Assessment of High Staphylococcus aureus MIC and Poor Patient Outcomes

Staphylococcus aureus (S aureus) is a common cause of infection within the hospital and in the community.¹ Treatment is based on the organism’s susceptibility to methicillin and is referred to as either MRSA (methicillin-resistant S aureus) or MSSA (methicillin-susceptible 
S aureus). As antibiotic resistance has evolved, patients with S aureus (especially MRSA) infections have become more difficult to treat. Susceptibility testing guides treatment of these infections and determines the minimum inhibitory concentration (MIC) for each antibiotic. A MIC is the minimum concentration of an antibiotic that will inhibit the visible growth of the organism after incubation.

Related: Experts Debate Infection Control Merits of ‘Bare Beneath the Elbows’

Vancomycin has remained the mainstay for treatment of patients with MRSA infections. An increasing number of infections with high documented MICs to vancomycin are raising concern that resistance may be developing. Clinical controversy exists within the infectious disease community as to whether vancomycin is less effective against S aureus infections with a vancomycin MIC of ≥ 2 µg/mL, contributing to poor patient outcomes.²

The Clinical and Laboratory Standards Institute (CLSI) lowered the breakpoint for vancomycin in 2006 from > 4 µg/mL to > 2 µg/mL.³ Breakpoints delineate MIC values that are considered susceptible, nonsusceptible, or resistant to an antibiotic. The CLSI breakpoint change points to an increase in vancomycin resistance and supports the need for further discussion and insight.

A 2012 meta-analysis was conducted to determine whether an association exists between S aureus infections with vancomycin MIC values ≥ 2 µg/mL and the effectiveness of the therapy.² Twenty-two studies were included with a primary outcome of 30-day mortality. A review of MRSA data revealed a statistically significant association between high vancomycin MICs (≥ 1.5 µg/mL) and increased mortality (P < .01), regardless of the source of infection. When limiting the data to Etest (bioMérieux, Marcy L’Etoile, France) MIC testing for MRSA bloodstream infections (BSIs), a vancomycin MIC ≥ 1.5 µg/mL was not associated with increased mortality (P = .08). Comparing data for MIC ≥ 2 µg/mL and ≤ 1.5 µg/mL, found that MICs ≥ 2 µg/mL were associated with increased mortality (P < .01). Analysis of the 11 studies that included data on treatment failure concluded that S aureus infections with a vancomycin MIC ≥ 1.5 µg/mL were associated with an increased risk of treatment failure in both MSSA and MRSA infections (P < .01) and that treatment failure was more likely in MRSA BSIs than in non-BSIs (P < .01).Evidence to support a possible correlation between high S aureus vancomycin MICs and poor patient outcomes came from a 2013 meta-analysis.³ The specific aim of this study was to examine the correlations between vancomycin MIC, patient mortality, and treatment failure. A MIC ≥ 1.5 µg/mL and ≥ 1.0 µg/mL were used to classify MICs as high when determined by Etest and broth microdilution (BMD), respectively. Analysis revealed an association between high vancomycin MICs and increased risk of treatment failure (relative risk [RR] 1.40, 95% confidence interval [CI] 1.15-1.71) and overall mortality (RR 1.42, 95% CI 1.08-1.87). Similarly, a sensitivity analysis on S aureus BSIs with high vancomycin MICs revealed an increased risk of mortality (RR 1.46, 95% CI 1.06-2.01) and treatment failure (RR 1.37, 95% CI 1.09-1.73).

