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ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 3  |  Page : 248-252

Initial dose of vancomycin in adult patients at a major tertiary care hospital in Saudi Arabia: A retrospective observational study


1 Department of Pharmaceutical Care, King Fahad Central Hospital, Saudi Arabia
2 Department of Clinical Pharmacy, Pharmacy Practice Research Unit, Faculty of Pharmacy, Jazan University, Jazan, Saudi Arabia
3 Department of Internal Medicine, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
4 Department of Clinical Pharmacy, Pharmacy Practice Research Unit, Faculty of Pharmacy, Jazan University, Jazan; Department of Pharmaceutical Care, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

Date of Submission22-Jul-2020
Date of Decision05-Sep-2020
Date of Acceptance03-Oct-2020
Date of Web Publication07-Nov-2020

Correspondence Address:
Abdulkarim M Meraya
Department of Clinical Pharmacy, Pharmacy Practice Research Unit, Faculty of Pharmacy, Jazan University, Jazan, 45142
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjhs.sjhs_72_20

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  Abstract 


Background: Therapeutic drug monitoring is commonly performed to confirm the safe and effective use of the vancomycin; however, the facility for it is not available in many hospitals. Many clinicians use conventional fixed dose of 1000 mg every 12 h irrespective of the body weight. Aim: The aim of the study was to assess the appropriateness of vancomycin initial dose in adult patients with normal renal function. Setting and Design: This was a retrospective observational study involving medical records of patients treated with intravenous vancomycin during January 1, 2016–December 30, 2016, at a major tertiary care hospital in southern region of Saudi Arabia. Materials and Methods: The study was conducted based on electronic medical records of the patients who received intravenous vancomycin, aged ≥ 18 years, weighing more than 50 kg, and with normal renal functions during the period of the study. Chi-square tests were used for categorical variables. Multivariable logistic regressions were computed to examine the relationships between the explanatory variables and the appropriateness of vancomycin dose. Results: The study evaluated records of 456 adult patients, of which 63.8% were male. As per vancomycin dose received, 229 patients received suboptimal dosing of vancomycin when the dose was recalculated using actual body weight. The majority of the prescriptions of junior residents (68.5%) were using an optimal initial dose of vancomycin as compared to 43.6% of the senior residents or 48% of the consultants. Conclusions: A significant number of patients were receiving suboptimal initial dose of vancomycin. Junior residents were more meticulous with the initial vancomycin dosing.

Keywords: Dosing, methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, therapeutic monitoring, Vancomycin


How to cite this article:
Mubarki S, Menachery SJ, Darraj MA, Meraya AM, Khormi YM. Initial dose of vancomycin in adult patients at a major tertiary care hospital in Saudi Arabia: A retrospective observational study. Saudi J Health Sci 2020;9:248-52

How to cite this URL:
Mubarki S, Menachery SJ, Darraj MA, Meraya AM, Khormi YM. Initial dose of vancomycin in adult patients at a major tertiary care hospital in Saudi Arabia: A retrospective observational study. Saudi J Health Sci [serial online] 2020 [cited 2021 Jan 15];9:248-52. Available from: https://www.saudijhealthsci.org/text.asp?2020/9/3/248/300293




  Introduction Top


Vancomycin, which was developed as an alternative therapy to penicillin in the 1950s to “vanquish” resistant Staphylococcus aureus strains, is still playing a pivotal role as an antimicrobial agent for the management of methicillin-resistant S. aureus (MRSA) infections across the world.[1] The early formulations of this glycopeptide antibiotic were linked to a high risk of nephrotoxicity in the past, and it was attributed to a higher amount of impurities present in the commercial preparations of the antibiotic. These impurities were often referred as “Mississippi Mud” which was minimized with advancements in the fermentation techniques in its production process resulting in a significant reduction in adverse events, particularly the incidence and severity of nephrotoxicity.

