (p < 0.001) lower median total daily dose (2000 mg versus 2500 mg) and lower AUC24/MIC ratio (385 versus 495) as compared to personalized doses. In conclusion, the personalized pharmacokinetic dosingmethodwas signi icantly more able to achieve the targeted AUC24/MIC ratio. Vancomycin personalized dosing should be considered in the Malaysian private hospital setting.


Vancomycin, Conventional Dose, Personalized Dose, Pharmacokinetic
A Pharmacist led vancomycin dosing is not a common practice in private hospital settings of the Malaysian healthcare system. The lack of this pharmacist led system has led to conventional vancomycin dosing without considering the differences in patients pharmacokinetic parameters. This study aims to compare the differences in vancomycin doses between conventional dosing and pharmacist-led personalized pharmacokinetic dosing. A retrospective pilot study was conducted on inpatient adults who were prescribed with intravenous vancomycin in a private hospital. Personalized vancomycin doses were retrospectively calculated by using the pharmacokinetic parameters and was then compared with the actual conventional doses used in the patients. The area under concentration curve over 24 hours/minimum inhibitory concentration (AUC 24 /MIC) ratio achieved by the doses was also compared. The targeted AUC 24 /MIC ratio was 400-600 to ensure ef icacy and safety of the therapy. A total of 24 patients with a median age of 55.50 years were conveniently sampled. The patients were mostly male (58.3%) and were admitted to the neurosurgical ward (33.3%). Vancomycin was mainly prescribed as empirical treatment (58.3%) for a median treatment period of 5.00 days (IQR 4.00 -7.00 days). The conventional doses had signi icant (p < 0.001) lower median total daily dose (2000 mg versus 2500 mg) and lower AUC 24 /MIC ratio (385 versus 495) as compared to personalized doses. In conclusion, the personalized pharmacokinetic dosing method was signi icantly more able to achieve the targeted AUC 24 /MIC ratio. Vancomycin personalized dosing should be considered in the Malaysian private hospital setting.

