Laura Smith, PharmD

Staphylococcus aureus is one the most common pathogens isolated in nosocomial and community‐onset bloodstream infections (BSI) in the United States.[1, 2] S aureus bacteremia (SAB) has been reported in the literature to have substantial morbidity and mortality, with rates ranging between 15% and 60% worldwide.[3, 4, 5, 6] In the United States, patients with infections due to S aureus have on average 3 times the length of hospital stay than inpatients without these infections (14.3 days vs 4.5 days; P<0.01).[7] Healthcare costs are negatively impacted by these infections. In a recent meta‐analysis, Zimlichman et al.[8] reported that central‐line BSI (CLABSI) and surgical‐site infection (SSI) caused by methicillin‐resistant S aureus (MRSA) resulted in the highest estimated costs associated with hospital‐acquired infections in the United States ($58,614 [95% CI: $16,760‐$174,755] for CLABSI and $42,300 [95% CI: $4,005‐$82,670] for SSIs).

Appropriate management of SAB includes not only selecting the correct antimicrobial based on susceptibilities but also timely control of the source of infection, appropriate use of ancillary studies when indicated, and pharmacokinetic and pharmacodynamic therapeutic monitoring of antimicrobial therapy when vancomycin is used.[9] Consultation with an infectious diseases (ID) specialist has been associated with increased compliance with evidence‐based strategies in the management of SAB,[10, 11, 12, 13, 14] such as appropriate antibiotic choice, optimized duration of treatment, removal of the source of infection, and better use of cardiac echocardiography, resulting in improved outcomes.[13, 14]

Some, but not all, institutions have adopted bundles,[14] mandatory ID consultation[10] or daily prospective audit and feedback review[15] as part of antimicrobial stewardship program (ASP) interventions aiming to optimize the management of SABs. As part of our ASP quality improvement activities we performed the present study to determine our institutional rate of clinical failure in the treatment of SAB, to identify current practice patterns in the delivery of processes of care, and evaluate their association with clinical outcomes of hospitalized patients with SAB to identify future areas of improvement.

METHODS

A retrospective cohort study was performed at a 1558 licensed‐bed tertiary teaching hospital in Miami, Florida. All hospitalized patients 18 years of age or older with at least 1 positive blood culture with MRSA or methicillin‐susceptible S aureus (MSSA) between January 1, 2012 and April 30, 2013 were included. Patients were identified from the electronic microbiology laboratory database. For the purposes of this study, only the first episode of SAB was included in the analysis. Patients were excluded if aged younger than 18 years or if SAB was detected in an outpatient setting. The primary outcome was clinical failure, defined as a composite endpoint of in‐hospital mortality or persistent bacteremia; persistent bacteremia was defined as bacteremia for 7 or more days after the first positive blood culture. S aureus isolates were identified by standard methods.[16] Species identification was performed by latex agglutination. Antimicrobial susceptibility testing was performed using an automated system (Vitek 2; bioMerieux, Durham, NC) according to standard guidelines.

Data collected included baseline demographics, comorbidities, and treating healthcare provider's service; provider's service was categorized into 1 of 5 groups: internal medicine (academic), internal medicine (hospitalist), surgery, trauma, or neurosurgery. Duration of bacteremia was recorded and defined as the time between first positive and first negative blood culture. The time of first positive culture was defined as the date in which the culture was obtained. Patients who failed to have at least 1 follow‐up blood culture were not counted toward the main outcome. Additionally, presence of a foreign body (cardiac device, orthopedic prosthesis, tunneled catheter, nontunneled catheter) and presumed source of infection as documented in the electronic medical record by the treating service was also collected. Infections were considered community associated when onset of bacteremia occurred within the first 72 hours of admission, and hospital associated if onset of bacteremia occurred after 72 hours of admission.

Based on current practice guidelines,[9] the variables considered processes of care were the time to obtain the first follow‐up blood culture, time from first positive blood culture to initiation of appropriate antibiotic therapy (defined as a loading dose of vancomycin of 15 mg/kg, or a ‐lactam if the organism was susceptible), time to obtain the first vancomycin trough (when indicated), time from first positive blood culture to consultation with ID specialist, appropriate antibiotic de‐escalation (vancomycin to ‐lactam antibiotic if the organism was susceptible and the patient had no allergies or contraindications), and obtaining an echocardiographic study (transthoracic echocardiogram or transesophageal echocardiogram).

Statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). Differences in proportions were analyzed with ² or Fisher exact test, accordingly. Differences in means among continuous variables were evaluated using independent samples of paired samples t tests as appropriate for the analysis. Continuous variables were dichotomized using a clinically established cutoff to determine relative risk (RR). A univariate analysis of risk factors associated with clinical failure was performed. Multivariable analyses were performed using logistic regression. Models were created using the backward stepwise approach and included all variables found to be statistically significant at less than 0.05 level in the univariate model and those of clinical significance. The study was reviewed and approved by the institutional review boards at the University of Miami and Jackson Memorial Hospital.