Related: The Importance of an Antimicrobial Stewardship Program

The most recent meta-analysis (published in 2014) included patients with S aureus bacteremia and evaluated the association of high S aureus vancomycin MIC with an increased risk of mortality.⁴ A high MIC was defined as ≥ 1.5 µg/mL by Etest and ≥ 2.0 µg/mL by BMD. The analysis of 38 studies found a nonstatistically significant difference in mortality risk (P = .43). Further analysis was performed to determine whether the vancomycin MIC cutoff plays a role in increased mortality. No statistically significant difference in mortality was found when using a vancomycin MIC ≥ 1.5 µg/mL, ≥ 2.0 µg/mL, ≥ 4.0 µg/mL, or ≥ 8.0 µg/mL. The authors argued that their differing conclusions from other meta-analyses may be due to the inclusion of only bacteremias rather than all infection types, and although there was not a statistically significant difference, increased risk of mortality could not be excluded.

Related: Results Mixed in Hospital Efforts to Tackle Antimicrobial Resistance

Although conclusions of published meta-analyses differ, the results highlight the necessity of using clinical judgment in treating patients with S aureus infections with high MIC values and to consider the primary source and severity of infection. A confounding factor to direct comparison of the literature is the variations based on the method of MIC determination and testing (Etest vs BMD).

Additionally, all 3 studies addressed the importance of considering clinical patient factors that may lead to poorer prognosis as well as the difficultly in achieving necessary vancomycin levels with limited toxicity. The risk of increased mortality in patients with high vancomycin MICs cannot be ruled out at this time. Therefore, additional patient factors as well as the potential toxicities that may result from vancomycin therapy should be considered when using vancomycin in treating patients with S aureus infections.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Staphylococcus aureus (S aureus) is a common cause of infection within the hospital and in the community.¹ Treatment is based on the organism’s susceptibility to methicillin and is referred to as either MRSA (methicillin-resistant S aureus) or MSSA (methicillin-susceptible 
S aureus). As antibiotic resistance has evolved, patients with S aureus (especially MRSA) infections have become more difficult to treat. Susceptibility testing guides treatment of these infections and determines the minimum inhibitory concentration (MIC) for each antibiotic. A MIC is the minimum concentration of an antibiotic that will inhibit the visible growth of the organism after incubation.

Related: Experts Debate Infection Control Merits of ‘Bare Beneath the Elbows’

Vancomycin has remained the mainstay for treatment of patients with MRSA infections. An increasing number of infections with high documented MICs to vancomycin are raising concern that resistance may be developing. Clinical controversy exists within the infectious disease community as to whether vancomycin is less effective against S aureus infections with a vancomycin MIC of ≥ 2 µg/mL, contributing to poor patient outcomes.²

The Clinical and Laboratory Standards Institute (CLSI) lowered the breakpoint for vancomycin in 2006 from > 4 µg/mL to > 2 µg/mL.³ Breakpoints delineate MIC values that are considered susceptible, nonsusceptible, or resistant to an antibiotic. The CLSI breakpoint change points to an increase in vancomycin resistance and supports the need for further discussion and insight.

A 2012 meta-analysis was conducted to determine whether an association exists between S aureus infections with vancomycin MIC values ≥ 2 µg/mL and the effectiveness of the therapy.² Twenty-two studies were included with a primary outcome of 30-day mortality. A review of MRSA data revealed a statistically significant association between high vancomycin MICs (≥ 1.5 µg/mL) and increased mortality (P < .01), regardless of the source of infection. When limiting the data to Etest (bioMérieux, Marcy L’Etoile, France) MIC testing for MRSA bloodstream infections (BSIs), a vancomycin MIC ≥ 1.5 µg/mL was not associated with increased mortality (P = .08). Comparing data for MIC ≥ 2 µg/mL and ≤ 1.5 µg/mL, found that MICs ≥ 2 µg/mL were associated with increased mortality (P < .01). Analysis of the 11 studies that included data on treatment failure concluded that S aureus infections with a vancomycin MIC ≥ 1.5 µg/mL were associated with an increased risk of treatment failure in both MSSA and MRSA infections (P < .01) and that treatment failure was more likely in MRSA BSIs than in non-BSIs (P < .01).Evidence to support a possible correlation between high S aureus vancomycin MICs and poor patient outcomes came from a 2013 meta-analysis.³ The specific aim of this study was to examine the correlations between vancomycin MIC, patient mortality, and treatment failure. A MIC ≥ 1.5 µg/mL and ≥ 1.0 µg/mL were used to classify MICs as high when determined by Etest and broth microdilution (BMD), respectively. Analysis revealed an association between high vancomycin MICs and increased risk of treatment failure (relative risk [RR] 1.40, 95% confidence interval [CI] 1.15-1.71) and overall mortality (RR 1.42, 95% CI 1.08-1.87). Similarly, a sensitivity analysis on S aureus BSIs with high vancomycin MICs revealed an increased risk of mortality (RR 1.46, 95% CI 1.06-2.01) and treatment failure (RR 1.37, 95% CI 1.09-1.73).

