ED Vancomycin Use: Dosing Practices, Associated Outcomes
Knowledge of patient characteristics, infectious sources, and antibiotic pharmacokinetics can aid in the choice of antibiotic and also the optimal dose to be administered. As the ED is the first treatment site for many infections, the role the ED plays in adequately treating infections, properly dosing antibiotics to attain therapeutic levels, and contributing to antibiotic resistance is vital.
Our study, which represents the largest study to date describing vancomycin dosing in the ED, was designed not only to simply describe what is occurring in the ED with respect to this drug, but also to examine potential outcomes associated with ED dosing. Vancomycin was given most commonly for skin and soft tissue infections (SSTI). The majority of these infections may represent simple cutaneous abscesses, which generally do not require antibiotic therapy, but rather incision and drainage alone, as demonstrated by multiple trials. Furthermore, many of these infections may be due to community-acquired MRSA, which is more often susceptible to a greater number of antibiotic classes than is health care-associated MRSA, and may therefore obviate the need for vancomcyin in many cases.
A dose of 1 gram of vancomycin is administered to most patients receiving the drug (92.2%), despite that dose being outside the recommended weight-based dose in the great majority of patients. This leads to inappropriate dosing in 77.9% of patients, with the majority of patients being underdosed. Weight-based dosing is recommended, and at least one study demonstrates that a 1-gram dosing regimen is inadequate to attain therapeutic levels. There are likely multiple factors associated with choosing a 1-gram-based dosing strategy in the ED. Given limited time, computer order entry, and the preformulation of vancomycin in 1-gram bags, "clicking" the order for a 1-gram dose is quicker and more convenient in an otherwise hectic ED setting. Fear of nephrotoxicity may also be influential, as some studies do show nephrotoxicity associated with vancomycin. Our data suggest that although serum creatinine did not influence dosing accuracy, patients with supratherapeutic vancomcyin levels did have higher peak creatinine levels. However, the role that vancomycin plays in contributing to nephrotoxicity is debated. Most data suggest that unless vancomycin is administered with other nephrotoxic agents, the incidence of acute kidney injury is very low.
Patient weight was the only significant predictor of dosing inaccuracy, and was highly influential. Each 10-kg increase in patient weight was associated with a nearly eightfold increase in the likelihood of being underdosed. Physiological changes associated with obesity, such as increased volume of distribution and drug clearance, make the dosing of antimicrobials challenging in this patient cohort. Our study shows that increasing weight causes substantial dosing inaccuracy and should be studied further, as this is an area with significant room for improvement.
This study also shows that the ED dosing of vancomycin has potential effects on patient outcome. Patients dosed in the ED with more than 20 mg/kg of vancomycin spent more time in the hospital, and were almost twice as likely to die before hospital discharge. ED dosing was also highly influential on subsequent vancomycin levels, which also contributed to patient outcome, as patients dosed with vancomycin in the ED with supratherapeutic vancomycin levels had worse outcomes with respect to hospital length of stay, peak creatinine, and death.
We hypothesized that patients 1) receiving lower doses of vancomycin and 2) with lower levels, would have worse outcomes. Our results did not support these hypotheses. This may reflect the discord between vancomycin dosing guidelines and empiric dosing in the ED. The vancomycin guidelines are intended for patients with known or highly suspected MRSA infections, and are based mainly on non-randomized, observational data. No empiric dosing guidelines exist, and whether current guidelines can be applied to the ED with any validity is unknown. Although the ED dosing of vancomycin matters, only a small fraction of patients given vancomycin in the ED have a MRSA infection, and even a smaller fraction have serious infections with higher MICs for which higher dosing would be clinically important. Although our data show the great majority of patients in the ED are dosed outside the recommended range, this likely does not represent a majority of patients receiving ineffective treatment. It does, however, reveal that patients without MRSA infections are likely overexposed to vancomycin, and real-time diagnostic tests are needed to identify patients with MRSA infections, which could assist the Emergency Physician in the decision to dose with vancomycin or not.
Finally, the majority of patients given vancomycin in the ED will be given vancomycin after admission to the hospital at a dose unchanged from the ED dose. Care in the ED impacts long-term outcome across multiple clinical arenas. This is not a new finding. The fact that most vancomycin dosing was continued unchanged after admission to the hospital, despite being administered outside of recommended range in the majority of patients, again highlights the fact that ED treatment is highly influential on subsequent inpatient care. This also likely influenced the subtherapeutic vancomycin levels seen in a majority of the patients in this study. Interventions to improve dosing indication and accuracy could have a significant impact on hospital practice.