RESULTS

During the study period, 241 patients with a first episode of SAB were identified. MRSA and MSSA were isolated in 124 (51.4%) and 117 (48.5%) patients, respectively. Demographic and clinical characteristics of the study population based on isolate are summarized in Table 1. One hundred seventy‐nine (74.3%) patients were under the care of internal medicine services. There was no association between treating service (medical vs surgical) and clinical failure.

The onset of infection occurred in the community in 77 (62.1%) patients with MRSA and in 77 (65.8%) patients with MSSA. The documented source of bacteremia was unknown in 30% of patients with MRSA and 44% of those with MSSA BSI. When ID specialists were consulted, patients were more likely to have a source of infection identified (RR: 1.5; 95% confidence interval [CI]: 1.2‐1.8; P<0.0001). The most commonly documented sources of infection were CLABSI, which occurred in 32 (25.8%) patients with MRSA and 21 (17.9%) patients with MSSA, followed by skin and soft tissue infections in 24 (19.3%) patients with MRSA BSI and 20 (17.1%) patients with MSSA BSI. All patients with CLABSI had documentation of catheter removal.

Clinical failure (defined as in‐hospital mortality or persistent bacteremia) occurred in 78 (32.4%) patients. Of these, 50 (20.7%) represented in‐hospital mortality, and 31 (12.9%) had persistent bacteremia. Table 2 summarizes the demographic and clinical characteristics associated with clinical failure. In the univariate analysis, the variables statistically significantly associated with clinical failure were: age greater than 60 years (RR: 1.4; 95% CI: 1.1‐1.8; P=0.001), bacteremia due to MRSA (RR: 1.7; 95% CI: 1.1‐2.5; P=0.008), white race (RR: 0.7; 95% CI: 0.6‐1; P=0.03), acute kidney injury during admission (RR: 2.2; 95% CI: 1.3‐3.7; P=0.004), presence of nontunneled central venous catheters at the onset of bacteremia (RR: 1.9; 95% CI: 1.3‐2.7; P=0.004), and endocarditis (RR: 2.9; 95% CI: 2.1‐3.9; P<0.0001). In the multivariable analysis, age greater than 60 years and endocarditis were found to be independent risk factors for the development of clinical failure.

DISCUSSION

Our study showed a significant rate of morbidity associated with S aureus bacteremia and identified processes of care in the management of SAB that impact patient outcomes.

Our results show that early consultation with an ID specialist was associated with a decreased risk of developing clinical failure, increased likelihood of identification of a source of infection, and positively impacted administration of appropriate antibiotic therapy, especially in cases of MSSA BSI, with overall improvement in patient outcomes. However, consultation with an ID specialist was only obtained in 40.2% of our cases, which is consistent with published data.[10, 11, 12, 13] Consultation with an ID specialist itself did not impact clinical failure, but rather timeliness in obtaining expert guidance was associated with better outcomes. As shown in previous studies,[10, 11, 12, 13, 14] compliance with the standards of care and patient prognosis are improved when ID specialists are involved in the management of SAB. Our study reiterates that early consultation with an ID specialist has a positive outcome in patient care, as opposed to delaying consultation once the patient has persistent bacteremia for more than 7 days. This association could be explained by considering that the majority of the standards of care are time sensitive, which include: obtaining surveillance blood cultures 48 to 96 hours after initial detection[10] or initiating therapy,[11, 14] removal of foci of infection,[10, 11, 12, 14] use of parenteral ‐lactams for the treatment of MSSA,[10, 11, 13, 14] performing echocardiography when clinically indicated,[10, 11, 13, 14] and appropriate duration of therapy.[10, 13, 14] Importantly, studies have shown that when ID specialists' recommendations are followed, patients are more likely to be cured,[10, 11, 13] and are less likely to relapse.[10, 11, 12] Given the complexities of treating patients with SAB and high rates of clinical failures, routine guidance could be beneficial to healthcare providers as part of a multidisciplinary structured strategy that is set in motion the moment a patient with SAB is identified by the microbiology laboratory. The processes of care outlined in this this study can serve as quality of care indicators and be integrated into a structured strategy to optimize the management of SAB.

