Pharmacology

Methicillin-resistant Staphylococcus aureus (MRSA) is a Gram positive, round bacterium. The bacteria has evolved to withstand attacks from antibiotics and has made MRSA resistant to traditional antibiotics, such as β-lactams, resulting in difficult-to-treat infections. The presence of a genetic mutation within the mecA gene, which codes for the penicillin-binding protein 2a (PBP2a), differentiates MRSA from methicillin-susceptible Staphylococcus aureus (MSSA). Presence of the PBP2a protein allows Staphylococcus aureus (S aureus)to overcome β-lactam antibiotics’ method of killing by allowing the bacteria to continue to divide and grow.

β-lactam antibiotics cause cell death in susceptible isolates by binding to penicillin-binding proteins, which inhibits transpeptidation within the cell wall via inactivation of the penicillin-binding protein. By inhibiting cell wall synthesis, the cell loses its integrity and leaks its contents, causing cell death. Penicillin-binding protein 2a is a modified protein that has a low affinity for β-lactam antibiotics, allowing MRSA to survive and making it dangerous and difficult to eradicate.

First described in 1961, MRSA’s prevalence steadily increased in the following decades. It is the most common cause of skin and soft tissue infections presenting to emergency departments in the U.S.¹ About 20% of bloodstream infections are caused by S aureus, and in 2003, nearly two-thirds of hospital-onset S aureus infections were methicillin-resistant in U.S. intensive-care units (ICUs).² It has been shown that patients with MRSA bacteremia have worse overall outcomes, including increased mortality, greater lengths of stay, and increased costs, compared with those with MSSA infections.^2,3 In 2011, MRSA infections caused an estimated 11,000 deaths, making fast and accurate detection of MRSA a crucial step in appropriate antimicrobial therapy selection.⁴

Currently, the Clinical and Laboratory Standards Institute (CLSI) recommends testing for MRSA by using phenotypic or genotypic methods. Phenotypic methods test for the observable characteristics of an organism, whereas a genotypic method identifies the specific gene that the organism carries. Recommended phenotypic methods include the latex agglutination test for PBP2a, the cefoxitin disk screen test, and a plate containing 6 μg/mL of oxacillin in Mueller-Hinton agar supplemented with sodium chloride.⁵ These methods have varying sensitivity and specificity and take between 48 to 72 hours to provide a result.

Within the past 15 years, a newer, genotypic, method of MRSA detection was approved by the FDA with high sensitivity and specificity. This method uses polymerase chain reaction (PCR) to identify the mecA gene. Polymerase chain reaction is a technique used to copy and amplify a specific segment of DNA, making thousands to millions of copies. If present, the MRSA PCR amplifies the mecA gene that makes S aureus resistant to methicillin and other β-lactams, which confirms that the specimen contains MRSA. The FDA has approved the use of MRSA PCR nasal swabs to detect MRSA in patients at risk of nasal colonization. While previously discussed methods may take between 2 and 3 days to confirm presence of MRSA, PCR can identify MRSA in about 1 hour.⁶

If a S aureus infection is suspected, empiric therapy often includes coverage of both MSSA and MRSA, due to the high morbidity and mortality associated with these infections. However, continuing an unneeded or unduly broad antibiotic, such as those that cover MRSA, can cause unintended consequences, such as toxicities, emerging resistance, or selection for pathogenic organisms.⁷ Therefore, empiric broad antibiotic therapy should be de-escalated as soon as possible, which further emphasizes the need for quick and accurate detection of the infecting organism. De-escalation of therapy can lead to a shorter length of stay and decreased mortality.^8,9 Conversely, quick identification of infections caused by MRSA would allow therapy to be broadened to cover MRSA in infected patients, which could potentially decrease patient morbidity and mortality.

Nasal MRSA PCR Colonization

Rapid identification of a causative organism is crucial to determine appropriate antibiotic therapy. Fortunately, PCR is a very rapid method of detecting MRSA, and the use of MRSA PCR nasal swabs may be an effective way to predict whether MRSA is the organism causing an infection at various anatomical sites. If a patient has a suspected infection on admission, a MRSA PCR nasal swab often is completed to determine whether a patient’s nares are colonized with MRSA. However, there is no clear consensus in the literature regarding the correlation between MRSA nasal colonization and an infection caused by MRSA, making it difficult for clinicians to confidently de-escalate therapy on a negative MRSA PCR or broaden therapy on a positive result. The purpose of this literature review was to determine whether a MRSA PCR nasal swab can be used as a surrogate marker for MRSA infections at various sites.

Pneumonia has many potential causative organisms, many of which are covered empirically with guideline-directed therapy. The predictive power of MRSA PCR nasal swabs may allow clinicians to prescribe earlier directed therapy. A retrospective cohort study performed at a tertiary care center looked at the clinical usefulness of a MRSA PCR nasal swab in the treatment of pneumonia.¹⁰ Patients were included in the trial if they had a MRSA PCR nasal swab within 1 month of their blood or sputum culture as well as confirmed pneumonia. After analysis of 435 patients, the MRSA PCR nasal swab showed the following performance characteristics for detecting culture-proven MRSA: 88.0% sensitivity, 90.1% specificity, 35.4% positive predictive value (PPV), and 99.2% negative predictive value (NPV). Due to the high negative predictive value, the results indicated that discontinuation of MRSA antibiotic coverage would be appropriate for noncritically ill patients with pneumonia who had a negative MRSA PCR nasal swab.

Another retrospective study was performed by Johnson and colleagues to determine the association between MRSA PCR nasal swabs and the causative organism in pneumonia.¹¹ Patients were included in the trial if they had a MRSA PCR nasal swab and a lower respiratory culture yielding S aureus within 48 hours of hospital admission. After analysis of 72 patients, MRSA PCR nasal swabs demonstrated the following diagnostic characteristics for detecting culture-proven MRSA: 93.3% sensitivity, 95.2% specificity, 93.3%PPV, and 95.2% NPV. These results suggest that early nasal swab MRSA PCR tests can predict the absence of MRSA reliably and may help guide the discontinuation of MRSA-directed empiric antibiotic therapy.

In addition, Giancola retrospectively studied the relationship between MRSA PCR nasal swabs and the likelihood of pneumonia caused by MRSA in intensive and intermediate care units.¹² An analysis of 200 patients revealed high concordance between respiratory cultures and MRSA PCR nasal swab results with the following characteristics: 90.5% sensitivity, 79.9% specificity, 34.5% PPV, and 98.6% NPV. These test characteristics suggested that MRSA PCR nasal swabs might be a useful stewardship tool to allow for discontinuation of anti-MRSA therapy in critically ill patients with confirmed pneumonia.

Another retrospective analysis conducted by Baby and colleagues took a different approach to determine the clinical usefulness of MRSA PCR nasal swabs in the treatment of pneumonia.¹³ The primary outcome, mean duration of MRSA-targeted therapy, was reduced by 46.6 hours in the group who received a pharmacist-ordered MRSA PCR nasal swab compared with the group that did not receive a MRSA PCR nasal swab (P < .01) Per protocol, pharmacists were authorized to order a MRSA PCR nasal swab for patients who were prescribed vancomycin or linezolid for pneumonia. On receipt of the MRSA PCR nasal swab results, pharmacists were instructed to recommend discontinuation of anti-MRSA therapy if the PCR was negative for MRSA.

Results of this study indicated there were no significant differences in time to clinical improvement between preprotocol and postprotocol implementation (1.8 days vs 2.3 days, respectively; P = .54), length of stay (11.0 days vs 8.2 days, respectively; P = .22), or mortality (14.8% vs 6.7%, respectively; P = .41). The MRSA PCR nasal swabs allowed for a reduction in duration of anti-MRSA therapy without adverse effects on outcomes and provided a statistically significant reduction in the incidence of acute kidney injury during therapy in the postprotocol implementation group (26% vs 3.3%; P = .02), likely due to decreased exposure to vancomycin. Collectively, these studies indicate that MRSA PCR nasal swabs can be clinically useful in making decisions regarding discontinuation of MRSA-targeted therapy in pneumonia when MRSA PCR nasal swabs are negative.

A wider variety of infection sites were studied in a 2008 retrospective review of nearly 5,800 MRSA PCR nasal swabs taken within 24 hours (before or after) of a clinical culture that resulted growth of any organism.¹⁴ The goal of this study was to determine whether MRSA nasal colonization could predict MRSA involvement at various suspected infection sites. Overall, 217 patients (67.2%) with positive MRSA clinical cultures had a positive MRSA PCR nasal swab. The concordance between MRSA PCR nasal swabs and infection sites was highest with positive urine cultures (77%) and lowest in “other” infection sites (60%, primarily abdomen, buttock, and breast). Respiratory infections showed a 75% concordance between MRSA PCR nasal swabs and infection sites, as well as the following characteristics: 75% sensitivity, 90% specificity, 30% PPV, and 98% NPV. Additionally, infection site concordance was higher when clinical cultures grew clindamycin-resistant MRSA (71.3%) vs clindamycin-susceptible MRSA (59.3%; P = .04).

Overall, a positive MRSA PCR nasal swab increased the likelihood of MRSA at the primary infection site but was not clinically significant or consistent across infection sites. As seen in other studies, a negative MRSA PCR nasal swab could be useful for lowering concern for MRSA involvement in the primary infection, as evidenced by the following characteristics for all infection sites: 67% sensitivity, 90% specificity, 27% PPV, and 98% NPV.

Sarkionda and colleagues evaluated the clinical usefulness of MRSA PCR nasal swabs in the ICU setting in patients with a lower respiratory tract infection (RTI) or bloodstream infection.¹⁵ A total of 749 patients received a MRSA PCR nasal swab before admission to the ICU and were included in this study. The concordance between MRSA PCR nasal swabs and the causative organism was analyzed in patients who developed a MRSA lower respiratory infection (N = 120) and a MRSA bloodstream infection (N = 78) and demonstrated the following characteristics: 24.2% sensitivity, 78.5% specificity, 17.7% PPV, and 84.4% NPV; and 23.1% sensitivity, 78.2% specificity, 11.0% PPV, and 89.7% NPV, respectively. The authors concluded that the MRSA nasal swab results are not useful for making decisions regarding the need of empiric antimicrobial therapy targeting MRSA infections in lower respiratory infections and bloodstream infections. However, due to the high NPV in this study, one might conclude that negative MRSA PCR nasal swabs could still be used to de-escalate therapy, which is in agreement with the results from Dangerfield and Johnson.^10,11

Similarly, results from a retrospective chart review demonstrated a lack of predictive value by the MRSA PCR nasal swab.¹⁶ Of 1,203 adult patients admitted to an ICU at a single center, 57 positive MRSA colonized and 122 negative MRSA colonized patients’ charts were randomly selected. The presence of MRSA lower RTI or bloodstream infections was found to be 3.51% vs 2.46% in the colonized and noncolonized groups, respectively (P = .46). These results led to the conclusion that a positive MRSA PCR nasal swab alone should not be used to make decisions regarding empiric MRSA antibiotic coverage.

An alternative approach to MRSA surveillance was taken by Harris in a prospective cohort of 12,080 adults with a suspected infection on admission to a non-ICU.¹⁷ Patients were screened with a 2-question tool to determine whether they were high risk for a MRSA infection. The 2 questions were “Have you been admitted to any health care facility in the last 12 months?” and “Do you have a skin infection (eg, boil, abscess, spider bite, or cellulitis) at this time?” If patients answered yes to either question, they were considered high risk, and a MRSA PCR nasal swab was ordered.

Patients who answered no to both questions were considered low risk and did not receive a MRSA PCR nasal swab. In total, 623 of 5,609 patients (11.1%) identified as high risk had a positive MRSA PCR nasal swab, and 148 of these 623 patients (23.8%) developed a MRSA-positive clinical culture. Only 121 of 4,986 patients (2.4%) who were high risk and had a negative MRSA PCR nasal swab went on to develop a MRSA-positive clinical culture (98% NPV). Additionally, 104 of 6,741 patients (1.6%) who answered no to both screening questions developed a MRSA-positive clinical culture (98% NPV). Results indicated that a high percentage of patients who were at high risk for MRSA (yes response to either question) and had a positive MRSA PCR nasal swab also had a positive clinical culture for MRSA. Conversely, a very small percentage of high-risk patients with a negative MRSA PCR nasal swab developed a positive clinical culture for MRSA.

The screening tool proved very effective as the low-risk group had the lowest number of patients (1.6%) develop a positive clinical culture for MRSA. It may be deduced that combination use of MRSA colonization testing via PCR nasal swabs in conjunction with a screening tool may be an effective method to identify patients in whom anti-MRSA therapy can be safely discontinued.

Conclusion

Based on the results of previously described studies, sufficient data may exist to support the discontinuation of MRSA-targeted therapy in noncritically ill patients with confirmed or suspected pneumonia and a negative MRSA PCR nasal swab. Insufficient evidence exists, however, to support a broadening of antimicrobial therapy to include anti-MRSA coverage in individuals with a positive MRSA PCR nasal swab, regardless of the infection site.

Clinical judgment should be used when determining empiric antimicrobial therapy and for appropriateness of de-escalation of therapy in critically ill patients. Once a patient stabilizes, a negative MRSA PCR nasal swab could be considered as supporting evidence to discontinue anti-MRSA therapy, especially in patients with lower respiratory infections, such as pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is a Gram positive, round bacterium. The bacteria has evolved to withstand attacks from antibiotics and has made MRSA resistant to traditional antibiotics, such as β-lactams, resulting in difficult-to-treat infections. The presence of a genetic mutation within the mecA gene, which codes for the penicillin-binding protein 2a (PBP2a), differentiates MRSA from methicillin-susceptible Staphylococcus aureus (MSSA). Presence of the PBP2a protein allows Staphylococcus aureus (S aureus)to overcome β-lactam antibiotics’ method of killing by allowing the bacteria to continue to divide and grow.

β-lactam antibiotics cause cell death in susceptible isolates by binding to penicillin-binding proteins, which inhibits transpeptidation within the cell wall via inactivation of the penicillin-binding protein. By inhibiting cell wall synthesis, the cell loses its integrity and leaks its contents, causing cell death. Penicillin-binding protein 2a is a modified protein that has a low affinity for β-lactam antibiotics, allowing MRSA to survive and making it dangerous and difficult to eradicate.

First described in 1961, MRSA’s prevalence steadily increased in the following decades. It is the most common cause of skin and soft tissue infections presenting to emergency departments in the U.S.¹ About 20% of bloodstream infections are caused by S aureus, and in 2003, nearly two-thirds of hospital-onset S aureus infections were methicillin-resistant in U.S. intensive-care units (ICUs).² It has been shown that patients with MRSA bacteremia have worse overall outcomes, including increased mortality, greater lengths of stay, and increased costs, compared with those with MSSA infections.^2,3 In 2011, MRSA infections caused an estimated 11,000 deaths, making fast and accurate detection of MRSA a crucial step in appropriate antimicrobial therapy selection.⁴

Currently, the Clinical and Laboratory Standards Institute (CLSI) recommends testing for MRSA by using phenotypic or genotypic methods. Phenotypic methods test for the observable characteristics of an organism, whereas a genotypic method identifies the specific gene that the organism carries. Recommended phenotypic methods include the latex agglutination test for PBP2a, the cefoxitin disk screen test, and a plate containing 6 μg/mL of oxacillin in Mueller-Hinton agar supplemented with sodium chloride.⁵ These methods have varying sensitivity and specificity and take between 48 to 72 hours to provide a result.