The increase in vancomycin use is likely multi-factorial. The immediate concern in the ED may be treatment failure more than antibiotic resistance. This may influence a low threshold to dose vancomycin in patients with little or no risk factors for MRSA. MRSA infections are known to be increasing, and an increasing number of ED visits are due to MRSA SSTIs. There is also an increased incidence of severe sepsis in the United States, and clinicians are increasingly aware of the benefits of early, appropriate antimicrobial therapy for the critically ill, infected patient. With an ED mortality rate of only 0.3% and an inpatient mortality of 7.4%, we believe this plays a minor role in the increased vancomycin use at our institution. Vancomycin use can be limited in the ED given the existing literature that suggests that vancomycin is unnecessary when treating uncomplicated SSTI, and MRSA is unlikely to be involved in intra-abdominal infections and urinary tract infections. Vancomycin exhibits time-dependent killing, requiring an adequate area under the concentration curve divided by the MIC, to achieve efficacy. Based on these pharmacokinetic properties, its use in patients who are discharged from the ED (533 in this study) after only one dose should be strongly discouraged as well.
This study was a carefully controlled analysis of retrospective data, but several limitations affect the interpretation of our findings. First, the retrospective nature of the data collection can be criticized, but we carefully selected robust measurements (i.e., weight, drug administration dose) that would have reflected data available to the treating clinician. Further, data were electronically abstracted from medical records systems and validated across repeated measurements to minimize data entry error. Although these data are robust, we have not elucidated patient or disease factors that may have contributed to non-recommended dosing regimens. There is no way to capture all of the factors associated with patient care that may have influenced the decision to not only give vancomycin, but also at a particular dose.
The division of ED diagnoses into diagnostic categories was somewhat arbitrary. Given the myriad of diagnoses generated by the electronic medical record, there was no logical way to analyze them all separately in a meaningful fashion without a grouping strategy. The definition of "dosing accuracy" can be debated as well. Although some clinicians disagree on vancomycin dosing, based on guideline recommendations, we believe our definition of 15–20 mg/kg to be the correct accepted dosing. Similarly, we defined a "therapeutic" vancomycin level as as 15–20 μg/mL. This more aggressive level is generally recommended to improve clinical outcomes for complicated infections. We thought this cutoff appropriate, based on the changing susceptibility pattern, MIC breakpoints, and local guidelines at our institution. It is possible though, that with a median vancomycin level of 12.0, some patients labeled as subtherapeutic with respect to level were indeed adequately treated. Vancomycin dosing has changed over the last 25 years as MRSA has become more prevalent and the MIC of isolates has increased. Some of these trends are somewhat geographic, so the single-center nature of our study may reduce the external validity to similar centers with similar antibiograms. The generalizability of this study may not be able to be extended to centers where vancomycin use is less and MRSA less prevalent.
This study included all patients to whom vancomycin was given empirically in the ED. This does not take into consideration indication or appropriateness, as many patients without a MRSA infection could have been dosed with vancomycin. Although this may make the dose prescribed a less critical issue, we believe it is important to give a real-world account of how vancomycin is actually being used in the ED.
This study is also limited by a lack of microbiological data, and measurements of severity of illness. Across a broad cohort of ED patients treated empirically, perhaps guideline dosing recommendations cannot be applied. It is possible that, in patients with MRSA infections, underdosing and subtherapeutic levels would have been associated with worse outcomes, secondary to lack of adequate antimicrobial therapy. Our data suggest that most of the adverse effects associated with ED vancomycin use are secondary to a higher dosing strategy. This may reflect patients without MRSA infections who could only be harmed by an aggressive dosing strategy, and saw no benefit to vancomycin use given a lack of a MRSA infection. It is also possible that physicians opted for higher doses due to a higher severity of illness or different clinical infectious sources in those patients. However, on multivariable analysis, vasopressor use and pulmonary source were not influential on dosing accuracy, and dosing accuracy exerted no influence on outcome in patients admitted to the ICU. There are many confounders, including severity of illness, which may have contributed to these clinical outcomes, and a cause-effect relationship with vancomycin dosing cannot be established based on these data. Therefore, the results should be interpreted in context of these limitations.