Although spectrum of activity of vancomycin is limited to Gram-positive bacteria, it is an indispensible antibiotic in management of several life-threatening infections such as meningitis, sepsis, pneumonia, and infective endocarditis caused by these organisms. MRSA infections continue to be of global concern and vancomycin is still considered as an important parenteral treatment option for serious infections caused by susceptible strains of these resistant organisms. Colitis resulting from Clostridium difficile responds to vancomycin therapy in a significant number of patients. Vancomycin is often the substitute of choice for management of serious infections caused by susceptible Gram-positive organisms with contraindication for beta-lactams which is usually due to hypersensitivity.[1]

The therapeutic window of vancomycin is narrow and this warrants dosing of vancomycin to be more patient specific to make it optimal. Therapeutic monitoring of plasma levels of vancomycin is often adopted to maintain it within the therapeutic range when treatment duration exceeds 5 days.[2] Measurement of trough levels of vancomycin is preferred over peak concentrations for therapeutic monitoring safety and efficacy.[3] The trough concentration of vancomycin is recommended to be maintained above 10 mg/L to prevent emergence of resistance according to the Infectious Diseases Society of America (IDSA).[3] The trough concentration is recommended to be raised and maintained in the range of 15–20 mg/L for more severe infections.[4] Patients infected with strains of MRSA having minimum inhibitory concentration (MIC) of vancomycin >2 mg/L are better managed with alternative antibiotics due to toxicity concerns that is present with use of higher dose of vancomycin that will be needed to achieve this.[3] Vancomycin concentration can remain in subtherapeutic levels or reach toxic blood concentration levels if patients are not optimally dosed, leading to significant toxicity or therapeutic failure. Suboptimal vancomycin concentration level is often associated with the conventional 1000 mg twice daily dosing due to variation the body weight and also in the volume of distribution.[5] For these reasons, IDSA and the Society of Infectious Diseases Pharmacist recommendations encourage calculating initial dosage of vancomycin according to the actual body weight (ABW) and then to modify the dose depending on serum concentration level to attain optimal therapeutic levels and avoid the risk of toxicity or treatment failure.[3]

Nephrotoxicity and ototoxicity are considered to be the main toxic effects associated with vancomycin treatment. After improved formulations became available, vancomycin-related nephrotoxicity and ototoxicity have become less common, unless they are used concurrently with other nephrotoxic or ototoxic medications like aminoglycosides.

Earlier studies reported suboptimal vancomycin usage rates ranging from 28% to 70% worldwide.[6] Despite development of various strategies and guidelines aimed to minimize emergence and dissemination of resistant strains, vancomycin continues to be used indiscriminately resulting in development of resistance strains, increasing the health-care expenditure, and sometimes, associated with increased morbidity and mortality.[7]

Some strains of previously susceptible bacteria have become resistant to vancomycin currently. There are reports of vancomycin-resistant S. aureus (VRSA) since the beginning of this millennium. Vancomycin-resistant Enterococcus (VRE) isolates which were originally reported from Europe three decades ago soon made its way to the United States and then to the rest of the world.[8] Thereafter, reports of serious infections by these resistant organisms have been showing an upward trend globally.[9]

The burden of MRSA infections and VRE on health care is significant. MRSA infections were reported to have a 22% higher mortality rate when compared with infections caused by the methicillin-sensitive S. aureus (MSSA).[10] The mortality rate associated with MRSA bacteremia was shown to have double mortality rate when compared to MSSA bacteremia using a random-effects model.[11] This scenario is likely to be complicated if VRSA strains emerge globally in a significant way like MRSA. Similar impact like MRSA was observed with VRE infections showing higher mortality rates and health-care costs compared with vancomycin sensitive enterococcal infections.[12] This emphasizes the importance of using an optimal dose of vancomycin to prevent the emergence of resistance.

Guidelines formulated by the IDSA and the Centers for Disease Control and prevention (CDC) for management of MRSA infections and monitoring of vancomycin therapy for optimal dosing and prevention of development of resistant strains are currently in practice in several health-care centers.[1] Recommendations have also been established for antimicrobial stewardship aimed at guaranteeing the optimal utilization of vancomycin. The CDC recommendations through its Hospital Infection Control Practices Advisory Committee in this regard are often considered as a benchmark.[13] These recommendations from various health organizations to optimize antimicrobial therapy and monitoring mostly targeted treatment in the inpatient setting.[14] There is also a concerning rise in the prevalence of antimicrobial-resistant microorganisms in the community and in ambulatory care settings as indicated by the emerging reports of community-acquired MRSA infections and the increasing prevalence of penicillin-resistant Streptococcus pneumoniae infections.[15]

Limited literature is available about vancomycin use in hospitals across the Kingdom of Saudi Arabia. The present study aims to review the compliance with administration of an initial dose of vancomycin according to ABW by retrospectively recalculating the initial dose of vancomycin that was administered, according to the ABW of adult patients who had normal renal function tests.


  Materials and Methods Top


It was a retrospective observational study conducted at a major tertiary care hospital in the southern region of Saudi Arabia. The study was based on electronic medical records (EMRs) of patients who had received parenteral vancomycin during the defined period.