Related: The Importance of an Antimicrobial Stewardship Program

The most recent meta-analysis (published in 2014) included patients with S aureus bacteremia and evaluated the association of high S aureus vancomycin MIC with an increased risk of mortality.⁴ A high MIC was defined as ≥ 1.5 µg/mL by Etest and ≥ 2.0 µg/mL by BMD. The analysis of 38 studies found a nonstatistically significant difference in mortality risk (P = .43). Further analysis was performed to determine whether the vancomycin MIC cutoff plays a role in increased mortality. No statistically significant difference in mortality was found when using a vancomycin MIC ≥ 1.5 µg/mL, ≥ 2.0 µg/mL, ≥ 4.0 µg/mL, or ≥ 8.0 µg/mL. The authors argued that their differing conclusions from other meta-analyses may be due to the inclusion of only bacteremias rather than all infection types, and although there was not a statistically significant difference, increased risk of mortality could not be excluded.

Related: Results Mixed in Hospital Efforts to Tackle Antimicrobial Resistance

Although conclusions of published meta-analyses differ, the results highlight the necessity of using clinical judgment in treating patients with S aureus infections with high MIC values and to consider the primary source and severity of infection. A confounding factor to direct comparison of the literature is the variations based on the method of MIC determination and testing (Etest vs BMD).

Additionally, all 3 studies addressed the importance of considering clinical patient factors that may lead to poorer prognosis as well as the difficultly in achieving necessary vancomycin levels with limited toxicity. The risk of increased mortality in patients with high vancomycin MICs cannot be ruled out at this time. Therefore, additional patient factors as well as the potential toxicities that may result from vancomycin therapy should be considered when using vancomycin in treating patients with S aureus infections.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Staphylococcus aureus (S aureus) is a common cause of infection within the hospital and in the community.¹ Treatment is based on the organism’s susceptibility to methicillin and is referred to as either MRSA (methicillin-resistant S aureus) or MSSA (methicillin-susceptible 
S aureus). As antibiotic resistance has evolved, patients with S aureus (especially MRSA) infections have become more difficult to treat. Susceptibility testing guides treatment of these infections and determines the minimum inhibitory concentration (MIC) for each antibiotic. A MIC is the minimum concentration of an antibiotic that will inhibit the visible growth of the organism after incubation.

Related: Experts Debate Infection Control Merits of ‘Bare Beneath the Elbows’

Vancomycin has remained the mainstay for treatment of patients with MRSA infections. An increasing number of infections with high documented MICs to vancomycin are raising concern that resistance may be developing. Clinical controversy exists within the infectious disease community as to whether vancomycin is less effective against S aureus infections with a vancomycin MIC of ≥ 2 µg/mL, contributing to poor patient outcomes.²

The Clinical and Laboratory Standards Institute (CLSI) lowered the breakpoint for vancomycin in 2006 from > 4 µg/mL to > 2 µg/mL.³ Breakpoints delineate MIC values that are considered susceptible, nonsusceptible, or resistant to an antibiotic. The CLSI breakpoint change points to an increase in vancomycin resistance and supports the need for further discussion and insight.