Within the past 15 years, a newer, genotypic, method of MRSA detection was approved by the FDA with high sensitivity and specificity. This method uses polymerase chain reaction (PCR) to identify the mecA gene. Polymerase chain reaction is a technique used to copy and amplify a specific segment of DNA, making thousands to millions of copies. If present, the MRSA PCR amplifies the mecA gene that makes S aureus resistant to methicillin and other β-lactams, which confirms that the specimen contains MRSA. The FDA has approved the use of MRSA PCR nasal swabs to detect MRSA in patients at risk of nasal colonization. While previously discussed methods may take between 2 and 3 days to confirm presence of MRSA, PCR can identify MRSA in about 1 hour.⁶

If a S aureus infection is suspected, empiric therapy often includes coverage of both MSSA and MRSA, due to the high morbidity and mortality associated with these infections. However, continuing an unneeded or unduly broad antibiotic, such as those that cover MRSA, can cause unintended consequences, such as toxicities, emerging resistance, or selection for pathogenic organisms.⁷ Therefore, empiric broad antibiotic therapy should be de-escalated as soon as possible, which further emphasizes the need for quick and accurate detection of the infecting organism. De-escalation of therapy can lead to a shorter length of stay and decreased mortality.^8,9 Conversely, quick identification of infections caused by MRSA would allow therapy to be broadened to cover MRSA in infected patients, which could potentially decrease patient morbidity and mortality.

Nasal MRSA PCR Colonization

Rapid identification of a causative organism is crucial to determine appropriate antibiotic therapy. Fortunately, PCR is a very rapid method of detecting MRSA, and the use of MRSA PCR nasal swabs may be an effective way to predict whether MRSA is the organism causing an infection at various anatomical sites. If a patient has a suspected infection on admission, a MRSA PCR nasal swab often is completed to determine whether a patient’s nares are colonized with MRSA. However, there is no clear consensus in the literature regarding the correlation between MRSA nasal colonization and an infection caused by MRSA, making it difficult for clinicians to confidently de-escalate therapy on a negative MRSA PCR or broaden therapy on a positive result. The purpose of this literature review was to determine whether a MRSA PCR nasal swab can be used as a surrogate marker for MRSA infections at various sites.

Pneumonia has many potential causative organisms, many of which are covered empirically with guideline-directed therapy. The predictive power of MRSA PCR nasal swabs may allow clinicians to prescribe earlier directed therapy. A retrospective cohort study performed at a tertiary care center looked at the clinical usefulness of a MRSA PCR nasal swab in the treatment of pneumonia.¹⁰ Patients were included in the trial if they had a MRSA PCR nasal swab within 1 month of their blood or sputum culture as well as confirmed pneumonia. After analysis of 435 patients, the MRSA PCR nasal swab showed the following performance characteristics for detecting culture-proven MRSA: 88.0% sensitivity, 90.1% specificity, 35.4% positive predictive value (PPV), and 99.2% negative predictive value (NPV). Due to the high negative predictive value, the results indicated that discontinuation of MRSA antibiotic coverage would be appropriate for noncritically ill patients with pneumonia who had a negative MRSA PCR nasal swab.

Another retrospective study was performed by Johnson and colleagues to determine the association between MRSA PCR nasal swabs and the causative organism in pneumonia.¹¹ Patients were included in the trial if they had a MRSA PCR nasal swab and a lower respiratory culture yielding S aureus within 48 hours of hospital admission. After analysis of 72 patients, MRSA PCR nasal swabs demonstrated the following diagnostic characteristics for detecting culture-proven MRSA: 93.3% sensitivity, 95.2% specificity, 93.3%PPV, and 95.2% NPV. These results suggest that early nasal swab MRSA PCR tests can predict the absence of MRSA reliably and may help guide the discontinuation of MRSA-directed empiric antibiotic therapy.

In addition, Giancola retrospectively studied the relationship between MRSA PCR nasal swabs and the likelihood of pneumonia caused by MRSA in intensive and intermediate care units.¹² An analysis of 200 patients revealed high concordance between respiratory cultures and MRSA PCR nasal swab results with the following characteristics: 90.5% sensitivity, 79.9% specificity, 34.5% PPV, and 98.6% NPV. These test characteristics suggested that MRSA PCR nasal swabs might be a useful stewardship tool to allow for discontinuation of anti-MRSA therapy in critically ill patients with confirmed pneumonia.

Another retrospective analysis conducted by Baby and colleagues took a different approach to determine the clinical usefulness of MRSA PCR nasal swabs in the treatment of pneumonia.¹³ The primary outcome, mean duration of MRSA-targeted therapy, was reduced by 46.6 hours in the group who received a pharmacist-ordered MRSA PCR nasal swab compared with the group that did not receive a MRSA PCR nasal swab (P < .01) Per protocol, pharmacists were authorized to order a MRSA PCR nasal swab for patients who were prescribed vancomycin or linezolid for pneumonia. On receipt of the MRSA PCR nasal swab results, pharmacists were instructed to recommend discontinuation of anti-MRSA therapy if the PCR was negative for MRSA.

Results of this study indicated there were no significant differences in time to clinical improvement between preprotocol and postprotocol implementation (1.8 days vs 2.3 days, respectively; P = .54), length of stay (11.0 days vs 8.2 days, respectively; P = .22), or mortality (14.8% vs 6.7%, respectively; P = .41). The MRSA PCR nasal swabs allowed for a reduction in duration of anti-MRSA therapy without adverse effects on outcomes and provided a statistically significant reduction in the incidence of acute kidney injury during therapy in the postprotocol implementation group (26% vs 3.3%; P = .02), likely due to decreased exposure to vancomycin. Collectively, these studies indicate that MRSA PCR nasal swabs can be clinically useful in making decisions regarding discontinuation of MRSA-targeted therapy in pneumonia when MRSA PCR nasal swabs are negative.

A wider variety of infection sites were studied in a 2008 retrospective review of nearly 5,800 MRSA PCR nasal swabs taken within 24 hours (before or after) of a clinical culture that resulted growth of any organism.¹⁴ The goal of this study was to determine whether MRSA nasal colonization could predict MRSA involvement at various suspected infection sites. Overall, 217 patients (67.2%) with positive MRSA clinical cultures had a positive MRSA PCR nasal swab. The concordance between MRSA PCR nasal swabs and infection sites was highest with positive urine cultures (77%) and lowest in “other” infection sites (60%, primarily abdomen, buttock, and breast). Respiratory infections showed a 75% concordance between MRSA PCR nasal swabs and infection sites, as well as the following characteristics: 75% sensitivity, 90% specificity, 30% PPV, and 98% NPV. Additionally, infection site concordance was higher when clinical cultures grew clindamycin-resistant MRSA (71.3%) vs clindamycin-susceptible MRSA (59.3%; P = .04).

Overall, a positive MRSA PCR nasal swab increased the likelihood of MRSA at the primary infection site but was not clinically significant or consistent across infection sites. As seen in other studies, a negative MRSA PCR nasal swab could be useful for lowering concern for MRSA involvement in the primary infection, as evidenced by the following characteristics for all infection sites: 67% sensitivity, 90% specificity, 27% PPV, and 98% NPV.

Sarkionda and colleagues evaluated the clinical usefulness of MRSA PCR nasal swabs in the ICU setting in patients with a lower respiratory tract infection (RTI) or bloodstream infection.¹⁵ A total of 749 patients received a MRSA PCR nasal swab before admission to the ICU and were included in this study. The concordance between MRSA PCR nasal swabs and the causative organism was analyzed in patients who developed a MRSA lower respiratory infection (N = 120) and a MRSA bloodstream infection (N = 78) and demonstrated the following characteristics: 24.2% sensitivity, 78.5% specificity, 17.7% PPV, and 84.4% NPV; and 23.1% sensitivity, 78.2% specificity, 11.0% PPV, and 89.7% NPV, respectively. The authors concluded that the MRSA nasal swab results are not useful for making decisions regarding the need of empiric antimicrobial therapy targeting MRSA infections in lower respiratory infections and bloodstream infections. However, due to the high NPV in this study, one might conclude that negative MRSA PCR nasal swabs could still be used to de-escalate therapy, which is in agreement with the results from Dangerfield and Johnson.^10,11

Similarly, results from a retrospective chart review demonstrated a lack of predictive value by the MRSA PCR nasal swab.¹⁶ Of 1,203 adult patients admitted to an ICU at a single center, 57 positive MRSA colonized and 122 negative MRSA colonized patients’ charts were randomly selected. The presence of MRSA lower RTI or bloodstream infections was found to be 3.51% vs 2.46% in the colonized and noncolonized groups, respectively (P = .46). These results led to the conclusion that a positive MRSA PCR nasal swab alone should not be used to make decisions regarding empiric MRSA antibiotic coverage.

An alternative approach to MRSA surveillance was taken by Harris in a prospective cohort of 12,080 adults with a suspected infection on admission to a non-ICU.¹⁷ Patients were screened with a 2-question tool to determine whether they were high risk for a MRSA infection. The 2 questions were “Have you been admitted to any health care facility in the last 12 months?” and “Do you have a skin infection (eg, boil, abscess, spider bite, or cellulitis) at this time?” If patients answered yes to either question, they were considered high risk, and a MRSA PCR nasal swab was ordered.

Patients who answered no to both questions were considered low risk and did not receive a MRSA PCR nasal swab. In total, 623 of 5,609 patients (11.1%) identified as high risk had a positive MRSA PCR nasal swab, and 148 of these 623 patients (23.8%) developed a MRSA-positive clinical culture. Only 121 of 4,986 patients (2.4%) who were high risk and had a negative MRSA PCR nasal swab went on to develop a MRSA-positive clinical culture (98% NPV). Additionally, 104 of 6,741 patients (1.6%) who answered no to both screening questions developed a MRSA-positive clinical culture (98% NPV). Results indicated that a high percentage of patients who were at high risk for MRSA (yes response to either question) and had a positive MRSA PCR nasal swab also had a positive clinical culture for MRSA. Conversely, a very small percentage of high-risk patients with a negative MRSA PCR nasal swab developed a positive clinical culture for MRSA.

The screening tool proved very effective as the low-risk group had the lowest number of patients (1.6%) develop a positive clinical culture for MRSA. It may be deduced that combination use of MRSA colonization testing via PCR nasal swabs in conjunction with a screening tool may be an effective method to identify patients in whom anti-MRSA therapy can be safely discontinued.

Conclusion

Based on the results of previously described studies, sufficient data may exist to support the discontinuation of MRSA-targeted therapy in noncritically ill patients with confirmed or suspected pneumonia and a negative MRSA PCR nasal swab. Insufficient evidence exists, however, to support a broadening of antimicrobial therapy to include anti-MRSA coverage in individuals with a positive MRSA PCR nasal swab, regardless of the infection site.

Clinical judgment should be used when determining empiric antimicrobial therapy and for appropriateness of de-escalation of therapy in critically ill patients. Once a patient stabilizes, a negative MRSA PCR nasal swab could be considered as supporting evidence to discontinue anti-MRSA therapy, especially in patients with lower respiratory infections, such as pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is a Gram positive, round bacterium. The bacteria has evolved to withstand attacks from antibiotics and has made MRSA resistant to traditional antibiotics, such as β-lactams, resulting in difficult-to-treat infections. The presence of a genetic mutation within the mecA gene, which codes for the penicillin-binding protein 2a (PBP2a), differentiates MRSA from methicillin-susceptible Staphylococcus aureus (MSSA). Presence of the PBP2a protein allows Staphylococcus aureus (S aureus)to overcome β-lactam antibiotics’ method of killing by allowing the bacteria to continue to divide and grow.

β-lactam antibiotics cause cell death in susceptible isolates by binding to penicillin-binding proteins, which inhibits transpeptidation within the cell wall via inactivation of the penicillin-binding protein. By inhibiting cell wall synthesis, the cell loses its integrity and leaks its contents, causing cell death. Penicillin-binding protein 2a is a modified protein that has a low affinity for β-lactam antibiotics, allowing MRSA to survive and making it dangerous and difficult to eradicate.

First described in 1961, MRSA’s prevalence steadily increased in the following decades. It is the most common cause of skin and soft tissue infections presenting to emergency departments in the U.S.¹ About 20% of bloodstream infections are caused by S aureus, and in 2003, nearly two-thirds of hospital-onset S aureus infections were methicillin-resistant in U.S. intensive-care units (ICUs).² It has been shown that patients with MRSA bacteremia have worse overall outcomes, including increased mortality, greater lengths of stay, and increased costs, compared with those with MSSA infections.^2,3 In 2011, MRSA infections caused an estimated 11,000 deaths, making fast and accurate detection of MRSA a crucial step in appropriate antimicrobial therapy selection.⁴

Currently, the Clinical and Laboratory Standards Institute (CLSI) recommends testing for MRSA by using phenotypic or genotypic methods. Phenotypic methods test for the observable characteristics of an organism, whereas a genotypic method identifies the specific gene that the organism carries. Recommended phenotypic methods include the latex agglutination test for PBP2a, the cefoxitin disk screen test, and a plate containing 6 μg/mL of oxacillin in Mueller-Hinton agar supplemented with sodium chloride.⁵ These methods have varying sensitivity and specificity and take between 48 to 72 hours to provide a result.

Within the past 15 years, a newer, genotypic, method of MRSA detection was approved by the FDA with high sensitivity and specificity. This method uses polymerase chain reaction (PCR) to identify the mecA gene. Polymerase chain reaction is a technique used to copy and amplify a specific segment of DNA, making thousands to millions of copies. If present, the MRSA PCR amplifies the mecA gene that makes S aureus resistant to methicillin and other β-lactams, which confirms that the specimen contains MRSA. The FDA has approved the use of MRSA PCR nasal swabs to detect MRSA in patients at risk of nasal colonization. While previously discussed methods may take between 2 and 3 days to confirm presence of MRSA, PCR can identify MRSA in about 1 hour.⁶

If a S aureus infection is suspected, empiric therapy often includes coverage of both MSSA and MRSA, due to the high morbidity and mortality associated with these infections. However, continuing an unneeded or unduly broad antibiotic, such as those that cover MRSA, can cause unintended consequences, such as toxicities, emerging resistance, or selection for pathogenic organisms.⁷ Therefore, empiric broad antibiotic therapy should be de-escalated as soon as possible, which further emphasizes the need for quick and accurate detection of the infecting organism. De-escalation of therapy can lead to a shorter length of stay and decreased mortality.^8,9 Conversely, quick identification of infections caused by MRSA would allow therapy to be broadened to cover MRSA in infected patients, which could potentially decrease patient morbidity and mortality.

Nasal MRSA PCR Colonization

Rapid identification of a causative organism is crucial to determine appropriate antibiotic therapy. Fortunately, PCR is a very rapid method of detecting MRSA, and the use of MRSA PCR nasal swabs may be an effective way to predict whether MRSA is the organism causing an infection at various anatomical sites. If a patient has a suspected infection on admission, a MRSA PCR nasal swab often is completed to determine whether a patient’s nares are colonized with MRSA. However, there is no clear consensus in the literature regarding the correlation between MRSA nasal colonization and an infection caused by MRSA, making it difficult for clinicians to confidently de-escalate therapy on a negative MRSA PCR or broaden therapy on a positive result. The purpose of this literature review was to determine whether a MRSA PCR nasal swab can be used as a surrogate marker for MRSA infections at various sites.

Pneumonia has many potential causative organisms, many of which are covered empirically with guideline-directed therapy. The predictive power of MRSA PCR nasal swabs may allow clinicians to prescribe earlier directed therapy. A retrospective cohort study performed at a tertiary care center looked at the clinical usefulness of a MRSA PCR nasal swab in the treatment of pneumonia.¹⁰ Patients were included in the trial if they had a MRSA PCR nasal swab within 1 month of their blood or sputum culture as well as confirmed pneumonia. After analysis of 435 patients, the MRSA PCR nasal swab showed the following performance characteristics for detecting culture-proven MRSA: 88.0% sensitivity, 90.1% specificity, 35.4% positive predictive value (PPV), and 99.2% negative predictive value (NPV). Due to the high negative predictive value, the results indicated that discontinuation of MRSA antibiotic coverage would be appropriate for noncritically ill patients with pneumonia who had a negative MRSA PCR nasal swab.

