Clinical Infectious Diseases Advance Access published June 16, 2015
1 Double gram-positive coverage for Acute Bacterial Skin and Skin Structure Infections: Has the Eagle
cr ipt
landed?
Christopher M. Bland1, P. Brandon Bookstaver2 1
Clinical Assistant Professor, University of Georgia College of Pharmacy, Savannah, GA 31405, Co-
director of Southeastern Research Group Endeavor (SERGE-45), 706-267-5123
2
29208, Co-director of Southeastern Research Group Endeavor (SERGE-45)
Ac
ce
pt ed
M
an
Corresponding author: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
us
Associate Professor and Vice Chair, SC College of Pharmacy, University of South Carolina, Columbia, SC
2 Double gram-positive coverage for Acute Bacterial Skin and Skin Structure Infections: Has the Eagle landed?
cr ipt
In 1952 Harry Eagle discovered that penicillin was much less effective in high inoculum streptococcal infections, specifically Group A streptococcus (GAS). [1] Certain strains of streptococcal and
staphylococcal species have demonstrated paradoxically reduced activity in higher concentrations
versus lower concentrations of penicillin. These resistance mechanisms have been often described as the “Eagle effect” and have led to examination of non-cell wall modifying agents, such as protein
One of the major challenges of many “in vitro” known effects is determining whether or not they translate clinically “in vivo”. Some of these include pharmacodynamic parameters for efficacy, true
an
clinical effects of toxin inhibition, and antimicrobial synergy and antagonism with various combination therapies.
Clindamycin, a protein synthesis inhibitor, is often used in combination with high-dose penicillin therapy
M
for necrotizing skin/skin structure infections due to S. pyogenes. More recently two observational studies have demonstrated decreased mortality of invasive GAS infections when clindamycin was used adjunctively in the management of these patients. [2, 3] The benefit is most likely due to toxin inhibition
pt ed
which previously had been demonstrated primarily through in vitro and animal studies but may now be demonstrating a true “in vivo” benefit. The 2011 Infectious Diseases Society of America MethicillinResistant Staphylococcus aureus (MRSA) clinical practice guidelines do not routinely recommend protein synthesis inhibitors in the management of invasive MRSA disease, although some experts utilize this practice for infections such as necrotizing pneumonia. [4] The use of clindamycin as adjunctive therapy in the treatment of hospitalized acute bacterial skin and skin structure infections is not currently
ce
recommended in adults. Vancomycin monotherapy is the most commonly utilized antimicrobial treatment in conjunction with incision and drainage if an abscess is present. However, the empirical use of two gram-positive agents for treatment of ABSSSI could have far reaching stewardship implications
Ac
with over 600,000 hospital discharges annually in the United States. ABSSSI remains the most common presentation of MRSA infection. In this issue Wargo et al. present intriguing data comparing vancomycin monotherapy to vancomycin plus clindamycin combination therapy for both hospital length of stay (LOS) and 90-day readmissions. [5] While hospital LOS was not different between the groups, LOS was reduced in patients receiving
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
us
synthesis inhibitors, for empirical and definitive therapy in these infections.
3 combination therapy (at least 48 hours) who presented with abscess with MRSA the most common pathogen isolated. Readmission rates were also significantly lower in those patients receiving combination therapy. Some limitations include single center study, low overall numbers of readmissions,
cr ipt
and documentation of degree of critical illness such as ICU stay or presence of bacteremia.