Regarding optimal timing for follow‐up blood cultures, our results show that delays in obtaining follow‐up blood cultures (more than 4 days from onset of bacteremia) was independently associated with increased risk of clinical failure. Timely follow‐up blood cultures have been previously identified as quality of care indicators.[10, 11, 13, 14] Compliance with obtaining follow‐up blood cultures improves when this step is integrated into a bundle of care.[14]

Antimicrobial therapy was promptly initiated in the majority of the patients in our study. However, areas for improvement were identified. Vancomycin was the empirical therapy of choice in most of the cases, but an appropriate dose was only received by 65% of the patients, and vancomycin levels after the fourth dose were obtained in 85.9% of instances when indicated. Although in our cohort these results were not significantly associated with clinical failure, previous studies have described attainment of a target therapeutic vancomycin trough (1520 mg/dL) as a factor for treatment success.[17, 18] This problem could be addressed through physician education on therapeutic drug monitoring,[19] as well as through an ASP intervention, which have successfully led efforts to improve vancomycin utilization and dosing.[20] Among patients with MSSA BSI, therapy with ‐lactams was associated with improved outcomes, and was more likely to be administered when an ID specialist was consulted. This is in accordance with previous studies that have shown that higher rates of appropriate antimicrobial therapy are achieved when ID specialists are involved in management of SAB.[10, 11, 13, 14] The use of ‐lactams for treatment of MSSA BSI has been consistently associated with lower SAB‐related mortality and relapse.[21, 22, 23, 24, 25, 26]

Echocardiographic studies were obtained in only half of the patients in our cohort, and they were twice more likely to be obtained when an ID specialist was consulted. Although we did not evaluate the appropriateness of the echocardiographic study, the increased proportion of studies performed when ID specialists were consulted could indicate a more in‐depth evaluation of the case. Moreover, in our cohort, when ID specialists where involved in direct patient care, a source of infection was more likely to be identified. This is in accordance with previous studies proposing that because evaluation by ID specialists are more detailed, they lead to increased use in ancillary studies and recognition of complicated cases.[10, 12]

Limitations of this study include its retrospective design and the fact that it was performed in a single institution. The source of infection was defined as documented by treating providers and not by independent diagnostic criteria. Antibiotic use was collected throughout duration of admission, and was not followed after patients were discharged, as these data were not available on the electronic medical record for all patients. Deaths that may have occurred after hospital discharge were not included. We did not account for elevated vancomycin minimum inhibitory concentration as a risk factor for the main outcome, and adjustment of vancomycin based on serum levels was not factored in. Acute kidney injury was accounted for anytime during hospitalization, but not in relation to antimicrobial administration. Despite the limitations, our study has strengths that make our results generalizable. Although our institution is a single medical center, it serves a large and diverse population as reflected in our cases. Even though this is a retrospective cohort study, the use of a centralized electronic medical record allowed us to identify each aspect of the management of SAB, as implemented by different treating services (medical and surgical), as continuous variables (days) rather than only in a dichotomous fashion. Moreover, by being a community teaching hospital, we were able to explore aspects of the practice of physicians in training versus practicing clinicians. These results could be extrapolated to other healthcare facilities aiming to improve the management of SAB.

CONCLUSIONS

Our results suggest that obtaining timely follow‐up blood cultures, use of ‐lactams in patients with MSSA BSI, and early consultation with infectious diseases are the processes of care that could serve as quality and patient‐safety indicators for the management of SAB. These results contribute to a growing body of evidence supporting the implementation of structured processes of care to optimize the management and clinical outcomes of hospitalized patients with SAB.

Disclosure: Nothing to report.

Staphylococcus aureus is one the most common pathogens isolated in nosocomial and community‐onset bloodstream infections (BSI) in the United States.[1, 2] S aureus bacteremia (SAB) has been reported in the literature to have substantial morbidity and mortality, with rates ranging between 15% and 60% worldwide.[3, 4, 5, 6] In the United States, patients with infections due to S aureus have on average 3 times the length of hospital stay than inpatients without these infections (14.3 days vs 4.5 days; P<0.01).[7] Healthcare costs are negatively impacted by these infections. In a recent meta‐analysis, Zimlichman et al.[8] reported that central‐line BSI (CLABSI) and surgical‐site infection (SSI) caused by methicillin‐resistant S aureus (MRSA) resulted in the highest estimated costs associated with hospital‐acquired infections in the United States ($58,614 [95% CI: $16,760‐$174,755] for CLABSI and $42,300 [95% CI: $4,005‐$82,670] for SSIs).

Appropriate management of SAB includes not only selecting the correct antimicrobial based on susceptibilities but also timely control of the source of infection, appropriate use of ancillary studies when indicated, and pharmacokinetic and pharmacodynamic therapeutic monitoring of antimicrobial therapy when vancomycin is used.[9] Consultation with an infectious diseases (ID) specialist has been associated with increased compliance with evidence‐based strategies in the management of SAB,[10, 11, 12, 13, 14] such as appropriate antibiotic choice, optimized duration of treatment, removal of the source of infection, and better use of cardiac echocardiography, resulting in improved outcomes.[13, 14]

Some, but not all, institutions have adopted bundles,[14] mandatory ID consultation[10] or daily prospective audit and feedback review[15] as part of antimicrobial stewardship program (ASP) interventions aiming to optimize the management of SABs. As part of our ASP quality improvement activities we performed the present study to determine our institutional rate of clinical failure in the treatment of SAB, to identify current practice patterns in the delivery of processes of care, and evaluate their association with clinical outcomes of hospitalized patients with SAB to identify future areas of improvement.