INTRODUCTION
Vancomycin is the key therapeutic option for the treatment of highly resistant gram positive infections caused by methicillin resistant Staphylococcus aureus (MRSA) and methicillin resistant coagulase negative Staphylococcus species (Liu et al., 2011). A previous study from Malaysia reported that 21% of nosocomial bacteraemia were caused by MRSA (Ahmad et al., 2010). Besides, there was an increase in the prevalence of MRSA in Malaysia from 17% to 44.1% in around 20 years (Ahmad et al., 2009;Rohani et al., 2000). Vancomycin is a large glycopeptide compound that is not absorbed orally and is eliminated primarily through kidney (Matzke et al., 1986). During haemodialysis, the vancomycin dialysability was minimal (0-5%) with conventional low lux dialyser. Most dialysis centres nowadays use high lux dialysers with a median percentage of dialysability around 31% (Petejova et al., 2012). Vancomycin is a drug with narrow therapeutic window. Serum drug concentration must achieve speci ic therapeutic range to ensure optimum treatment (Pharmacy Practice & Development Division, 2019). Serum trough concentration is one of the methods to monitor vancomycin toxicity and ef icacy as vancomycin poses a time dependent bactericidal effect. Area under concentration curve over 24 hours/minimum inhibitory concentration (AUC 24 /MIC) ratio is another method of vancomycin therapeutic effect monitoring (Rybak et al., 2020). AUC 24 /MIC ratio of ≥ 400 is recommended as it has been associated with greater clinical success and more rapid bacterial eradication (Moise-Broder et al., 2004).
Serum trough concentration of 15-20 mg/L is the surrogate marker for AUC 24 /MIC of ≥ 400 for a MIC of ≤ 1.0 mg/L (Álvarez et al., 2016). Hence, the Infectious Disease Society of America (IDSA) recommended 15-20 mg/L as the targeted trough concentration of vancomycin for critically ill adults and >10 mg/L for all other adult patients (Liu et al., 2011). Currently, increasing MIC value of MRSA strains has been observed in Malaysian hospitals. A total of 95% of the MRSA strains found to have a vancomycin MIC of ≥ 1.0 mg/L (Ahmad et al., 2010). Therefore, optimal vancomycin dosing is important as newer and effective agents to target highly resistant grampositive organisms is limited. The conventional dosing regimen of vancomycin is a daily dose of 2000 mg divided to either 500 mg every 6 hourly or 1000 mg every 12 hourly for adults with normal kidney function (P izer, 2018). The dose can be given as 15-20 mg/kg of actual body weight every 8 to 12 hourly as an alternative if the patient's weight data is available (Rybak et al., 2009).
The above mentioned conventional method of vancomycin dosing is a common practice among private hospitals in Malaysia which generally do not establish a therapeutic drug monitoring system for personalized pharmacokinetic dosing. The personalized dosing method considers the patient's kidney function and pharmacokinetic parameters such as the volume of distribution and elimination rate constant in the determination of vancomycin dosing regimen (Matzke et al., 1984). This ensures the dose can achieve the targeted serum concentration and AUC 24 /MIC to optimize the therapeutic effect (Phar-macy Practice & Development Division, 2019). The personalized dosing is routinely practiced among the government hospitals in Malaysia by the clinical pharmacists (Pharmacy Practice & Development Division, 2019). The pharmacist-led clinical pharmacokinetic services are well-established among the Malaysian government hospitals in which therapeutic drug monitoring on narrow therapeutic index drugs are performed (Rahman et al., 2013). The serum drug concentrations are monitored in therapeutic drug monitoring. Subsequently, personalized pharmacokinetic parameters can be determined from the serum concentrations. The patient's dosing regimen can be adjusted accordingly to the serum concentration and the personalized pharmacokinetic parameters (Pharmacy Practice & Development Division, 2019).
Personalized dosing method allows patients with speci ic disease states and conditions to have an individualized target serum concentration and a customized pharmacokinetic parameter (Bauer, 2008). Pharmacokinetic monitoring of vancomycin was cost effective for those who received concomitant nephrotoxins, intensive care and oncology patients (Darko et al., 2003). Besides, a systematic review suggested that patients who underwent therapeutic drug monitoring have higher rates of therapeutic ef icacy and reduced rates of kidney toxicity than those who not under the monitoring (Ye et al., 2013). Personalized dosing method has been shown to improve treatment outcomes, reduce adverse effects and costs (Darko et al., 2003;Ye et al., 2013). A prospective randomized trial suggested personalized pharmacokinetic dosing over conventional dosing method of aminoglycosides (Begg et al., 1989). Besides, a previous study concluded that personalized dosing method significantly reduced time to attain desire vancomycin trough concentration (Miller et al., 2018).
In the presence of pharmacy-led vancomycin dosing and monitoring system, the percentage of patients achieving vancomycin serum therapeutic levels were increased while the percentage of acute kidney injury was decreased (Momattin et al., 2016). Nevertheless, the Malaysian private hospitals are generally using conventional dosing method for vancomycin. There is a lack of pharmacists led therapeutic drug monitoring in private hospitals to guide the dosing of vancomycin. Without the monitoring of serum drug concentration, the vancomycin dose can still be personalized by performing a pharmacokinetic calculation based on a patient's kidney function and body weight (Pharmacy Practice & Development Division, 2019). There is a need to compare the use of conventional versus pharmacist led personalized pharmacokinetic dosing method for vancomycin in the Malaysian private hospital setting. This pilot study, therefore, aimed to evaluate the differences in the dose by using a conventional dosing method compared to personalized pharmacokinetic dosing method for vancomycin therapy in a private hospital in Malaysia. The difference in AUC 24 /MIC ratio achieved by these two dosing methods was also assessed.

Study design
This was a single centre retrospective observational pilot study conducted at KPJ Johor Specialist Hospital, a 243 bedded private hospital in southern part of peninsular Malaysia, consisting of intensive care units, pediatric, orthopedic, surgical, oncology, geriatrics, obstetrics and gynecology specialties. This study has granted ethics approval from KPJ Research Ethics Review Committee and Human Ethics Committee of Universiti Sains Malaysia (ethics approval number: USM/JEPeM/18100612). The inclusion criteria were adult patients admitted to the ward and received intravenous vancomycin treatment as part of inpatient therapy. Patients who were below the age of 18 years old, without documented body weight or serum creatinine level, received continuous renal replacement therapy at the same time as vancomycin administration were excluded from the study.

Data collection
Warded patients who received vancomycin therapy from 1 st January 2016 to 31 st August 2018 were identi ied through pharmacy records. The patients' case notes and medication charts were traced from the medical report department and retrospectively screened for eligibility to be recruited in the study. Convenient sampling was used in patient recruitment. The patients data were collected and recorded in a speci ically designed data collection form. The data collected were including patients age, gender, ethnicity, height, body weight, infection type and site of the positive MRSA culture, serial blood urea nitrogen, serial serum creatinine, luid balance, serial vancomycin dosage regimes and duration of therapy. Additionally, patient's exposure to nephrotoxic agents, including radiographic contrast agents, aminoglycosides, diuretics, cyclosporin, tacrolimus, nonsteroidal in lammatory drugs, cyclooxygenase-2 (COX-2) inhibitors, as well as angiotensin converting enzyme inhibitors and angiotensin receptor blocking agents were recorded. The patient's comorbidity information was also collected to calculate the Charlson Comor-bidity Index scores.