Another retrospective study was performed by Johnson and colleagues to determine the association between MRSA PCR nasal swabs and the causative organism in pneumonia.¹¹ Patients were included in the trial if they had a MRSA PCR nasal swab and a lower respiratory culture yielding S aureus within 48 hours of hospital admission. After analysis of 72 patients, MRSA PCR nasal swabs demonstrated the following diagnostic characteristics for detecting culture-proven MRSA: 93.3% sensitivity, 95.2% specificity, 93.3%PPV, and 95.2% NPV. These results suggest that early nasal swab MRSA PCR tests can predict the absence of MRSA reliably and may help guide the discontinuation of MRSA-directed empiric antibiotic therapy.

In addition, Giancola retrospectively studied the relationship between MRSA PCR nasal swabs and the likelihood of pneumonia caused by MRSA in intensive and intermediate care units.¹² An analysis of 200 patients revealed high concordance between respiratory cultures and MRSA PCR nasal swab results with the following characteristics: 90.5% sensitivity, 79.9% specificity, 34.5% PPV, and 98.6% NPV. These test characteristics suggested that MRSA PCR nasal swabs might be a useful stewardship tool to allow for discontinuation of anti-MRSA therapy in critically ill patients with confirmed pneumonia.

Another retrospective analysis conducted by Baby and colleagues took a different approach to determine the clinical usefulness of MRSA PCR nasal swabs in the treatment of pneumonia.¹³ The primary outcome, mean duration of MRSA-targeted therapy, was reduced by 46.6 hours in the group who received a pharmacist-ordered MRSA PCR nasal swab compared with the group that did not receive a MRSA PCR nasal swab (P < .01) Per protocol, pharmacists were authorized to order a MRSA PCR nasal swab for patients who were prescribed vancomycin or linezolid for pneumonia. On receipt of the MRSA PCR nasal swab results, pharmacists were instructed to recommend discontinuation of anti-MRSA therapy if the PCR was negative for MRSA.

Results of this study indicated there were no significant differences in time to clinical improvement between preprotocol and postprotocol implementation (1.8 days vs 2.3 days, respectively; P = .54), length of stay (11.0 days vs 8.2 days, respectively; P = .22), or mortality (14.8% vs 6.7%, respectively; P = .41). The MRSA PCR nasal swabs allowed for a reduction in duration of anti-MRSA therapy without adverse effects on outcomes and provided a statistically significant reduction in the incidence of acute kidney injury during therapy in the postprotocol implementation group (26% vs 3.3%; P = .02), likely due to decreased exposure to vancomycin. Collectively, these studies indicate that MRSA PCR nasal swabs can be clinically useful in making decisions regarding discontinuation of MRSA-targeted therapy in pneumonia when MRSA PCR nasal swabs are negative.

A wider variety of infection sites were studied in a 2008 retrospective review of nearly 5,800 MRSA PCR nasal swabs taken within 24 hours (before or after) of a clinical culture that resulted growth of any organism.¹⁴ The goal of this study was to determine whether MRSA nasal colonization could predict MRSA involvement at various suspected infection sites. Overall, 217 patients (67.2%) with positive MRSA clinical cultures had a positive MRSA PCR nasal swab. The concordance between MRSA PCR nasal swabs and infection sites was highest with positive urine cultures (77%) and lowest in “other” infection sites (60%, primarily abdomen, buttock, and breast). Respiratory infections showed a 75% concordance between MRSA PCR nasal swabs and infection sites, as well as the following characteristics: 75% sensitivity, 90% specificity, 30% PPV, and 98% NPV. Additionally, infection site concordance was higher when clinical cultures grew clindamycin-resistant MRSA (71.3%) vs clindamycin-susceptible MRSA (59.3%; P = .04).

Overall, a positive MRSA PCR nasal swab increased the likelihood of MRSA at the primary infection site but was not clinically significant or consistent across infection sites. As seen in other studies, a negative MRSA PCR nasal swab could be useful for lowering concern for MRSA involvement in the primary infection, as evidenced by the following characteristics for all infection sites: 67% sensitivity, 90% specificity, 27% PPV, and 98% NPV.

Sarkionda and colleagues evaluated the clinical usefulness of MRSA PCR nasal swabs in the ICU setting in patients with a lower respiratory tract infection (RTI) or bloodstream infection.¹⁵ A total of 749 patients received a MRSA PCR nasal swab before admission to the ICU and were included in this study. The concordance between MRSA PCR nasal swabs and the causative organism was analyzed in patients who developed a MRSA lower respiratory infection (N = 120) and a MRSA bloodstream infection (N = 78) and demonstrated the following characteristics: 24.2% sensitivity, 78.5% specificity, 17.7% PPV, and 84.4% NPV; and 23.1% sensitivity, 78.2% specificity, 11.0% PPV, and 89.7% NPV, respectively. The authors concluded that the MRSA nasal swab results are not useful for making decisions regarding the need of empiric antimicrobial therapy targeting MRSA infections in lower respiratory infections and bloodstream infections. However, due to the high NPV in this study, one might conclude that negative MRSA PCR nasal swabs could still be used to de-escalate therapy, which is in agreement with the results from Dangerfield and Johnson.^10,11

Similarly, results from a retrospective chart review demonstrated a lack of predictive value by the MRSA PCR nasal swab.¹⁶ Of 1,203 adult patients admitted to an ICU at a single center, 57 positive MRSA colonized and 122 negative MRSA colonized patients’ charts were randomly selected. The presence of MRSA lower RTI or bloodstream infections was found to be 3.51% vs 2.46% in the colonized and noncolonized groups, respectively (P = .46). These results led to the conclusion that a positive MRSA PCR nasal swab alone should not be used to make decisions regarding empiric MRSA antibiotic coverage.

An alternative approach to MRSA surveillance was taken by Harris in a prospective cohort of 12,080 adults with a suspected infection on admission to a non-ICU.¹⁷ Patients were screened with a 2-question tool to determine whether they were high risk for a MRSA infection. The 2 questions were “Have you been admitted to any health care facility in the last 12 months?” and “Do you have a skin infection (eg, boil, abscess, spider bite, or cellulitis) at this time?” If patients answered yes to either question, they were considered high risk, and a MRSA PCR nasal swab was ordered.

Patients who answered no to both questions were considered low risk and did not receive a MRSA PCR nasal swab. In total, 623 of 5,609 patients (11.1%) identified as high risk had a positive MRSA PCR nasal swab, and 148 of these 623 patients (23.8%) developed a MRSA-positive clinical culture. Only 121 of 4,986 patients (2.4%) who were high risk and had a negative MRSA PCR nasal swab went on to develop a MRSA-positive clinical culture (98% NPV). Additionally, 104 of 6,741 patients (1.6%) who answered no to both screening questions developed a MRSA-positive clinical culture (98% NPV). Results indicated that a high percentage of patients who were at high risk for MRSA (yes response to either question) and had a positive MRSA PCR nasal swab also had a positive clinical culture for MRSA. Conversely, a very small percentage of high-risk patients with a negative MRSA PCR nasal swab developed a positive clinical culture for MRSA.

The screening tool proved very effective as the low-risk group had the lowest number of patients (1.6%) develop a positive clinical culture for MRSA. It may be deduced that combination use of MRSA colonization testing via PCR nasal swabs in conjunction with a screening tool may be an effective method to identify patients in whom anti-MRSA therapy can be safely discontinued.

Conclusion

Based on the results of previously described studies, sufficient data may exist to support the discontinuation of MRSA-targeted therapy in noncritically ill patients with confirmed or suspected pneumonia and a negative MRSA PCR nasal swab. Insufficient evidence exists, however, to support a broadening of antimicrobial therapy to include anti-MRSA coverage in individuals with a positive MRSA PCR nasal swab, regardless of the infection site.

Clinical judgment should be used when determining empiric antimicrobial therapy and for appropriateness of de-escalation of therapy in critically ill patients. Once a patient stabilizes, a negative MRSA PCR nasal swab could be considered as supporting evidence to discontinue anti-MRSA therapy, especially in patients with lower respiratory infections, such as pneumonia.

Ashley L. Adams, PharmD. What are the key leadership attributes of pharmacy leaders?

Julie A. Groppi, PharmD. As a pharmacy leader, you have to be confident in what you do as a pharmacist and not only look at what you are doing now but what you can do in the future. You always have to look for that next apple to pick, because you have to be willing to accept change and help influence change, even though many people do not like change. As a supervisor, I ran a large and growing clinical pharmacy program. I remember many colleagues saying, “You mean, I have to do this now?” I would always try to bring the conversation around with staff to ensure that the benefit of the change or ‘what is in it for you’ was included in the approach. If you are a leader, communicating with physicians, pharmacists, or VA leadership, you just need to sell it to show why it is important and how the change will improve the process. If you don’t, then you won’t be able facilitate or sustain the momentum needed for change.

One important aspect of being a change leader is to make sure you listen (and talk) to those working in the area on a daily basis when you are going through your processes and trying to create change on what is going happen. It is important to make sure your stakeholders are involved and heard while you think about all of your potential obstacles; this is something that I always have tried to do. Also, reflecting on where you have been and what you have done will help you to think differently and is something you should do both professionally and personally. I may not need to know every aspect of the process, but I need to know the obstacles to figure out ways to prevent or break down those walls and solve those underlying issues.

Dr. Adams. What are some of the challenges and opportunities you have found in pharmacy leadership

Dr. Groppi. I think the challenges [are related to] the sheer volume of work that is out there. Having the ability to be able to separate and think about where you want your team to go is the challenge of any leader. When you are right in the middle of it, you tend to focus on the task at hand to get the work done. One week, it is pain management, and then the next week it is hepatitis C, and then it’s assessing acute care services, then gaps or problems somewhere else. There are always different obstacles and different initiatives (pressures) coming at you. You have to not lose your sense of where you want to go. Often, many people cannot stop and look at the whole picture.

I joined the Clinical Pharmacy Practice office in 2011, and one of the first things we were challenged with when the office started was to write guidelines, create policies, and develop tools that would help guide the practice. However, when we started sending out resources to the field, many people were too busy with what was going on at their local facility to focus on what we had developed, so we had to step back. We brainstormed some ideas and looked at our peers in other offices who had demonstrated success. When we started discussing pharmacist scope of practice agreements, I looked at nursing service and their movement related to scope of practice and how it had impacted change in the profession over the past several years.

Nursing has great infrastructure and support for its program. They created many different types of clinical practice councils within nursing, and they were able to institute a lot of changes and spread their initiatives. We thought, “Why don’t we do this for clinical pharmacy?” So we started doing more outreach to the different sites and had discussions with our advisory board, which resulted in the development of the National Clinical Pharmacy Practice Council (NCPPC). We promoted facility and VISN councils to start talking about practice issues and regularly discussing our initiatives as a part of teleconferences, so we could gain support and keep the momentum. Now the NCPPC has grown and everyone is excited about what is happening. It is having a multipronged effect to impact clinical practice.

Dr. Adams. When you are starting on a new project, how do you and your fellow coworkers decide which one is the best to pursue?

Dr. Groppi. We just do them all—I’m joking... sometimes it feels that way. It’s really hard. There are a lot of different things happening at once and many competing priorities, so we try to do as many things as possible. We will assist with requests that come through the Central Office or questions coming from other program offices related to clinical pharmacy practice and we try to get involved and help support and share the success stories of our pharmacist roles as much as possible. For example, the National Nephrology Office contacted us, about the anticoagulation directive. They wanted to do something similar for nephrology since so many pharmacists were effectively and safely managing erythropoietin stimulating agents. This started a conversation.

Often, the priorities come from patient demand such as in primary care. When VA was implementing patient aligned care teams (PACTs), PBM had to ensure that we had conversations ready to describe clinical pharmacy practice in this area. The same thing occurred with hepatitis C. There were new drugs approved and roles for pharmacists, and often there were not enough providers to care for patients. It became an opportunity.

Frequently, choices are based on what we think will be the largest yield and the biggest gaps in care. Other times, it is based on national priorities. We look at the strategic plan for VA and develop our initiatives accordingly. What’s a new priority or component of the strategic plan for this year? What’s the plan for next year or moving forward? Telepharmacy a few years ago or telehealth is an example. We were making sure to describe our practice in the area and then set goals that are going to sustain the profession.

We focused on PACTs during the first few years as we had hundreds of pharmacists practicing. The next big area was specialty and acute care. We started leading workgroups and focused on policies and guidance to share strong practices. The past several years the focus has been on pain management because everyone is struggling with the number of veterans on opioids. When there is a big crisis, you have to hit it full force and look for opportunities that exist. Antimicrobial stewardship was another great example where we were able to provide help and describe the important role of pharmacists based on the strong practices we have across VA. Many times prioritization is on demand, but always keeping in mind what is happening around you and how it supports our VHA strategic plan.

Dr. Adams. What would be your main advice for future pharmacy leaders? Just taking those opportunities and going with them?

Dr. Groppi. Yes. Look for the spot where you might be able to make a positive impact on patient care for the better and improve outcomes with medications. There are data saying that about 80% of treatment is postdiagnosis, and we are quibbling over roles for clinical pharmacy specialists in the team. There is plenty of work that can be done, more than we as a profession or any single profession can often take on. Why don’t we just look for the opportunities to help? There are enough pieces of pie to go around, so let’s just say the pharmacist’s role is to provide management of medications, this is where we can really help. Look for any of these gaps and go for it. Don’t be afraid.

Ashley L. Adams, PharmD. What are the key leadership attributes of pharmacy leaders?

Julie A. Groppi, PharmD. As a pharmacy leader, you have to be confident in what you do as a pharmacist and not only look at what you are doing now but what you can do in the future. You always have to look for that next apple to pick, because you have to be willing to accept change and help influence change, even though many people do not like change. As a supervisor, I ran a large and growing clinical pharmacy program. I remember many colleagues saying, “You mean, I have to do this now?” I would always try to bring the conversation around with staff to ensure that the benefit of the change or ‘what is in it for you’ was included in the approach. If you are a leader, communicating with physicians, pharmacists, or VA leadership, you just need to sell it to show why it is important and how the change will improve the process. If you don’t, then you won’t be able facilitate or sustain the momentum needed for change.

One important aspect of being a change leader is to make sure you listen (and talk) to those working in the area on a daily basis when you are going through your processes and trying to create change on what is going happen. It is important to make sure your stakeholders are involved and heard while you think about all of your potential obstacles; this is something that I always have tried to do. Also, reflecting on where you have been and what you have done will help you to think differently and is something you should do both professionally and personally. I may not need to know every aspect of the process, but I need to know the obstacles to figure out ways to prevent or break down those walls and solve those underlying issues.

Dr. Adams. What are some of the challenges and opportunities you have found in pharmacy leadership

Dr. Groppi. I think the challenges [are related to] the sheer volume of work that is out there. Having the ability to be able to separate and think about where you want your team to go is the challenge of any leader. When you are right in the middle of it, you tend to focus on the task at hand to get the work done. One week, it is pain management, and then the next week it is hepatitis C, and then it’s assessing acute care services, then gaps or problems somewhere else. There are always different obstacles and different initiatives (pressures) coming at you. You have to not lose your sense of where you want to go. Often, many people cannot stop and look at the whole picture.

I joined the Clinical Pharmacy Practice office in 2011, and one of the first things we were challenged with when the office started was to write guidelines, create policies, and develop tools that would help guide the practice. However, when we started sending out resources to the field, many people were too busy with what was going on at their local facility to focus on what we had developed, so we had to step back. We brainstormed some ideas and looked at our peers in other offices who had demonstrated success. When we started discussing pharmacist scope of practice agreements, I looked at nursing service and their movement related to scope of practice and how it had impacted change in the profession over the past several years.