METHODS

A retrospective cohort study was performed at a 1558 licensed‐bed tertiary teaching hospital in Miami, Florida. All hospitalized patients 18 years of age or older with at least 1 positive blood culture with MRSA or methicillin‐susceptible S aureus (MSSA) between January 1, 2012 and April 30, 2013 were included. Patients were identified from the electronic microbiology laboratory database. For the purposes of this study, only the first episode of SAB was included in the analysis. Patients were excluded if aged younger than 18 years or if SAB was detected in an outpatient setting. The primary outcome was clinical failure, defined as a composite endpoint of in‐hospital mortality or persistent bacteremia; persistent bacteremia was defined as bacteremia for 7 or more days after the first positive blood culture. S aureus isolates were identified by standard methods.[16] Species identification was performed by latex agglutination. Antimicrobial susceptibility testing was performed using an automated system (Vitek 2; bioMerieux, Durham, NC) according to standard guidelines.

Data collected included baseline demographics, comorbidities, and treating healthcare provider's service; provider's service was categorized into 1 of 5 groups: internal medicine (academic), internal medicine (hospitalist), surgery, trauma, or neurosurgery. Duration of bacteremia was recorded and defined as the time between first positive and first negative blood culture. The time of first positive culture was defined as the date in which the culture was obtained. Patients who failed to have at least 1 follow‐up blood culture were not counted toward the main outcome. Additionally, presence of a foreign body (cardiac device, orthopedic prosthesis, tunneled catheter, nontunneled catheter) and presumed source of infection as documented in the electronic medical record by the treating service was also collected. Infections were considered community associated when onset of bacteremia occurred within the first 72 hours of admission, and hospital associated if onset of bacteremia occurred after 72 hours of admission.

Based on current practice guidelines,[9] the variables considered processes of care were the time to obtain the first follow‐up blood culture, time from first positive blood culture to initiation of appropriate antibiotic therapy (defined as a loading dose of vancomycin of 15 mg/kg, or a ‐lactam if the organism was susceptible), time to obtain the first vancomycin trough (when indicated), time from first positive blood culture to consultation with ID specialist, appropriate antibiotic de‐escalation (vancomycin to ‐lactam antibiotic if the organism was susceptible and the patient had no allergies or contraindications), and obtaining an echocardiographic study (transthoracic echocardiogram or transesophageal echocardiogram).

Statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). Differences in proportions were analyzed with ² or Fisher exact test, accordingly. Differences in means among continuous variables were evaluated using independent samples of paired samples t tests as appropriate for the analysis. Continuous variables were dichotomized using a clinically established cutoff to determine relative risk (RR). A univariate analysis of risk factors associated with clinical failure was performed. Multivariable analyses were performed using logistic regression. Models were created using the backward stepwise approach and included all variables found to be statistically significant at less than 0.05 level in the univariate model and those of clinical significance. The study was reviewed and approved by the institutional review boards at the University of Miami and Jackson Memorial Hospital.

RESULTS

During the study period, 241 patients with a first episode of SAB were identified. MRSA and MSSA were isolated in 124 (51.4%) and 117 (48.5%) patients, respectively. Demographic and clinical characteristics of the study population based on isolate are summarized in Table 1. One hundred seventy‐nine (74.3%) patients were under the care of internal medicine services. There was no association between treating service (medical vs surgical) and clinical failure.

The onset of infection occurred in the community in 77 (62.1%) patients with MRSA and in 77 (65.8%) patients with MSSA. The documented source of bacteremia was unknown in 30% of patients with MRSA and 44% of those with MSSA BSI. When ID specialists were consulted, patients were more likely to have a source of infection identified (RR: 1.5; 95% confidence interval [CI]: 1.2‐1.8; P<0.0001). The most commonly documented sources of infection were CLABSI, which occurred in 32 (25.8%) patients with MRSA and 21 (17.9%) patients with MSSA, followed by skin and soft tissue infections in 24 (19.3%) patients with MRSA BSI and 20 (17.1%) patients with MSSA BSI. All patients with CLABSI had documentation of catheter removal.