Patients treated with intravenous vancomycin during January 1, 2016–December 30, 2016, at a major tertiary care hospital in the southern region of Saudi Arabia were included in the study. According to the inclusion criteria, EMRs of all subjects receiving intravenous vancomycin for any condition, aged ≥18 years weighing more than 50 kg, and with normal renal functions during the specified period of study were considered for the study. As it was a retrospective observational study with no interventions, no informed consent was obtained for this study. A dose was considered to be optimal if the recalculated dose was in the range of 15–20 mg/kg. Any doses below 15 mg/kg were considered suboptimal while patients on conventional dosing who received doses above 20 mg/kg were considered supraoptimal or inappropriately high dose. A patient was considered to have received conventional dose if the patient was receiving 1000 mg twice daily dosing. Patients who received initial vancomycin therapy without culture reports were considered as empirical therapy, while those who were started after culture report were considered as definitive therapy.

The vancomycin therapy was analyzed across all variables including sex, definitive or empirical therapy, prescribing physician's rank, and other chronic comorbid conditions.

Chi-square tests were conducted for variables such as sex, physician ranks, and other chronic comorbid conditions. Multivariable logistic regressions were computed to examine the relationships between the explanatory variables and the appropriateness of vancomycin dose.

In the regression models, sex, physicians rank, and the presence of other comorbid conditions were included.


  Results Top


The present study consisted of a total of 456 EMRs of eligible patients who were on intravenous vancomycin either as definitive therapy or empirical therapy during the defined study period. The data from EMRs of these patients were used for the analysis.

The eligible patients included 36.2% females and 63.8% males. As per the recorded initial dose, 229 patients received suboptimal dosing of vancomycin when the dose was recalculated using ABW, while the remaining received optimal dose. It was noted that 43.0% of the females and 54.3% of the males received suboptimal dosing of vancomycin. The remaining 57.0% of female patients and 45.7% of male patients had optimal dosing regimen. None of the patients received inappropriately high dose [Table 1].
Table 1: Characteristics of the study sample by vancomycin dosing status (n=456) row percentages

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There were 456 prescriptions for vancomycin during this period and among them, 73 were prescribed by junior residents, 163 by senior residents, and 219 were by consultants. Interestingly, it was observed that the 68.5% of prescriptions by the junior residents were using optimal initial dose of vancomycin compared to 43.6% by the senior physicians or 48% by the consultants (P = 0.001) [Table 1].

All the patients receiving vancomycin during the study period were given initial vancomycin dose as a part of empirical therapy. Comorbid conditions that could affect vancomycin dosing were present in 238 patients and 42.4% of them were on suboptimal dosing, while 58.7% of the patients without comorbid conditions were on suboptimal dosing of vancomycin.

[Table 2] shows odds ratios (ORs) and their 95% confidence intervals (CIs) for explanatory variables from logistic regressions. In the adjusted analyses, senior residents (OR = 2.59, 95% CI = 1.42–4.69) and consultants (OR = 2.04, 95% CI = 1.14–3.63) were more likely to prescribe an inappropriate dose of vancomycin after controlling for sex and comorbid conditions. Adults with comorbid conditions were significantly less likely to be given inappropriate vancomycin dose (OR = 0.61, 95% CI = 0.41–0.90).
Table 2: Adjusted odds ratio and 95% confidence intervals for explanatory variables from logistic regressions outcome: Optimal dosing

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  Discussion Top


Our study retrospectively evaluated the appropriateness of vancomycin dose that was administered in the hospitalized normal renal function patients based on dose recalculated depending on ABW. Due to its narrow therapeutic index, the subtherapeutic dose trough concentration level was found to be associated with the conventional dose of 1000 mg every 12 h. An appropriate dosing and administration of vancomycin depends on weight and renal function of the patient, infection severity and location, and pathogen susceptibility. Hence, judicious dosing is required for individualizing therapy and monitoring of serum concentration is pertinent for optimizing vancomycin dosing.[16] In addition, the probable risk of nephrotoxicity or ototoxicity appears to be minimal with vancomycin alone at standard doses of 1000 mg (15 mg/kg) twice a day or an initial loading dose of 25–30 mg/kg, followed by an increment of 250 mg based on actual serum concentration levels to reach a therapeutic goal. Subsequently, continuous administration of the antibacterial agent is unlikely to significantly alter the patient outcome in comparison with the intermittent dosing schedule. Vancomycin in doses of 4 g/day or more has been recently reported to be associated with higher rates of nephrotoxicity.[17]