Nursing has great infrastructure and support for its program. They created many different types of clinical practice councils within nursing, and they were able to institute a lot of changes and spread their initiatives. We thought, “Why don’t we do this for clinical pharmacy?” So we started doing more outreach to the different sites and had discussions with our advisory board, which resulted in the development of the National Clinical Pharmacy Practice Council (NCPPC). We promoted facility and VISN councils to start talking about practice issues and regularly discussing our initiatives as a part of teleconferences, so we could gain support and keep the momentum. Now the NCPPC has grown and everyone is excited about what is happening. It is having a multipronged effect to impact clinical practice.

Dr. Adams. When you are starting on a new project, how do you and your fellow coworkers decide which one is the best to pursue?

Dr. Groppi. We just do them all—I’m joking... sometimes it feels that way. It’s really hard. There are a lot of different things happening at once and many competing priorities, so we try to do as many things as possible. We will assist with requests that come through the Central Office or questions coming from other program offices related to clinical pharmacy practice and we try to get involved and help support and share the success stories of our pharmacist roles as much as possible. For example, the National Nephrology Office contacted us, about the anticoagulation directive. They wanted to do something similar for nephrology since so many pharmacists were effectively and safely managing erythropoietin stimulating agents. This started a conversation.

Often, the priorities come from patient demand such as in primary care. When VA was implementing patient aligned care teams (PACTs), PBM had to ensure that we had conversations ready to describe clinical pharmacy practice in this area. The same thing occurred with hepatitis C. There were new drugs approved and roles for pharmacists, and often there were not enough providers to care for patients. It became an opportunity.

Frequently, choices are based on what we think will be the largest yield and the biggest gaps in care. Other times, it is based on national priorities. We look at the strategic plan for VA and develop our initiatives accordingly. What’s a new priority or component of the strategic plan for this year? What’s the plan for next year or moving forward? Telepharmacy a few years ago or telehealth is an example. We were making sure to describe our practice in the area and then set goals that are going to sustain the profession.

We focused on PACTs during the first few years as we had hundreds of pharmacists practicing. The next big area was specialty and acute care. We started leading workgroups and focused on policies and guidance to share strong practices. The past several years the focus has been on pain management because everyone is struggling with the number of veterans on opioids. When there is a big crisis, you have to hit it full force and look for opportunities that exist. Antimicrobial stewardship was another great example where we were able to provide help and describe the important role of pharmacists based on the strong practices we have across VA. Many times prioritization is on demand, but always keeping in mind what is happening around you and how it supports our VHA strategic plan.

Dr. Adams. What would be your main advice for future pharmacy leaders? Just taking those opportunities and going with them?

Dr. Groppi. Yes. Look for the spot where you might be able to make a positive impact on patient care for the better and improve outcomes with medications. There are data saying that about 80% of treatment is postdiagnosis, and we are quibbling over roles for clinical pharmacy specialists in the team. There is plenty of work that can be done, more than we as a profession or any single profession can often take on. Why don’t we just look for the opportunities to help? There are enough pieces of pie to go around, so let’s just say the pharmacist’s role is to provide management of medications, this is where we can really help. Look for any of these gaps and go for it. Don’t be afraid.

Ashley L. Adams, PharmD. What are the key leadership attributes of pharmacy leaders?

Julie A. Groppi, PharmD. As a pharmacy leader, you have to be confident in what you do as a pharmacist and not only look at what you are doing now but what you can do in the future. You always have to look for that next apple to pick, because you have to be willing to accept change and help influence change, even though many people do not like change. As a supervisor, I ran a large and growing clinical pharmacy program. I remember many colleagues saying, “You mean, I have to do this now?” I would always try to bring the conversation around with staff to ensure that the benefit of the change or ‘what is in it for you’ was included in the approach. If you are a leader, communicating with physicians, pharmacists, or VA leadership, you just need to sell it to show why it is important and how the change will improve the process. If you don’t, then you won’t be able facilitate or sustain the momentum needed for change.

One important aspect of being a change leader is to make sure you listen (and talk) to those working in the area on a daily basis when you are going through your processes and trying to create change on what is going happen. It is important to make sure your stakeholders are involved and heard while you think about all of your potential obstacles; this is something that I always have tried to do. Also, reflecting on where you have been and what you have done will help you to think differently and is something you should do both professionally and personally. I may not need to know every aspect of the process, but I need to know the obstacles to figure out ways to prevent or break down those walls and solve those underlying issues.

Dr. Adams. What are some of the challenges and opportunities you have found in pharmacy leadership

Dr. Groppi. I think the challenges [are related to] the sheer volume of work that is out there. Having the ability to be able to separate and think about where you want your team to go is the challenge of any leader. When you are right in the middle of it, you tend to focus on the task at hand to get the work done. One week, it is pain management, and then the next week it is hepatitis C, and then it’s assessing acute care services, then gaps or problems somewhere else. There are always different obstacles and different initiatives (pressures) coming at you. You have to not lose your sense of where you want to go. Often, many people cannot stop and look at the whole picture.

I joined the Clinical Pharmacy Practice office in 2011, and one of the first things we were challenged with when the office started was to write guidelines, create policies, and develop tools that would help guide the practice. However, when we started sending out resources to the field, many people were too busy with what was going on at their local facility to focus on what we had developed, so we had to step back. We brainstormed some ideas and looked at our peers in other offices who had demonstrated success. When we started discussing pharmacist scope of practice agreements, I looked at nursing service and their movement related to scope of practice and how it had impacted change in the profession over the past several years.

Nursing has great infrastructure and support for its program. They created many different types of clinical practice councils within nursing, and they were able to institute a lot of changes and spread their initiatives. We thought, “Why don’t we do this for clinical pharmacy?” So we started doing more outreach to the different sites and had discussions with our advisory board, which resulted in the development of the National Clinical Pharmacy Practice Council (NCPPC). We promoted facility and VISN councils to start talking about practice issues and regularly discussing our initiatives as a part of teleconferences, so we could gain support and keep the momentum. Now the NCPPC has grown and everyone is excited about what is happening. It is having a multipronged effect to impact clinical practice.

Dr. Adams. When you are starting on a new project, how do you and your fellow coworkers decide which one is the best to pursue?

Dr. Groppi. We just do them all—I’m joking... sometimes it feels that way. It’s really hard. There are a lot of different things happening at once and many competing priorities, so we try to do as many things as possible. We will assist with requests that come through the Central Office or questions coming from other program offices related to clinical pharmacy practice and we try to get involved and help support and share the success stories of our pharmacist roles as much as possible. For example, the National Nephrology Office contacted us, about the anticoagulation directive. They wanted to do something similar for nephrology since so many pharmacists were effectively and safely managing erythropoietin stimulating agents. This started a conversation.

Often, the priorities come from patient demand such as in primary care. When VA was implementing patient aligned care teams (PACTs), PBM had to ensure that we had conversations ready to describe clinical pharmacy practice in this area. The same thing occurred with hepatitis C. There were new drugs approved and roles for pharmacists, and often there were not enough providers to care for patients. It became an opportunity.

Frequently, choices are based on what we think will be the largest yield and the biggest gaps in care. Other times, it is based on national priorities. We look at the strategic plan for VA and develop our initiatives accordingly. What’s a new priority or component of the strategic plan for this year? What’s the plan for next year or moving forward? Telepharmacy a few years ago or telehealth is an example. We were making sure to describe our practice in the area and then set goals that are going to sustain the profession.

We focused on PACTs during the first few years as we had hundreds of pharmacists practicing. The next big area was specialty and acute care. We started leading workgroups and focused on policies and guidance to share strong practices. The past several years the focus has been on pain management because everyone is struggling with the number of veterans on opioids. When there is a big crisis, you have to hit it full force and look for opportunities that exist. Antimicrobial stewardship was another great example where we were able to provide help and describe the important role of pharmacists based on the strong practices we have across VA. Many times prioritization is on demand, but always keeping in mind what is happening around you and how it supports our VHA strategic plan.

Dr. Adams. What would be your main advice for future pharmacy leaders? Just taking those opportunities and going with them?

Dr. Groppi. Yes. Look for the spot where you might be able to make a positive impact on patient care for the better and improve outcomes with medications. There are data saying that about 80% of treatment is postdiagnosis, and we are quibbling over roles for clinical pharmacy specialists in the team. There is plenty of work that can be done, more than we as a profession or any single profession can often take on. Why don’t we just look for the opportunities to help? There are enough pieces of pie to go around, so let’s just say the pharmacist’s role is to provide management of medications, this is where we can really help. Look for any of these gaps and go for it. Don’t be afraid.

The FDA has made it easier and faster for health care professionals (HCPs) to get up-to-date drug safety information for the more than 18,000 approved drugs via its Drug Safety Labeling Changes (SLCs) database. The FDA Center for Drug Evaluation and Research recently launched a new searchable and downloadable database for SLCs information (http://www.fda.gov/slc). In most cases, the improved website provides supplemental labeling information within days of a safety label change. Now when a physician or other HCP prescribes a medicine using an e-prescribing system, the updated drug safety information displays much faster than it did with the previous safety labeling changes system. Here’s how.

Shortly after FDA approval of the new drug safety information for an existing drug, the information is entered into the safety labeling changes database. Health information technology (IT) vendors that provide clinical and drug information support for hospitals and pharmacies are then alerted to integrate the updated data into their systems as well. Instead of waiting weeks for the monthly release of all safety labeling updates, this information now is accessible within days.

Although SLCs have been available online for many years, previously they were aggregated and posted only monthly. This time frame meant that if a new safety concern was reflected in an approved labeling change early in a month, then the information was not publicly posted until the following month—4 to 5 weeks later. The FDA recognized the need to apply new digital functionalities to shorten the time between an SLC approval and the public availability of the safety information. Between January 2015 and July 2016, FDA made more than 1,500 SLCs (Table).

As health care professionals know, the “labeling” of a medicine includes detailed information provided in the package insert that accompanies the drug whether it’s on the box, inside the product box, or folded and glued to the lid of a bottle. The product labeling includes a summary for the safe and effective use of the drug and is generally intended for use by prescribers and pharmacists.

However, when a drug is approved, not every safety concern or risk potential can be identified or known. Safety information can change multiple times over the lifetime of a drug as the FDA learns about new risks, interactions with other medications, and adverse effects.

After the FDA becomes aware of new safety information, changes to the product labeling may be required. That’s why postmarketing safety oversight is essential to learn more about the effects of medicines when they are used by a large number of people over a long period. If new safety concerns emerge after a medicine is used in a real-world setting, the FDA may require a “Safety Labeling Change.” The FDA’s new, faster connection between updated safety information and safety alerts on the pharmacy computer system can help build improved confidence into each drug prescription.

The new SLCs website contains a database of changed safety information from all sections of the label that addresses a drug’s safety, including:

• Boxed warning
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Patient counseling information/patient information/medication guide

Health care providers, health IT vendors, and the public now have access to critical safety data that can impact the health of a patient faster than before.

Providing drug safety labeling changes quickly to health care vendors facilitates having the data further integrated into systems frequently accessed by HCPs. It also carries SLC data downstream for integration into drug information systems and other electronic venues, such as social media, news feeds, and websites, with vast reach among health care professionals, patients, and consumers. Some of these include WebMD, Medscape, American Society of Health-System Pharmacists, PDR.net, Epocrates, First Databank, and Yahoo Health.

The data files are downloadable in a comma-separated values format—a feature that allows information to be gathered faster. There also are hyperlinks to the labeling revisions at Drugs@FDA, and notifications are sent to subscribers via an RSS feed.

The FDA continues to pursue and provide innovative ways to rapidly access important information that protects and advances public health and will work to better identify class labeling changes. The FDA’s primary goal for the redesigned SLC Internet interface is to deliver drug safety labeling changes as quickly and efficiently as possible, to help create and promote better patient health.

The FDA has made it easier and faster for health care professionals (HCPs) to get up-to-date drug safety information for the more than 18,000 approved drugs via its Drug Safety Labeling Changes (SLCs) database. The FDA Center for Drug Evaluation and Research recently launched a new searchable and downloadable database for SLCs information (http://www.fda.gov/slc). In most cases, the improved website provides supplemental labeling information within days of a safety label change. Now when a physician or other HCP prescribes a medicine using an e-prescribing system, the updated drug safety information displays much faster than it did with the previous safety labeling changes system. Here’s how.

Shortly after FDA approval of the new drug safety information for an existing drug, the information is entered into the safety labeling changes database. Health information technology (IT) vendors that provide clinical and drug information support for hospitals and pharmacies are then alerted to integrate the updated data into their systems as well. Instead of waiting weeks for the monthly release of all safety labeling updates, this information now is accessible within days.

Although SLCs have been available online for many years, previously they were aggregated and posted only monthly. This time frame meant that if a new safety concern was reflected in an approved labeling change early in a month, then the information was not publicly posted until the following month—4 to 5 weeks later. The FDA recognized the need to apply new digital functionalities to shorten the time between an SLC approval and the public availability of the safety information. Between January 2015 and July 2016, FDA made more than 1,500 SLCs (Table).

As health care professionals know, the “labeling” of a medicine includes detailed information provided in the package insert that accompanies the drug whether it’s on the box, inside the product box, or folded and glued to the lid of a bottle. The product labeling includes a summary for the safe and effective use of the drug and is generally intended for use by prescribers and pharmacists.

However, when a drug is approved, not every safety concern or risk potential can be identified or known. Safety information can change multiple times over the lifetime of a drug as the FDA learns about new risks, interactions with other medications, and adverse effects.

After the FDA becomes aware of new safety information, changes to the product labeling may be required. That’s why postmarketing safety oversight is essential to learn more about the effects of medicines when they are used by a large number of people over a long period. If new safety concerns emerge after a medicine is used in a real-world setting, the FDA may require a “Safety Labeling Change.” The FDA’s new, faster connection between updated safety information and safety alerts on the pharmacy computer system can help build improved confidence into each drug prescription.

The new SLCs website contains a database of changed safety information from all sections of the label that addresses a drug’s safety, including:

• Boxed warning
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Patient counseling information/patient information/medication guide

Health care providers, health IT vendors, and the public now have access to critical safety data that can impact the health of a patient faster than before.

Providing drug safety labeling changes quickly to health care vendors facilitates having the data further integrated into systems frequently accessed by HCPs. It also carries SLC data downstream for integration into drug information systems and other electronic venues, such as social media, news feeds, and websites, with vast reach among health care professionals, patients, and consumers. Some of these include WebMD, Medscape, American Society of Health-System Pharmacists, PDR.net, Epocrates, First Databank, and Yahoo Health.

The data files are downloadable in a comma-separated values format—a feature that allows information to be gathered faster. There also are hyperlinks to the labeling revisions at Drugs@FDA, and notifications are sent to subscribers via an RSS feed.

The FDA continues to pursue and provide innovative ways to rapidly access important information that protects and advances public health and will work to better identify class labeling changes. The FDA’s primary goal for the redesigned SLC Internet interface is to deliver drug safety labeling changes as quickly and efficiently as possible, to help create and promote better patient health.

The FDA has made it easier and faster for health care professionals (HCPs) to get up-to-date drug safety information for the more than 18,000 approved drugs via its Drug Safety Labeling Changes (SLCs) database. The FDA Center for Drug Evaluation and Research recently launched a new searchable and downloadable database for SLCs information (http://www.fda.gov/slc). In most cases, the improved website provides supplemental labeling information within days of a safety label change. Now when a physician or other HCP prescribes a medicine using an e-prescribing system, the updated drug safety information displays much faster than it did with the previous safety labeling changes system. Here’s how.

Shortly after FDA approval of the new drug safety information for an existing drug, the information is entered into the safety labeling changes database. Health information technology (IT) vendors that provide clinical and drug information support for hospitals and pharmacies are then alerted to integrate the updated data into their systems as well. Instead of waiting weeks for the monthly release of all safety labeling updates, this information now is accessible within days.