Clinical failure (defined as in‐hospital mortality or persistent bacteremia) occurred in 78 (32.4%) patients. Of these, 50 (20.7%) represented in‐hospital mortality, and 31 (12.9%) had persistent bacteremia. Table 2 summarizes the demographic and clinical characteristics associated with clinical failure. In the univariate analysis, the variables statistically significantly associated with clinical failure were: age greater than 60 years (RR: 1.4; 95% CI: 1.1‐1.8; P=0.001), bacteremia due to MRSA (RR: 1.7; 95% CI: 1.1‐2.5; P=0.008), white race (RR: 0.7; 95% CI: 0.6‐1; P=0.03), acute kidney injury during admission (RR: 2.2; 95% CI: 1.3‐3.7; P=0.004), presence of nontunneled central venous catheters at the onset of bacteremia (RR: 1.9; 95% CI: 1.3‐2.7; P=0.004), and endocarditis (RR: 2.9; 95% CI: 2.1‐3.9; P<0.0001). In the multivariable analysis, age greater than 60 years and endocarditis were found to be independent risk factors for the development of clinical failure.

DISCUSSION

Our study showed a significant rate of morbidity associated with S aureus bacteremia and identified processes of care in the management of SAB that impact patient outcomes.

Our results show that early consultation with an ID specialist was associated with a decreased risk of developing clinical failure, increased likelihood of identification of a source of infection, and positively impacted administration of appropriate antibiotic therapy, especially in cases of MSSA BSI, with overall improvement in patient outcomes. However, consultation with an ID specialist was only obtained in 40.2% of our cases, which is consistent with published data.[10, 11, 12, 13] Consultation with an ID specialist itself did not impact clinical failure, but rather timeliness in obtaining expert guidance was associated with better outcomes. As shown in previous studies,[10, 11, 12, 13, 14] compliance with the standards of care and patient prognosis are improved when ID specialists are involved in the management of SAB. Our study reiterates that early consultation with an ID specialist has a positive outcome in patient care, as opposed to delaying consultation once the patient has persistent bacteremia for more than 7 days. This association could be explained by considering that the majority of the standards of care are time sensitive, which include: obtaining surveillance blood cultures 48 to 96 hours after initial detection[10] or initiating therapy,[11, 14] removal of foci of infection,[10, 11, 12, 14] use of parenteral ‐lactams for the treatment of MSSA,[10, 11, 13, 14] performing echocardiography when clinically indicated,[10, 11, 13, 14] and appropriate duration of therapy.[10, 13, 14] Importantly, studies have shown that when ID specialists' recommendations are followed, patients are more likely to be cured,[10, 11, 13] and are less likely to relapse.[10, 11, 12] Given the complexities of treating patients with SAB and high rates of clinical failures, routine guidance could be beneficial to healthcare providers as part of a multidisciplinary structured strategy that is set in motion the moment a patient with SAB is identified by the microbiology laboratory. The processes of care outlined in this this study can serve as quality of care indicators and be integrated into a structured strategy to optimize the management of SAB.

Regarding optimal timing for follow‐up blood cultures, our results show that delays in obtaining follow‐up blood cultures (more than 4 days from onset of bacteremia) was independently associated with increased risk of clinical failure. Timely follow‐up blood cultures have been previously identified as quality of care indicators.[10, 11, 13, 14] Compliance with obtaining follow‐up blood cultures improves when this step is integrated into a bundle of care.[14]

Antimicrobial therapy was promptly initiated in the majority of the patients in our study. However, areas for improvement were identified. Vancomycin was the empirical therapy of choice in most of the cases, but an appropriate dose was only received by 65% of the patients, and vancomycin levels after the fourth dose were obtained in 85.9% of instances when indicated. Although in our cohort these results were not significantly associated with clinical failure, previous studies have described attainment of a target therapeutic vancomycin trough (1520 mg/dL) as a factor for treatment success.[17, 18] This problem could be addressed through physician education on therapeutic drug monitoring,[19] as well as through an ASP intervention, which have successfully led efforts to improve vancomycin utilization and dosing.[20] Among patients with MSSA BSI, therapy with ‐lactams was associated with improved outcomes, and was more likely to be administered when an ID specialist was consulted. This is in accordance with previous studies that have shown that higher rates of appropriate antimicrobial therapy are achieved when ID specialists are involved in management of SAB.[10, 11, 13, 14] The use of ‐lactams for treatment of MSSA BSI has been consistently associated with lower SAB‐related mortality and relapse.[21, 22, 23, 24, 25, 26]

Echocardiographic studies were obtained in only half of the patients in our cohort, and they were twice more likely to be obtained when an ID specialist was consulted. Although we did not evaluate the appropriateness of the echocardiographic study, the increased proportion of studies performed when ID specialists were consulted could indicate a more in‐depth evaluation of the case. Moreover, in our cohort, when ID specialists where involved in direct patient care, a source of infection was more likely to be identified. This is in accordance with previous studies proposing that because evaluation by ID specialists are more detailed, they lead to increased use in ancillary studies and recognition of complicated cases.[10, 12]