Discussion
Knowledge of patient characteristics, infectious sources, and antibiotic pharmacokinetics can aid in the choice of antibiotic and also the optimal dose to be administered. As the ED is the first treatment site for many infections, the role the ED plays in adequately treating infections, properly dosing antibiotics to attain therapeutic levels, and contributing to antibiotic resistance is vital.
Our study, which represents the largest study to date describing vancomycin dosing in the ED, was designed not only to simply describe what is occurring in the ED with respect to this drug, but also to examine potential outcomes associated with ED dosing. Vancomycin was given most commonly for skin and soft tissue infections (SSTI). The majority of these infections may represent simple cutaneous abscesses, which generally do not require antibiotic therapy, but rather incision and drainage alone, as demonstrated by multiple trials. Furthermore, many of these infections may be due to community-acquired MRSA, which is more often susceptible to a greater number of antibiotic classes than is health care-associated MRSA, and may therefore obviate the need for vancomcyin in many cases.
A dose of 1 gram of vancomycin is administered to most patients receiving the drug (92.2%), despite that dose being outside the recommended weight-based dose in the great majority of patients. This leads to inappropriate dosing in 77.9% of patients, with the majority of patients being underdosed. Weight-based dosing is recommended, and at least one study demonstrates that a 1-gram dosing regimen is inadequate to attain therapeutic levels. There are likely multiple factors associated with choosing a 1-gram-based dosing strategy in the ED. Given limited time, computer order entry, and the preformulation of vancomycin in 1-gram bags, "clicking" the order for a 1-gram dose is quicker and more convenient in an otherwise hectic ED setting. Fear of nephrotoxicity may also be influential, as some studies do show nephrotoxicity associated with vancomycin. Our data suggest that although serum creatinine did not influence dosing accuracy, patients with supratherapeutic vancomcyin levels did have higher peak creatinine levels. However, the role that vancomycin plays in contributing to nephrotoxicity is debated. Most data suggest that unless vancomycin is administered with other nephrotoxic agents, the incidence of acute kidney injury is very low.
Patient weight was the only significant predictor of dosing inaccuracy, and was highly influential. Each 10-kg increase in patient weight was associated with a nearly eightfold increase in the likelihood of being underdosed. Physiological changes associated with obesity, such as increased volume of distribution and drug clearance, make the dosing of antimicrobials challenging in this patient cohort. Our study shows that increasing weight causes substantial dosing inaccuracy and should be studied further, as this is an area with significant room for improvement.
This study also shows that the ED dosing of vancomycin has potential effects on patient outcome. Patients dosed in the ED with more than 20 mg/kg of vancomycin spent more time in the hospital, and were almost twice as likely to die before hospital discharge. ED dosing was also highly influential on subsequent vancomycin levels, which also contributed to patient outcome, as patients dosed with vancomycin in the ED with supratherapeutic vancomycin levels had worse outcomes with respect to hospital length of stay, peak creatinine, and death.
We hypothesized that patients 1) receiving lower doses of vancomycin and 2) with lower levels, would have worse outcomes. Our results did not support these hypotheses. This may reflect the discord between vancomycin dosing guidelines and empiric dosing in the ED. The vancomycin guidelines are intended for patients with known or highly suspected MRSA infections, and are based mainly on non-randomized, observational data. No empiric dosing guidelines exist, and whether current guidelines can be applied to the ED with any validity is unknown. Although the ED dosing of vancomycin matters, only a small fraction of patients given vancomycin in the ED have a MRSA infection, and even a smaller fraction have serious infections with higher MICs for which higher dosing would be clinically important. Although our data show the great majority of patients in the ED are dosed outside the recommended range, this likely does not represent a majority of patients receiving ineffective treatment. It does, however, reveal that patients without MRSA infections are likely overexposed to vancomycin, and real-time diagnostic tests are needed to identify patients with MRSA infections, which could assist the Emergency Physician in the decision to dose with vancomycin or not.
Finally, the majority of patients given vancomycin in the ED will be given vancomycin after admission to the hospital at a dose unchanged from the ED dose. Care in the ED impacts long-term outcome across multiple clinical arenas. This is not a new finding. The fact that most vancomycin dosing was continued unchanged after admission to the hospital, despite being administered outside of recommended range in the majority of patients, again highlights the fact that ED treatment is highly influential on subsequent inpatient care. This also likely influenced the subtherapeutic vancomycin levels seen in a majority of the patients in this study. Interventions to improve dosing indication and accuracy could have a significant impact on hospital practice.