Although SLCs have been available online for many years, previously they were aggregated and posted only monthly. This time frame meant that if a new safety concern was reflected in an approved labeling change early in a month, then the information was not publicly posted until the following month—4 to 5 weeks later. The FDA recognized the need to apply new digital functionalities to shorten the time between an SLC approval and the public availability of the safety information. Between January 2015 and July 2016, FDA made more than 1,500 SLCs (Table).

As health care professionals know, the “labeling” of a medicine includes detailed information provided in the package insert that accompanies the drug whether it’s on the box, inside the product box, or folded and glued to the lid of a bottle. The product labeling includes a summary for the safe and effective use of the drug and is generally intended for use by prescribers and pharmacists.

However, when a drug is approved, not every safety concern or risk potential can be identified or known. Safety information can change multiple times over the lifetime of a drug as the FDA learns about new risks, interactions with other medications, and adverse effects.

After the FDA becomes aware of new safety information, changes to the product labeling may be required. That’s why postmarketing safety oversight is essential to learn more about the effects of medicines when they are used by a large number of people over a long period. If new safety concerns emerge after a medicine is used in a real-world setting, the FDA may require a “Safety Labeling Change.” The FDA’s new, faster connection between updated safety information and safety alerts on the pharmacy computer system can help build improved confidence into each drug prescription.

The new SLCs website contains a database of changed safety information from all sections of the label that addresses a drug’s safety, including:

• Boxed warning
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Patient counseling information/patient information/medication guide

Health care providers, health IT vendors, and the public now have access to critical safety data that can impact the health of a patient faster than before.

Providing drug safety labeling changes quickly to health care vendors facilitates having the data further integrated into systems frequently accessed by HCPs. It also carries SLC data downstream for integration into drug information systems and other electronic venues, such as social media, news feeds, and websites, with vast reach among health care professionals, patients, and consumers. Some of these include WebMD, Medscape, American Society of Health-System Pharmacists, PDR.net, Epocrates, First Databank, and Yahoo Health.

The data files are downloadable in a comma-separated values format—a feature that allows information to be gathered faster. There also are hyperlinks to the labeling revisions at Drugs@FDA, and notifications are sent to subscribers via an RSS feed.

The FDA continues to pursue and provide innovative ways to rapidly access important information that protects and advances public health and will work to better identify class labeling changes. The FDA’s primary goal for the redesigned SLC Internet interface is to deliver drug safety labeling changes as quickly and efficiently as possible, to help create and promote better patient health.

More than one-third of Americans and > 20% of veterans have obesity with a body mass index (BMI) ≥ 30 kg/m².^1,2 It is well documented that patients with obesity have altered lipid metabolism, drug distribution, and drug clearance.^3-5 As many as 8.2 million Americans may receive statin (3-hydroxymethylglutaryl coenzyme A reductase inhibitors) prescriptions if the American College of Cardiology/American Heart Association 2013 Cholesterol Guidelines are followed; therefore, it is important to examine how the efficacy of these drugs is altered in patients with obesity.⁶

Multiple studies have examined the benefits of statin therapy through lowering low-density lipoprotein cholesterol (LDL-C); however, few have examined the impact of obesity on statin efficacy. For example, only 18% of subjects in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial were classified as having obesity, and subjects in the Scandinavian Simvastatin Survival Study (4S) trial had a mean BMI of only 26 kg/m².^7,8 Though statins decreased mortality in both of these studies, it is unknown whether the lipid-lowering effects were the same for participants with and without obesity. The Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated a decrease in major cardiovascular events and all-cause mortality with atorvastatin 10 mg daily therapy in a sample where more than one-third of subjects had obesity.⁹ However, the mean baseline BMI of subjects in both study groups was only 28 kg/m², and outcomes for those with and without obesity were not compared.⁹

Studies that have examined statin efficacy in those with and without obesity include the Heart Protection Study (HPS), a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), and a meta-analysis by Blassetto and colleagues. The HPS examined the event rate of vascular events with simvastatin 40 mg daily in patients with diabetes mellitus (DM).¹⁰ Though these subgroups were compared in HPS, no statistical difference was demonstrated between these groups for the rate of vascular events among those with and without DM.¹⁰ However, the obesity subgroup’s event rate ratios were consistently higher than were those for the nonobese group.¹⁰

A post hoc analysis of WOSCOPS examined obesity as a factor for change in LDL-C with pravastatin 40 mg therapy.¹¹ Though the authors found that no significant difference was present between those with and those without obesity, the data supporting this claim were not disclosed, which makes drawing clinical conclusions from this analysis difficult.¹¹ A meta-analysis by Blassetto and colleagues examined the association between rosuvastatin’s efficacy in lowering LDL-C among the subgroups of hypertension, atherosclerosis, type 2 DM, and obesity.¹² Though these subgroups were not compared statistically, the obesity subgroup had the lowest mean percent change in lowering LDL-C. Moreover, patients without obesity were not examined as a subgroup.¹²

With the expected increase in statin therapy and a significant portion of the U.S. population having obesity, it is necessary to determine if obesity alters the efficacy of statins. This study was conducted to determine the effect of obesity on the percent change in LDL-C with statin therapy within a veteran population.

Methods

This study was a retrospective review examining follow-up data from January 1, 2009 to July 1, 2014 from the VA Midsouth Healthcare Network. This network services more than 350,000 patients each year in Tennessee, Kentucky, and West Virginia. Data were gathered and analyzed on the VA Informatics and Computing Infrastructure (VINCI) servers. Patients were included in this study if they were aged ≥ 18 years with a new filled prescription for simvastatin 20 mg or simvastatin 40 mg daily. Simvastatin was chosen because it was the formulary statin during the study period. This study was approved by the James H. Quillen VAMC/East Tennessee State University Institutional Review Board.

Patients were excluded if they had received treatment for hyperlipidemia (niacin, colestyramine, colestipol, colesevelam, other statins, gemfibrozil, fenofibrate, omega-3 ethyl esters, ezetimibe) during the 6 weeks prior to the initial fill date of the statin prescription. Patients whose simvastatin therapy did not span the follow-up period from the time of filling to the follow-up lipid panel were excluded, as were those who had not filled a simvastatin prescription within 30 days of their baseline lipid panel. Also excluded were patients who were newly established at the VA, pregnant, or receiving concomitant antihyperlipidemia agents, dialysis, or interacting medications (tacrolimus, cyclosporine, atazanavir, darunavir, nelfinavir, saquinavir, ritonavir, indinavir, lopinavir, tipranavir, fosamprenavir, fluconazole, voriconazole, itraconazole, voriconazole, posaconazole, amiodarone, or colchicine). Patients with a BMI < 18 kg/m², hepatic failure as measured by an aspartate transaminase/alanine transaminase (AST/ALT) ratio > 3 times the upper limit of normal, hepatitis, a history of alcoholism, any change in statin dose prior to follow-up cholesterol values, or no follow-up LDL-C values also were excluded.

The baseline data collected included age, sex, weight, height, BMI, hemoglobin A_1c, LDL-C, ALT/AST, and serum creatinine (SCr). All other laboratory results were required to be within 270 days of the time the lipid panel was obtained. The index date was set as the date the initial prescription was filled between February 1, 2009 and April 1, 2014. Follow-up levels for LDL-C were obtained 40 to 95 days after the index date. Direct LDL-C values were preferred unless only calculated values were available. Calculated LDL-C values were determined by using the Friedewald equation. An audit of 150 patient charts was conducted to ensure the integrity of data pulled from the database.

The percent changes in LDL-C were calculated for those with and without obesity for both simvastatin 20 mg daily and simvastatin 40 mg daily. The primary outcome was the percent change in LDL-C from baseline. All laboratory values were compared using independent 2-tailed t tests with α set to .05. To have an 80% chance of detecting a 5% difference in percent change in LDL-C between the experimental and control groups, 129 patients were required. To determine whether an association was present, a correlation between BMI and percent change in LDL-C was conducted. All statistics were conducted using SAS software (Cary, North Carolina).

Results

From January 2009 through July 2014, 35,216 patients were initially screened. The majority of patients did not have a baseline LDL-C value and were excluded. A total of 1,183 patients with simvastatin 20 mg daily (BMI < 30 = 661; BMI ≥ 30 = 1,122) and 478 patients with simvastatin 40 mg daily (BMI < 30 = 259; BMI ≥ 30 = 219) met the inclusion criteria.

Baseline characteristics were similar between groups except for a slightly higher age in both groups without obesity (Table). Hepatic and renal serum markers indicated a baseline of adequate organ function for drug clearance for all groups. The mean baseline BMI of those without obesity was about 26 kg/m², which is considered overweight. Baseline LDL-C values were clinically similar for those with and without obesity, though statistically different (145 mg/dL for the nonobese group and 141 mg/dL for the obese group, P < .05). The percent change in LDL-C was not statistically significant for those with and without obesity for simvastatin 20 mg daily (P = .293) or simvastatin 40 mg daily (P = .2773) (Figure). No correlation was found between the continuous percent change in LDL-C and continuous BMI for either simvastatin dosage (r² = 0.0016 and 0.0028, respectively).

Discussion

In this retrospective chart review, it was determined that obesity did not affect the percent change in LDL-C from baseline with statin therapy. The HPS found similar results as a secondary endpoint, although that study was underpowered.¹⁰ In this study, all groups met power, and there was still no difference between those with and without obesity.

Nicholls and colleagues examined REVERSAL study data to determine whether BMI greater than the median BMI impacted inflammatory markers or lipid levels with atorvastatin 80 mg daily or pravastatin 40 mg daily. The REVERSAL study authors found no difference in percent change LDL-C between those above the median BMI compared with those below the median BMI for patients on pravastatin therapy. However, the authors did find a difference in percent change LDL-C with atorvastatin therapy.¹³ No difference in percent change LDL-C was present with simvastatin therapy in this study. As simvastatin is more lipophilic than is atorvastatin, lipophilicity remains an area for further study for statin therapy in patients with obesity.

The surrogate marker of percent change in LDL-C was used for the primary outcome in this study. The ACC/AHA 2013 guidelines and the National Lipid Association 2014 guidelines recommend an alternative goal of 30% to 50% change in LDL-C from baseline.^14,15 Using this clinically relevant marker compensated for differences in baseline LDL-C and limited the effect of these differences on the primary outcome of this study.

Limitations

This study did not include patients who were underweight (BMI < 18 kg/m²), as these patients have previously demonstrated decreased outcomes with statin therapy.¹⁶ However, this limits these data to only those patients that have a BMI of at least 18 kg/m². Limitations of this study also included the inability to consider adherence and lifestyle changes. These limitations were unavoidable due to the nature of a retrospective chart review.

Conclusion

The prevalence of obesity is increasing, and it is a disease that alters pharmacokinetics and lipid metabolism. Though this study did not find a difference between the LDL-C-lowering efficacy of simvastatin in those with and without obesity, continued study of the effect of obesity on the efficacy of medications is vital.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the James H. Qullen VAMC in Mountain Home, Tennessee.

More than one-third of Americans and > 20% of veterans have obesity with a body mass index (BMI) ≥ 30 kg/m².^1,2 It is well documented that patients with obesity have altered lipid metabolism, drug distribution, and drug clearance.^3-5 As many as 8.2 million Americans may receive statin (3-hydroxymethylglutaryl coenzyme A reductase inhibitors) prescriptions if the American College of Cardiology/American Heart Association 2013 Cholesterol Guidelines are followed; therefore, it is important to examine how the efficacy of these drugs is altered in patients with obesity.⁶

Multiple studies have examined the benefits of statin therapy through lowering low-density lipoprotein cholesterol (LDL-C); however, few have examined the impact of obesity on statin efficacy. For example, only 18% of subjects in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial were classified as having obesity, and subjects in the Scandinavian Simvastatin Survival Study (4S) trial had a mean BMI of only 26 kg/m².^7,8 Though statins decreased mortality in both of these studies, it is unknown whether the lipid-lowering effects were the same for participants with and without obesity. The Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated a decrease in major cardiovascular events and all-cause mortality with atorvastatin 10 mg daily therapy in a sample where more than one-third of subjects had obesity.⁹ However, the mean baseline BMI of subjects in both study groups was only 28 kg/m², and outcomes for those with and without obesity were not compared.⁹

Studies that have examined statin efficacy in those with and without obesity include the Heart Protection Study (HPS), a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), and a meta-analysis by Blassetto and colleagues. The HPS examined the event rate of vascular events with simvastatin 40 mg daily in patients with diabetes mellitus (DM).¹⁰ Though these subgroups were compared in HPS, no statistical difference was demonstrated between these groups for the rate of vascular events among those with and without DM.¹⁰ However, the obesity subgroup’s event rate ratios were consistently higher than were those for the nonobese group.¹⁰

A post hoc analysis of WOSCOPS examined obesity as a factor for change in LDL-C with pravastatin 40 mg therapy.¹¹ Though the authors found that no significant difference was present between those with and those without obesity, the data supporting this claim were not disclosed, which makes drawing clinical conclusions from this analysis difficult.¹¹ A meta-analysis by Blassetto and colleagues examined the association between rosuvastatin’s efficacy in lowering LDL-C among the subgroups of hypertension, atherosclerosis, type 2 DM, and obesity.¹² Though these subgroups were not compared statistically, the obesity subgroup had the lowest mean percent change in lowering LDL-C. Moreover, patients without obesity were not examined as a subgroup.¹²

With the expected increase in statin therapy and a significant portion of the U.S. population having obesity, it is necessary to determine if obesity alters the efficacy of statins. This study was conducted to determine the effect of obesity on the percent change in LDL-C with statin therapy within a veteran population.

Methods

This study was a retrospective review examining follow-up data from January 1, 2009 to July 1, 2014 from the VA Midsouth Healthcare Network. This network services more than 350,000 patients each year in Tennessee, Kentucky, and West Virginia. Data were gathered and analyzed on the VA Informatics and Computing Infrastructure (VINCI) servers. Patients were included in this study if they were aged ≥ 18 years with a new filled prescription for simvastatin 20 mg or simvastatin 40 mg daily. Simvastatin was chosen because it was the formulary statin during the study period. This study was approved by the James H. Quillen VAMC/East Tennessee State University Institutional Review Board.

Patients were excluded if they had received treatment for hyperlipidemia (niacin, colestyramine, colestipol, colesevelam, other statins, gemfibrozil, fenofibrate, omega-3 ethyl esters, ezetimibe) during the 6 weeks prior to the initial fill date of the statin prescription. Patients whose simvastatin therapy did not span the follow-up period from the time of filling to the follow-up lipid panel were excluded, as were those who had not filled a simvastatin prescription within 30 days of their baseline lipid panel. Also excluded were patients who were newly established at the VA, pregnant, or receiving concomitant antihyperlipidemia agents, dialysis, or interacting medications (tacrolimus, cyclosporine, atazanavir, darunavir, nelfinavir, saquinavir, ritonavir, indinavir, lopinavir, tipranavir, fosamprenavir, fluconazole, voriconazole, itraconazole, voriconazole, posaconazole, amiodarone, or colchicine). Patients with a BMI < 18 kg/m², hepatic failure as measured by an aspartate transaminase/alanine transaminase (AST/ALT) ratio > 3 times the upper limit of normal, hepatitis, a history of alcoholism, any change in statin dose prior to follow-up cholesterol values, or no follow-up LDL-C values also were excluded.

The baseline data collected included age, sex, weight, height, BMI, hemoglobin A_1c, LDL-C, ALT/AST, and serum creatinine (SCr). All other laboratory results were required to be within 270 days of the time the lipid panel was obtained. The index date was set as the date the initial prescription was filled between February 1, 2009 and April 1, 2014. Follow-up levels for LDL-C were obtained 40 to 95 days after the index date. Direct LDL-C values were preferred unless only calculated values were available. Calculated LDL-C values were determined by using the Friedewald equation. An audit of 150 patient charts was conducted to ensure the integrity of data pulled from the database.

