Joyce E. Broyles, PharmD, BCNSP

Enterococci have been identified as a causative organism in approximately 10% of all nosocomial bloodstream infections (BSIs).1, 2 In 2006, the Infectious Diseases Society of America identified vancomycin‐ resistant Enterococcus faecium (VRE) as 1 of 6 microbes considered to be among the most dangerous due to high rates of resistance and a limited number of effective antimicrobials.3 E. faecium has exhibited high rates of glycopeptide resistance with as many as 60% of isolates from BSIs being resistant to vancomycin.2, 4 Due to increasing resistance to glycopeptides, vancomycin has become obsolete in the treatment of E. faecium infections.5

A limited number of antimicrobials are available for the treatment of infections due to VRE. Agents active in vitro are quinupristin‐dalfopristin, tigecycline, linezolid, and daptomycin. Quinupristin‐dalfopristin was one of the first agents approved for use in VRE infections; however, treatment with this agent has been limited because of mediocre clinical response rates, undesirable adverse effects, high cost, and insufficient E. faecalis activity.6, 7 Tigecycline is not an optimal antibiotic for the treatment of VRE bacteremia, because serum concentrations achieved after administration are inadequate to treat BSIs.7 In contrast, linezolid and daptomycin have evinced efficacy against VRE bacteremia, with reported microbiologic response rates of 85% and 80%, respectively.7, 8 One inherent difference between these antibiotics that may theoretically affect their use in immunocompromised patients is that linezolid is bacteriostatic, whereas daptomycin is bactericidal. It has been postulated that by using a bactericidal antibiotic such as daptomycin in the immunocompromised host, one may achieve superior clinical and microbiologic response rates.3, 7, 9, 10

Since the introduction of the oxazolidinone linezolid in 2000, widespread use has led to reports of linezolid‐resistant VRE as well as nosocomial transmission of linezolid‐resistant VRE in hospitals.4, 1114 Despite linezolid being a key antibiotic for the treatment of VRE infections over the last 10 years, development of resistance along with potential hematologic and neurologic toxicity during long‐term use remains a concern.7, 8 Although daptomycin is active against several resistant organisms, including VRE, the evidence supporting use of daptomycin for VRE BSI is limited to case reports or small case series.7, 9 Moreover, daptomycin has not received US Food and Drug Administration approval for the treatment of VRE infections,15 and emerging data regarding daptomycin‐nonsusceptible enterococci (Minimum Inhibitory Concentration, MIC >4 mg/L) highlight a new problem for this multidrug‐resistant pathogen.16, 17 Few studies in recent years have compared these 2 antibiotics in the treatment of VRE BSIs.4, 18, 19 Due to the high rates of vancomycin resistance reported at our institution and the ubiquitous use of linezolid and daptomycin in the treatment of VRE bacteremia, we chose to evaluate response rates for these antibiotics in an effort to add to previously published literature on this topic.

MATERIALS AND METHODS

RESULTS

DISCUSSION

Vergis et al21 reported that infections with VRE compared with vancomycin‐sensitive infections were associated with a higher rate of mortality and that the chosen antimicrobial therapy may play a pivotal role in the risk of death. Our retrospective study suggests that linezolid and daptomycin appear to be equally efficacious for the treatment of VRE BSIs. The results from our study for clinical and microbiologic cure rates for linezolid and daptomycin are similar to previously published data.7, 8 In accordance with previous studies,4 our data demonstrate that there is a higher rate of recurrence in patients treated with daptomycin. This finding may be explained by the fact that the daptomycin group was comprised of more complex patients with a greater disease burden versus the linezolid group; therefore, they were more susceptible to a recurrent VRE infection. In our study, patients who were treated with daptomycin were 5.5 times more likely to have a recurrent infection than linezolid‐treated patients. However, this finding must be scrutinized, because over half of the patients with recurrence either received an inappropriate dose or had high MICs to daptomycin.

Despite there being few clinical and microbiologic outcome data with daptomycin, our study proposes that a bactericidal antibiotic and a bacteriostatic antibiotic have comparable efficacy in the treatment of VRE BSIs. Previous literature has mainly comprised case studies or series that have evaluated clinical outcomes with daptomycin in the treatment of VRE BSIs. Gallagher et al7 reported the results of a retrospective case series of 30 patients with VRE bacteremia who were treated with daptomycin. In this study, microbiologic cure was achieved in 80% of patients, with clinical success in 59% of the patients. In 2009, Mave et al4 compared clinical outcomes between daptomycin and linezolid in the treatment of VRE bacteremia. Reported results demonstrated a microbiologic cure rate of 90% for daptomycin versus 88% for linezolid.4 Moreover, there were no differences in mortality between the groups in our study. In 2010, Crank et al18 reported no differences in mortality (in‐hospital) for hospitalized patients with VRE BSIs treated with linezolid or daptomycin. Our results seem to be consistent with what has been published previously concerning clinical outcomes associated with linezolid or daptomycin in the treatment of VRE BSI.

The average daptomycin dose received in our patients was 6.1 mg/kg with doses ranging from 3.410.4 mg/kg. The underdosing as well as higher MICs to daptomycin may have contributed to a higher rate of recurrence. Previous reports state that Enterococcus species may have higher MICs to daptomycin than Staphylococcus or Streptococcus species; consequently, higher doses may be needed to adequately treat enterococcal infections.7 In the aforementioned study by Gallagher et al,7 doses of daptomycin 6 mg/kg were associated with a positive clinical outcome in 81% of patients compared with 31% if the dose used was <6 mg/kg. Linezolid is dosed 600 mg every 12 hours by mouth or intravenously, with no variations. There have been no studies comparing the uniform dosing of linezolid to the weight‐based dosing of daptomycin and their effects on outcomes.

Patients particularly susceptible to VRE infections include those with neutropenia and/or cancer, patients receiving long‐term hemodialysis, and liver transplant recipients.3, 22, 23 Upon review of this immunocompromised population, we noted no statistically significant differences in overall outcomes. A study by Kraft et al.24 supports the findings in our study that both drugs appear useful in the treatment of VRE bacteremia in patients with hematologic malignancy. We did identify a difference, albeit nonsignificant, in LOS for daptomycin versus linezolid in patients with a history of liver transplantation. Again, the level of care that these patients needed compared with the general population may explain this difference. As mentioned previously, another pertinent factor would be the dose of daptomycin used in these patients, because the dose can affect clinical success. Because all of the other patients had a similar LOS, we cannot determine that the increased LOS seen in liver transplant patients treated with daptomycin was solely due to daptomycin use. The reason for the increased LOS seems to be multifactorial. In the neutropenic population, a difference in LOS was also recognized, but follow‐up complete blood count values were not collected for these patients to determine whether linezolid contributed to further bone marrow suppression leading to an increase in LOS. For both of these patient populations, the number of patients included is very small (n = 21 for neutropenia total, n = 13 for liver transplant total), which can lead to a high degree of variance.