Personalized pharmacokinetic dose calculation
The personalized vancomycin doses were manually calculated by the principle investigator ( irst author) by using pharmacokinetic formulae listed below. The elimination rate constant (k e ) was computed using Equation (1) from Matzke et al. (1984).
The body weight used for Cockcroft-Gault equation was varied (Winter, 2010). Actual body weight was used in underweight patients and ideal body weight in patients of normal weight as showed in Equations (4) and (5) (Winter et al., 2012). For overweight, obese, and morbidly obese patients, adjusted body weight as showed in Equation (6) was used (Winter et al., 2012). The body weight categories were based on the following body mass index (BMI) structure: underweight patients, BMI of less than 18.5 kg/m 2 ; normal weight patients, 18.5-22.9 kg/m 2 ; overweight patients, 23.0-27.4 kg/m 2 ; obese patients, 27.5-39.9 kg/m 2 ; and morbidly obese patients, 40 kg/m 2 or greater (Ministry of Health Malaysia, 2004).
Male IBW = 50 + 0.9 (Ht in cm − 152) Female IBW = 45.5 + 0.9 (Ht in cm − 152) (5) Vancomycin clearance (Cl) was assumed as equal to creatinine clearance as vancomycin is mainly excreted by the kidney in adults ≥ 18 years old (Winter et al., 2012). The volume of distribution (Vd) was calculated using the patient's personalized vancomycin Cl (in L/h unit) and elimination rate constant as showed in Equation (7) (Winter et al., 2012).
Peak serum concentration (Cmax) was set at 25-30 mg/L whereas trough serum concentration (Cmin) was set at 14-16 mg/L in accordance with the recommendation to achieve AUC 24 /MIC ratio of ≥ 400 (Álvarez et al., 2016). In cases where the organism's MIC was available, the target Cmin would be based on the MIC, with a target of 8 to 10 times the reported MIC (Pharmacy Services UK Health Care, 2017). The infusion time (t inf ) of vancomycin was assumed as one hour for doses ≤ 1000 mg and two hours for doses that were > 1000 mg (Malaysian Society of Intensive Care, 2017). New dosing interval was calculated using the formula in Equation (8) (Matzke et al., 1984) and was rounded up to 8, 12, 18, 24, 36, 48 and 72 hours.
Dosing interval, New personalized vancomycin dose was then calculated using the pharmacokinetic infusion formula based on one compartmental model as listed in Equation (9) (Winter et al., 2012) below and was rounded up to the nearest 50 mg.
The AUC 24 /MIC ratio was calculated as listed in Equation (10) (Pharmacy Practice & Development Division, 2019). The daily AUC 24 /MIC ratio was computed based on patient's 24-hour daily dose for both conventional and personalized dosing method as showed in Equation (9), vancomycin clearance as showed in Equations (2) and (3) in L/h unit and the MIC of the infecting pathogen. Any missing MIC value from the data will be assumed as 1.0 mg/dL. This assumption was based on Malaysian local data (Ahmad et al., 2010).

Data analysis
The completed calculated personalized vancomycin pharmacokinetic doses were reviewed and double checked by the co-investigator (second author) for the completeness and accuracy of the data. All statistical analyses were performed using IBM SPSS ® version 24. Mann-Whitney U test was used to compare the actual administered doses (conventional dosing) and calculated pharmacokinetic doses (personalized dosing) in the context of dose differences and AUC 24 /MIC ratio differences. The Wilcoxon signed rank test was used to compare the differences between kidney function at baseline and at the end of therapy in the patients received conventional vancomycin doses. A p value of < 0.05 was deemed statistically signi icant.