The use of higher doses of vancomycin may be justified when treating infections caused by organisms having higher MIC like MRSA. However, routine use of such doses of vancomycin is not recommended empirically unless suspected nosocomial infection in hospitalized patients. Monitoring of serum concentrations for vancomycin has been recommended to minimize toxicity for patients receiving higher dose and prolonged therapy and for those who are at risk of nephrotoxicity or ototoxicity.[3]

The antibacterial resistance of microbes in an intensive care setting is also very important as it may result in the reduced effectiveness of antimicrobial agents and even result in therapeutic failure. Many health-care practitioners prefer vancomycin as it shows positive effects in attaining therapeutic targets when used appropriately, and it has shown the potential in decreasing the overuse of antibiotics. Fair and Tor in 2014 reported that the sluggish development in antimicrobial research for a long period of time and the startling rise of bacterial resistance driven by faulty policies and practices have resulted in a dangerous and confusing situation in the field of antimicrobial use and research. However, recent all-round efforts have been shedding light on this dilemma.[18] Glatard et al. reported that different methods applied for a renal function evaluation should not be viewed exchangeable for pharmacokinetic modeling and model-based assessment of vancomycin doses in old subjects.[19] Our study aims to make the utilization of vancomycin more judicious by minimizing inappropriate dosing and thereby reducing the risk of bacterial resistance occurrence.

In our study, a significant number of subjects were receiving a suboptimal initial dose of vancomycin, giving an indication that many physicians were using the conventional dose irrespective of the body weight of the patients. This indicates that majority of the heavy built, overweight, or obese patients were receiving suboptimal dose in the hospital. There were no patients receiving inappropriately high dose in the sample, partly due to exclusion of patients below 50 kg.

Our study also noted that the junior residents were more careful with dosing of vancomycin as compared to senior residents and consultants. Only 31.51% of the vancomycin prescriptions by junior residents were inappropriate as compared to 56.4% by senior residents and 52% by consultants. It is likely that junior residents were more careful in calculating the initial dose correctly than others and that the senior residents and consultants were more casual with initial dosing with vancomycin. It is also likely that some of the consultants were less meticulous with initial dosing of vancomycin than the junior residents.

The present study has many advantages such as the use of large sample size from a tertiary hospital that serves more than 1.5 million population in the southern region of Saudi Arabia. Furthermore, findings from this study show the practice in prescribing vancomycin in a real-world setting. In addition, our results highlighted the need for routine monitoring of vancomycin dosing in all health-care settings. However, this study also has some limitations. By using the EMRs data, we cannot eliminate some risk of bias; inaccurate information or missing data related to the use of EMRs. Furthermore, we were not able to measure other clinical factors that may affect the vancomycin dosing.


  Conclusions Top


This study highlighted the need to carefully review the initial dosing of vancomycin therapy in adult cases as practised in a number of hospitals in Saudi Arabia and emphasized the need to adopt actual body weight-based initial dosing. This is necessary to minimize the risk of emergence of resistant strains and subsequent treatment failure. This is particularly crucial in hospitals without facilities to monitor the plasma levels of vancomycin.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-55.  Back to cited text no. 1
    
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Uttley AH, Collins CH, Naidoo J, George RC. Vancomycin-resistant enterococci. Lancet 1988;1:57-8.  Back to cited text no. 4
    
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Bell JM, Paton JC, Turnidge J. Emergence of vancomycin-resistant Enterococci in Australia: Phenotypic and genotypic characteristics of isolates. J Clin Microbiol 1998;36:2187-90.  Back to cited text no. 5
    
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Shlaes DM, Gerding DN, John JF Jr., Craig WA, Bornstein DL, Duncan RA, et al. Society for healthcare epidemiology of America and Infectious Disease Society of America Joint Committee on the Prevention of Antimicrobial Resistance: Guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997;18:275-91.  Back to cited text no. 14
    
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Lake KD, Peterson CD. A simplified dosing method for initiating vancomycin therapy. Pharmacotherapy 1985;5:340-4.  Back to cited text no. 16
    
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Fair RJ, Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspect Medicin Chem 2014;6:25-64.  Back to cited text no. 18
    
19.
Glatard A, Bourguignon L, Jelliffe RW, Maire P, Neely MN, Goutelle S. Influence of renal function estimation on pharmacokinetic modeling of vancomycin in elderly patients. Antimicrob Agents Chemother 2015;59:2986-94.  Back to cited text no. 19
    



 
 
    Tables

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