Limitations of this study include its retrospective design and the fact that it was performed in a single institution. The source of infection was defined as documented by treating providers and not by independent diagnostic criteria. Antibiotic use was collected throughout duration of admission, and was not followed after patients were discharged, as these data were not available on the electronic medical record for all patients. Deaths that may have occurred after hospital discharge were not included. We did not account for elevated vancomycin minimum inhibitory concentration as a risk factor for the main outcome, and adjustment of vancomycin based on serum levels was not factored in. Acute kidney injury was accounted for anytime during hospitalization, but not in relation to antimicrobial administration. Despite the limitations, our study has strengths that make our results generalizable. Although our institution is a single medical center, it serves a large and diverse population as reflected in our cases. Even though this is a retrospective cohort study, the use of a centralized electronic medical record allowed us to identify each aspect of the management of SAB, as implemented by different treating services (medical and surgical), as continuous variables (days) rather than only in a dichotomous fashion. Moreover, by being a community teaching hospital, we were able to explore aspects of the practice of physicians in training versus practicing clinicians. These results could be extrapolated to other healthcare facilities aiming to improve the management of SAB.

CONCLUSIONS

Our results suggest that obtaining timely follow‐up blood cultures, use of ‐lactams in patients with MSSA BSI, and early consultation with infectious diseases are the processes of care that could serve as quality and patient‐safety indicators for the management of SAB. These results contribute to a growing body of evidence supporting the implementation of structured processes of care to optimize the management and clinical outcomes of hospitalized patients with SAB.

Disclosure: Nothing to report.

Staphylococcus aureus is one the most common pathogens isolated in nosocomial and community‐onset bloodstream infections (BSI) in the United States.[1, 2] S aureus bacteremia (SAB) has been reported in the literature to have substantial morbidity and mortality, with rates ranging between 15% and 60% worldwide.[3, 4, 5, 6] In the United States, patients with infections due to S aureus have on average 3 times the length of hospital stay than inpatients without these infections (14.3 days vs 4.5 days; P<0.01).[7] Healthcare costs are negatively impacted by these infections. In a recent meta‐analysis, Zimlichman et al.[8] reported that central‐line BSI (CLABSI) and surgical‐site infection (SSI) caused by methicillin‐resistant S aureus (MRSA) resulted in the highest estimated costs associated with hospital‐acquired infections in the United States ($58,614 [95% CI: $16,760‐$174,755] for CLABSI and $42,300 [95% CI: $4,005‐$82,670] for SSIs).

Appropriate management of SAB includes not only selecting the correct antimicrobial based on susceptibilities but also timely control of the source of infection, appropriate use of ancillary studies when indicated, and pharmacokinetic and pharmacodynamic therapeutic monitoring of antimicrobial therapy when vancomycin is used.[9] Consultation with an infectious diseases (ID) specialist has been associated with increased compliance with evidence‐based strategies in the management of SAB,[10, 11, 12, 13, 14] such as appropriate antibiotic choice, optimized duration of treatment, removal of the source of infection, and better use of cardiac echocardiography, resulting in improved outcomes.[13, 14]

Some, but not all, institutions have adopted bundles,[14] mandatory ID consultation[10] or daily prospective audit and feedback review[15] as part of antimicrobial stewardship program (ASP) interventions aiming to optimize the management of SABs. As part of our ASP quality improvement activities we performed the present study to determine our institutional rate of clinical failure in the treatment of SAB, to identify current practice patterns in the delivery of processes of care, and evaluate their association with clinical outcomes of hospitalized patients with SAB to identify future areas of improvement.

METHODS

A retrospective cohort study was performed at a 1558 licensed‐bed tertiary teaching hospital in Miami, Florida. All hospitalized patients 18 years of age or older with at least 1 positive blood culture with MRSA or methicillin‐susceptible S aureus (MSSA) between January 1, 2012 and April 30, 2013 were included. Patients were identified from the electronic microbiology laboratory database. For the purposes of this study, only the first episode of SAB was included in the analysis. Patients were excluded if aged younger than 18 years or if SAB was detected in an outpatient setting. The primary outcome was clinical failure, defined as a composite endpoint of in‐hospital mortality or persistent bacteremia; persistent bacteremia was defined as bacteremia for 7 or more days after the first positive blood culture. S aureus isolates were identified by standard methods.[16] Species identification was performed by latex agglutination. Antimicrobial susceptibility testing was performed using an automated system (Vitek 2; bioMerieux, Durham, NC) according to standard guidelines.