RESULTS
A total of 24 patients were recruited in the study ( Comparison between dosing method showed that the average total daily dose of vancomycin received by the patients (using conventional dosing) was signi icantly lower than if personalized pharmacokinetic dosing were used. The patients in this study received a median ixed dose of vancomycin 2000 mg daily (IQR: 1500 -2000 mg). When calculated using the personalized pharmacokinetic method, a higher median total daily dose requirement of 2500 mg (IQR: 1900 -3300 mg) was observed. This trend was also observed when evaluating the total daily dose on a day-by-day basis, whereby the patients were consistently being prescribed signi icantly lower conventional doses than the calculated personalized pharmacokinetic doses (Table 2).
Vancomycin AUC 24 /MIC ratio achieved in both dosing method is illustrated in  COX-2 inhibitors = cyclooxygenase-2 inhibitors 6.1 mmol/L (IQR: 3.8 -19.2). Regarding adverse effects monitoring, the kidney function trend of the patients who were prescribed conventional vancomycin doses were reviewed. The results showed that the median blood urea nitrogen, serum creatinine, creatinine clearance, and urine output at day 4 were not differed signi icantly compared to baseline (day 1) (Table 4).

DISCUSSION
This study observed a signi icant difference in total daily vancomycin doses between conventional and personalized pharmacokinetic dosing method. The patients were more likely to receive lower doses through conventional vancomycin dosing method.
This result was consistent with the study indings from Begg et al., conducted on another nephrotoxic drug class aminoglycosides whereby conventional doses or 'physician intuition' doses were reportedly much lower than the personalized pharmacokinetic doses (Begg et al., 1989). Without guidance from serum drug concentrations monitoring, physicians tend to be rather cautious in dosing vancomycin in patients with intact kidney function. However, in critically ill patients with increased volume of distribution and the presence of augmented renal clear- ance, standardized dosing of vancomycin is insuf icient (Mustafa et al., 2018). Subtherapeutic dosing will lead to inadequate bactericidal killing effect and possible treatment failure. Furthermore, insuf icient dosing may facilitate the development of drugresistant microorganisms (Appelbaum, 2007).
Average attainment of AUC 24 /MIC ratio of <400 was observed in the prescribed conventional vancomycin doses in this study. Based on the American Society of Hospital System Pharmacists guideline, an AUC 24 /MIC ratio of ≥ 400 is a predictor of successful vancomycin therapy in organism eradication (Rybak et al., 2009). AUC 24 /MIC ratio of < 400 has been notoriously associated with treatment failure for MRSA in adults (Men et al., 2016). The low AUC 24 /MIC ratio of <400 could increase all-cause mortality and treatment failure rates by 50% as compared to the ratio of ≥ 400 (Men et al., 2016). A simple evaluation of conventional dosing practice of 1000 mg every 12 hours for a young adult with normal kidney function (creatinine clearance of ≥ 100 mL/min) and average weight (70 kg) would only yield a 24-hour drug AUC of approximately 300 mgh/L. Unless the microorganism has a vancomycin MIC of 0.5 mg/L, this dosage regimen will not generate the targeted AUC 24 /MIC ratio of ≥ 400. Indeed, the recent revised consensus guideline recommended that the vancomycin MIC should be assumed as 1.0 mg/L and the AUC 24 /MIC ratio should be achieved 400-600 to ensure the ef icacy and safety of vancomycin therapy (Rybak et al., 2020). Vancomycin MIC determination was not routinely carried out on clinical isolates of MRSA at the present study in the private hospital unless the patients did not respond to their initial treatment. However, it is justi iable to assume MIC as 1.0 mg/L based on a previous multicentre study in Malaysia which demonstrate 95% of MRSA had vancomycin MIC of ≥ 1 mg/L (Álvarez et al., 2016). Based on the personalized pharmacokinetic calculation in the present study, an average daily dose of 2500 mg would be required to achieve AUC 24 /MIC ratio of > 400. Nevertheless, this daily dosage requirement is slightly lower than the daily dosage of 3000-4000 mg reported by a previous study which involves more critically ill patients in ICU (del Mar Fernández de Gatta Garcia et al., 2007).
Nephrotoxicity is the main concern of vancomycin  *All the variables showed no signi icant difference between baseline (day 1) and day 4 (p values: 0.26 for blood urea nitrogen, 0.813 for serum creatinine, 0.953 for creatinine clearance and 0.074 for urine output; Z scores from Wilcoxon signed-rank tests: -1.125 for blood urea nitrogen, -0.237 for serum creatinine, -0.059 for creatinine clearance and -1.789 for urine output). therapy. Lodise et al., directly examine the relationship between AUC and nephrotoxicity and found that in 27 patients with AUC 24 /MIC > 1300, 26% (7 patients) had developed nephrotoxicity (Lodise et al., 2009). Meanwhile, Neely et al., proposed an AUC 24 /MIC of 700 as the upper level of safe vancomycin exposure with minimal nephrotoxicity risk for the treatment of infections with MIC ≤ 1.5 mg/L (Neely et al., 2014). Besides, the recent revised consensus guideline stated that the AUC 24 /MIC ratio (with MIC assumed as 1.0 mg/L) of 400 -600 would ensure the ef icacy and safety of vancomycin therapy (Rybak et al., 2020). In the present study, the conventional dosing resulted in a lower AUC 24 /MIC ratio and a lower risk of nephrotoxicity than personalized dosing, but at the expense of reduced ef icacy. Conversely, the personalized dosing method managed to achieve the AUC 24 /MIC ratio in the range of 400 to 600, which could avoid the risk of nephrotoxicity and at the same time maintain the ef icacy of treatment.
In this study, the patients have received conventional vancomycin doses and the kidney functions at the end of therapy did not differ signi icantly from the baseline. This is not surprising as the majority of vancomycin in this study were used as empirical treatment with an average duration of ive days. Studies have demonstrated the strong relationship between acute kidney injury and vancomycin exposures (Bamgbola, 2016). Longer duration of therapy exceeding seven days correlate with a higher risk of nephrotoxicity (Contreiras et al., 2014). There was 12% greater incidence of acute kidney injury for each additional day of treatment with vancomycin (Cano et al., 2012). Besides a duration of therapy, the high dosage used is another factor that results in increased vancomycin exposures and vancomycin-induced acute kidney injury (Wong-Beringer et al., 2011). This often poses a clinical dilemma as aggressive dosing is required to curb the trend of MIC creep. A study by Lodise et al. demonstrated a dose-toxicity relationship with a daily dose of vancomycin in excess of 4000 mg increases the likelihood of acute kidney injury by more than threefold (Lodise et al., 2008). In another study, 21% of patients on high-dose therapy (achieved trough serum concentration of 15−20 mg/L) for more than one week, and 30% of those treated for more than two weeks sustained nephrotoxicity (Hidayat et al., 2006). In the present study, an average of 2000 mg per day of conventional vancomycin dosage used with a relatively short duration of therapy could explain the retainment of baseline kidney function throughout the therapy. Nevertheless, the personalized dosing using pharmacokinetic method showed an average total daily dose of only 2500 mg, which is far less than the maximum dose of 4000 mg which could lead to increases risk of nephrotoxicity (Lodise et al., 2008).
Susceptibility to vancomycin nephrotoxicity is profoundly confounded by other clinical events that compromise glomerular iltration, such as haemodynamic instability and concurrent administration of nephrotoxic agents -most notably, aminoglycosides (Rybak et al., 1990). In a prospective trial of 168 patients that compared three treatment modalities, acute kidney injury was noted in 5% of those treated with vancomycin, 22% of those who had vancomycin and aminoglycoside, and 11% of those treated with gentamicin only (Rybak et al., 1990). In the present study, merely one out of 24 patients received concomitant aminoglycosides therapy. Coadministration with other nephrotoxic agents, including loop diuretics, COX-2 inhibitors and ARB were found in a few patients. However, the majority of the patients did not receive any concomitant nephrotoxic drugs. This study may not have captured the vancomycin renal toxicity synergism relationship with other nephrotoxic agents, because of the short duration of vancomycin treatment.