The increase in vancomycin use is likely multi-factorial. The immediate concern in the ED may be treatment failure more than antibiotic resistance. This may influence a low threshold to dose vancomycin in patients with little or no risk factors for MRSA. MRSA infections are known to be increasing, and an increasing number of ED visits are due to MRSA SSTIs. There is also an increased incidence of severe sepsis in the United States, and clinicians are increasingly aware of the benefits of early, appropriate antimicrobial therapy for the critically ill, infected patient. With an ED mortality rate of only 0.3% and an inpatient mortality of 7.4%, we believe this plays a minor role in the increased vancomycin use at our institution. Vancomycin use can be limited in the ED given the existing literature that suggests that vancomycin is unnecessary when treating uncomplicated SSTI, and MRSA is unlikely to be involved in intra-abdominal infections and urinary tract infections. Vancomycin exhibits time-dependent killing, requiring an adequate area under the concentration curve divided by the MIC, to achieve efficacy. Based on these pharmacokinetic properties, its use in patients who are discharged from the ED (533 in this study) after only one dose should be strongly discouraged as well.
Limitations
This study was a carefully controlled analysis of retrospective data, but several limitations affect the interpretation of our findings. First, the retrospective nature of the data collection can be criticized, but we carefully selected robust measurements (i.e., weight, drug administration dose) that would have reflected data available to the treating clinician. Further, data were electronically abstracted from medical records systems and validated across repeated measurements to minimize data entry error. Although these data are robust, we have not elucidated patient or disease factors that may have contributed to non-recommended dosing regimens. There is no way to capture all of the factors associated with patient care that may have influenced the decision to not only give vancomycin, but also at a particular dose.
The division of ED diagnoses into diagnostic categories was somewhat arbitrary. Given the myriad of diagnoses generated by the electronic medical record, there was no logical way to analyze them all separately in a meaningful fashion without a grouping strategy. The definition of "dosing accuracy" can be debated as well. Although some clinicians disagree on vancomycin dosing, based on guideline recommendations, we believe our definition of 15–20 mg/kg to be the correct accepted dosing. Similarly, we defined a "therapeutic" vancomycin level as as 15–20 μg/mL. This more aggressive level is generally recommended to improve clinical outcomes for complicated infections. We thought this cutoff appropriate, based on the changing susceptibility pattern, MIC breakpoints, and local guidelines at our institution. It is possible though, that with a median vancomycin level of 12.0, some patients labeled as subtherapeutic with respect to level were indeed adequately treated. Vancomycin dosing has changed over the last 25 years as MRSA has become more prevalent and the MIC of isolates has increased. Some of these trends are somewhat geographic, so the single-center nature of our study may reduce the external validity to similar centers with similar antibiograms. The generalizability of this study may not be able to be extended to centers where vancomycin use is less and MRSA less prevalent.
This study included all patients to whom vancomycin was given empirically in the ED. This does not take into consideration indication or appropriateness, as many patients without a MRSA infection could have been dosed with vancomycin. Although this may make the dose prescribed a less critical issue, we believe it is important to give a real-world account of how vancomycin is actually being used in the ED.
This study is also limited by a lack of microbiological data, and measurements of severity of illness. Across a broad cohort of ED patients treated empirically, perhaps guideline dosing recommendations cannot be applied. It is possible that, in patients with MRSA infections, underdosing and subtherapeutic levels would have been associated with worse outcomes, secondary to lack of adequate antimicrobial therapy. Our data suggest that most of the adverse effects associated with ED vancomycin use are secondary to a higher dosing strategy. This may reflect patients without MRSA infections who could only be harmed by an aggressive dosing strategy, and saw no benefit to vancomycin use given a lack of a MRSA infection. It is also possible that physicians opted for higher doses due to a higher severity of illness or different clinical infectious sources in those patients. However, on multivariable analysis, vasopressor use and pulmonary source were not influential on dosing accuracy, and dosing accuracy exerted no influence on outcome in patients admitted to the ICU. There are many confounders, including severity of illness, which may have contributed to these clinical outcomes, and a cause-effect relationship with vancomycin dosing cannot be established based on these data. Therefore, the results should be interpreted in context of these limitations.
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