The percent changes in LDL-C were calculated for those with and without obesity for both simvastatin 20 mg daily and simvastatin 40 mg daily. The primary outcome was the percent change in LDL-C from baseline. All laboratory values were compared using independent 2-tailed t tests with α set to .05. To have an 80% chance of detecting a 5% difference in percent change in LDL-C between the experimental and control groups, 129 patients were required. To determine whether an association was present, a correlation between BMI and percent change in LDL-C was conducted. All statistics were conducted using SAS software (Cary, North Carolina).

Results

From January 2009 through July 2014, 35,216 patients were initially screened. The majority of patients did not have a baseline LDL-C value and were excluded. A total of 1,183 patients with simvastatin 20 mg daily (BMI < 30 = 661; BMI ≥ 30 = 1,122) and 478 patients with simvastatin 40 mg daily (BMI < 30 = 259; BMI ≥ 30 = 219) met the inclusion criteria.

Baseline characteristics were similar between groups except for a slightly higher age in both groups without obesity (Table). Hepatic and renal serum markers indicated a baseline of adequate organ function for drug clearance for all groups. The mean baseline BMI of those without obesity was about 26 kg/m², which is considered overweight. Baseline LDL-C values were clinically similar for those with and without obesity, though statistically different (145 mg/dL for the nonobese group and 141 mg/dL for the obese group, P < .05). The percent change in LDL-C was not statistically significant for those with and without obesity for simvastatin 20 mg daily (P = .293) or simvastatin 40 mg daily (P = .2773) (Figure). No correlation was found between the continuous percent change in LDL-C and continuous BMI for either simvastatin dosage (r² = 0.0016 and 0.0028, respectively).

Discussion

In this retrospective chart review, it was determined that obesity did not affect the percent change in LDL-C from baseline with statin therapy. The HPS found similar results as a secondary endpoint, although that study was underpowered.¹⁰ In this study, all groups met power, and there was still no difference between those with and without obesity.

Nicholls and colleagues examined REVERSAL study data to determine whether BMI greater than the median BMI impacted inflammatory markers or lipid levels with atorvastatin 80 mg daily or pravastatin 40 mg daily. The REVERSAL study authors found no difference in percent change LDL-C between those above the median BMI compared with those below the median BMI for patients on pravastatin therapy. However, the authors did find a difference in percent change LDL-C with atorvastatin therapy.¹³ No difference in percent change LDL-C was present with simvastatin therapy in this study. As simvastatin is more lipophilic than is atorvastatin, lipophilicity remains an area for further study for statin therapy in patients with obesity.

The surrogate marker of percent change in LDL-C was used for the primary outcome in this study. The ACC/AHA 2013 guidelines and the National Lipid Association 2014 guidelines recommend an alternative goal of 30% to 50% change in LDL-C from baseline.^14,15 Using this clinically relevant marker compensated for differences in baseline LDL-C and limited the effect of these differences on the primary outcome of this study.

Limitations

This study did not include patients who were underweight (BMI < 18 kg/m²), as these patients have previously demonstrated decreased outcomes with statin therapy.¹⁶ However, this limits these data to only those patients that have a BMI of at least 18 kg/m². Limitations of this study also included the inability to consider adherence and lifestyle changes. These limitations were unavoidable due to the nature of a retrospective chart review.

Conclusion

The prevalence of obesity is increasing, and it is a disease that alters pharmacokinetics and lipid metabolism. Though this study did not find a difference between the LDL-C-lowering efficacy of simvastatin in those with and without obesity, continued study of the effect of obesity on the efficacy of medications is vital.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the James H. Qullen VAMC in Mountain Home, Tennessee.

More than one-third of Americans and > 20% of veterans have obesity with a body mass index (BMI) ≥ 30 kg/m².^1,2 It is well documented that patients with obesity have altered lipid metabolism, drug distribution, and drug clearance.^3-5 As many as 8.2 million Americans may receive statin (3-hydroxymethylglutaryl coenzyme A reductase inhibitors) prescriptions if the American College of Cardiology/American Heart Association 2013 Cholesterol Guidelines are followed; therefore, it is important to examine how the efficacy of these drugs is altered in patients with obesity.⁶

Multiple studies have examined the benefits of statin therapy through lowering low-density lipoprotein cholesterol (LDL-C); however, few have examined the impact of obesity on statin efficacy. For example, only 18% of subjects in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial were classified as having obesity, and subjects in the Scandinavian Simvastatin Survival Study (4S) trial had a mean BMI of only 26 kg/m².^7,8 Though statins decreased mortality in both of these studies, it is unknown whether the lipid-lowering effects were the same for participants with and without obesity. The Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated a decrease in major cardiovascular events and all-cause mortality with atorvastatin 10 mg daily therapy in a sample where more than one-third of subjects had obesity.⁹ However, the mean baseline BMI of subjects in both study groups was only 28 kg/m², and outcomes for those with and without obesity were not compared.⁹

Studies that have examined statin efficacy in those with and without obesity include the Heart Protection Study (HPS), a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), and a meta-analysis by Blassetto and colleagues. The HPS examined the event rate of vascular events with simvastatin 40 mg daily in patients with diabetes mellitus (DM).¹⁰ Though these subgroups were compared in HPS, no statistical difference was demonstrated between these groups for the rate of vascular events among those with and without DM.¹⁰ However, the obesity subgroup’s event rate ratios were consistently higher than were those for the nonobese group.¹⁰

A post hoc analysis of WOSCOPS examined obesity as a factor for change in LDL-C with pravastatin 40 mg therapy.¹¹ Though the authors found that no significant difference was present between those with and those without obesity, the data supporting this claim were not disclosed, which makes drawing clinical conclusions from this analysis difficult.¹¹ A meta-analysis by Blassetto and colleagues examined the association between rosuvastatin’s efficacy in lowering LDL-C among the subgroups of hypertension, atherosclerosis, type 2 DM, and obesity.¹² Though these subgroups were not compared statistically, the obesity subgroup had the lowest mean percent change in lowering LDL-C. Moreover, patients without obesity were not examined as a subgroup.¹²

With the expected increase in statin therapy and a significant portion of the U.S. population having obesity, it is necessary to determine if obesity alters the efficacy of statins. This study was conducted to determine the effect of obesity on the percent change in LDL-C with statin therapy within a veteran population.

Methods

This study was a retrospective review examining follow-up data from January 1, 2009 to July 1, 2014 from the VA Midsouth Healthcare Network. This network services more than 350,000 patients each year in Tennessee, Kentucky, and West Virginia. Data were gathered and analyzed on the VA Informatics and Computing Infrastructure (VINCI) servers. Patients were included in this study if they were aged ≥ 18 years with a new filled prescription for simvastatin 20 mg or simvastatin 40 mg daily. Simvastatin was chosen because it was the formulary statin during the study period. This study was approved by the James H. Quillen VAMC/East Tennessee State University Institutional Review Board.

Patients were excluded if they had received treatment for hyperlipidemia (niacin, colestyramine, colestipol, colesevelam, other statins, gemfibrozil, fenofibrate, omega-3 ethyl esters, ezetimibe) during the 6 weeks prior to the initial fill date of the statin prescription. Patients whose simvastatin therapy did not span the follow-up period from the time of filling to the follow-up lipid panel were excluded, as were those who had not filled a simvastatin prescription within 30 days of their baseline lipid panel. Also excluded were patients who were newly established at the VA, pregnant, or receiving concomitant antihyperlipidemia agents, dialysis, or interacting medications (tacrolimus, cyclosporine, atazanavir, darunavir, nelfinavir, saquinavir, ritonavir, indinavir, lopinavir, tipranavir, fosamprenavir, fluconazole, voriconazole, itraconazole, voriconazole, posaconazole, amiodarone, or colchicine). Patients with a BMI < 18 kg/m², hepatic failure as measured by an aspartate transaminase/alanine transaminase (AST/ALT) ratio > 3 times the upper limit of normal, hepatitis, a history of alcoholism, any change in statin dose prior to follow-up cholesterol values, or no follow-up LDL-C values also were excluded.

The baseline data collected included age, sex, weight, height, BMI, hemoglobin A_1c, LDL-C, ALT/AST, and serum creatinine (SCr). All other laboratory results were required to be within 270 days of the time the lipid panel was obtained. The index date was set as the date the initial prescription was filled between February 1, 2009 and April 1, 2014. Follow-up levels for LDL-C were obtained 40 to 95 days after the index date. Direct LDL-C values were preferred unless only calculated values were available. Calculated LDL-C values were determined by using the Friedewald equation. An audit of 150 patient charts was conducted to ensure the integrity of data pulled from the database.

The percent changes in LDL-C were calculated for those with and without obesity for both simvastatin 20 mg daily and simvastatin 40 mg daily. The primary outcome was the percent change in LDL-C from baseline. All laboratory values were compared using independent 2-tailed t tests with α set to .05. To have an 80% chance of detecting a 5% difference in percent change in LDL-C between the experimental and control groups, 129 patients were required. To determine whether an association was present, a correlation between BMI and percent change in LDL-C was conducted. All statistics were conducted using SAS software (Cary, North Carolina).

Results

From January 2009 through July 2014, 35,216 patients were initially screened. The majority of patients did not have a baseline LDL-C value and were excluded. A total of 1,183 patients with simvastatin 20 mg daily (BMI < 30 = 661; BMI ≥ 30 = 1,122) and 478 patients with simvastatin 40 mg daily (BMI < 30 = 259; BMI ≥ 30 = 219) met the inclusion criteria.

Baseline characteristics were similar between groups except for a slightly higher age in both groups without obesity (Table). Hepatic and renal serum markers indicated a baseline of adequate organ function for drug clearance for all groups. The mean baseline BMI of those without obesity was about 26 kg/m², which is considered overweight. Baseline LDL-C values were clinically similar for those with and without obesity, though statistically different (145 mg/dL for the nonobese group and 141 mg/dL for the obese group, P < .05). The percent change in LDL-C was not statistically significant for those with and without obesity for simvastatin 20 mg daily (P = .293) or simvastatin 40 mg daily (P = .2773) (Figure). No correlation was found between the continuous percent change in LDL-C and continuous BMI for either simvastatin dosage (r² = 0.0016 and 0.0028, respectively).

Discussion

In this retrospective chart review, it was determined that obesity did not affect the percent change in LDL-C from baseline with statin therapy. The HPS found similar results as a secondary endpoint, although that study was underpowered.¹⁰ In this study, all groups met power, and there was still no difference between those with and without obesity.

Nicholls and colleagues examined REVERSAL study data to determine whether BMI greater than the median BMI impacted inflammatory markers or lipid levels with atorvastatin 80 mg daily or pravastatin 40 mg daily. The REVERSAL study authors found no difference in percent change LDL-C between those above the median BMI compared with those below the median BMI for patients on pravastatin therapy. However, the authors did find a difference in percent change LDL-C with atorvastatin therapy.¹³ No difference in percent change LDL-C was present with simvastatin therapy in this study. As simvastatin is more lipophilic than is atorvastatin, lipophilicity remains an area for further study for statin therapy in patients with obesity.

The surrogate marker of percent change in LDL-C was used for the primary outcome in this study. The ACC/AHA 2013 guidelines and the National Lipid Association 2014 guidelines recommend an alternative goal of 30% to 50% change in LDL-C from baseline.^14,15 Using this clinically relevant marker compensated for differences in baseline LDL-C and limited the effect of these differences on the primary outcome of this study.

Limitations

This study did not include patients who were underweight (BMI < 18 kg/m²), as these patients have previously demonstrated decreased outcomes with statin therapy.¹⁶ However, this limits these data to only those patients that have a BMI of at least 18 kg/m². Limitations of this study also included the inability to consider adherence and lifestyle changes. These limitations were unavoidable due to the nature of a retrospective chart review.

Conclusion

The prevalence of obesity is increasing, and it is a disease that alters pharmacokinetics and lipid metabolism. Though this study did not find a difference between the LDL-C-lowering efficacy of simvastatin in those with and without obesity, continued study of the effect of obesity on the efficacy of medications is vital.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the James H. Qullen VAMC in Mountain Home, Tennessee.

Inefficiencies in the operating room (OR) can occur before, during, and between cases and lead to multiple problems, including delays in the delivery of patient care. They also have a negative financial impact for the institution and cause frustration for surgeons, anesthesiologists, and other OR staff. Ultimately, delays lead to dissatisfaction among patients and health care providers. Operating room efficiency increasingly is becoming a marker of the quality of surgical care.

The Institute of Medicine (IOM) identified timeliness and efficiency as 2 of 6 areas for improvement for U.S. hospitals.¹ Organizations such as the Centers for Medicare and Medicaid Services, Agency for Healthcare Research and Quality, IOM, Institute for Healthcare Improvement, The Joint Commission, Leapfrog Group, and National Quality Forum are beginning to monitor patient care workflow in order to improve quality while reducing costs.²

About 187 million Americans take at least 1 prescription drug.³ An estimated 20% to 50% of patients do not take their medications as prescribed and are said to be nonadherent with therapy.^4,5 Nonadherence to medication also has been shown to result in increased health risks and costs of up to $290 billion.⁶ Patients who receive pharmacist services achieve better clinical outcomes for chronic diseases than national standards.⁷

Among patients with a chronic disease, poor adherence tends to result in poor outcomes and increased medical costs. Yet these are the patients who face the most risks in surgery and require the most preoperative care. Several studies have evaluated the frequency of medication nonadherence prior to surgery and its effect on surgery cancellations. These studies have examined a variety of factors related to patient preoperative education, medications, food intake, bowel prep, etc.

In a VA Puget Sound Health Care System study, 23% of patients undergoing ambulatory surgery were nonadherent to preoperative medication instructions.⁸ Studies have found that up to 7% of cancellations were impacted by medication nonadherence and preoperative education.^9-13 Furthermore, studies using large-scale databases have found medically treatable conditions as a significant source of surgical delay.¹⁴ Had these conditions been treated a priori, delay in surgery would not have occurred. Unfortunately, it is not clear whether the delays were the result of missed preoperative checks or medication nonadherence.

Ensuring patient safety, including reducing medical errors and adverse events (AEs), is imperative in the surgical workflow. In 1999, the IOM estimated that medical error was a leading cause of death in the U.S. and resulted in up to 100,000 deaths annually.¹⁵

In a retrospective study of 15,000 cases, Gawande and colleagues found that 66% of all AEs were surgical and 54% of these were preventable.¹⁶ In addition to improving reporting systems, creating a culture of safety with all members of the health care team and building a partnership with patients during preoperative visits can ensure increased adherence and reduced medication AEs. In a neurosurgical cohort of patients, Bernstein and colleagues found that 85% of patients were subjected to at least 1 error; 10% of the errors were major, and 65% were deemed preventable.¹⁷

The purpose of this study is to evaluate whether redundancy built into the patient care protocols prior to surgery helps catch errors as demonstrated in time-out analyses.¹⁸ Decreasing these errors would lead to fewer surgical cancellations and medical workup delays. The authors hypothesize that a structured preoperative pharmacologic workup would result in decreased preoperative delay in the surgical workflow.

Methods

The study protocol was reviewed and determined to be a quality improvement/quality assurance initiative, which exempted it from institutional review board or other oversight committee review, at the Minneapolis VA Health Care System. The VA OR Efficiency Task Force identified medication adherence as a possible source of delay. A study therefore was undertaken to determine the adherence rate and how it impacted operative delays. Data were extracted from this study to test the stated hypothesis and compare with historic data.