Limitations
It is important to note that there were limitations to this pilot study. The retrospective analysis allowed only written clinical considerations to be assessed, hence open it up to confounding and bias that may well be avoided with prospective study methods. Besides, there was a lack of therapeutic drug monitoring of the vancomycin serum concentration and clinical outcomes assessment in the study. Despite the above-mentioned limitations, this pilot study has gained insight into the ef icacy of vancomycin treatment which can be considerably improved by personalized dosing using pharmacokinetic methods. The study indings are valuable as baseline data for future prospective study in Malaysian private hospital settings in the area of personalized dosing approach, particularly the assessment on clinical outcomes and cost-effectiveness of the vancomycin treatment.

CONCLUSIONS
This study observed a signi icant difference in total daily vancomycin doses between conventional and personalized pharmacokinetic dosing method. The patients were generally received vancomycin at a conventional standard dosage of 1000 mg every 12 hourly, which failed to achieve the target AUC 24 /MIC ratio. Whereas, personalized pharmacokinetic dose prediction method allows individual dosage adjust-ment to achieve the goal of a target for vancomycin effectiveness. The results of this study highlight the importance of dosing personalization to avoid any potential delay in ef icacy or development of resistance from sub-therapeutic vancomycin dose. As there is variability in vancomycin dose requirement, the Malaysian private hospital should consider using personalized pharmacokinetic rather than conventional weight-based or ixed-dose to optimize vancomycin therapy.