Vancomycin because of its cell wall activity could potentially have less overall clinical cure in high
inoculum infections such as abscesses compared to protein synthesis inhibitors. Therefore “double
coverage” empirically with a ribosomal inhibitor such as clindamycin may provide additional clinical
benefit especially in more critically ill patients. Another potential option would be linezolid monotherapy
us
patients for complicated skin and soft tissue infections. [6] While clindamycin monotherapy is often used in pediatrics, caution should be given in adults as diverse geographical differences in susceptibility
an
exist making empiric coverage not optimal in some areas of the United States. The likely increased risk of C. difficile with clindamycin relative to other common agents used for ABSSSI such as vancomycin is an important point to consider. While no cases of C. difficile infection (CDI) were found in this analysis it
M
is unknown how patients may have presented to a different healthcare access point for treatment of CDI. The benefit of other protein synthesis inhibitors, such as doxycycline, is unknown but of interest due to potential decreased risk of C. difficile acquisition. [7]
pt ed
Reduced 90-day readmissions with empirical combination therapy of vancomycin plus clindamycin compared to vancomycin monotherapy in the Wargo study was also an interesting finding. However, it is more likely that definitive antimicrobial therapy correlates with 90-day readmission rates. The three most common discharge antibiotics were sulfamethoxazole/trimethoprim, clindamycin, and doxycycline respectively. The optimal definitive antibiotic therapy is unknown and as evidenced by the study varies
ce
widely by prescriber which occurs often in clinical practice. Definitive antimicrobial selection is often based on a number of different variables including patient allergies, drug interactions, host comorbidities, and prescriber preference as opposed to strong clinical evidence. Combination therapy
Ac
patients were much more likely to receive clindamycin as part of their home regimen (39% vs. 15.5%). Interestingly the combination group received nearly two less days of discharge antimicrobial therapy (8.6 days vs. 10.2 days) reinforcing the stewardship principle that shortened durations of therapy in ABSSSI after definitive incision and drainage remains prudent. While 90-day readmission rates were
significantly different, it is not known how many patients in each group accessed other points in the healthcare setting (e.g. primary care provider’s office) for further treatment of their ABSSSI.
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
which has demonstrated improved clinical cure compared to vancomycin in one subset analysis of MRSA
4 Data regarding management strategies of ABSSSI in the emergency department is an important limitation in current practice. Specific areas of need include predictors of admission as well as recurrence which is a hallmark of ABSSSI specifically abscesses due to S. aureus. Research is currently
cr ipt
ongoing to delineate the role of newly approved long-acting agents dalbavancin and oritavancin which may offer the unique benefit of preventing admission to the hospital for ABSSSI management.
Antimicrobial stewardship is best defined as using the narrowest therapy possible to obtain optimal
clinical outcomes while minimizing adverse effects. [8] For most infections this should be accomplished
through monotherapy. Examination of cell wall active agents plus protein synthesis inhibitors deserves
us
as tetracyclines or oxazolidinones should be evaluated as well. Therefore while using combination therapy for invasive streptococcal and staphylococcal infections is not an alien concept, the eagle has
an
not quite yet landed for empirical coverage for hospitalized patients with ABSSSIs.
M
Disclosures: Dr. Bookstaver has received consulting fees and grant support from Durata outside the submitted work. Dr. Bland has received consultant fees from Theravance and consulting fees and lecture
References
pt ed
fees from Cubist Pharmaceuticals outside the submitted work.
1. Eagle H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med 1952; 13:389-99. 2. Carpetis JR, Jacoby P, Carville K, Ang SJ, Curtis N, Andrews R. Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group a streptococcal
ce
infections. Clin Infect Dis 2014;59:358-65.
3. Linner A, Darenberg J, Sjolin J, Henriques-Normark B, Norrby-Teglund A. Clinical Efficacy of Polyspecific Intravenous Immunoglobulin Therapy in Patients With Streptococcal Toxic Shock
Ac
Syndrome: A Comparative Observational Study. Clin Infect Dis 2014;59:851-7.
4. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-e55.
5. Wargo KA, McCreary EK, English TM. Vancomycin combined with clindamycin for the treatment of acute bactereial skin and skin-structure infections. Clin Infect Dis 2015.
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
dedication to a randomized double-blinded multicenter manner. Other protein synthesis inhibitors such
5 6. Weigelt J, Itani K, Stevens D, Lau W, Dryden W, Kniersch C; Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005;49:2260-6.
cr ipt
7. Turner RB, Smith CB, Martello JL, Slain D. Role of doxycycline in Clostridium difficile infection acquisition. Ann Pharmacother 2014;48:772-6.
8. Dellit TH, Owens RC, McGowan Jr. JE, Gerding DN, Weinstein RA, Burke JP, et al. Infectious
Diseases Society of America and the Society of Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clin Infect Dis
an M pt ed ce Ac
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
us
2007;44:159-77.