Fifty consecutive patients undergoing neurosurgical procedures from May 2010 through July 2010 were retrospectively reviewed and evaluated. All patients had a preoperative consultation with a pharmacist and the neurosurgery coordinator who reviewed all medications with the patient and gave specific instructions on which medications should be continued or discontinued prior to the surgery date. This information was documented on the OR Medication Compliance Worksheet and included in the patient’s preoperative chart by the neurosurgery coordinator. On the day of surgery, all active medications on this chart were reviewed with the patient by the anesthesiologist and documented on the OR Medication Compliance Worksheet. The worksheet was then sent to the neurosurgery coordinator for secondary review and analysis.

To evaluate delays, the authors reviewed the patient anesthesiology records. Delays were defined as either cancellations of the case due to medication nonadherence, which would make it unsafe to proceed with surgery, or minor delays due to medication nonadherence, which required further preoperative assessment and workup before proceeding with surgery. Cancelled cases were defined as cases on the final copy of the published OR schedule that did not occur.

Medication Adherence Program

In order to ensure medication adherence prior to surgery there were 5 points of contact with a patient from the time the patient was scheduled for surgery and the date of the surgery (Figure 1):

1.  The coordinator reviewed medications with patient at time of scheduling
2. A letter was sent with specific instructions about medications
3. Preoperative medicine clearance
4. Preoperative neurosurgery appointment
5. Call from pharmacist 1 week before surgery
   

Results

The authors reviewed 10 months of the neurosurgical service prior to initiation of the protocol. Of 317 analyzed cases, 30 were delayed/cancelled. Among these, 5 cases with the possibility of a 6th were cancelled due to medication issues. Following the initialization of the study, 50 patients underwent preoperative counseling with the pharmacist and the neurosurgery coordinator and had an OR Medication Compliance Worksheet created.

Review of the OR Medication Compliance Worksheet demonstrated that 2 patients were nonadherent with their medications.

Discussion

The OR is one of the most expensive areas in an acute care hospital.² Cancellations or delays can have significant negative financial implications (about $1,500 per hour of lost revenue).¹⁹ In order to improve OR efficiency and reduce preoperative delays, the causes of preoperative delays must be determined.

Some delays and cancellations result from either preoperative or perioperative issues. Prolonged wait time and postponement may cause preoperative delays. Perioperative delays include delays in getting into the OR once the patient has arrived in the hospital as well as delays during the operation. These delays can be due to both human error and system deficiencies.²⁰

One Toronto, Canada study looked at the different etiologies for delays in cranial and spinal procedures and found that equipment failure followed by physical transit into the OR were the top reasons for delays.²¹ These researchers also found that first cases each day sometimes had a higher incidence of delays than did subsequent cases because several ORs prepare to start simultaneously, which causes an increased demand on hospital support services (eg, registration desk, imaging department, nurses in the patient holding area, or transportation). The number of these support staff remains constant throughout the day, whereas the first-case patients all arrive at about the same time, causing a bottleneck in the early morning. The authors looked at 1 facet of the delay problem as an ongoing analysis for hospital efficiency improvement.

With the implementation of a simple 5-step process, medication adherence was > 90% and the impact of nonadherence on surgical procedure delays was eliminated during the trial period. In this sample, nonadherence did not impact surgery, which resulted in fewer delays and cancellations. The process emphasized repetition and communication, involving 5 reminders between the date of OR scheduling and the date of the actual surgery. The authors found that in this quality improvement study, redundancy in the workflow actually improved the efficiency of the patient’s hospital course.

Within the OR, there are many perspectives to consider for improving OR efficiency. For instance, Archer and colleagues present several distinct perspectives: that of the health care institution, the individual practitioner, the patient, and evidenced-based medicine.² According to Strum and colleagues, OR inefficiency is the sum of under- and overutilized time and efficiency is highest when OR inefficiency is minimized.²² An OR is considered underutilized when it is staffed at regular wages but not used for surgery, setup, or cleanup. An OR is considered overutilized when the OR staff receives overtime wages, multiplied by the relative cost of overtime compared with straight time. Delayed or cancelled surgeries can result in idle operating room staff, while repeat or correlative studies (ie, electrocardiogram, drug levels) may overutilize support services.

Limitations

This study has obvious limitations due to its small scale. Because the protocol implementation resulted in few delays, a very large cohort would have been necessary to attain statistical power.

Conclusion

By improving OR efficiency and reducing preoperative delays, surgical capacity can be increased.

In this study, the authors demonstrate that with little addition of cost, medication nonadherence can be reduced or eliminated as an issue for surgical delays. With the implementation of the 5-step reminder process as well as the addition of a pharmacist consultation/visit, medication adherence was > 90% among preoperative patients in this small study. With the number of patients with complex medication regimens, increasing medication adherence in the preoperative period is not only important in reducing operative delays, but also an opportunity to ensure the patient is safe and optimally treated. ˜

Inefficiencies in the operating room (OR) can occur before, during, and between cases and lead to multiple problems, including delays in the delivery of patient care. They also have a negative financial impact for the institution and cause frustration for surgeons, anesthesiologists, and other OR staff. Ultimately, delays lead to dissatisfaction among patients and health care providers. Operating room efficiency increasingly is becoming a marker of the quality of surgical care.

The Institute of Medicine (IOM) identified timeliness and efficiency as 2 of 6 areas for improvement for U.S. hospitals.¹ Organizations such as the Centers for Medicare and Medicaid Services, Agency for Healthcare Research and Quality, IOM, Institute for Healthcare Improvement, The Joint Commission, Leapfrog Group, and National Quality Forum are beginning to monitor patient care workflow in order to improve quality while reducing costs.²

About 187 million Americans take at least 1 prescription drug.³ An estimated 20% to 50% of patients do not take their medications as prescribed and are said to be nonadherent with therapy.^4,5 Nonadherence to medication also has been shown to result in increased health risks and costs of up to $290 billion.⁶ Patients who receive pharmacist services achieve better clinical outcomes for chronic diseases than national standards.⁷

Among patients with a chronic disease, poor adherence tends to result in poor outcomes and increased medical costs. Yet these are the patients who face the most risks in surgery and require the most preoperative care. Several studies have evaluated the frequency of medication nonadherence prior to surgery and its effect on surgery cancellations. These studies have examined a variety of factors related to patient preoperative education, medications, food intake, bowel prep, etc.

In a VA Puget Sound Health Care System study, 23% of patients undergoing ambulatory surgery were nonadherent to preoperative medication instructions.⁸ Studies have found that up to 7% of cancellations were impacted by medication nonadherence and preoperative education.^9-13 Furthermore, studies using large-scale databases have found medically treatable conditions as a significant source of surgical delay.¹⁴ Had these conditions been treated a priori, delay in surgery would not have occurred. Unfortunately, it is not clear whether the delays were the result of missed preoperative checks or medication nonadherence.

Ensuring patient safety, including reducing medical errors and adverse events (AEs), is imperative in the surgical workflow. In 1999, the IOM estimated that medical error was a leading cause of death in the U.S. and resulted in up to 100,000 deaths annually.¹⁵

In a retrospective study of 15,000 cases, Gawande and colleagues found that 66% of all AEs were surgical and 54% of these were preventable.¹⁶ In addition to improving reporting systems, creating a culture of safety with all members of the health care team and building a partnership with patients during preoperative visits can ensure increased adherence and reduced medication AEs. In a neurosurgical cohort of patients, Bernstein and colleagues found that 85% of patients were subjected to at least 1 error; 10% of the errors were major, and 65% were deemed preventable.¹⁷

The purpose of this study is to evaluate whether redundancy built into the patient care protocols prior to surgery helps catch errors as demonstrated in time-out analyses.¹⁸ Decreasing these errors would lead to fewer surgical cancellations and medical workup delays. The authors hypothesize that a structured preoperative pharmacologic workup would result in decreased preoperative delay in the surgical workflow.

Methods

The study protocol was reviewed and determined to be a quality improvement/quality assurance initiative, which exempted it from institutional review board or other oversight committee review, at the Minneapolis VA Health Care System. The VA OR Efficiency Task Force identified medication adherence as a possible source of delay. A study therefore was undertaken to determine the adherence rate and how it impacted operative delays. Data were extracted from this study to test the stated hypothesis and compare with historic data.

Fifty consecutive patients undergoing neurosurgical procedures from May 2010 through July 2010 were retrospectively reviewed and evaluated. All patients had a preoperative consultation with a pharmacist and the neurosurgery coordinator who reviewed all medications with the patient and gave specific instructions on which medications should be continued or discontinued prior to the surgery date. This information was documented on the OR Medication Compliance Worksheet and included in the patient’s preoperative chart by the neurosurgery coordinator. On the day of surgery, all active medications on this chart were reviewed with the patient by the anesthesiologist and documented on the OR Medication Compliance Worksheet. The worksheet was then sent to the neurosurgery coordinator for secondary review and analysis.

To evaluate delays, the authors reviewed the patient anesthesiology records. Delays were defined as either cancellations of the case due to medication nonadherence, which would make it unsafe to proceed with surgery, or minor delays due to medication nonadherence, which required further preoperative assessment and workup before proceeding with surgery. Cancelled cases were defined as cases on the final copy of the published OR schedule that did not occur.

Medication Adherence Program

In order to ensure medication adherence prior to surgery there were 5 points of contact with a patient from the time the patient was scheduled for surgery and the date of the surgery (Figure 1):

1.  The coordinator reviewed medications with patient at time of scheduling
2. A letter was sent with specific instructions about medications
3. Preoperative medicine clearance
4. Preoperative neurosurgery appointment
5. Call from pharmacist 1 week before surgery
   

Results

The authors reviewed 10 months of the neurosurgical service prior to initiation of the protocol. Of 317 analyzed cases, 30 were delayed/cancelled. Among these, 5 cases with the possibility of a 6th were cancelled due to medication issues. Following the initialization of the study, 50 patients underwent preoperative counseling with the pharmacist and the neurosurgery coordinator and had an OR Medication Compliance Worksheet created.

Review of the OR Medication Compliance Worksheet demonstrated that 2 patients were nonadherent with their medications.

Discussion

The OR is one of the most expensive areas in an acute care hospital.² Cancellations or delays can have significant negative financial implications (about $1,500 per hour of lost revenue).¹⁹ In order to improve OR efficiency and reduce preoperative delays, the causes of preoperative delays must be determined.

Some delays and cancellations result from either preoperative or perioperative issues. Prolonged wait time and postponement may cause preoperative delays. Perioperative delays include delays in getting into the OR once the patient has arrived in the hospital as well as delays during the operation. These delays can be due to both human error and system deficiencies.²⁰

One Toronto, Canada study looked at the different etiologies for delays in cranial and spinal procedures and found that equipment failure followed by physical transit into the OR were the top reasons for delays.²¹ These researchers also found that first cases each day sometimes had a higher incidence of delays than did subsequent cases because several ORs prepare to start simultaneously, which causes an increased demand on hospital support services (eg, registration desk, imaging department, nurses in the patient holding area, or transportation). The number of these support staff remains constant throughout the day, whereas the first-case patients all arrive at about the same time, causing a bottleneck in the early morning. The authors looked at 1 facet of the delay problem as an ongoing analysis for hospital efficiency improvement.

With the implementation of a simple 5-step process, medication adherence was > 90% and the impact of nonadherence on surgical procedure delays was eliminated during the trial period. In this sample, nonadherence did not impact surgery, which resulted in fewer delays and cancellations. The process emphasized repetition and communication, involving 5 reminders between the date of OR scheduling and the date of the actual surgery. The authors found that in this quality improvement study, redundancy in the workflow actually improved the efficiency of the patient’s hospital course.

Within the OR, there are many perspectives to consider for improving OR efficiency. For instance, Archer and colleagues present several distinct perspectives: that of the health care institution, the individual practitioner, the patient, and evidenced-based medicine.² According to Strum and colleagues, OR inefficiency is the sum of under- and overutilized time and efficiency is highest when OR inefficiency is minimized.²² An OR is considered underutilized when it is staffed at regular wages but not used for surgery, setup, or cleanup. An OR is considered overutilized when the OR staff receives overtime wages, multiplied by the relative cost of overtime compared with straight time. Delayed or cancelled surgeries can result in idle operating room staff, while repeat or correlative studies (ie, electrocardiogram, drug levels) may overutilize support services.

Limitations

This study has obvious limitations due to its small scale. Because the protocol implementation resulted in few delays, a very large cohort would have been necessary to attain statistical power.

Conclusion

By improving OR efficiency and reducing preoperative delays, surgical capacity can be increased.

In this study, the authors demonstrate that with little addition of cost, medication nonadherence can be reduced or eliminated as an issue for surgical delays. With the implementation of the 5-step reminder process as well as the addition of a pharmacist consultation/visit, medication adherence was > 90% among preoperative patients in this small study. With the number of patients with complex medication regimens, increasing medication adherence in the preoperative period is not only important in reducing operative delays, but also an opportunity to ensure the patient is safe and optimally treated. ˜

Inefficiencies in the operating room (OR) can occur before, during, and between cases and lead to multiple problems, including delays in the delivery of patient care. They also have a negative financial impact for the institution and cause frustration for surgeons, anesthesiologists, and other OR staff. Ultimately, delays lead to dissatisfaction among patients and health care providers. Operating room efficiency increasingly is becoming a marker of the quality of surgical care.

The Institute of Medicine (IOM) identified timeliness and efficiency as 2 of 6 areas for improvement for U.S. hospitals.¹ Organizations such as the Centers for Medicare and Medicaid Services, Agency for Healthcare Research and Quality, IOM, Institute for Healthcare Improvement, The Joint Commission, Leapfrog Group, and National Quality Forum are beginning to monitor patient care workflow in order to improve quality while reducing costs.²

About 187 million Americans take at least 1 prescription drug.³ An estimated 20% to 50% of patients do not take their medications as prescribed and are said to be nonadherent with therapy.^4,5 Nonadherence to medication also has been shown to result in increased health risks and costs of up to $290 billion.⁶ Patients who receive pharmacist services achieve better clinical outcomes for chronic diseases than national standards.⁷

Among patients with a chronic disease, poor adherence tends to result in poor outcomes and increased medical costs. Yet these are the patients who face the most risks in surgery and require the most preoperative care. Several studies have evaluated the frequency of medication nonadherence prior to surgery and its effect on surgery cancellations. These studies have examined a variety of factors related to patient preoperative education, medications, food intake, bowel prep, etc.

In a VA Puget Sound Health Care System study, 23% of patients undergoing ambulatory surgery were nonadherent to preoperative medication instructions.⁸ Studies have found that up to 7% of cancellations were impacted by medication nonadherence and preoperative education.^9-13 Furthermore, studies using large-scale databases have found medically treatable conditions as a significant source of surgical delay.¹⁴ Had these conditions been treated a priori, delay in surgery would not have occurred. Unfortunately, it is not clear whether the delays were the result of missed preoperative checks or medication nonadherence.

Ensuring patient safety, including reducing medical errors and adverse events (AEs), is imperative in the surgical workflow. In 1999, the IOM estimated that medical error was a leading cause of death in the U.S. and resulted in up to 100,000 deaths annually.¹⁵

In a retrospective study of 15,000 cases, Gawande and colleagues found that 66% of all AEs were surgical and 54% of these were preventable.¹⁶ In addition to improving reporting systems, creating a culture of safety with all members of the health care team and building a partnership with patients during preoperative visits can ensure increased adherence and reduced medication AEs. In a neurosurgical cohort of patients, Bernstein and colleagues found that 85% of patients were subjected to at least 1 error; 10% of the errors were major, and 65% were deemed preventable.¹⁷

The purpose of this study is to evaluate whether redundancy built into the patient care protocols prior to surgery helps catch errors as demonstrated in time-out analyses.¹⁸ Decreasing these errors would lead to fewer surgical cancellations and medical workup delays. The authors hypothesize that a structured preoperative pharmacologic workup would result in decreased preoperative delay in the surgical workflow.