This study has several limitations. This was a retrospective review; therefore, we had no control over the selection of therapy. This may be reflected in an apparent preferential use of daptomycin in immunocompromised patients. Furthermore, 62% of linezolid patients and 54% of daptomycin patients received an antibiotic before initial therapy that could have potentially altered response rates. Due to the paucity of documentation surrounding initial site of infection, some of the positive cultures may represent potential contamination, because VRE may contaminate skin.25 Contamination seems implausible, however, because patients were seen by an infectious disease physician and had at least 1 documented positive VRE blood culture. We chose arbitrary definitions for clinical cure, microbiologic cure, microbiologic failure, recurrence, and reinfection. Previous studies have used their own definitions leading to discrepancies in reporting. Another limitation was that follow‐up cultures were not obtained on all of the patients, which was needed to determine rates of recurrence, reinfection, and microbiologic cure. MICs to daptomycin were not reported in 30% of our patients, potentially altering the recurrence rate seen in the daptomycin‐treated patients. Because clinical cure was not documented in the chart, it was inferred from the laboratory values and vital sign information. One investigator analyzed all of the values and made the determination of clinical cure, allowing for a consistent approach to data review.

In the face of the imposing threat of a highly resistant organism such as VRE with a limited number of efficacious antibiotics, antimicrobial selection becomes increasingly important and is requisite to clinical and microbiological success. To our knowledge, this is one of the largest studies to date comparing the efficacy of linezolid with that of daptomycin in the treatment of VRE bacteremia. Both of these agents are effective for the treatment of VRE BSIs. Nevertheless, specific factors related to the medication (eg, dose, route of administration) as well as the patient (eg, comorbid conditions, acuity of illness) should be taken into consideration when selecting an initial antimicrobial agent. Because the treatment of VRE BSIs continues to be a challenge, larger prospective randomized controlled trials are needed to corroborate our results and determine the optimal therapy for this serious infection.

Enterococci have been identified as a causative organism in approximately 10% of all nosocomial bloodstream infections (BSIs).1, 2 In 2006, the Infectious Diseases Society of America identified vancomycin‐ resistant Enterococcus faecium (VRE) as 1 of 6 microbes considered to be among the most dangerous due to high rates of resistance and a limited number of effective antimicrobials.3 E. faecium has exhibited high rates of glycopeptide resistance with as many as 60% of isolates from BSIs being resistant to vancomycin.2, 4 Due to increasing resistance to glycopeptides, vancomycin has become obsolete in the treatment of E. faecium infections.5

A limited number of antimicrobials are available for the treatment of infections due to VRE. Agents active in vitro are quinupristin‐dalfopristin, tigecycline, linezolid, and daptomycin. Quinupristin‐dalfopristin was one of the first agents approved for use in VRE infections; however, treatment with this agent has been limited because of mediocre clinical response rates, undesirable adverse effects, high cost, and insufficient E. faecalis activity.6, 7 Tigecycline is not an optimal antibiotic for the treatment of VRE bacteremia, because serum concentrations achieved after administration are inadequate to treat BSIs.7 In contrast, linezolid and daptomycin have evinced efficacy against VRE bacteremia, with reported microbiologic response rates of 85% and 80%, respectively.7, 8 One inherent difference between these antibiotics that may theoretically affect their use in immunocompromised patients is that linezolid is bacteriostatic, whereas daptomycin is bactericidal. It has been postulated that by using a bactericidal antibiotic such as daptomycin in the immunocompromised host, one may achieve superior clinical and microbiologic response rates.3, 7, 9, 10

Since the introduction of the oxazolidinone linezolid in 2000, widespread use has led to reports of linezolid‐resistant VRE as well as nosocomial transmission of linezolid‐resistant VRE in hospitals.4, 1114 Despite linezolid being a key antibiotic for the treatment of VRE infections over the last 10 years, development of resistance along with potential hematologic and neurologic toxicity during long‐term use remains a concern.7, 8 Although daptomycin is active against several resistant organisms, including VRE, the evidence supporting use of daptomycin for VRE BSI is limited to case reports or small case series.7, 9 Moreover, daptomycin has not received US Food and Drug Administration approval for the treatment of VRE infections,15 and emerging data regarding daptomycin‐nonsusceptible enterococci (Minimum Inhibitory Concentration, MIC >4 mg/L) highlight a new problem for this multidrug‐resistant pathogen.16, 17 Few studies in recent years have compared these 2 antibiotics in the treatment of VRE BSIs.4, 18, 19 Due to the high rates of vancomycin resistance reported at our institution and the ubiquitous use of linezolid and daptomycin in the treatment of VRE bacteremia, we chose to evaluate response rates for these antibiotics in an effort to add to previously published literature on this topic.

MATERIALS AND METHODS

RESULTS

DISCUSSION

Vergis et al21 reported that infections with VRE compared with vancomycin‐sensitive infections were associated with a higher rate of mortality and that the chosen antimicrobial therapy may play a pivotal role in the risk of death. Our retrospective study suggests that linezolid and daptomycin appear to be equally efficacious for the treatment of VRE BSIs. The results from our study for clinical and microbiologic cure rates for linezolid and daptomycin are similar to previously published data.7, 8 In accordance with previous studies,4 our data demonstrate that there is a higher rate of recurrence in patients treated with daptomycin. This finding may be explained by the fact that the daptomycin group was comprised of more complex patients with a greater disease burden versus the linezolid group; therefore, they were more susceptible to a recurrent VRE infection. In our study, patients who were treated with daptomycin were 5.5 times more likely to have a recurrent infection than linezolid‐treated patients. However, this finding must be scrutinized, because over half of the patients with recurrence either received an inappropriate dose or had high MICs to daptomycin.

Despite there being few clinical and microbiologic outcome data with daptomycin, our study proposes that a bactericidal antibiotic and a bacteriostatic antibiotic have comparable efficacy in the treatment of VRE BSIs. Previous literature has mainly comprised case studies or series that have evaluated clinical outcomes with daptomycin in the treatment of VRE BSIs. Gallagher et al7 reported the results of a retrospective case series of 30 patients with VRE bacteremia who were treated with daptomycin. In this study, microbiologic cure was achieved in 80% of patients, with clinical success in 59% of the patients. In 2009, Mave et al4 compared clinical outcomes between daptomycin and linezolid in the treatment of VRE bacteremia. Reported results demonstrated a microbiologic cure rate of 90% for daptomycin versus 88% for linezolid.4 Moreover, there were no differences in mortality between the groups in our study. In 2010, Crank et al18 reported no differences in mortality (in‐hospital) for hospitalized patients with VRE BSIs treated with linezolid or daptomycin. Our results seem to be consistent with what has been published previously concerning clinical outcomes associated with linezolid or daptomycin in the treatment of VRE BSI.

The average daptomycin dose received in our patients was 6.1 mg/kg with doses ranging from 3.410.4 mg/kg. The underdosing as well as higher MICs to daptomycin may have contributed to a higher rate of recurrence. Previous reports state that Enterococcus species may have higher MICs to daptomycin than Staphylococcus or Streptococcus species; consequently, higher doses may be needed to adequately treat enterococcal infections.7 In the aforementioned study by Gallagher et al,7 doses of daptomycin 6 mg/kg were associated with a positive clinical outcome in 81% of patients compared with 31% if the dose used was <6 mg/kg. Linezolid is dosed 600 mg every 12 hours by mouth or intravenously, with no variations. There have been no studies comparing the uniform dosing of linezolid to the weight‐based dosing of daptomycin and their effects on outcomes.

Patients particularly susceptible to VRE infections include those with neutropenia and/or cancer, patients receiving long‐term hemodialysis, and liver transplant recipients.3, 22, 23 Upon review of this immunocompromised population, we noted no statistically significant differences in overall outcomes. A study by Kraft et al.24 supports the findings in our study that both drugs appear useful in the treatment of VRE bacteremia in patients with hematologic malignancy. We did identify a difference, albeit nonsignificant, in LOS for daptomycin versus linezolid in patients with a history of liver transplantation. Again, the level of care that these patients needed compared with the general population may explain this difference. As mentioned previously, another pertinent factor would be the dose of daptomycin used in these patients, because the dose can affect clinical success. Because all of the other patients had a similar LOS, we cannot determine that the increased LOS seen in liver transplant patients treated with daptomycin was solely due to daptomycin use. The reason for the increased LOS seems to be multifactorial. In the neutropenic population, a difference in LOS was also recognized, but follow‐up complete blood count values were not collected for these patients to determine whether linezolid contributed to further bone marrow suppression leading to an increase in LOS. For both of these patient populations, the number of patients included is very small (n = 21 for neutropenia total, n = 13 for liver transplant total), which can lead to a high degree of variance.

This study has several limitations. This was a retrospective review; therefore, we had no control over the selection of therapy. This may be reflected in an apparent preferential use of daptomycin in immunocompromised patients. Furthermore, 62% of linezolid patients and 54% of daptomycin patients received an antibiotic before initial therapy that could have potentially altered response rates. Due to the paucity of documentation surrounding initial site of infection, some of the positive cultures may represent potential contamination, because VRE may contaminate skin.25 Contamination seems implausible, however, because patients were seen by an infectious disease physician and had at least 1 documented positive VRE blood culture. We chose arbitrary definitions for clinical cure, microbiologic cure, microbiologic failure, recurrence, and reinfection. Previous studies have used their own definitions leading to discrepancies in reporting. Another limitation was that follow‐up cultures were not obtained on all of the patients, which was needed to determine rates of recurrence, reinfection, and microbiologic cure. MICs to daptomycin were not reported in 30% of our patients, potentially altering the recurrence rate seen in the daptomycin‐treated patients. Because clinical cure was not documented in the chart, it was inferred from the laboratory values and vital sign information. One investigator analyzed all of the values and made the determination of clinical cure, allowing for a consistent approach to data review.

In the face of the imposing threat of a highly resistant organism such as VRE with a limited number of efficacious antibiotics, antimicrobial selection becomes increasingly important and is requisite to clinical and microbiological success. To our knowledge, this is one of the largest studies to date comparing the efficacy of linezolid with that of daptomycin in the treatment of VRE bacteremia. Both of these agents are effective for the treatment of VRE BSIs. Nevertheless, specific factors related to the medication (eg, dose, route of administration) as well as the patient (eg, comorbid conditions, acuity of illness) should be taken into consideration when selecting an initial antimicrobial agent. Because the treatment of VRE BSIs continues to be a challenge, larger prospective randomized controlled trials are needed to corroborate our results and determine the optimal therapy for this serious infection.

Enterococci have been identified as a causative organism in approximately 10% of all nosocomial bloodstream infections (BSIs).1, 2 In 2006, the Infectious Diseases Society of America identified vancomycin‐ resistant Enterococcus faecium (VRE) as 1 of 6 microbes considered to be among the most dangerous due to high rates of resistance and a limited number of effective antimicrobials.3 E. faecium has exhibited high rates of glycopeptide resistance with as many as 60% of isolates from BSIs being resistant to vancomycin.2, 4 Due to increasing resistance to glycopeptides, vancomycin has become obsolete in the treatment of E. faecium infections.5

A limited number of antimicrobials are available for the treatment of infections due to VRE. Agents active in vitro are quinupristin‐dalfopristin, tigecycline, linezolid, and daptomycin. Quinupristin‐dalfopristin was one of the first agents approved for use in VRE infections; however, treatment with this agent has been limited because of mediocre clinical response rates, undesirable adverse effects, high cost, and insufficient E. faecalis activity.6, 7 Tigecycline is not an optimal antibiotic for the treatment of VRE bacteremia, because serum concentrations achieved after administration are inadequate to treat BSIs.7 In contrast, linezolid and daptomycin have evinced efficacy against VRE bacteremia, with reported microbiologic response rates of 85% and 80%, respectively.7, 8 One inherent difference between these antibiotics that may theoretically affect their use in immunocompromised patients is that linezolid is bacteriostatic, whereas daptomycin is bactericidal. It has been postulated that by using a bactericidal antibiotic such as daptomycin in the immunocompromised host, one may achieve superior clinical and microbiologic response rates.3, 7, 9, 10

Since the introduction of the oxazolidinone linezolid in 2000, widespread use has led to reports of linezolid‐resistant VRE as well as nosocomial transmission of linezolid‐resistant VRE in hospitals.4, 1114 Despite linezolid being a key antibiotic for the treatment of VRE infections over the last 10 years, development of resistance along with potential hematologic and neurologic toxicity during long‐term use remains a concern.7, 8 Although daptomycin is active against several resistant organisms, including VRE, the evidence supporting use of daptomycin for VRE BSI is limited to case reports or small case series.7, 9 Moreover, daptomycin has not received US Food and Drug Administration approval for the treatment of VRE infections,15 and emerging data regarding daptomycin‐nonsusceptible enterococci (Minimum Inhibitory Concentration, MIC >4 mg/L) highlight a new problem for this multidrug‐resistant pathogen.16, 17 Few studies in recent years have compared these 2 antibiotics in the treatment of VRE BSIs.4, 18, 19 Due to the high rates of vancomycin resistance reported at our institution and the ubiquitous use of linezolid and daptomycin in the treatment of VRE bacteremia, we chose to evaluate response rates for these antibiotics in an effort to add to previously published literature on this topic.

MATERIALS AND METHODS

RESULTS

DISCUSSION

Vergis et al21 reported that infections with VRE compared with vancomycin‐sensitive infections were associated with a higher rate of mortality and that the chosen antimicrobial therapy may play a pivotal role in the risk of death. Our retrospective study suggests that linezolid and daptomycin appear to be equally efficacious for the treatment of VRE BSIs. The results from our study for clinical and microbiologic cure rates for linezolid and daptomycin are similar to previously published data.7, 8 In accordance with previous studies,4 our data demonstrate that there is a higher rate of recurrence in patients treated with daptomycin. This finding may be explained by the fact that the daptomycin group was comprised of more complex patients with a greater disease burden versus the linezolid group; therefore, they were more susceptible to a recurrent VRE infection. In our study, patients who were treated with daptomycin were 5.5 times more likely to have a recurrent infection than linezolid‐treated patients. However, this finding must be scrutinized, because over half of the patients with recurrence either received an inappropriate dose or had high MICs to daptomycin.

Despite there being few clinical and microbiologic outcome data with daptomycin, our study proposes that a bactericidal antibiotic and a bacteriostatic antibiotic have comparable efficacy in the treatment of VRE BSIs. Previous literature has mainly comprised case studies or series that have evaluated clinical outcomes with daptomycin in the treatment of VRE BSIs. Gallagher et al7 reported the results of a retrospective case series of 30 patients with VRE bacteremia who were treated with daptomycin. In this study, microbiologic cure was achieved in 80% of patients, with clinical success in 59% of the patients. In 2009, Mave et al4 compared clinical outcomes between daptomycin and linezolid in the treatment of VRE bacteremia. Reported results demonstrated a microbiologic cure rate of 90% for daptomycin versus 88% for linezolid.4 Moreover, there were no differences in mortality between the groups in our study. In 2010, Crank et al18 reported no differences in mortality (in‐hospital) for hospitalized patients with VRE BSIs treated with linezolid or daptomycin. Our results seem to be consistent with what has been published previously concerning clinical outcomes associated with linezolid or daptomycin in the treatment of VRE BSI.

The average daptomycin dose received in our patients was 6.1 mg/kg with doses ranging from 3.410.4 mg/kg. The underdosing as well as higher MICs to daptomycin may have contributed to a higher rate of recurrence. Previous reports state that Enterococcus species may have higher MICs to daptomycin than Staphylococcus or Streptococcus species; consequently, higher doses may be needed to adequately treat enterococcal infections.7 In the aforementioned study by Gallagher et al,7 doses of daptomycin 6 mg/kg were associated with a positive clinical outcome in 81% of patients compared with 31% if the dose used was <6 mg/kg. Linezolid is dosed 600 mg every 12 hours by mouth or intravenously, with no variations. There have been no studies comparing the uniform dosing of linezolid to the weight‐based dosing of daptomycin and their effects on outcomes.

Patients particularly susceptible to VRE infections include those with neutropenia and/or cancer, patients receiving long‐term hemodialysis, and liver transplant recipients.3, 22, 23 Upon review of this immunocompromised population, we noted no statistically significant differences in overall outcomes. A study by Kraft et al.24 supports the findings in our study that both drugs appear useful in the treatment of VRE bacteremia in patients with hematologic malignancy. We did identify a difference, albeit nonsignificant, in LOS for daptomycin versus linezolid in patients with a history of liver transplantation. Again, the level of care that these patients needed compared with the general population may explain this difference. As mentioned previously, another pertinent factor would be the dose of daptomycin used in these patients, because the dose can affect clinical success. Because all of the other patients had a similar LOS, we cannot determine that the increased LOS seen in liver transplant patients treated with daptomycin was solely due to daptomycin use. The reason for the increased LOS seems to be multifactorial. In the neutropenic population, a difference in LOS was also recognized, but follow‐up complete blood count values were not collected for these patients to determine whether linezolid contributed to further bone marrow suppression leading to an increase in LOS. For both of these patient populations, the number of patients included is very small (n = 21 for neutropenia total, n = 13 for liver transplant total), which can lead to a high degree of variance.

This study has several limitations. This was a retrospective review; therefore, we had no control over the selection of therapy. This may be reflected in an apparent preferential use of daptomycin in immunocompromised patients. Furthermore, 62% of linezolid patients and 54% of daptomycin patients received an antibiotic before initial therapy that could have potentially altered response rates. Due to the paucity of documentation surrounding initial site of infection, some of the positive cultures may represent potential contamination, because VRE may contaminate skin.25 Contamination seems implausible, however, because patients were seen by an infectious disease physician and had at least 1 documented positive VRE blood culture. We chose arbitrary definitions for clinical cure, microbiologic cure, microbiologic failure, recurrence, and reinfection. Previous studies have used their own definitions leading to discrepancies in reporting. Another limitation was that follow‐up cultures were not obtained on all of the patients, which was needed to determine rates of recurrence, reinfection, and microbiologic cure. MICs to daptomycin were not reported in 30% of our patients, potentially altering the recurrence rate seen in the daptomycin‐treated patients. Because clinical cure was not documented in the chart, it was inferred from the laboratory values and vital sign information. One investigator analyzed all of the values and made the determination of clinical cure, allowing for a consistent approach to data review.

In the face of the imposing threat of a highly resistant organism such as VRE with a limited number of efficacious antibiotics, antimicrobial selection becomes increasingly important and is requisite to clinical and microbiological success. To our knowledge, this is one of the largest studies to date comparing the efficacy of linezolid with that of daptomycin in the treatment of VRE bacteremia. Both of these agents are effective for the treatment of VRE BSIs. Nevertheless, specific factors related to the medication (eg, dose, route of administration) as well as the patient (eg, comorbid conditions, acuity of illness) should be taken into consideration when selecting an initial antimicrobial agent. Because the treatment of VRE BSIs continues to be a challenge, larger prospective randomized controlled trials are needed to corroborate our results and determine the optimal therapy for this serious infection.

Hyperglycemia and insulin resistance are common occurrences in critically ill patients, even those without a past medical history of diabetes.1, 2 This hyperglycemic state is associated with adverse outcomes, including severe infections, polyneuropathy, multiple‐organ failure, and death.3 Several studies have shown benefit in keeping patients' blood glucose (BG) tightly controlled.37 In a randomized controlled study, strict BG control (80‐110 mg/dL) with an insulin drip significantly reduced morbidity and mortality in critically ill patients.3 A recent meta‐analysis concluded that avoiding BG levels >150 mg/dL appeared to be crucial to reducing mortality in a mixed medical and surgical intensive care unit (ICU) population.7

The Diabetes Mellitus Insulin‐Glucose Infusion in Acute Myocardial Infarction study addressed the issue of tight glycemic control both acutely and chronically in 620 diabetic patients postmyocardial infarction. Patients were randomized to tight glycemic control (126‐180 mg/dL) followed by a transition to maintenance insulin or to standard care. This intervention demonstrated a sustained mortality reduction of 7.5% at 1 year.8 In contrast, the CREATE‐ECLA study showed a neutral mortality benefit of a short‐term (24‐hour) insulin infusion in postmyocardial infarction patients.9 These data demonstrate the need for clinicians to consider insulin requirements throughout the hospital stay and after discharge. To date, there are no published studies evaluating glycemic control following discontinuation of an intensive insulin protocol (IIP). Therefore, the current study was conducted to compare BG control during the use of an IIP and for the 5 days following intensive insulin therapy.

METHODS

RESULTS

A total of 171 patients received the IIP during the study period. Ninety‐seven patients did not meet inclusion criteria because they received the IIP for less than 24 hours. Of the 74 patients meeting inclusion criteria, 9 were excluded (5 had insufficient glucose data, 3 were cared for by an endocrinologist, and 1 died while receiving the IIP). Thus, 65 patients were included in the study.

Table 1 lists the baseline demographics for all patients and those with and without a history of diabetes mellitus (DM). The majority of the patients (n = 49) underwent a surgical procedure, with the most common procedure being coronary artery bypass graft (n = 38). Patients undergoing coronary artery bypass graft had the IIP included in their standard postoperative order set. The majority of patients were considered stable during the 12 hours prior to discontinuation of the IIP, including 23 patients with a history of DM. Of the 65 patients who were included in the study, 25 (38.5%) received a scheduled insulin order following discontinuation of the IIP, whereas 38 (58.5%) received some form of sliding‐scale insulin (SSI). Additionally, 2 (3%) patients did not receive any form of insulin order after stopping the IIP. Of those receiving scheduled insulin, 15 (60%) received neutral protamine Hagedorn, 5 (20%) received glargine, 5 (20%) received 70/30, and 1 (4%) received regular insulin. Of those receiving SSI only, the prescribed frequency was as follows: every 4 hours for 17 (45%), before meals and at bedtime for 15 (39%), every 6 hours for 5 (13%), and every 2 hours for 1 (3%).

A total of 562 glucose measurements were collected during the last 12 hours on the IIP, whereas 201 were collected during the first 12 hours immediately following the IIP. Patients demonstrated a significant increase in BG (mean standard deviation) during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP (168 50 mg/dL versus 123 26 mg/dL, P < 0.001). This corresponded to a significant decrease in the median (interquartile range) insulin administered during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP [8 (0‐18) units versus 40 (22‐65) units, P < 0.001; Figure 1]. A total of 1914 BG measurements were collected during the follow‐up period. Figure 2 shows mean BG values for all patients on the IIP compared to mean BG values for each day of the follow‐up period. There was a significant increase in mean BG measurements when the IIP was compared to each day of the follow‐up period, but there was no difference between days of the follow‐up period. Table 2 shows the proportion of patients experiencing at least 1 episode of hyperglycemia (BG > 150 mg/dL), significant hyperglycemia (BG > 200 mg/dL), severe hyperglycemia (BG > 300 mg/dL), or hypoglycemia (BG < 60 mg/dL) while receiving the IIP and during the follow‐up period. When comparing the IIP to the follow‐up period, we found a significant increase in the proportion of patients with at least 1 BG > 150 mg/dL. This was also true for patients with a BG of > 200 mg/dL.

Figure 1

Figure 2

The only independent predictor of a greater than 30% change in mean BG was the requirement for more than 20 units of insulin (>1.7 units/hour) during the last 12 hours on the IIP. The odds of a greater than 30% change was 4.62 times higher (95% confidence interval: 1.1718.17) in patients requiring more than 20 units during the last 12 hours on IIP after adjustments for stability on the protocol and past medical history of diabetes. Stability on the protocol was not identified as an independent predictor, with an adjusted odds ratio of 2.40 (95% confidence interval: 0.797.32).

DISCUSSION

This is the first study to describe glycemic control following the transition from an IIP to subcutaneous insulin. We observed that during the 5 days following discontinuation of an IIP, patients had significantly elevated mean BG values. These data are highlighted by the fact that patients received significantly less insulin during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP. Additionally, a larger than expected proportion of patients exhibited at least 1 episode of hyperglycemia during the follow‐up period. We also found that an increased insulin requirement of >1.7 units/hour during the last 12 hours of the IIP was an independent risk factor for a greater than 30% increase in mean BG on day 1 of the follow‐up period.

Increasing evidence demonstrates that the development of hyperglycemia in the hospital setting is a marker of poor clinical outcome and mortality. In fact, hyperglycemia has been associated with prolonged hospital stay, infection, disability after discharge, and death in patients on general surgical and medical wards.1012 This makes the increase in mean BG found in our study following discontinuation of the IIP a concern.

SSI with subcutaneous short‐acting insulin has been used for inpatients as the standard of care for many years. However, evidence supporting the effectiveness of SSI alone is lacking, and it is not recommended by the American Diabetes Association.13 Queale et al.14 showed that SSI regimens when used alone were associated with suboptimal glycemic control and a 3‐fold higher risk of hyperglycemic episodes.1 Two retrospective studies have also demonstrated that SSI is less effective and widely variable in comparison with proactive preventative therapy.15, 16 In the current study, 58.5% of patients received SSI alone during the follow‐up period. As indicated in Figure 1, there was a significant increase in mean BG during this time interval. The choice of an inappropriate insulin regimen might be a contributing factor to poor glycemic control.

Because only 38.5% of patients were transitioned to scheduled insulin in our study, one possible strategy to help improve glycemic control would be to transition patients to a scheduled insulin regimen. Umpierrez et al.12 conducted a prospective, multicenter randomized trial to compare the efficacy and safety of a basal‐bolus insulin regimen with that of SSI in hospitalized type 2 diabetics. These authors found that patients treated with insulin glargine and glulisine had greater improvement in glycemic control than those treated with SSI (P < 0.01).12 Interestingly, the basal‐bolus method provides a maintenance insulin regimen that is aggressively titrated upward as well as an adjustable SSI based on insulin sensitivity. Patients in the current study may have benefited from a similar approach as many did not have their scheduled insulin adjusted despite persistent hyperglycemia.

With the increasing evidence for tight glycemic control in the ICU, a standardized transition from an intensive insulin infusion to a subcutaneous basal‐bolus regimen or other scheduled regimen is needed. To date, the current study is the first to describe this transition. Based on these data, recommendations for transitioning patients off an IIP provided by Furnary and Braithwaite17 should be considered by clinicians. In fact, one of their proposed predictors for unsuccessful transition was an insulin requirement of 2 units/hour. Indeed, the only independent risk factor for poor glycemic control identified in the current study was a requirement of >20 units (>1.7 units/hour) during the last 12 hours of the IIP. Further research is required to verify the other predictors suggested by Furnary and Braithwaite. They recommended using a standardized conversion protocol to transition patients off an IIP.

More recently, Kitabchi et al.18 recommended that a BG target of less than 180 mg/dL be maintained for the hospitalized patient.18 Although our study showed a mean BG less than 180 mg/dL during the follow‐up period, the variability in these values raises concerns for individual patients.

The current study is limited by its size and retrospective nature. As with all retrospective studies, the inability to control the implementation and discontinuation of the IIP may confound the results. However, this study demonstrates a real world experience with an IIP and illustrates the difficulties with transitioning patients to a subcutaneous regimen. BG values and administered insulin were collected only for the last 12 hours on the IIP. This duration is considered appropriate as this time period is used clinically at MUH, and previous recommendations for transitioning patients suggest using a time period of 6 to 8 hours to guide the transition insulin regimen.17 In addition, data regarding the severity of illness and new onset of infections were not collected for patients in the study. Both could affect glucose control. All patients had to be in an ICU to receive the IIP, but their location during the follow‐up period varied. Although these data were not available, control of BG is a problem that should be addressed whether the patient is in the ICU or not. Another possible limitation of the study was the identification of patients with or without a past medical history of DM. The inability to identify new‐onset or previously undiagnosed DM may have affected analyses based on this variable.

CONCLUSIONS

This study demonstrated a significant increase in mean BG following discontinuation of an IIP; this corresponded to a significant decrease in the amount of insulin administered. This increase was sustained for a period of at least 5 days. Additionally, an independent risk factor for poor glycemic control immediately following discontinuation of an IIP was an insulin requirement of >1.7 units/hour during the previous 12 hours. Further study into transitioning off an IIP is warranted.

Hyperglycemia and insulin resistance are common occurrences in critically ill patients, even those without a past medical history of diabetes.1, 2 This hyperglycemic state is associated with adverse outcomes, including severe infections, polyneuropathy, multiple‐organ failure, and death.3 Several studies have shown benefit in keeping patients' blood glucose (BG) tightly controlled.37 In a randomized controlled study, strict BG control (80‐110 mg/dL) with an insulin drip significantly reduced morbidity and mortality in critically ill patients.3 A recent meta‐analysis concluded that avoiding BG levels >150 mg/dL appeared to be crucial to reducing mortality in a mixed medical and surgical intensive care unit (ICU) population.7

The Diabetes Mellitus Insulin‐Glucose Infusion in Acute Myocardial Infarction study addressed the issue of tight glycemic control both acutely and chronically in 620 diabetic patients postmyocardial infarction. Patients were randomized to tight glycemic control (126‐180 mg/dL) followed by a transition to maintenance insulin or to standard care. This intervention demonstrated a sustained mortality reduction of 7.5% at 1 year.8 In contrast, the CREATE‐ECLA study showed a neutral mortality benefit of a short‐term (24‐hour) insulin infusion in postmyocardial infarction patients.9 These data demonstrate the need for clinicians to consider insulin requirements throughout the hospital stay and after discharge. To date, there are no published studies evaluating glycemic control following discontinuation of an intensive insulin protocol (IIP). Therefore, the current study was conducted to compare BG control during the use of an IIP and for the 5 days following intensive insulin therapy.

METHODS

RESULTS

A total of 171 patients received the IIP during the study period. Ninety‐seven patients did not meet inclusion criteria because they received the IIP for less than 24 hours. Of the 74 patients meeting inclusion criteria, 9 were excluded (5 had insufficient glucose data, 3 were cared for by an endocrinologist, and 1 died while receiving the IIP). Thus, 65 patients were included in the study.

Table 1 lists the baseline demographics for all patients and those with and without a history of diabetes mellitus (DM). The majority of the patients (n = 49) underwent a surgical procedure, with the most common procedure being coronary artery bypass graft (n = 38). Patients undergoing coronary artery bypass graft had the IIP included in their standard postoperative order set. The majority of patients were considered stable during the 12 hours prior to discontinuation of the IIP, including 23 patients with a history of DM. Of the 65 patients who were included in the study, 25 (38.5%) received a scheduled insulin order following discontinuation of the IIP, whereas 38 (58.5%) received some form of sliding‐scale insulin (SSI). Additionally, 2 (3%) patients did not receive any form of insulin order after stopping the IIP. Of those receiving scheduled insulin, 15 (60%) received neutral protamine Hagedorn, 5 (20%) received glargine, 5 (20%) received 70/30, and 1 (4%) received regular insulin. Of those receiving SSI only, the prescribed frequency was as follows: every 4 hours for 17 (45%), before meals and at bedtime for 15 (39%), every 6 hours for 5 (13%), and every 2 hours for 1 (3%).

A total of 562 glucose measurements were collected during the last 12 hours on the IIP, whereas 201 were collected during the first 12 hours immediately following the IIP. Patients demonstrated a significant increase in BG (mean standard deviation) during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP (168 50 mg/dL versus 123 26 mg/dL, P < 0.001). This corresponded to a significant decrease in the median (interquartile range) insulin administered during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP [8 (0‐18) units versus 40 (22‐65) units, P < 0.001; Figure 1]. A total of 1914 BG measurements were collected during the follow‐up period. Figure 2 shows mean BG values for all patients on the IIP compared to mean BG values for each day of the follow‐up period. There was a significant increase in mean BG measurements when the IIP was compared to each day of the follow‐up period, but there was no difference between days of the follow‐up period. Table 2 shows the proportion of patients experiencing at least 1 episode of hyperglycemia (BG > 150 mg/dL), significant hyperglycemia (BG > 200 mg/dL), severe hyperglycemia (BG > 300 mg/dL), or hypoglycemia (BG < 60 mg/dL) while receiving the IIP and during the follow‐up period. When comparing the IIP to the follow‐up period, we found a significant increase in the proportion of patients with at least 1 BG > 150 mg/dL. This was also true for patients with a BG of > 200 mg/dL.

Figure 1

Figure 2

The only independent predictor of a greater than 30% change in mean BG was the requirement for more than 20 units of insulin (>1.7 units/hour) during the last 12 hours on the IIP. The odds of a greater than 30% change was 4.62 times higher (95% confidence interval: 1.1718.17) in patients requiring more than 20 units during the last 12 hours on IIP after adjustments for stability on the protocol and past medical history of diabetes. Stability on the protocol was not identified as an independent predictor, with an adjusted odds ratio of 2.40 (95% confidence interval: 0.797.32).

DISCUSSION

This is the first study to describe glycemic control following the transition from an IIP to subcutaneous insulin. We observed that during the 5 days following discontinuation of an IIP, patients had significantly elevated mean BG values. These data are highlighted by the fact that patients received significantly less insulin during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP. Additionally, a larger than expected proportion of patients exhibited at least 1 episode of hyperglycemia during the follow‐up period. We also found that an increased insulin requirement of >1.7 units/hour during the last 12 hours of the IIP was an independent risk factor for a greater than 30% increase in mean BG on day 1 of the follow‐up period.

Increasing evidence demonstrates that the development of hyperglycemia in the hospital setting is a marker of poor clinical outcome and mortality. In fact, hyperglycemia has been associated with prolonged hospital stay, infection, disability after discharge, and death in patients on general surgical and medical wards.1012 This makes the increase in mean BG found in our study following discontinuation of the IIP a concern.

SSI with subcutaneous short‐acting insulin has been used for inpatients as the standard of care for many years. However, evidence supporting the effectiveness of SSI alone is lacking, and it is not recommended by the American Diabetes Association.13 Queale et al.14 showed that SSI regimens when used alone were associated with suboptimal glycemic control and a 3‐fold higher risk of hyperglycemic episodes.1 Two retrospective studies have also demonstrated that SSI is less effective and widely variable in comparison with proactive preventative therapy.15, 16 In the current study, 58.5% of patients received SSI alone during the follow‐up period. As indicated in Figure 1, there was a significant increase in mean BG during this time interval. The choice of an inappropriate insulin regimen might be a contributing factor to poor glycemic control.

Because only 38.5% of patients were transitioned to scheduled insulin in our study, one possible strategy to help improve glycemic control would be to transition patients to a scheduled insulin regimen. Umpierrez et al.12 conducted a prospective, multicenter randomized trial to compare the efficacy and safety of a basal‐bolus insulin regimen with that of SSI in hospitalized type 2 diabetics. These authors found that patients treated with insulin glargine and glulisine had greater improvement in glycemic control than those treated with SSI (P < 0.01).12 Interestingly, the basal‐bolus method provides a maintenance insulin regimen that is aggressively titrated upward as well as an adjustable SSI based on insulin sensitivity. Patients in the current study may have benefited from a similar approach as many did not have their scheduled insulin adjusted despite persistent hyperglycemia.

With the increasing evidence for tight glycemic control in the ICU, a standardized transition from an intensive insulin infusion to a subcutaneous basal‐bolus regimen or other scheduled regimen is needed. To date, the current study is the first to describe this transition. Based on these data, recommendations for transitioning patients off an IIP provided by Furnary and Braithwaite17 should be considered by clinicians. In fact, one of their proposed predictors for unsuccessful transition was an insulin requirement of 2 units/hour. Indeed, the only independent risk factor for poor glycemic control identified in the current study was a requirement of >20 units (>1.7 units/hour) during the last 12 hours of the IIP. Further research is required to verify the other predictors suggested by Furnary and Braithwaite. They recommended using a standardized conversion protocol to transition patients off an IIP.

More recently, Kitabchi et al.18 recommended that a BG target of less than 180 mg/dL be maintained for the hospitalized patient.18 Although our study showed a mean BG less than 180 mg/dL during the follow‐up period, the variability in these values raises concerns for individual patients.

The current study is limited by its size and retrospective nature. As with all retrospective studies, the inability to control the implementation and discontinuation of the IIP may confound the results. However, this study demonstrates a real world experience with an IIP and illustrates the difficulties with transitioning patients to a subcutaneous regimen. BG values and administered insulin were collected only for the last 12 hours on the IIP. This duration is considered appropriate as this time period is used clinically at MUH, and previous recommendations for transitioning patients suggest using a time period of 6 to 8 hours to guide the transition insulin regimen.17 In addition, data regarding the severity of illness and new onset of infections were not collected for patients in the study. Both could affect glucose control. All patients had to be in an ICU to receive the IIP, but their location during the follow‐up period varied. Although these data were not available, control of BG is a problem that should be addressed whether the patient is in the ICU or not. Another possible limitation of the study was the identification of patients with or without a past medical history of DM. The inability to identify new‐onset or previously undiagnosed DM may have affected analyses based on this variable.

CONCLUSIONS

This study demonstrated a significant increase in mean BG following discontinuation of an IIP; this corresponded to a significant decrease in the amount of insulin administered. This increase was sustained for a period of at least 5 days. Additionally, an independent risk factor for poor glycemic control immediately following discontinuation of an IIP was an insulin requirement of >1.7 units/hour during the previous 12 hours. Further study into transitioning off an IIP is warranted.

Hyperglycemia and insulin resistance are common occurrences in critically ill patients, even those without a past medical history of diabetes.1, 2 This hyperglycemic state is associated with adverse outcomes, including severe infections, polyneuropathy, multiple‐organ failure, and death.3 Several studies have shown benefit in keeping patients' blood glucose (BG) tightly controlled.37 In a randomized controlled study, strict BG control (80‐110 mg/dL) with an insulin drip significantly reduced morbidity and mortality in critically ill patients.3 A recent meta‐analysis concluded that avoiding BG levels >150 mg/dL appeared to be crucial to reducing mortality in a mixed medical and surgical intensive care unit (ICU) population.7

The Diabetes Mellitus Insulin‐Glucose Infusion in Acute Myocardial Infarction study addressed the issue of tight glycemic control both acutely and chronically in 620 diabetic patients postmyocardial infarction. Patients were randomized to tight glycemic control (126‐180 mg/dL) followed by a transition to maintenance insulin or to standard care. This intervention demonstrated a sustained mortality reduction of 7.5% at 1 year.8 In contrast, the CREATE‐ECLA study showed a neutral mortality benefit of a short‐term (24‐hour) insulin infusion in postmyocardial infarction patients.9 These data demonstrate the need for clinicians to consider insulin requirements throughout the hospital stay and after discharge. To date, there are no published studies evaluating glycemic control following discontinuation of an intensive insulin protocol (IIP). Therefore, the current study was conducted to compare BG control during the use of an IIP and for the 5 days following intensive insulin therapy.

METHODS

RESULTS

A total of 171 patients received the IIP during the study period. Ninety‐seven patients did not meet inclusion criteria because they received the IIP for less than 24 hours. Of the 74 patients meeting inclusion criteria, 9 were excluded (5 had insufficient glucose data, 3 were cared for by an endocrinologist, and 1 died while receiving the IIP). Thus, 65 patients were included in the study.

Table 1 lists the baseline demographics for all patients and those with and without a history of diabetes mellitus (DM). The majority of the patients (n = 49) underwent a surgical procedure, with the most common procedure being coronary artery bypass graft (n = 38). Patients undergoing coronary artery bypass graft had the IIP included in their standard postoperative order set. The majority of patients were considered stable during the 12 hours prior to discontinuation of the IIP, including 23 patients with a history of DM. Of the 65 patients who were included in the study, 25 (38.5%) received a scheduled insulin order following discontinuation of the IIP, whereas 38 (58.5%) received some form of sliding‐scale insulin (SSI). Additionally, 2 (3%) patients did not receive any form of insulin order after stopping the IIP. Of those receiving scheduled insulin, 15 (60%) received neutral protamine Hagedorn, 5 (20%) received glargine, 5 (20%) received 70/30, and 1 (4%) received regular insulin. Of those receiving SSI only, the prescribed frequency was as follows: every 4 hours for 17 (45%), before meals and at bedtime for 15 (39%), every 6 hours for 5 (13%), and every 2 hours for 1 (3%).