1 Double gram-positive coverage for Acute Bacterial Skin and Skin Structure Infections: Has the Eagle
cr ipt
landed?
Christopher M. Bland1, P. Brandon Bookstaver2 1
Clinical Assistant Professor, University of Georgia College of Pharmacy, Savannah, GA 31405, Co-
director of Southeastern Research Group Endeavor (SERGE-45), 706-267-5123
2
29208, Co-director of Southeastern Research Group Endeavor (SERGE-45)
Ac
ce
pt ed
M
an
Corresponding author: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
us
Associate Professor and Vice Chair, SC College of Pharmacy, University of South Carolina, Columbia, SC
2 Double gram-positive coverage for Acute Bacterial Skin and Skin Structure Infections: Has the Eagle landed?
cr ipt
In 1952 Harry Eagle discovered that penicillin was much less effective in high inoculum streptococcal infections, specifically Group A streptococcus (GAS). [1] Certain strains of streptococcal and
staphylococcal species have demonstrated paradoxically reduced activity in higher concentrations
versus lower concentrations of penicillin. These resistance mechanisms have been often described as the “Eagle effect” and have led to examination of non-cell wall modifying agents, such as protein
One of the major challenges of many “in vitro” known effects is determining whether or not they translate clinically “in vivo”. Some of these include pharmacodynamic parameters for efficacy, true
an
clinical effects of toxin inhibition, and antimicrobial synergy and antagonism with various combination therapies.
Clindamycin, a protein synthesis inhibitor, is often used in combination with high-dose penicillin therapy
M
for necrotizing skin/skin structure infections due to S. pyogenes. More recently two observational studies have demonstrated decreased mortality of invasive GAS infections when clindamycin was used adjunctively in the management of these patients. [2, 3] The benefit is most likely due to toxin inhibition
pt ed
which previously had been demonstrated primarily through in vitro and animal studies but may now be demonstrating a true “in vivo” benefit. The 2011 Infectious Diseases Society of America MethicillinResistant Staphylococcus aureus (MRSA) clinical practice guidelines do not routinely recommend protein synthesis inhibitors in the management of invasive MRSA disease, although some experts utilize this practice for infections such as necrotizing pneumonia. [4] The use of clindamycin as adjunctive therapy in the treatment of hospitalized acute bacterial skin and skin structure infections is not currently
ce
recommended in adults. Vancomycin monotherapy is the most commonly utilized antimicrobial treatment in conjunction with incision and drainage if an abscess is present. However, the empirical use of two gram-positive agents for treatment of ABSSSI could have far reaching stewardship implications
Ac
with over 600,000 hospital discharges annually in the United States. ABSSSI remains the most common presentation of MRSA infection. In this issue Wargo et al. present intriguing data comparing vancomycin monotherapy to vancomycin plus clindamycin combination therapy for both hospital length of stay (LOS) and 90-day readmissions. [5] While hospital LOS was not different between the groups, LOS was reduced in patients receiving
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
us
synthesis inhibitors, for empirical and definitive therapy in these infections.
3 combination therapy (at least 48 hours) who presented with abscess with MRSA the most common pathogen isolated. Readmission rates were also significantly lower in those patients receiving combination therapy. Some limitations include single center study, low overall numbers of readmissions,
cr ipt
and documentation of degree of critical illness such as ICU stay or presence of bacteremia.