A 2012 meta-analysis was conducted to determine whether an association exists between S aureus infections with vancomycin MIC values ≥ 2 µg/mL and the effectiveness of the therapy.² Twenty-two studies were included with a primary outcome of 30-day mortality. A review of MRSA data revealed a statistically significant association between high vancomycin MICs (≥ 1.5 µg/mL) and increased mortality (P < .01), regardless of the source of infection. When limiting the data to Etest (bioMérieux, Marcy L’Etoile, France) MIC testing for MRSA bloodstream infections (BSIs), a vancomycin MIC ≥ 1.5 µg/mL was not associated with increased mortality (P = .08). Comparing data for MIC ≥ 2 µg/mL and ≤ 1.5 µg/mL, found that MICs ≥ 2 µg/mL were associated with increased mortality (P < .01). Analysis of the 11 studies that included data on treatment failure concluded that S aureus infections with a vancomycin MIC ≥ 1.5 µg/mL were associated with an increased risk of treatment failure in both MSSA and MRSA infections (P < .01) and that treatment failure was more likely in MRSA BSIs than in non-BSIs (P < .01).Evidence to support a possible correlation between high S aureus vancomycin MICs and poor patient outcomes came from a 2013 meta-analysis.³ The specific aim of this study was to examine the correlations between vancomycin MIC, patient mortality, and treatment failure. A MIC ≥ 1.5 µg/mL and ≥ 1.0 µg/mL were used to classify MICs as high when determined by Etest and broth microdilution (BMD), respectively. Analysis revealed an association between high vancomycin MICs and increased risk of treatment failure (relative risk [RR] 1.40, 95% confidence interval [CI] 1.15-1.71) and overall mortality (RR 1.42, 95% CI 1.08-1.87). Similarly, a sensitivity analysis on S aureus BSIs with high vancomycin MICs revealed an increased risk of mortality (RR 1.46, 95% CI 1.06-2.01) and treatment failure (RR 1.37, 95% CI 1.09-1.73).

Related: The Importance of an Antimicrobial Stewardship Program

The most recent meta-analysis (published in 2014) included patients with S aureus bacteremia and evaluated the association of high S aureus vancomycin MIC with an increased risk of mortality.⁴ A high MIC was defined as ≥ 1.5 µg/mL by Etest and ≥ 2.0 µg/mL by BMD. The analysis of 38 studies found a nonstatistically significant difference in mortality risk (P = .43). Further analysis was performed to determine whether the vancomycin MIC cutoff plays a role in increased mortality. No statistically significant difference in mortality was found when using a vancomycin MIC ≥ 1.5 µg/mL, ≥ 2.0 µg/mL, ≥ 4.0 µg/mL, or ≥ 8.0 µg/mL. The authors argued that their differing conclusions from other meta-analyses may be due to the inclusion of only bacteremias rather than all infection types, and although there was not a statistically significant difference, increased risk of mortality could not be excluded.

Related: Results Mixed in Hospital Efforts to Tackle Antimicrobial Resistance

Although conclusions of published meta-analyses differ, the results highlight the necessity of using clinical judgment in treating patients with S aureus infections with high MIC values and to consider the primary source and severity of infection. A confounding factor to direct comparison of the literature is the variations based on the method of MIC determination and testing (Etest vs BMD).

Additionally, all 3 studies addressed the importance of considering clinical patient factors that may lead to poorer prognosis as well as the difficultly in achieving necessary vancomycin levels with limited toxicity. The risk of increased mortality in patients with high vancomycin MICs cannot be ruled out at this time. Therefore, additional patient factors as well as the potential toxicities that may result from vancomycin therapy should be considered when using vancomycin in treating patients with S aureus infections.

Additional Note
An earlier version of this article appeared in the Pharmacy Related Newsletter: The Capsule, of the William S. Middleton Memorial Veterans Hospital.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.