A total of 562 glucose measurements were collected during the last 12 hours on the IIP, whereas 201 were collected during the first 12 hours immediately following the IIP. Patients demonstrated a significant increase in BG (mean standard deviation) during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP (168 50 mg/dL versus 123 26 mg/dL, P < 0.001). This corresponded to a significant decrease in the median (interquartile range) insulin administered during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP [8 (0‐18) units versus 40 (22‐65) units, P < 0.001; Figure 1]. A total of 1914 BG measurements were collected during the follow‐up period. Figure 2 shows mean BG values for all patients on the IIP compared to mean BG values for each day of the follow‐up period. There was a significant increase in mean BG measurements when the IIP was compared to each day of the follow‐up period, but there was no difference between days of the follow‐up period. Table 2 shows the proportion of patients experiencing at least 1 episode of hyperglycemia (BG > 150 mg/dL), significant hyperglycemia (BG > 200 mg/dL), severe hyperglycemia (BG > 300 mg/dL), or hypoglycemia (BG < 60 mg/dL) while receiving the IIP and during the follow‐up period. When comparing the IIP to the follow‐up period, we found a significant increase in the proportion of patients with at least 1 BG > 150 mg/dL. This was also true for patients with a BG of > 200 mg/dL.

Figure 1

Figure 2

The only independent predictor of a greater than 30% change in mean BG was the requirement for more than 20 units of insulin (>1.7 units/hour) during the last 12 hours on the IIP. The odds of a greater than 30% change was 4.62 times higher (95% confidence interval: 1.1718.17) in patients requiring more than 20 units during the last 12 hours on IIP after adjustments for stability on the protocol and past medical history of diabetes. Stability on the protocol was not identified as an independent predictor, with an adjusted odds ratio of 2.40 (95% confidence interval: 0.797.32).

DISCUSSION

This is the first study to describe glycemic control following the transition from an IIP to subcutaneous insulin. We observed that during the 5 days following discontinuation of an IIP, patients had significantly elevated mean BG values. These data are highlighted by the fact that patients received significantly less insulin during the first 12 hours of the follow‐up period versus the last 12 hours of the IIP. Additionally, a larger than expected proportion of patients exhibited at least 1 episode of hyperglycemia during the follow‐up period. We also found that an increased insulin requirement of >1.7 units/hour during the last 12 hours of the IIP was an independent risk factor for a greater than 30% increase in mean BG on day 1 of the follow‐up period.

Increasing evidence demonstrates that the development of hyperglycemia in the hospital setting is a marker of poor clinical outcome and mortality. In fact, hyperglycemia has been associated with prolonged hospital stay, infection, disability after discharge, and death in patients on general surgical and medical wards.1012 This makes the increase in mean BG found in our study following discontinuation of the IIP a concern.

SSI with subcutaneous short‐acting insulin has been used for inpatients as the standard of care for many years. However, evidence supporting the effectiveness of SSI alone is lacking, and it is not recommended by the American Diabetes Association.13 Queale et al.14 showed that SSI regimens when used alone were associated with suboptimal glycemic control and a 3‐fold higher risk of hyperglycemic episodes.1 Two retrospective studies have also demonstrated that SSI is less effective and widely variable in comparison with proactive preventative therapy.15, 16 In the current study, 58.5% of patients received SSI alone during the follow‐up period. As indicated in Figure 1, there was a significant increase in mean BG during this time interval. The choice of an inappropriate insulin regimen might be a contributing factor to poor glycemic control.

Because only 38.5% of patients were transitioned to scheduled insulin in our study, one possible strategy to help improve glycemic control would be to transition patients to a scheduled insulin regimen. Umpierrez et al.12 conducted a prospective, multicenter randomized trial to compare the efficacy and safety of a basal‐bolus insulin regimen with that of SSI in hospitalized type 2 diabetics. These authors found that patients treated with insulin glargine and glulisine had greater improvement in glycemic control than those treated with SSI (P < 0.01).12 Interestingly, the basal‐bolus method provides a maintenance insulin regimen that is aggressively titrated upward as well as an adjustable SSI based on insulin sensitivity. Patients in the current study may have benefited from a similar approach as many did not have their scheduled insulin adjusted despite persistent hyperglycemia.

With the increasing evidence for tight glycemic control in the ICU, a standardized transition from an intensive insulin infusion to a subcutaneous basal‐bolus regimen or other scheduled regimen is needed. To date, the current study is the first to describe this transition. Based on these data, recommendations for transitioning patients off an IIP provided by Furnary and Braithwaite17 should be considered by clinicians. In fact, one of their proposed predictors for unsuccessful transition was an insulin requirement of 2 units/hour. Indeed, the only independent risk factor for poor glycemic control identified in the current study was a requirement of >20 units (>1.7 units/hour) during the last 12 hours of the IIP. Further research is required to verify the other predictors suggested by Furnary and Braithwaite. They recommended using a standardized conversion protocol to transition patients off an IIP.

More recently, Kitabchi et al.18 recommended that a BG target of less than 180 mg/dL be maintained for the hospitalized patient.18 Although our study showed a mean BG less than 180 mg/dL during the follow‐up period, the variability in these values raises concerns for individual patients.

The current study is limited by its size and retrospective nature. As with all retrospective studies, the inability to control the implementation and discontinuation of the IIP may confound the results. However, this study demonstrates a real world experience with an IIP and illustrates the difficulties with transitioning patients to a subcutaneous regimen. BG values and administered insulin were collected only for the last 12 hours on the IIP. This duration is considered appropriate as this time period is used clinically at MUH, and previous recommendations for transitioning patients suggest using a time period of 6 to 8 hours to guide the transition insulin regimen.17 In addition, data regarding the severity of illness and new onset of infections were not collected for patients in the study. Both could affect glucose control. All patients had to be in an ICU to receive the IIP, but their location during the follow‐up period varied. Although these data were not available, control of BG is a problem that should be addressed whether the patient is in the ICU or not. Another possible limitation of the study was the identification of patients with or without a past medical history of DM. The inability to identify new‐onset or previously undiagnosed DM may have affected analyses based on this variable.

CONCLUSIONS

This study demonstrated a significant increase in mean BG following discontinuation of an IIP; this corresponded to a significant decrease in the amount of insulin administered. This increase was sustained for a period of at least 5 days. Additionally, an independent risk factor for poor glycemic control immediately following discontinuation of an IIP was an insulin requirement of >1.7 units/hour during the previous 12 hours. Further study into transitioning off an IIP is warranted.