Vancomycin because of its cell wall activity could potentially have less overall clinical cure in high
inoculum infections such as abscesses compared to protein synthesis inhibitors. Therefore “double
coverage” empirically with a ribosomal inhibitor such as clindamycin may provide additional clinical
benefit especially in more critically ill patients. Another potential option would be linezolid monotherapy
us
patients for complicated skin and soft tissue infections. [6] While clindamycin monotherapy is often used in pediatrics, caution should be given in adults as diverse geographical differences in susceptibility
an
exist making empiric coverage not optimal in some areas of the United States. The likely increased risk of C. difficile with clindamycin relative to other common agents used for ABSSSI such as vancomycin is an important point to consider. While no cases of C. difficile infection (CDI) were found in this analysis it
M
is unknown how patients may have presented to a different healthcare access point for treatment of CDI. The benefit of other protein synthesis inhibitors, such as doxycycline, is unknown but of interest due to potential decreased risk of C. difficile acquisition. [7]
pt ed
Reduced 90-day readmissions with empirical combination therapy of vancomycin plus clindamycin compared to vancomycin monotherapy in the Wargo study was also an interesting finding. However, it is more likely that definitive antimicrobial therapy correlates with 90-day readmission rates. The three most common discharge antibiotics were sulfamethoxazole/trimethoprim, clindamycin, and doxycycline respectively. The optimal definitive antibiotic therapy is unknown and as evidenced by the study varies
ce
widely by prescriber which occurs often in clinical practice. Definitive antimicrobial selection is often based on a number of different variables including patient allergies, drug interactions, host comorbidities, and prescriber preference as opposed to strong clinical evidence. Combination therapy
Ac
patients were much more likely to receive clindamycin as part of their home regimen (39% vs. 15.5%). Interestingly the combination group received nearly two less days of discharge antimicrobial therapy (8.6 days vs. 10.2 days) reinforcing the stewardship principle that shortened durations of therapy in ABSSSI after definitive incision and drainage remains prudent. While 90-day readmission rates were
significantly different, it is not known how many patients in each group accessed other points in the healthcare setting (e.g. primary care provider’s office) for further treatment of their ABSSSI.
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
which has demonstrated improved clinical cure compared to vancomycin in one subset analysis of MRSA
4 Data regarding management strategies of ABSSSI in the emergency department is an important limitation in current practice. Specific areas of need include predictors of admission as well as recurrence which is a hallmark of ABSSSI specifically abscesses due to S. aureus. Research is currently
cr ipt
ongoing to delineate the role of newly approved long-acting agents dalbavancin and oritavancin which may offer the unique benefit of preventing admission to the hospital for ABSSSI management.
Antimicrobial stewardship is best defined as using the narrowest therapy possible to obtain optimal
clinical outcomes while minimizing adverse effects. [8] For most infections this should be accomplished
through monotherapy. Examination of cell wall active agents plus protein synthesis inhibitors deserves
us
as tetracyclines or oxazolidinones should be evaluated as well. Therefore while using combination therapy for invasive streptococcal and staphylococcal infections is not an alien concept, the eagle has
an
not quite yet landed for empirical coverage for hospitalized patients with ABSSSIs.
M
Disclosures: Dr. Bookstaver has received consulting fees and grant support from Durata outside the submitted work. Dr. Bland has received consultant fees from Theravance and consulting fees and lecture
References
pt ed
fees from Cubist Pharmaceuticals outside the submitted work.
1. Eagle H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med 1952; 13:389-99. 2. Carpetis JR, Jacoby P, Carville K, Ang SJ, Curtis N, Andrews R. Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group a streptococcal
ce
infections. Clin Infect Dis 2014;59:358-65.
3. Linner A, Darenberg J, Sjolin J, Henriques-Normark B, Norrby-Teglund A. Clinical Efficacy of Polyspecific Intravenous Immunoglobulin Therapy in Patients With Streptococcal Toxic Shock
Ac
Syndrome: A Comparative Observational Study. Clin Infect Dis 2014;59:851-7.
4. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-e55.
5. Wargo KA, McCreary EK, English TM. Vancomycin combined with clindamycin for the treatment of acute bactereial skin and skin-structure infections. Clin Infect Dis 2015.
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
dedication to a randomized double-blinded multicenter manner. Other protein synthesis inhibitors such
5 6. Weigelt J, Itani K, Stevens D, Lau W, Dryden W, Kniersch C; Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005;49:2260-6.
cr ipt
7. Turner RB, Smith CB, Martello JL, Slain D. Role of doxycycline in Clostridium difficile infection acquisition. Ann Pharmacother 2014;48:772-6.
8. Dellit TH, Owens RC, McGowan Jr. JE, Gerding DN, Weinstein RA, Burke JP, et al. Infectious
Diseases Society of America and the Society of Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clin Infect Dis
an M pt ed ce Ac
Downloaded from http://cid.oxfordjournals.org/ at New York University on June 19, 2015
us
2007;44:159-77.