Data collected included baseline demographics, comorbidities, and treating healthcare provider's service; provider's service was categorized into 1 of 5 groups: internal medicine (academic), internal medicine (hospitalist), surgery, trauma, or neurosurgery. Duration of bacteremia was recorded and defined as the time between first positive and first negative blood culture. The time of first positive culture was defined as the date in which the culture was obtained. Patients who failed to have at least 1 follow‐up blood culture were not counted toward the main outcome. Additionally, presence of a foreign body (cardiac device, orthopedic prosthesis, tunneled catheter, nontunneled catheter) and presumed source of infection as documented in the electronic medical record by the treating service was also collected. Infections were considered community associated when onset of bacteremia occurred within the first 72 hours of admission, and hospital associated if onset of bacteremia occurred after 72 hours of admission.

Based on current practice guidelines,[9] the variables considered processes of care were the time to obtain the first follow‐up blood culture, time from first positive blood culture to initiation of appropriate antibiotic therapy (defined as a loading dose of vancomycin of 15 mg/kg, or a ‐lactam if the organism was susceptible), time to obtain the first vancomycin trough (when indicated), time from first positive blood culture to consultation with ID specialist, appropriate antibiotic de‐escalation (vancomycin to ‐lactam antibiotic if the organism was susceptible and the patient had no allergies or contraindications), and obtaining an echocardiographic study (transthoracic echocardiogram or transesophageal echocardiogram).

Statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). Differences in proportions were analyzed with ² or Fisher exact test, accordingly. Differences in means among continuous variables were evaluated using independent samples of paired samples t tests as appropriate for the analysis. Continuous variables were dichotomized using a clinically established cutoff to determine relative risk (RR). A univariate analysis of risk factors associated with clinical failure was performed. Multivariable analyses were performed using logistic regression. Models were created using the backward stepwise approach and included all variables found to be statistically significant at less than 0.05 level in the univariate model and those of clinical significance. The study was reviewed and approved by the institutional review boards at the University of Miami and Jackson Memorial Hospital.

RESULTS

During the study period, 241 patients with a first episode of SAB were identified. MRSA and MSSA were isolated in 124 (51.4%) and 117 (48.5%) patients, respectively. Demographic and clinical characteristics of the study population based on isolate are summarized in Table 1. One hundred seventy‐nine (74.3%) patients were under the care of internal medicine services. There was no association between treating service (medical vs surgical) and clinical failure.

The onset of infection occurred in the community in 77 (62.1%) patients with MRSA and in 77 (65.8%) patients with MSSA. The documented source of bacteremia was unknown in 30% of patients with MRSA and 44% of those with MSSA BSI. When ID specialists were consulted, patients were more likely to have a source of infection identified (RR: 1.5; 95% confidence interval [CI]: 1.2‐1.8; P<0.0001). The most commonly documented sources of infection were CLABSI, which occurred in 32 (25.8%) patients with MRSA and 21 (17.9%) patients with MSSA, followed by skin and soft tissue infections in 24 (19.3%) patients with MRSA BSI and 20 (17.1%) patients with MSSA BSI. All patients with CLABSI had documentation of catheter removal.

Clinical failure (defined as in‐hospital mortality or persistent bacteremia) occurred in 78 (32.4%) patients. Of these, 50 (20.7%) represented in‐hospital mortality, and 31 (12.9%) had persistent bacteremia. Table 2 summarizes the demographic and clinical characteristics associated with clinical failure. In the univariate analysis, the variables statistically significantly associated with clinical failure were: age greater than 60 years (RR: 1.4; 95% CI: 1.1‐1.8; P=0.001), bacteremia due to MRSA (RR: 1.7; 95% CI: 1.1‐2.5; P=0.008), white race (RR: 0.7; 95% CI: 0.6‐1; P=0.03), acute kidney injury during admission (RR: 2.2; 95% CI: 1.3‐3.7; P=0.004), presence of nontunneled central venous catheters at the onset of bacteremia (RR: 1.9; 95% CI: 1.3‐2.7; P=0.004), and endocarditis (RR: 2.9; 95% CI: 2.1‐3.9; P<0.0001). In the multivariable analysis, age greater than 60 years and endocarditis were found to be independent risk factors for the development of clinical failure.

DISCUSSION

Our study showed a significant rate of morbidity associated with S aureus bacteremia and identified processes of care in the management of SAB that impact patient outcomes.

Our results show that early consultation with an ID specialist was associated with a decreased risk of developing clinical failure, increased likelihood of identification of a source of infection, and positively impacted administration of appropriate antibiotic therapy, especially in cases of MSSA BSI, with overall improvement in patient outcomes. However, consultation with an ID specialist was only obtained in 40.2% of our cases, which is consistent with published data.[10, 11, 12, 13] Consultation with an ID specialist itself did not impact clinical failure, but rather timeliness in obtaining expert guidance was associated with better outcomes. As shown in previous studies,[10, 11, 12, 13, 14] compliance with the standards of care and patient prognosis are improved when ID specialists are involved in the management of SAB. Our study reiterates that early consultation with an ID specialist has a positive outcome in patient care, as opposed to delaying consultation once the patient has persistent bacteremia for more than 7 days. This association could be explained by considering that the majority of the standards of care are time sensitive, which include: obtaining surveillance blood cultures 48 to 96 hours after initial detection[10] or initiating therapy,[11, 14] removal of foci of infection,[10, 11, 12, 14] use of parenteral ‐lactams for the treatment of MSSA,[10, 11, 13, 14] performing echocardiography when clinically indicated,[10, 11, 13, 14] and appropriate duration of therapy.[10, 13, 14] Importantly, studies have shown that when ID specialists' recommendations are followed, patients are more likely to be cured,[10, 11, 13] and are less likely to relapse.[10, 11, 12] Given the complexities of treating patients with SAB and high rates of clinical failures, routine guidance could be beneficial to healthcare providers as part of a multidisciplinary structured strategy that is set in motion the moment a patient with SAB is identified by the microbiology laboratory. The processes of care outlined in this this study can serve as quality of care indicators and be integrated into a structured strategy to optimize the management of SAB.

Regarding optimal timing for follow‐up blood cultures, our results show that delays in obtaining follow‐up blood cultures (more than 4 days from onset of bacteremia) was independently associated with increased risk of clinical failure. Timely follow‐up blood cultures have been previously identified as quality of care indicators.[10, 11, 13, 14] Compliance with obtaining follow‐up blood cultures improves when this step is integrated into a bundle of care.[14]

Antimicrobial therapy was promptly initiated in the majority of the patients in our study. However, areas for improvement were identified. Vancomycin was the empirical therapy of choice in most of the cases, but an appropriate dose was only received by 65% of the patients, and vancomycin levels after the fourth dose were obtained in 85.9% of instances when indicated. Although in our cohort these results were not significantly associated with clinical failure, previous studies have described attainment of a target therapeutic vancomycin trough (1520 mg/dL) as a factor for treatment success.[17, 18] This problem could be addressed through physician education on therapeutic drug monitoring,[19] as well as through an ASP intervention, which have successfully led efforts to improve vancomycin utilization and dosing.[20] Among patients with MSSA BSI, therapy with ‐lactams was associated with improved outcomes, and was more likely to be administered when an ID specialist was consulted. This is in accordance with previous studies that have shown that higher rates of appropriate antimicrobial therapy are achieved when ID specialists are involved in management of SAB.[10, 11, 13, 14] The use of ‐lactams for treatment of MSSA BSI has been consistently associated with lower SAB‐related mortality and relapse.[21, 22, 23, 24, 25, 26]

Echocardiographic studies were obtained in only half of the patients in our cohort, and they were twice more likely to be obtained when an ID specialist was consulted. Although we did not evaluate the appropriateness of the echocardiographic study, the increased proportion of studies performed when ID specialists were consulted could indicate a more in‐depth evaluation of the case. Moreover, in our cohort, when ID specialists where involved in direct patient care, a source of infection was more likely to be identified. This is in accordance with previous studies proposing that because evaluation by ID specialists are more detailed, they lead to increased use in ancillary studies and recognition of complicated cases.[10, 12]

Limitations of this study include its retrospective design and the fact that it was performed in a single institution. The source of infection was defined as documented by treating providers and not by independent diagnostic criteria. Antibiotic use was collected throughout duration of admission, and was not followed after patients were discharged, as these data were not available on the electronic medical record for all patients. Deaths that may have occurred after hospital discharge were not included. We did not account for elevated vancomycin minimum inhibitory concentration as a risk factor for the main outcome, and adjustment of vancomycin based on serum levels was not factored in. Acute kidney injury was accounted for anytime during hospitalization, but not in relation to antimicrobial administration. Despite the limitations, our study has strengths that make our results generalizable. Although our institution is a single medical center, it serves a large and diverse population as reflected in our cases. Even though this is a retrospective cohort study, the use of a centralized electronic medical record allowed us to identify each aspect of the management of SAB, as implemented by different treating services (medical and surgical), as continuous variables (days) rather than only in a dichotomous fashion. Moreover, by being a community teaching hospital, we were able to explore aspects of the practice of physicians in training versus practicing clinicians. These results could be extrapolated to other healthcare facilities aiming to improve the management of SAB.

CONCLUSIONS

Our results suggest that obtaining timely follow‐up blood cultures, use of ‐lactams in patients with MSSA BSI, and early consultation with infectious diseases are the processes of care that could serve as quality and patient‐safety indicators for the management of SAB. These results contribute to a growing body of evidence supporting the implementation of structured processes of care to optimize the management and clinical outcomes of hospitalized patients with SAB.

Disclosure: Nothing to report.