Methods

The study protocol was reviewed and determined to be a quality improvement/quality assurance initiative, which exempted it from institutional review board or other oversight committee review, at the Minneapolis VA Health Care System. The VA OR Efficiency Task Force identified medication adherence as a possible source of delay. A study therefore was undertaken to determine the adherence rate and how it impacted operative delays. Data were extracted from this study to test the stated hypothesis and compare with historic data.

Fifty consecutive patients undergoing neurosurgical procedures from May 2010 through July 2010 were retrospectively reviewed and evaluated. All patients had a preoperative consultation with a pharmacist and the neurosurgery coordinator who reviewed all medications with the patient and gave specific instructions on which medications should be continued or discontinued prior to the surgery date. This information was documented on the OR Medication Compliance Worksheet and included in the patient’s preoperative chart by the neurosurgery coordinator. On the day of surgery, all active medications on this chart were reviewed with the patient by the anesthesiologist and documented on the OR Medication Compliance Worksheet. The worksheet was then sent to the neurosurgery coordinator for secondary review and analysis.

To evaluate delays, the authors reviewed the patient anesthesiology records. Delays were defined as either cancellations of the case due to medication nonadherence, which would make it unsafe to proceed with surgery, or minor delays due to medication nonadherence, which required further preoperative assessment and workup before proceeding with surgery. Cancelled cases were defined as cases on the final copy of the published OR schedule that did not occur.

Medication Adherence Program

In order to ensure medication adherence prior to surgery there were 5 points of contact with a patient from the time the patient was scheduled for surgery and the date of the surgery (Figure 1):

1.  The coordinator reviewed medications with patient at time of scheduling
2. A letter was sent with specific instructions about medications
3. Preoperative medicine clearance
4. Preoperative neurosurgery appointment
5. Call from pharmacist 1 week before surgery
   

Results

The authors reviewed 10 months of the neurosurgical service prior to initiation of the protocol. Of 317 analyzed cases, 30 were delayed/cancelled. Among these, 5 cases with the possibility of a 6th were cancelled due to medication issues. Following the initialization of the study, 50 patients underwent preoperative counseling with the pharmacist and the neurosurgery coordinator and had an OR Medication Compliance Worksheet created.

Review of the OR Medication Compliance Worksheet demonstrated that 2 patients were nonadherent with their medications.

Discussion

The OR is one of the most expensive areas in an acute care hospital.² Cancellations or delays can have significant negative financial implications (about $1,500 per hour of lost revenue).¹⁹ In order to improve OR efficiency and reduce preoperative delays, the causes of preoperative delays must be determined.

Some delays and cancellations result from either preoperative or perioperative issues. Prolonged wait time and postponement may cause preoperative delays. Perioperative delays include delays in getting into the OR once the patient has arrived in the hospital as well as delays during the operation. These delays can be due to both human error and system deficiencies.²⁰

One Toronto, Canada study looked at the different etiologies for delays in cranial and spinal procedures and found that equipment failure followed by physical transit into the OR were the top reasons for delays.²¹ These researchers also found that first cases each day sometimes had a higher incidence of delays than did subsequent cases because several ORs prepare to start simultaneously, which causes an increased demand on hospital support services (eg, registration desk, imaging department, nurses in the patient holding area, or transportation). The number of these support staff remains constant throughout the day, whereas the first-case patients all arrive at about the same time, causing a bottleneck in the early morning. The authors looked at 1 facet of the delay problem as an ongoing analysis for hospital efficiency improvement.

With the implementation of a simple 5-step process, medication adherence was > 90% and the impact of nonadherence on surgical procedure delays was eliminated during the trial period. In this sample, nonadherence did not impact surgery, which resulted in fewer delays and cancellations. The process emphasized repetition and communication, involving 5 reminders between the date of OR scheduling and the date of the actual surgery. The authors found that in this quality improvement study, redundancy in the workflow actually improved the efficiency of the patient’s hospital course.

Within the OR, there are many perspectives to consider for improving OR efficiency. For instance, Archer and colleagues present several distinct perspectives: that of the health care institution, the individual practitioner, the patient, and evidenced-based medicine.² According to Strum and colleagues, OR inefficiency is the sum of under- and overutilized time and efficiency is highest when OR inefficiency is minimized.²² An OR is considered underutilized when it is staffed at regular wages but not used for surgery, setup, or cleanup. An OR is considered overutilized when the OR staff receives overtime wages, multiplied by the relative cost of overtime compared with straight time. Delayed or cancelled surgeries can result in idle operating room staff, while repeat or correlative studies (ie, electrocardiogram, drug levels) may overutilize support services.

Limitations

This study has obvious limitations due to its small scale. Because the protocol implementation resulted in few delays, a very large cohort would have been necessary to attain statistical power.

Conclusion

By improving OR efficiency and reducing preoperative delays, surgical capacity can be increased.

In this study, the authors demonstrate that with little addition of cost, medication nonadherence can be reduced or eliminated as an issue for surgical delays. With the implementation of the 5-step reminder process as well as the addition of a pharmacist consultation/visit, medication adherence was > 90% among preoperative patients in this small study. With the number of patients with complex medication regimens, increasing medication adherence in the preoperative period is not only important in reducing operative delays, but also an opportunity to ensure the patient is safe and optimally treated. ˜

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

IMODIUM (LOPERAMIDE HYDROCHLORIDE):

• New warning December 2016

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of Imodium (see WARNINGS and OVERDOSAGE).

Imodium is contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS).

Avoid Imodium dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

AUBAGIO (TERIFLUNOMIDE) TABLETS:

• Edited and updated warning December 2016

Risk of Teratogenicity
Aubagio is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with Aubagio in females of reproductive potential. Advise females of reproductive potential to use effective contraception during Aubagio treatment and during an accelerated drug elimination procedure after Aubagio treatment. Stop Aubagio and use an accelerated drug elimination procedure if the patient becomes pregnant.

PROMACTA (ELTROMBOPAG) TABLETS, FOR ORAL USE AND ORAL SUSPENSION:

• Edited and updated warning December 2016

Chronic Hepatitis C
Promacta may increase the risk of severe and potentially lifethreatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

ICLUSIG (PONATINIB HYDROCHLORIDE):

• Edited and updated warning December 2016

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion
Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion.

Venous Thromboembolism
Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure
Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

IMODIUM (LOPERAMIDE HYDROCHLORIDE):

• New warning December 2016

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of Imodium (see WARNINGS and OVERDOSAGE).

Imodium is contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS).

Avoid Imodium dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

AUBAGIO (TERIFLUNOMIDE) TABLETS:

• Edited and updated warning December 2016

Risk of Teratogenicity
Aubagio is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with Aubagio in females of reproductive potential. Advise females of reproductive potential to use effective contraception during Aubagio treatment and during an accelerated drug elimination procedure after Aubagio treatment. Stop Aubagio and use an accelerated drug elimination procedure if the patient becomes pregnant.

PROMACTA (ELTROMBOPAG) TABLETS, FOR ORAL USE AND ORAL SUSPENSION:

• Edited and updated warning December 2016

Chronic Hepatitis C
Promacta may increase the risk of severe and potentially lifethreatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

ICLUSIG (PONATINIB HYDROCHLORIDE):

• Edited and updated warning December 2016

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion
Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion.

Venous Thromboembolism
Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure
Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

IMODIUM (LOPERAMIDE HYDROCHLORIDE):

• New warning December 2016

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of Imodium (see WARNINGS and OVERDOSAGE).

Imodium is contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS).

Avoid Imodium dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

AUBAGIO (TERIFLUNOMIDE) TABLETS:

• Edited and updated warning December 2016

Risk of Teratogenicity
Aubagio is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with Aubagio in females of reproductive potential. Advise females of reproductive potential to use effective contraception during Aubagio treatment and during an accelerated drug elimination procedure after Aubagio treatment. Stop Aubagio and use an accelerated drug elimination procedure if the patient becomes pregnant.

PROMACTA (ELTROMBOPAG) TABLETS, FOR ORAL USE AND ORAL SUSPENSION:

• Edited and updated warning December 2016

Chronic Hepatitis C
Promacta may increase the risk of severe and potentially lifethreatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

ICLUSIG (PONATINIB HYDROCHLORIDE):

• Edited and updated warning December 2016

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion
Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion.

Venous Thromboembolism
Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure
Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients.

The IHS has partnered with 3 top American universities to give pharmacy students an opportunity to get real-life work experience and potentially careers at IHS facilities.

Related: Dangerous Staff Shortages in the IHS

In the IHS Advanced Pharmacy Practice Experience Program, PharmD candidates at Howard University, Purdue University, and the University of Southern California will join students from more than 80 universities in 39 states to complete rotations at IHS direct service facilities. “Many return to start their career in providing quality health care to the American Indian and Alaska Native community,” said Mary Smith, IHS principal deputy director.

“My experience with IHS as a student inspired me to apply to work here when I graduated,” said Fengyee Zhou, now a pharmacist at the IHS Whiteriver Indian Hospital in Arizona. “The level of teamwork among all health care disciplines and the extent to which pharmacists engage in patient care activities brought me back to Whiteriver.”

Related: What s the VA? The Largest Educator of Health Care Professionals in the U.S.

The IHS also offers internships, externships, rotations, and residencies to pharmacy, behavioral health, dentistry, optometry, nursing, and medical students.

The IHS has partnered with 3 top American universities to give pharmacy students an opportunity to get real-life work experience and potentially careers at IHS facilities.

Related: Dangerous Staff Shortages in the IHS

In the IHS Advanced Pharmacy Practice Experience Program, PharmD candidates at Howard University, Purdue University, and the University of Southern California will join students from more than 80 universities in 39 states to complete rotations at IHS direct service facilities. “Many return to start their career in providing quality health care to the American Indian and Alaska Native community,” said Mary Smith, IHS principal deputy director.

“My experience with IHS as a student inspired me to apply to work here when I graduated,” said Fengyee Zhou, now a pharmacist at the IHS Whiteriver Indian Hospital in Arizona. “The level of teamwork among all health care disciplines and the extent to which pharmacists engage in patient care activities brought me back to Whiteriver.”

Related: What s the VA? The Largest Educator of Health Care Professionals in the U.S.

The IHS also offers internships, externships, rotations, and residencies to pharmacy, behavioral health, dentistry, optometry, nursing, and medical students.

The IHS has partnered with 3 top American universities to give pharmacy students an opportunity to get real-life work experience and potentially careers at IHS facilities.

Related: Dangerous Staff Shortages in the IHS

In the IHS Advanced Pharmacy Practice Experience Program, PharmD candidates at Howard University, Purdue University, and the University of Southern California will join students from more than 80 universities in 39 states to complete rotations at IHS direct service facilities. “Many return to start their career in providing quality health care to the American Indian and Alaska Native community,” said Mary Smith, IHS principal deputy director.

“My experience with IHS as a student inspired me to apply to work here when I graduated,” said Fengyee Zhou, now a pharmacist at the IHS Whiteriver Indian Hospital in Arizona. “The level of teamwork among all health care disciplines and the extent to which pharmacists engage in patient care activities brought me back to Whiteriver.”

Related: What s the VA? The Largest Educator of Health Care Professionals in the U.S.

The IHS also offers internships, externships, rotations, and residencies to pharmacy, behavioral health, dentistry, optometry, nursing, and medical students.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. You can search these and other label changes in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

QUINOLONE:

• Edited and updated warning September 2016

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects

Discontinue immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid quinolones in patients with known history of myasthenia gravis. Because fluoroquinolones
have been associated with serious adverse reactions, reserve quinolones for use in patients who have no alternative treatment options for the following
indications:

Avelox (moxifloxacin hydrochloride): Avelox in sodium chloride 0.8% in plastic container; moxifloxacin hydrochloride; Cipro in dextrose 5% in plastic container):
Acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis.

Cipro (ciprofloxacin; ciprofloxacin hydrochloride): Acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and acute sinusitis.

Cipro XR; Noroxin (norfloxacin): Uncomplicated urinary tract infections.

Factive (gemifloxacin mesylate): Acute bacterial exacerbation of chronic bronchitis.

Levaquin (levofloxacin): Uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.
 

KRYSTEXXA (PEGLOTICASE):

• Added section to warning September 2016

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA (Title Updated)

Addition of: Screen patients at risk for G6PD deficiency prior to starting Krystexxa. Hemolysis and methemoglobinemia have been reported with Krystexxa in patients with G6PD deficiency. Do not administer Krystexxa to patients with G6PD deficiency.
 

PLAVIX (CLOPIDOGREL BISULFATE):

• Edited and updated warning September 2016

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
 

SYNJARDY (EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE):

• Edited and updated warning September 2016

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue Synjardy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
 

ZYDELIG (IDELALISIB)

• Edited and updated warning September 2016

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 11 % to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
• Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
• Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. You can search these and other label changes in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

QUINOLONE:

• Edited and updated warning September 2016

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects

Discontinue immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid quinolones in patients with known history of myasthenia gravis. Because fluoroquinolones
have been associated with serious adverse reactions, reserve quinolones for use in patients who have no alternative treatment options for the following
indications:

Avelox (moxifloxacin hydrochloride): Avelox in sodium chloride 0.8% in plastic container; moxifloxacin hydrochloride; Cipro in dextrose 5% in plastic container):
Acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis.

Cipro (ciprofloxacin; ciprofloxacin hydrochloride): Acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and acute sinusitis.

Cipro XR; Noroxin (norfloxacin): Uncomplicated urinary tract infections.

Factive (gemifloxacin mesylate): Acute bacterial exacerbation of chronic bronchitis.

Levaquin (levofloxacin): Uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.
 

KRYSTEXXA (PEGLOTICASE):

• Added section to warning September 2016

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA (Title Updated)

Addition of: Screen patients at risk for G6PD deficiency prior to starting Krystexxa. Hemolysis and methemoglobinemia have been reported with Krystexxa in patients with G6PD deficiency. Do not administer Krystexxa to patients with G6PD deficiency.
 

PLAVIX (CLOPIDOGREL BISULFATE):

• Edited and updated warning September 2016

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
 

SYNJARDY (EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE):

• Edited and updated warning September 2016

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue Synjardy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
 

ZYDELIG (IDELALISIB)

• Edited and updated warning September 2016

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 11 % to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
• Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
• Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. You can search these and other label changes in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

QUINOLONE:

• Edited and updated warning September 2016

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects

Discontinue immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid quinolones in patients with known history of myasthenia gravis. Because fluoroquinolones
have been associated with serious adverse reactions, reserve quinolones for use in patients who have no alternative treatment options for the following
indications:

Avelox (moxifloxacin hydrochloride): Avelox in sodium chloride 0.8% in plastic container; moxifloxacin hydrochloride; Cipro in dextrose 5% in plastic container):
Acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis.

Cipro (ciprofloxacin; ciprofloxacin hydrochloride): Acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and acute sinusitis.

Cipro XR; Noroxin (norfloxacin): Uncomplicated urinary tract infections.

Factive (gemifloxacin mesylate): Acute bacterial exacerbation of chronic bronchitis.

Levaquin (levofloxacin): Uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.
 

KRYSTEXXA (PEGLOTICASE):

• Added section to warning September 2016

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA (Title Updated)

Addition of: Screen patients at risk for G6PD deficiency prior to starting Krystexxa. Hemolysis and methemoglobinemia have been reported with Krystexxa in patients with G6PD deficiency. Do not administer Krystexxa to patients with G6PD deficiency.
 

PLAVIX (CLOPIDOGREL BISULFATE):

• Edited and updated warning September 2016

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
 

SYNJARDY (EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE):

• Edited and updated warning September 2016

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue Synjardy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
 

ZYDELIG (IDELALISIB)

• Edited and updated warning September 2016

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 11 % to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
• Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
• Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation.