1. Management of MRSA Infections in Adult Patients
2011 Clinical Practice Guidelines by the
Infectious Diseases Society of America
Catherine Liu, M.D.
Assistant Clinical Professor
Division of Infectious Diseases
University of California, San Francisco
This slideset is intended to provide an overview of the 2011 IDSA Clinical Practice Guidelines for the Management of MRSA Infections.
Copyright Infectious Diseases Society of America (IDSA) 2011

2. Panel Members Catherine Liu, MD Rachel J. Gorwitz, MD
Henry “Chip” Chambers, MD
Arnold S. Bayer, MD
Sara E. Cosgrove, MD
Robert S. Daum, MD
Scott K. Fridkin, MD
SPGC Liaison
Stan Deresinski, M.D.
Rachel J. Gorwitz, MD
Sheldon L. Kaplan, MD
A.W. Karchmer, MD
Donald P. Levine, MD
Barbara E. Murray, MD
Michael J. Rybak, PharmD
David A. Talan, MD
The guidelines panel consisted of 13 experts in the management of MRSA infection including two pediatric infectious diseases specialists, an infectious diseases pharmacist, two representatives from the Centers for Disease Control and Prevention, and an emergency medicine/ infectious disease specialist.
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3. Objectives
To provide evidence-based guidance to adult and pediatric clinicians managing patients with MRSA infections
To discuss the management of different clinical syndromes caused by MRSA
The guidelines do not address:
MRSA infection prevention strategies in healthcare settings (e.g. active surveillance testing, perioperative prophylaxis)
Management of outbreaks in community settings
The primary objectives of the guidelines are to provide evidence-based guidance to adult and pediatric clinicians managing patients with MRSA infections, focusing primarily on the management of clinical syndromes caused by MRSA. The guidelines do not address MRSA infection prevention strategies in healthcare settings such as active surveillance testing and perioperative prophylaxis – these issues are discussed in the 2008 SHEA/ IDSA guidelines on Strategies to Prevent Transmission of MRSA in Acute Care Hospitals. These guidelines also do not address the management of outbreaks in community settings.
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4. Background Panel first convened in 2007
Literature review performed via PUBMED between : mostly clinical human studies, but also experimental animal models and in vitro studies
Reviewed and endorsed by the Pediatric Infectious Diseases Society, American Academy of Pediatrics, and American College of Emergency Physicians
The guidelines panel first convened in 2007 and performed a literature review via PUBMED between Mostly human studies were included but studies from experimental animal models and in vitro studies were also included. These guidelines were reviewed and endorsed by the Pediatrics Infectious Diseases Society, American Academy of Pediatric s and American College of Emergency Physicians.
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5. Clinical Topics Skin and soft tissue infections
Recurrent skin and soft tissue infections
MRSA bacteremia and endocarditis
MRSA pneumonia
MRSA bone and joint infections
MRSA central nervous system infections
Role of combination or adjunctive therapies
Vancomycin dosing and monitoring
Vancomycin susceptibility testing
Management of persistent bacteremia and vancomycin treatment failures
MRSA neonatal infections
The guidelines address the following 11 topics listed on this slide with the goal of addressing some of the most common clinical syndromes caused by MRSA that are encountered by adult and pediatric clinicians.
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6. Evidence Grading System
Strength of recommendation A Good evidence to support a recommendation for or against use B Moderate evidence to support a recommendation for or against use C Poor evidence to support a recommendation Quality of evidence I Evidence from  1 properly randomized, controlled trial II Evidence from  1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from > 1 center); from multiple time-series; or from dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities; based on clinical experience, descriptive studies, or reports of expert committees.
The guidelines recommendations were graded in accordance with the Evidence Grading System used by IDSA. Each recommendation was graded according to the strength of recommendation and quality of evidence.
Source: The periodic health examination. Canadian Task Force on the Periodic Health Examination. Health Canada, 1979.
Adapted and reproduced with the permission of the Minister of Public Works and Government Services, Canada, 2009
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7. Case 1
32 y/o M with 3 days of an enlarging, painful lesion on his L thigh that he attributes to a “spider bite”.
T 36.9 BP 118/70 P 82
Case 1 is a 32 year old man who presents with 3 days of an enlarging painful lesion on his left thigh that he attributes to a spider bite. His vital signs are normal.
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8. What is the appropriate management of this patient?
Incision and drainage alone
Incision and drainage plus oral anti-MRSA antimicrobial agent
Oral anti-MRSA antimicrobial agent
This patient has a skin abscess and a key component in the management of abscesses is incision and drainage so choice C is incorrect. Whether oral antibiotics provide additional benefit (choice A vs. B) remains an area of controversy but currently available data suggests that incision and drainage alone may be sufficient for most simple abscesses.
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9. Abscesses Incision and drainage is the primary treatment (AII).
For simple abscesses or boils, I&D alone likely adequate
Do antibiotics provide additional benefit?
Multiple, observational studies: high cure rates with or without abx
3 RCTs of uncomplicated skin abscesses; 2 large NIH trials ongoing
p=.25
p=.12
p=.52
This slide summarizes the guidelines recommendations and currently available evidence on the management of abscesses. Multiple observational studies suggest that patients with abscesses have high cure rates whether they receive an active or inactive antibiotic against MRSA. There are 3 published randomized clinical trials of uncomplicated skin abscesses. The first study (Rajendran ’07) randomized patients to receive cephalexin and placebo and in retrospect, it was found that the majority of patients had an infection due to MRSA. Hence, this was in essence, a “double-placebo” study as the majority of patients in both groups were receiving an inactive antibiotic against MRSA. Despite this, cure rates were high, on the order of 85-90% with no significant difference between the cephalexin or placebo group. There were two studies published, one in pediatrics patients (Duong ’09) and the other in adults (Schmitz’10), both of which randomized patients to receive TMP-SMX or placebo. When looking at the primary outcome of clinical cure, there was no significant difference in either group for both studies.
cephalexin
TMP-SMX
TMP-SMX
Rajendran AAC 2007; 51:4044-8; Duong Ann Emerg Med 2009;55:401-7; Schmitz Ann Emerg Med 2010; 56:283-7
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10. Is clinical cure the only important endpoint?
Is clinical cure the only important endpoint? The Duong and Schmitz studies also examined a secondary outcome – the development of recurrent lesions. Interestingly, they found a significant difference in the rate of recurrent lesions (at least in the short term) – at 10 days and at 30 days in the 2 papers respectively, with the benefit seen in the antibiotic arm. These findings are intriguing but should be interpreted with caution because of small sample sizes and patient drop out. There are currently two large NIH-sponsored studies underway that will help to further define the role of antibiotics for simple abscesses.
Duong Ann Em Med 2009;55:401-7; Schmitz Ann Em Med 2010; 56:283-7; Talan Ann Em Med 2010; 55:412-14;
Spellburg Ann Em Med 2011; 57:183-4.
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11. Antibiotic therapy is recommended for abscesses associated with:
Severe, extensive disease, rapidly progressive with associated cellulitis or septic phlebitis
Signs & sx of systemic illness
Associated comorbidities, immunosuppressed
Extremes of age
Difficult to drain area (e.g. face, hand, genitalia)
Failure of prior I&D
There are selected situations in which the guidelines recommend use of antibiotic therapy in the management of abscesses. These include patients with severe, extensive disease that is rapidly progressive with associated cellulitis or septic phlebitis, patients with signs and symptoms of systemic disease, associated comorbidities or immunocompromised, patients who are very young or old and those with abscesses located in difficult to drain areas such as the face, hand , and genitalia. If the patient has failed previous incision and drainage, antibiotic therapy is also recommended.
(AIII)
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12. Microbiology of Purulent SSTIs
Let’s take a step back and review the microbiology of skin and soft tissue infections as this is important in guiding one’s choice of empiric therapy. In a study of patients presenting to 11 emergency rooms throughout the U.S. MRSA was found to be the dominant pathogen accounting for nearly 60% of the cases followed by MSSA. In contrast, B-hemolytic strep accounted for a much smaller proportion of these cases.
Moran NEJM 2006; 355:
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13. Purulent Cellulitis: S. aureus >>> -hemolytic strep
Cellulitis associated with purulent drainage or exudate without a drainable abscess
Empiric Rx for CA-MRSA is recommended (AII).
Empiric Rx for -hemolytic strep unlikely needed (AII).
Duration of therapy: 5-10 days, individualize based on clinical response (AII).
Based on this data, for purulent cellulitis, empiric therapy for CA-MRSA is recommended. Empiric Rx for B-hemolytic strep is unlikely to be needed. The duration of therapy is 5-10 days and should be individualized based on the clinical response.
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14. Outpatient purulent cellulitis: Empiric Rx for CA-MRSA
Drug
Adult Dose
Evidence Grade
TMP-SMX
1-2 DS BID
AII
Doxycycline, Minocycline
100 BID
Clindamycin
TID
Linezolid
600 BID
This table lists antibiotic choices for outpatient empiric therapy of CA-MRSA. None of these drugs have been compared head to head in any large, well-designed studies but several observational studies and small clinical trials suggest that these drugs are effective for outpatient purulent cellulitis. All of these receive AII level recommendations.
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15. Case 2
28 year old woman presents with erythema of her right arm over past 48 hours. There is no purulent drainage, exudate or abscess. No evidence of joint or bursa involvement.
T 37.0 BP 132/70 P 78
Case 2 is a 28 year old woman who presents with erythema of her left foot over the past 48 hours. There is no purulent drainage, exudate or abscess. Her temperature is 37.0 C, blood pressure 132/70, pulse 78
Courtesy of Thomas Sellers, MD,
CDC/ Emory University
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16. What is the appropriate management of this patient?
Clindamycin 300 mg PO tid
Cephalexin 500 mg QID, monitor clinically with addition of TMP/SMX if no response
Cephalexin 500 mg QID and TMP/ SMX 2 DS tab PO bid
This is a patient with non-purulent cellulitis. The question here is whether patients with nonpurulent cellulitis require empiric therapy for -hemolytic strep, CA-MRSA, or both. There are limited data to guide us and but the available evidence suggests that -hemolytic strep is the dominant pathogen here. Based on the guidelines recommendations, my personal choice would have been choice B though one could potentially make an argument for any one of these choices.
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17. Nonpurulent Cellulitis: -hemolytic strep vs. S. aureus?
Empiric Rx for -hemolytic strep recommended (AII)
Prospective study1, 248 hospitalized pts
73% due to -hemolytic strep (diagnosis by serologies for ASO and anti-DNAse-B, blood cultures); 27% with no identified cause.
Overall 96% response rate to -lactam antibiotic.
Retrospective study2
 treatment failures with TMP-SMX vs. -lactam or clindamycin
The role of CA-MRSA is unknown.
Empiric Rx for MRSA if fails to respond to -lactam
Consider in patients with systemic toxicity
For nonpurulent cellulitis, the absence of culturable material presents an inherent challenge to our ability to determine its microbiologic etiology and make decisions regarding empiric therapy. In a prospective study of 248 hospitalized patients with nonpurulent cellulitis, -hemolytic streptococci was found to be the dominant pathogen and was diagnosed by acute- and convalescent-serologic studies for anti-streptolysin-O and anti-DNAse-B antibodies or positive blood culture results.) Although no cause was identified in 27% of cases, the overall clinical response rate to a -lactam antibiotic was 96%. In a retrospective study in children with nonpurulent cellulitis, clindamycin did not confer any additional benefit when compared with -lactams but TMP-SMX was associated with a slightly higher failure rate. These two studies provide some evidence to suggest that -hemolytic streptococci may be the primary pathogen here. The relative contribution of CA-MRSA is unknown and empiric therapy for MRSA is recommended in patients who do not respond to -lactam therapy and should be considered in those with systemic toxicity.
1Jeng et al Medicine 2010; 89: Elliott et al Pediatrics 2009; 123:e959-66
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18. Outpatient nonpurulent cellulitis: Empiric Rx for -hemolytic streptococci +/- MRSA
Drug
Adult Dose
Cephalexin
500 QID
Dicloxacillin
Clindamycin*
TID
Linezolid*
600 BID
*Also have activity against CA-MRSA
This table lists choices of empiric antibiotics for outpatients presenting with non-purulent cellulitis. All of these options have activity against -hemolytic streptococci and MSSA while clindamycin and linezolid also have activity against CA-MRSA.
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19. Complicated SSTI
Surgical debridement & empiric therapy for MRSA pending cultures
Antibiotic
Adult
Evidence Grade
Vancomycin
15-20 mg/kg IV Q8-12 AI
Linezolid
600 mg PO/ IV BID
Daptomycin
4 mg/kg IV QD
Telavancin
10 mg/kg IV QD
Clindamycin
600 mg PO/IV Q8
AIII
For more complicated SSTI, surgical debridement is again a mainstay of therapy. In addition, to vancomycin, there are now several alternatives to vancomycin that are FDA approved for the treatment of complicated SSTI which have activity against MRSA. These include linezolid, daptomycin and telavancin, all of which receive AI level recommendations. Because of a recent FDA warning indicating an increased risk in all-cause mortality with tigecycline versus comparator drugs in a pooled analysis of clinical trials, tigecycline was not included in these guidelines, given the availability of multiple MRSA-active alternatives. Ceftaroline was FDA approved after the guidelines were published.
*Tigecycline associated with  mortality; consider alternate agent for MRSA SSTI
*Ceftaroline: FDA approved after guidelines
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20. Case 3
The patient in case 1 returns 4 weeks later with another abscess on his opposite thigh. He notes that after I & D of his first abscess, he didn’t keep his wound covered and occasionally touched the site to “make sure it was healing.” The site of his old abscess is clean with a well-healed scar. He undergoes I&D and receives 1 week of TMP-SMX.
The patient in case 1 returns 4 weeks later with another abscess on his opposite thigh. He notes that after I&D after of his first abscess, he did not keep his wound covered and occasionally touched the site to make sure it was healing properly. On exam, the site of his old abscess is clean with a well-healed scar. He undergoes I&D and receives 1 week of TMP/SMX.
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21. What is the appropriate management of this patient?
Emphasize personal hygiene measures
Decolonize with mupirocin and chlorhexidine showers
Decolonize with TMP-SMX and rifampin
A and B
A, B, and C
Given the lack of data to guide the management of recurrent SSTI, I don’t think there is necessarily a correct answer here but would have chosen A. Clearly this patient needs some basic education regarding personal hygiene and wound care and it is reasonable to start with this and decolonize with mupirocin and chlorhexidine if the patient develops another recurrence. Oral antibiotics should not be used as first line therapy for recurrent SSTI but considered only if infections recur despite other measures.
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22. What is the Management of Recurrent Skin and Soft Tissue Infections?
Host
One of the challenges to management of recurrent SSTI is that we don’t have a clear understanding of the pathogenesis of this disease but it likely involves a complex interplay between the host, environment, and pathogen.
The guidelines recommend a multifactorial approach targeting each of these individual components. Patients should be educated on personal hygiene and appropriate wound care; they should be instructed to cover draining wounds, wash their hands after touching infected skin or an item that has directly contacted a draining wound, and avoid reusing/ sharing personal items that have contacted infected skin.
The role of the environment in recurrent SSTI remains unknown but the guidelines suggests that one may consider cleaning high touch-surfaces such as counters, door knobs, bath tubs and toilet seats that may contact bare skin or uncovered infections.
Decolonization may be considered if a patient develops a recurrent SSTI despite optimizing wound care and hygiene measures or if there is evidence of ongoing household transmission.
Environment
Pathogen
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23. What is the Management of Recurrent Skin and Soft Tissue Infections?
Environmental Hygiene
Personal Hygiene
Cover draining wounds
Hand hygiene after touching infected skin
Avoid reusing/ sharing personal items if
active infection
Clean high-touch surfaces
-If above measures fail
-If ongoing household
transmission
Host
Environment
Pathogen
Environmental Hygiene (CIII)
Personal Hygiene/ Wound Care (AIII)
*Decolonization (CIII)
One of the challenges to management of recurrent SSTI is that we don’t have a clear understanding of the pathogenesis of this disease but it likely involves a complex interplay between the host, environment, and pathogen.
The guidelines recommend a multifactorial approach targeting each of these individual components. Patients should be educated on personal hygiene and appropriate wound care; they should be instructed to cover draining wounds, wash their hands after touching infected skin or an item that has directly contacted a draining wound, and avoid reusing/ sharing personal items that have contacted infected skin.
The role of the environment in recurrent SSTI remains unknown but the guidelines suggests that one may consider cleaning high touch-surfaces such as counters, door knobs, bath tubs and toilet seats that may contact bare skin or uncovered infections.
Decolonization may be considered if a patient develops a recurrent SSTI despite optimizing wound care and hygiene measures or if there is evidence of ongoing household transmission.
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24. Recurrent MRSA SSTI: Decolonization Regimens
Mupirocin twice daily x 5-10 days (CIII)
 recurrent MSSA SSTI in small RCT1
RCT military recruits: in CA-MRSA nasal colonization but not 1st time SSTI2
Mupirocin twice daily x 5-10 days AND topical skin antiseptic (e.g. chlorhexidine) x 5-14 days (CIII)
RCT military recruits: CHG wipes alone not  SSTI rates3, transient effect on colonization
Consider dilute bleach baths: ¼ cup per ¼ tub (13 gallons) of water for 15 min, 2x/week for 3 mnths
There are two decolonization strategies recommended by the guidelines, both of which receive CIII level recommendations given the absence of data demonstrating a clear benefit. Mupirocin can be given twice daily for 5-10 days or in combination with a topical skin antiseptic such as chlorhexidine. In a small randomized controlled trial of patients with recurrent MSSA furunculosis, a 5 day course of mupirocin, followed by repeated application on a monthly basis for 1 year, reduced the rate of recurrent SSTI. However, no studies among patients with recurrent MRSA SSTI have been performed. In a cluster randomized trial of military recruits, mupirocin decreased CA-MRSA nasal colonization but did not reduce the incidence of first time SSTI. Chlorhexidine impregnated wipes alone does not appear to reduce SSTI rates in a randomized trial. Some experts suggest the use of dilute bleach baths at a concentration of 1 teaspoon per gallon of bath water (1/4 cup per ¼ tub of water) for 15 minutes given twice weekly for ~ 3 months.
1Raz Arch Intern Med 1996; 156: ; 2Ellis MW AAC 2007; 51: Whitman ICHE 2010; 12:
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25. Oral Antibiotics for Decolonization?
Not routinely recommended for decolonization (AIII). An oral agent in combination with rifampin (if susceptible) may be considered if infections recur despite other measures (CIII).
Cochrane review1: No benefit of oral abx in MRSA eradication among patients in healthcare settings
Systematic review2: Rifampin + staph abx vs. staph abx alone
Rifampin combo superior in  S. aureus colonization
No studies evaluated impact on infection rates
Watch out for drug interactions, side effects, resistance
Oral antibiotics are not routinely recommended for decolonization but an oral agent in combination with rifampin (if susceptible) may be considered if infections recur despite other measures. A Cochrane review found no benefit of oral antibiotics for eradication of MRSA colonization among patients in the health care setting when compared with placebo, no treatment, or topical antibiotics; none of these studies examined their impact on infection rates. A systematic review found that a rifampin-based combination, compared with monotherapy with other oral antibiotics, was more likely to eradicate S. aureus carriage, but again, no studies examined infection rates as an outcome.
1Cochrane Review 2003; 4CD Falagas ME AJIC 2007; 35:
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26. Case 4
35 y/o F previously healthy with 4 days of fever, chills, myalgias, and cough. Now with increasing dyspnea and hemoptysis x 24 hrs
T38.7 P120 BP96/60 R24 89%RA
Moderate respiratory distress with coarse rhonchi
WBC 15, Hct 44, Plt 425
Rapid flu: + influenza A
Sputum gram stain/ cx: pending
Intubated, admitted to ICU
Case 4 is 35 y/o M previously healthy with 4 days of fever, chills, myalgias, and cough. He now presents with increasing dyspnea and hemoptysis x 24 hrs. His T38.7 P120 BP96/60 R24 89%RA and appears in moderate respiratory distress with coarse rhonchi on exam. His WBC 15, Hct 44, Plt 425, Rapid flu: + influenza A, sputum gram stain/ cx: pending. He is intubated and admitted to ICU. His CXR reveals a multifocal pneumonia.
Courtesy of Thomas File MD
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27. In addition to starting anti-influenza therapy, would you treat with antibiotics and if so which?
None
Ceftriaxone and azithromycin
Vancomycin and ceftriaxone and azithromycin
Linezolid and cefepime
The correct answer is choice C. As the patient is critically ill with a community-acquired pneumonia, empiric coverage for MRSA is recommended in addition to coverage for typical and atypical causes of bacterial pneumonia. Although linezolid is a reasonable choice for empiric MRSA coverage, choice D is incorrect for two reasons 1) antipseudomonal coverage is not routinely recommended in patients presenting with community-acquired pneumonia (2007 ATS/ IDSA guidelines for Management of Community-Acquired Pneumonia, CMS Core Measures); 2) No atypical bacterial pneumonia coverage is included.
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28. MRSA pneumonia Antibiotic Adult Evidence Grade Vancomycin
15-20 mg/kg IV Q8-12
AII
Linezolid
600 mg PO/ IV BID
Clindamycin
600 mg PO/IV TID
BIII
The antibiotics recommended by the guidelines for management of MRSA pneumonia include vancomycin, linezolid, and clindamycin. Vancomycin and linezolid are both given AII level recommendations and at the time of guidelines publication, there were no data to suggest that one antibiotic was superior to the other. Clindamycin is an alternative to vancomycin for the treatment of MRSA pneumonia in children and there are limited data regarding its use in adults.
Jung Crit Care Med 2010
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29. MRSA pneumonia: Vancomycin vs. Linezolid?
No difference in microbiologic success rates
No difference in eradication rates of MRSA
p= NS
p <.01
p <.03
Limitations of post-hoc analysis prevent drawing definitive conclusions
There were two studies where patients were randomized to receive either vancomycin or linezolid + aztreonam for the treatment of nosocomial pneumonia. In these two studies, there was no difference in the clinical cure rates, no difference in microbiologic success rates or in the eradication rates of MRSA. In a subsequent posthoc subgroup analysis of that looked at all patients with MRSA in both studies, those patients assigned to the vancomycin arm had lower rates of clinical cure and survival compared to linezolid. Due to limitations of this post hoc analysis, the guidelines assigned both vancomycin and linezolid AII level recommendations. These recommendations will be re-evaluated pending publication of the results of the ZEPHYr paper which compared vancomycin vs. linezolid head to head in a randomized controlled trial of patients with MRSA pneumonia.
1Rubinstein CID 2001;32:402-12; 2Wunderink Clin Therap 2003;25:980-92; 3Wunderink Chest 2003;124:
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30. MRSA pneumonia
Daptomycin should not be used for Rx of pneumonia, (inactivated by pulmonary surfactant)
Daptomycin may be used in patients with hematogenous septic pulmonary emboli1
Empiric Rx for MRSA recommended for severe CAP (ICU admission, necrotizing or cavitary infiltrates, or empyema)
Discontinue empiric Rx if cultures do not grow MRSA
Duration of therapy: 7-21 days
Daptomycin should not be used for treatment of pneumonia as it is inactivated by pulmonary surfactant but may be used in patients with hematogenous septic emboli. Although it remains an uncommon etiology of community acquired pneumonia, MRSA has emerged as a cause of severe CAP. The guidelines recommend empiric therapy for MRSA in patients presenting with severe CAP defined by any one of the following : 1) requirement for ICU admission; 2) necrotizing or cavitary infiltrates; 3) empyema. If blood or sputum cultures do not grow MRSA, empiric therapy should be discontinued.
1Rehm JAC 2008;62: ; Silverman JID 2005; 191:
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31. Case 5
60 year old male prison inmate presents with 4 days of fevers and chills and decreased L eye vision.
T 38.5 BP 102/71 P 104 R 20 O2 sat 98% RA weight 100 kg
Eye: Bilateral creamy white-yellow discharge, vitreous strands/ infiltrates, L eye - intraretinal hemorrhage
Heart: 2/6 systolic murmur at apex
Chest: CTAB
Skin: no peripheral stigmata of endocarditis
Labs: 15.5> 39 > 350 Cr 0.8
Started on IV vancomycin 1 gram every 12 hours
Case 5 is a 60 year old male prison inmate presents with 4 days of fevers and chills and decreased left eye vision.
T 38.5 BP 102/71 P 104 R 20 O2 sat 98% RA weight 100 kg
Eye: Bilateral creamy white-yellow discharge, vitreous strands/ infiltrates, L eye - intraretinal hemorrhage
Heart: 2/6 systolic murmur at apex
Chest: CTAB
Skin: no peripheral stigmata of endocarditis
Labs: 15.5> 39 > 350 Cr 0.8
He is started on IV vancomycin 1 gram every 12 hours
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32. Case continued HD #1 blood cx: 3/4 MRSA (vanco MIC 1) HD # 5
Received intravitreal injection of vancomycin
HD # 5
T 37.8 BP 138/70 P 113 R 16 O2 sat 96% RA
Alert and interactive, no new physical exam findings
Blood cx: 2/2 MRSA (vanco MIC 1)
Vancomycin trough 7 g/mL
HD #1 blood cx: 3/4 MRSA (vancomycin MIC 1)
Received intravitreal injection of vancomycin
HD # 5
T 37.8 BP 138/70 P 113 R 16 O2 sat 96% RA
Alert and interactive, no new physical exam findings
Blood cx: 2/2 MRSA (vancomycin MIC 1)
Vancomycin trough 7 ug/mL
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33. Echocardiogram 2 cm mitral valve vegetation
His echocardiogram reveals a large mobile 2 cm mitral valve vegetation
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34. Brain MRI
His brain MRI shows multiple scattered lesions concerning for septic emboli
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35. What changes to the patient’s antibiotics should be made?
Add gentamicin to vancomycin
Add rifampin to vancomycin
Increase vancomycin dose to 1.5 gram IV Q12 hrs, target goal trough of g/mL
Discontinue vancomycin and start IV daptomycin 6 mg/kg Q24 hrs
The correct answer is choice C. This patient initially received lower than ideal doses of vancomycin given his weight of 100 kg. The guidelines recommend against the addition of gentamicin or rifampin to vancomycin. Choice D is not necessarily incorrect but it is not clear that the patient’s ongoing bacteremia on hospital day 5 reflects vancomycin treatment failure vs. an inadequate trough. It would be important to confirm the daptomycin MIC prior to use of daptomycin.
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36. MRSA bacteremia and endocarditis
IV vancomycin (AII) or IV daptomycin 6 mg/kg QD (AI).
236 pts randomized to IV daptomycin 6 mg/kg QD vs. (vancomycin or nafcillin) + gentamicin 1 mg/kg Q8 x 4 days
Some experts recommend IV daptomycin 8-10 mg/kg QD (BIII).
IV vancomycin or IV daptomycin 6 mg/kg QD are recommended for the treatment of MRSA bacteremia and endocarditis. This recommendation is based on a randomized clinical trial of 236 patients who received either IV daptomycin or standard therapy (vancomycin for MRSA and nafcillin for MSSA) in combination with gentamicin for the first 4 days of therapy. In this study, there was no significant difference in the overall success rate or in the MRSA and MSSA subgroups. Vancomycin receives an AII level recommendation (rather than AI) because it was used in combination with gentamicin in this study. Because daptomycin exhibits concentration-dependent killing, some experts recommend doses of up to 8-10 mg/kg/ which appear to be safe although additional studies are needed to determine the efficacy of this approach.
Fowler VG NEJM 2006; 355:
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37. Is there a role for adjunctive gentamicin or rifampin
Is there a role for adjunctive gentamicin or rifampin? More is not always better…
Addition of gentamicin (AII) or rifampin (AI) to vancomycin is not recommended. No clear evidence of benefit.
Vanco +rifampin: 1 RCT MRSA endocarditis1
Vanco + gentamicin: in vitro data, but no clinical studies.
Nafcillin + gent vs. nafcillin RCT MSSA bacteremia:  duration of bacteremia x 1 day but no difference in morbidity/ mortality2
Vancomycin
Vancomycin + rifampin
p-value
Treatment failures
4/ 22 (18%)
2/20 (10%)
>.05
Median duration of bacteremia
7 days (5-11)
9 days (6-13)
Median duration of fever
7 days (3-8)
7 days (3-10)
The guidelines recommend against the addition of gentamicin or rifampin to vancomycin. There does not appear to be any evidence to suggest benefit of either combination. In a study where patients were randomized to receive vancomycin alone or vancomycin + rifampin, there was no significant difference in treatment failures, median duration of bacteremia, or median duration of fever. There are no clinical studies supporting a benefit of vancomycin + gentamicin. There was one randomized clinical trial of patients with MSSA bacteremia in which the combination of nafcillin + gentamicin shortened the duration of bacteremia by 1 day compared to those receiving nafcillin, but there was no difference in morbidity or mortality.
1Levine. Ann Intern Med 1991;115:674-80; 2Korzeniowski. Ann Intern Med 1982;4:
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38. Addition of gentamicin or rifampin to vancomycin is associated with  toxicity
 risk of nephrotoxicity with initial low-dose gentamicin1
 risk of elevated transaminases (≥ 5X baseline), drug interactions with rifampin, resistance concerns2
*Gentamicin was an independent predictor of clinically significant  in CrCl
The addition of gentamicin or rifampin to vancomycin is associated with increased toxicity. In the daptomycin bacteremia trial, a secondary analysis showed that those patients receiving initial low-dose gentamicin in combination with either vancomycin or an antistaphylococcal penicillin (ASP) had an increased risk of nephrotoxicity compared to daptomycin. Receipt of gentamicin was found to be an independent predictor of a clinically significant decline in creatinine clearance. The use of rifampin in combination with vancomycin has been associated with an increase in transaminases, drug interactions as well concerns over development of resistance.
1Fowler NEJM 2006;355:653-65; Cosgrove S CID 2009;48:713-21; 2Riedel D AAC 2008;52:2463-7
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39. MRSA bacteremia and endocarditis: Source control is critical
Identify source and extent of infection; eliminate and debride other sites of infection (AII).
Repeat blood cultures 2-4 days after initial positive cultures and as needed thereafter to document clearance of bacteremia (AII).
Echocardiography recommended for all patients with bacteremia (AII). TEE is preferred over TTE.
Evaluate for valve replacement surgery if:
vegetation > 10 mm, ≥ 1 embolic event, severe valvular insufficiency, valvular perforation, decompensated heart failure, perivalvular/ myocardial abscess, new heart block
In addition to antimicrobial therapy, it is critical to identify the source and extent of infection, with removal or debridement of other sites of infection whenever possible. Surveillance blood cultures are recommended 2-4 days after the initial positive cultures and as needed thereafter to document clearance of the bacteremia. Echocardiography is recommended for all patients with bacteremia and TEE is preferred in adult patients over TTE because of its superiority over TTE for detecting vegetations. Patients with endocarditis should be evaluated for valve replacement on the basis of clinical and echocardiographic criteria as per the 2005 AHA guidelines.
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40. Duration of therapy
Lower success rates in pts receiving < 14 days of therapy have been observed
Uncomplicated bacteremia: Minimum duration is 2 weeks if:
Exclude endocarditis
No implanted prostheses (e.g. prosthetic valves, cardiac devices, arthroplasties)
Negative follow-up blood cultures for MRSA at 2-4 days
Defervescence within 72 hours of therapy
No evidence of metastatic sites of infection
Complicated bacteremia (if do not meet above criteria): 4-6 weeks
Lower success rates have been observed in patients receiving < 14 days of therapy. The minimum duration of antibiotic therapy is 2 weeks for uncomplicated bacteremia which is defined as patients in whom endocarditis has been excluded, absence of implanted prostheses, negative follow up blood cultures for MRSA at 2-4 days, defervescence within 72 hours of therapy, no evidence of metastatic foci of infection. For patients who do not meet the above criteria, 4-6 weeks of therapy is recommended for complicated bacteremia.
1Fowler NEJM 2006;355:653-65; Cosgrove CID 2008;46:S386-93
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41. Vancomycin Dosing
IV vancomycin mg/kg (actual body weight) every 8-12 hrs, not to exceed 2 g per dose (BIII).
In seriously ill patients with suspected MRSA infection, a loading dose of mg/kg (actual body weight) may be considered (CIII).
Given risk of red man syndrome and possible anaphylaxis associated with large doses, consider prolonging infusion time 2 h and pre-medication with antihistamine .
Continuous infusion vancomycin is unlikely to substantially improve patient outcome, compared with intermittent dosing (AII).
Guidelines regarding dosing and monitoring of vancomycin are based on the consensus statement published by the American Society of Health Systems Pharmacists, IDSA and Society of Infectious Diseases Pharmacists. Vancomycin doses of mg/kg/day every 8-12 hour are recommended for adult patients on the basis of actual body weight and are adjusted for the patient’s estimated creatinine clearance, not to exceed 2 g per dose. In seriously ill patients with suspected MRSA infection, a loading dose of mg/kg (actual body weight) may be considered. Given the risk of red man syndrome and possible anaphylaxis associated with large doses of vancomycin, one should consider prolonging the infusion time to 2 hours and premedication with an antihistamine. Continuous infusion vancomycin is unlikely to substantially improve patient outcome, compared with intermittent dosing.
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42. Vancomycin Therapeutic Drug Monitoring
Obtain serum troughs at steady state (b/f 4th or 5th dose) (BII).
Monitoring of peak vancomycin concentrations is not recommended (BII).
For serious infections (e.g. bacteremia, endocarditis, osteomyelitis, pneumonia, severe SSTI [nec fasc]), target vancomycin trough concentrations of g/mL (BII).
For most patients with SSTI with normal renal function and not obese, traditional doses of 1 g Q12 are adequate and trough monitoring is not required (BII).
Trough vancomycin concentrations are the most accurate and practical method to guide vancomycin dosing. Serum troughs should be obtained at steady state conditions, prior to the 4th or 5th dose. Monitoring of peak vancomycin concentrations is not recommended. For serious infections (e.g. bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia, and severe SSTI (e.g. necrotizing fasciitis), target vancomycin trough concentrations of ug/mL. For most patients with SSTI who have normal renal function and are not obese, traditional doses of 1 gram every 12 hours are adequate and trough monitoring is not required on the basis of studies demonstrating an excellent clinical response rate without a more aggressive dosing strategy.
Moise-Broder Clin Pharmacok 2004;43:925-42; Jeffres Chest 2006; 130:947-55; Arbeit R CID 2004;38: ; Weigelt AAC 2005; 49:2260-6; Stryjewski CID 2008;46: ; Lipsky JAC 2005;55:240-5; Breedt AAC 2005; 49:
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43. Targeting Higher Vancomycin Troughs: What is the Evidence?
pK/pD: Higher troughs likelihood of achieving target AUC/ MIC
AUC/ MIC ≥ 400 vs. <400 associated with improved clinical/ microbiologic response1
Resistance: Lower troughs may select for resistant subpopulations (e.g. hVISA)3.
Clinical outcomes: Unclear correlation between  troughs4
Further clinical study is needed
Watch for potential  nephrotoxicity
Mean Trough
Mean AUC2
9.4 µg/mL
318 ± 111 µg/h/mL
20.4 µg/mL
418 ± 152 µg/h/mL
What is the evidence to support higher vancomycin troughs? From a pK/pD standpoint, higher troughs increase the likelihood of achieving your target AUC/ MIC which is the primary pharmacodynamic parameter that predicts efficacy of vancomycin. A single study of patients with S. aureus lower respiratory tract infections reported than an AUC/ MIC ≥ 400 compared with an AUC/MIC < 400 was associated with improved clinical response and microbiologic eradication. In a separate study involving patients with MRSA health care-associated pneumonia, a mean trough concentration of 9.4 ug/mL was associated with a mean AUC of 318 mg/h/mL while a mean trough of 20 ug/mL was associated with a mean AUC of 418 ug/h/mL. Vancomycin trough concentrations < 10 have been associated with treatment failures, perhaps due to selection of hVISA. Clinical data to support higher target troughs are limited and they have not been clearly associated with improved outcomes or mortality although a recent study published after guidelines publications suggests targeting troughs of and AUC/ MIC ≥ 400 is associated with lower rates of vancomycin treatment failures.
1Moise-Broder Clin Pharmacok 2004;43:925-42; 2Jeffres Chest 2006; 130: Charles P CID 2004;38:448-51; 3Jeffres M Chest 2006; 4Hidayat L Arch Intern Med 2006;166: ; Lodise AAC 2008;52: ; Maor JID 2009;199:619-24
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44. A few words on Vanco MICs….
Mohr CID 2007;44:
Probability of achieving target AUC/ MIC is 0% if vancomycin MIC = 2 µg/mL with low or high-dose vancomycin
Vanco MICs of 2 µg/mL associated with  vanco Rx failures1
“MIC creep” observed in some centers but not others2
Perhaps due to clonal dissemination or technical artifact
The probability of achieving a target AUC/ MIC > 400 is 0% for a vancomycin MIC or 2 µg/ML whether low or high-dose vancomycin strategies are used. Several studies suggest a higher rate of vancomycin treatment failures among isolates with a vancomycin MIC of 2 µg/mL compared to those with vancomycin MIC < 2 µg/mL. Some centers have observed a vancomycin “MIC creep” but this has not been seen in others. In one study, MRSA isolates with a vancomycin > 1 µg/mL was primarily attributable to clonal dissemination and it is also possible that MIC creep observed in some institutions may be due to technical artifact depending on changes in test methods used.
1Sakoulas JCM 2004;42: ; Hidayat L Arch Intern Med 2006;166: ; Lodise AAC 2008;52: ; Maor JID 2009;199: Alos JAC 2008;62:773-5; Holmes AAC 2008;52:757-60; Jones CID 2006;42:S13-24; Sader AAC 2009; 53:
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45. Vancomycin Susceptibility Testing
There is considerable variability in MIC results depending on method used
Certain methods (Etest, Microscan, BD-Phoenix) report higher MICs than reference methods while others (Sensititre and Vitek 2) tend to undercall resistance
Acceptable variability for MIC methods is +/- one doubling dilution (e.g. is MIC of 1 really 2 or vice versa?)
There appears to be considerable variability in MIC results depending on the methods used. Certain methods such as Etest, Microscan, and BD-Phoenix report MIC values that are higher than those reported by reference broth microdilution, while Sensititre and Vitek 2 systems tend to undercall resistance. One challenge is that acceptable variability for MIC methods is ± 1 doubling dilution which makes it difficult to distinguish between an MIC of 1 vs. 2 µg/mL and vice versa.
Swenson JCM 2009; 47:2013-7
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46. Detection of Isolates with Vancomycin MIC of ≤ 2 µg/mL
In a study of 1800 randomly selected MRSA bloodstream isolates from 9 US hospitals, MICs were determined using reference broth microdilution and Etest. When reference broth microdilution was used, 97% of the isolates had an MIC of ≤ 1. When Etest was used, only 10% had an MIC of ≤ 1, with almost 1/3 having an MIC of 2.
N=1800
Sader AAC 2009; 53:
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47. How should Vancomycin MIC Results be used to Guide Therapy?
For isolates with a vanco MIC ≤ 2 µg/mL, the patient’s clinical response should determine continued use of vancomycin, independent of the MIC (AIII).
If clinical and microbiological response to vanco, continue with close follow-up
If no clinical or microbiologic response despite adequate debridement and removal of other foci of infection, alternative to vancomycin is recommended regardless of MIC.
For isolates with a vancomycin MIC  2 µg/mL (VISA or VRSA), an alternative to vancomycin should be used (AIII).
Because current susceptibility methods are unable to reliably distinguish MICs of 1ug/mL from MICs of 2 µg/mL, the guidelines recommends the following:
For isolates with a vancomycin MIC of ≤ 2, the patient’s clinical response should determine continued use of vancomycin independent of the MIC:
If the patient has had a clinical and microbiologic response to vancomycin, then it may be continued with close follow-up.
If the patient has not had a clinical or microbiologic response to vancomycin despite adequate debridement and removal of other foci of infection, an alternative to vancomycin is recommended regardless of MIC.
For isolates with a vancomycin MIC > 2 µg/mL (e.g. VISA or VRSA), an alternative to vancomycin should be used.
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48. Case continued… Vancomycin dose increased to 1.5g Q 12 hours
HD #6 blood cx: 2/2 MRSA (vanco MIC 1), vanco trough 13 (drawn before 3rd dose)
HD #8 blood cx: 2/2 MRSA (vanco MIC 1, dapto MIC ≤ 0.5)
HD #9 blood cx: prelim 1/ 2 Staph spp
T37.2 BP132/84 HR94 R18 O % RA
R eye –retinal detachment
No other significant changes to physical exam
Repeat Echo:  vegetation size with longer mobile element and extension along the annulus
Returning back to the case, the patient’s vancomycin dose is increased to 1.5g every 12 hours. The results of follow blood culture results are as follows:
HD #6 blood cx: 2/2 MRSA (vancomycin MIC 1), vancomycin trough 13 (drawn before 3rd dose)
HD #8 blood cx: 2/2 MRSA ( vancomycin MIC 1, daptomycin MIC ≤ 0.5)
HD #9 blood cx: prelim 1/ 2 Staph spp
His T37.2 BP132/84 HR94 R18 O % RA
R eye –retinal detachment
No other significant changes to physical exam
Repeat Echo: Increased vegetation size with longer mobile element and extension along the annulus
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49. In addition to CT surgery eval, what changes to the patient’s antibiotics, if any, should be made?
No changes to his antibiotics should be made
Add gentamicin to vancomycin
Discontinue vancomycin and start IV daptomycin 8 mg/kg Q24 hrs
Discontinue vancomycin and start IV daptomycin 8 mg/kg Q24 hrs + linezolid 600 mg BID
The management of patients with persistent MRSA bacteremia remains a challenge but based on the guidelines recommendations, choice D would be the most appropriate answer of the choices provided. As the patient has been bacteremic now for 9 days and appears to have clinical evidence of worsening endocarditis, alternative therapy to vancomycin should be considered. As discussed in previous slides, the addition of gentamicin to vancomycin is not recommended. Although there are no clinical data and additional study is needed, some experts suggest the use of high dose daptomycin in combination with another agent when managing patients with persistent bacteremia treated with vancomycin. These agents may include gentamicin, rifampin, linezolid, TMP-SMX, or a beta-lactam antibiotic. Synergy has been described in vitro and in some animal models of these drugs.
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50. Defining Vancomycin Treatment Failure: Approach to Persistent MRSA Bacteremia
Median time to clearance of bacteremia1,2,3:
Consideration factors when contemplating change in therapy:
Patient’s overall clinical response
Vancomycin trough concentrations
Results of susceptibility testing (e.g. vanco MIC)
Presence of and ability to remove other foci of infection
MSSA with -lactam abx
3-4 days
MRSA with vancomycin, daptomycin
7-9 days
The point at which the patient should be considered to have experienced treatment failure and alternative therapy sought is a complex issue. The median time to clearance of bacteremia in those patients with MRSA treated with vancomycin or daptomycin is 7-9 days, compared to 3-4 days in those patients with MSSA bacteremia treated with a -lactam antibiotic. Several factors should be considered when contemplating a change in antimicrobial therapy including:
The patient’s overall clinical response
Vancomycin trough concentrations
Results of susceptibility testing
Presence of and ability to remove other foci of infection
1Korzeniowski Ann Intern Med 1982;4:496-50; 2Levine Ann Intern Med 1991;115:674-80;
3Fowler NEJM 2006;355:653-65
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51. Management of Persistent MRSA Bacteremia on Vancomycin Therapy
Consider change in therapy if:
Unsatisfactory clinical response, regardless of MIC or
2) Vanco MIC = 2
Day of vancomycin therapy
No change in therapy if:
Clinically responding
and
Vanco MIC < 2
Although modification of therapy should generally be considered if the patient is persistently bacteremic after 1 week of vancomycin therapy, the threshold to change therapy may be earlier if the patient’s clinical condition is worsening or if the vancomycin MIC = 2 µg/mL particularly in the septic or critically ill patient. On the other hand, no immediate change in therapy may be indicated if the patient is clinically responding and the vancomycin MIC is < 2 µg/mL; in many cases the bloodstream will clear with continued vancomycin therapy.
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52. Persistent MRSA Bacteremia/ Vancomycin Treatment Failures: Therapeutic Considerations
In general, recommend a change in therapy rather than addition of other agents (e.g. rifampin/ gentamicin) to vanco
High-dose daptomycin (10 mg/kg/day), if susceptible, in combination with another agent (BIII):
Gentamicin 1 mg/kg IV Q8
Rifampin 600 mg PO/ IV QD or mg PO/ IV twice daily
Linezolid 600 mg PO/ IV BID
TMP-SMX 5 mg/kg IV BID
-lactam antibiotic
Note: prior vanco exposure and elevated vanco MICs associated with  dapto MICs (> 1 µg/mL).
In general, when constructing an alternate regimen in the setting of vancomycin treatment failure, the guidelines recommends a change in therapy rather than the addition of other agents (e.g rifampin and gentamicin) to vancomycin. If susceptible, daptomycin at a dose of 10 mg/kg/dose is recommended in combination with a second agent such as gentamicin, rifampin, linezolid, TMP-SMX, or a -lactam antibiotic. There is some in vitro data to suggest potential synergy when daptomycin is given in combination with these agents although further clinical data is needed. It is important to confirm daptomycin susceptibility as isolates with vancomycin MICs ≥ 2 µg/mL may have daptomycin MICs in the nonsusceptible range and in vitro susceptibility to vancomycin may select for higher daptomycin MICs.
LaPlante K AAC 2004;48: ;Tsuji BT AAC 2005;49: ;Credito AAC 2007;51:1504-7; Baltch A AC 2008;52: ;Rose W AAC 2008;52:831-6;Falagas ME JAC 2006;58:273-80;Steed AAC 2010;54: ;Yang AAC 2010; 54:3161-9
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53. How to manage reduced susceptibility to vancomycin and daptomycin?
Quinupristin-dalfopristin 7.5 mg/kg/dose IV Q8 (CIII)
Used successfully in vanco Rx failures, but lower response rates for endocarditis and bacteremia of unknown source
TMP-SMX 5 mg/kg/dose IV BID (CIII)
In vitro study: combo of dapto + TMP-SMX vs. dapto alone had more rapidly bactericidal activity for a dapto non-susceptible strain
Linezolid 600 mg PO/ IV BID (CIII)
Case series suggest success when used alone or in combination with other abx; poor outcomes for left-sided endocarditis.
Telavancin 10 mg/kg/dose IV QD (CIII)
1 case report of persistent MRSA bacteremia successfully treated
There are even less data to guide the management of patients with isolates that are nonsusceptible to both vancomycin and daptomycin and who are experiencing failure of therapy. Quinupristin-dalfoprsitin has been used successfully as salvage therapy in patients with vancomycin treatment failure, although response rates were lower for patients with endocarditis and bacteremia of unknown source. TMP-SMX is bactericidal in vitro but was inferior to vancomycin for the treatment of S. aureus infections, although all treatment failures occurred among those with MSSA infection, whereas all patients with MRSA infection were cured. Some experts suggest the addition of gentamicin or rifampin if TMP-SMX is used as salvage therapy. The combination of daptomycin and TMP-SMX had rapid bactericidal activity compared to daptomycin alone for a daptomycin non-susceptible strain in an in vitro study. Linezolid has been used with some success in several series either alone or in combination with other agents (e.g. rifampin, fusidic acid, gentamicin, amikacin, and carbapenem) but outcomes for left-sided endocarditis have been poor. There is one case report of persistent MRSA bacteremia in a patient with tricuspid valve endocarditis that was successfully treated with telavancin.
Sander A Int Care Med 2002;28: ; Markowitz N Ann Intern Med 1992;117:390-8; Steed AAC 2010;54: ; Falagas ME JAC 2006;58:273-80; Nace JAC 2010;65:
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54. Case follow-up HD #9 blood cultures: 1/ 2 MRSA
Daptomycin + linezolid started
R vitrectomy performed
HD #11 blood cultures : negative
HD #15 OR for valve replacement surgery
Intraoperative cultures mitral valve vegetation: + MRSA
Complicated course: status epilepticus, ventilator-associated pneumonia, PEA arrest 2 to submassive PE, eventually recovered and discharged to SNF
Received daptomycin 10 mg/kg QD + rifampin 300 mg TID for 6 weeks after MVR.
On HD#9, blood cultures are drawn and 1 of 2 cultures returns positive for MRSA. Daptomycin and linezolid are started and a right vitrectomy is performed. On HD #11 blood cultures are negative (difficult to know if this was due to the change in therapy or if the cultures would have cleared had vancomycin therapy been continued) and the patient goes to the OR on HD #15 for valve replacement surgery. Cultures of the mitral valve vegetation taken intraoperatively grow MRSA. The patient’s hospital course was complicated by status epilepticus, ventilator-associated pneumonia, PEA arrest secondary to a submassive pulmonary embolus. He eventually recovered and was discharged to a skilled nursing facility. He received a combination of daptomycin 10 mg/kg daily and rifampin 300 mg TID for 6 weeks after his mitral valve replacement.
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55. MRSA bone and joint infections
Surgical debridement is mainstay of therapy (AII).
Some experts recommend adding rifampin BID:
Animal models, small human trials of MSSA osteomyelitis
Retrospective study: cure rate of 80%, no added benefit if debridement occurred
Antibiotic
Dose
Evidence grade
Vancomycin
15-20 mg/kg IV Q8-12
BII
Daptomycin
6 mg/kg IV QD
Linezolid
600 mg PO/ IV BID
TMP-SMX + rifampin
4 mg/kg/dose (TMP) BID
600 mg QD (rifampin)
Clindamycin
600 mg PO/ IV Q8
BIII
Surgical debridement and drainage of associated soft tissue abscesses is the mainstay of therapy for MRSA osteomyelitis. Despite concerns about poor bone penetration and relative inefficacy in animal models, vancomycin remains the primary treatment of MRSA osteomyelitis. Failure rates of up to 35-46% have been reported, and compared with β-lactam therapy, patients with S. aureus osteomyelitis treated with vancomycin had a 2-fold higher recurrence rate. Due to unsatisfactory responses to vancomycin, some experts have recommended the addition of rifampin because of its excellent penetration into bone and biofilm. In animal models of S. aureus osteomyelitis, therapy with rifampin combined with a second agent is more effective than is therapy with the companion agent given alone. In 2 small trials of MSSA osteomyelitis, higher cure rates were associated with receipt of rifampin combination therapy. In one study, this approach resulted in cure rates of up to 80% while another study showed no added benefit if debridement occurred.
Other options for the treatment of osteomyelitis discussed in the guidelines are listed in the table.
Perlroth Arch Intern Med 2008;168:805-19;Dombrowski J Infect 2008;57:110-5; Livorsi J Infect 2008;57:128-31
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56. Oral vs. IV vs. IV/ PO therapy?
Optimal route of administration not established (AII).
Chronic non-axial MSSA osteo, randomized trial1
Retrospective cohort (MRSA subset)2
IV cloxacillin
(6 wks IV/ 2 wks PO)
PO cotrimoxazole + rifampin X 8 wks
P-value
Cure rate
91%
89%
1.0
IV (median 6 wks)*
IV (median 2 wks), then PO (median 42 days)
P-value
Cure rate
65%
.99
The optimal route of administration of antibiotic therapy has not been established. Parenteral, oral, or initial parenteral therapy followed by oral therapy may be used depending on the individual patient circumstances. In a randomized trial of adult patients with chronic nonvertebral MSSA osteomyelitis, equivalent cure rates of ~ 90% were achieved with 8 weeks of oral cotrimoxazole and rifampin as well as 6 weeks of IV cloxacillin followed by 2 weeks of oral therapy. In another study of MSSA and MRSA osteomyelitis, similar outcomes were observed in those patients who received prolonged parenteral therapy and those who received oral step-down therapy. Over 50% of regimens included rifampin in combination with another agent following initial parenteral therapy.
*61 % also received oral therapy for median PO 21 days
** Median total duration of total therapy 60 and 56 days in both groups
1Euba AAC 2009;53: ; 2Daver J Infect 2007;54:539-44
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57. Duration of therapy? Optimal duration is unknown; minimum 8 wks (AII).
Hematogenous MSSA vertebral osteo: 8 wks vs < 8 wks associated with improved outcomes1,2
Some experts suggest an additional 1-3 months (and possibly longer for chronic infection or if no debridement) of oral rifampin-based combination therapy (CIII)
The optimal duration of therapy for osteomyelitis is unknown. Antibiotic therapy for 8 weeks, compared with shorter durations, has been associated with improved outcomes in those with S. aureus osteomyelitis. Some experts suggest oral consolidative treatment after a course of parenteral therapy for an additional 1-3 months and possibly longer for treatment of chronic infection, if debridement is not performed or if inflammatory markers remain elevated.
1Jensen Arch Intern Med 1998;158:509-17; 2Priest S Med J 2005;98:854-62
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58. MRSA Infections of the Central Nervous System
Treatment difficult due to blood-brain barrier
Antibiotic
CSF penetration
CSF concentration
Comment
Vancomycin
(BII)
1-5%
2-6 µg/mL
Some experts recommend adding rifampin1 (BIII)
Linezolid
66%
Peak 7-10 µg/mL
Trough µg/mL
Successful use in few case reports, small case series2
TMP-SMX
(CIII)
TMP 13-53%
SMX 17-63%
TMP µg/mL
SMX µg/mL
Few case reports, only MSSA3
Treatment of MRSA infections of the central nervous system is difficult because of the critical location of these infections and the blood brain barrier. CSF penetration of vancomycin is poor, approximately 1% and 5% for uninflamed and inflamed meninges, respectively with maximum CSF concentrations of 2-6 µg/mL. Because it achieves bactericidal concentrations in CSF, some experts recommend rifampin in combination with vancomycin for meningitis and other CNS infections, despite a paucity of clinical data demonstrating benefit of this combination. Linezolid has good CSF penetration, as high as 66% with CSF peak and trough concentrations of 7-10 µg/mL and µg/mL, respectively. There are several case reports and small case series describing successful use of linezolid in CNS infections. TMP-SMX has similar CSF penetration for inflamed and uninflamed meninges, 13-53% for TMP and 17-63% for SMX; CSF concentrations range from µg/mL for TMP and µg/mL for SMX. There are few case reports describing successful use of TMP-SMX but these have only included patients with MSSA.
1Von Specht EJCMID 2006;25:267-9; Dylewski J CJIDMM 2004;15:336-8; Pintado EJCMID 2002;21:864-8; 2Ntziora Ann Pharm 2007;41: ; Gallagher J Infect 2008; ; 3Vartzelis Infect 2005;33:36-8; Levitz Ann Intern Med 1984; 100:881-90
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59. Management of MRSA infections of the Central Nervous System
CNS Shunt infections/ meningitis
Shunt removal is recommended; replace only when CSF cultures are repeatedly negative (AII).
Intraventricular vancomycin or daptomycin may be considered if not responding to systemic therapy1.
Brain abscess, subdural empyema, spinal epidural abscess
Neurosurgical evaluation for incision and drainage (AII).
Septic cavernous or dural venous sinus thrombosis
Debride contiguous sites of infection or abscess (AII).
Role of anticoagulation controversial due to risk of intracranial hemorrhage
For CNS shunt infections, shunt removal is recommended and it should not be replaced until CSF cultures are repeatedly negative. Although there are very limited data to guide use, intraventricular vancomycin or daptomycin may be considered in patients who have ventricular access or who do not respond to systemic antimicrobial therapy. For patients with a brain abscess, subdural empyema, or spinal epidural abscess, neurosurgical evaluation for incision and drainage is recommended. For septic cavernous or dural venous sinus thrombosis, contiguous sites of infection or abscess should be debrided. Due to the risk of intracranial hemorrhage, anticoagulation remains controversial.
1Pfausler J Neurosurg 2003;98:1040-4; Amod J Infect 2005; 50:252-7;Elvy JAC 2008;61:46102
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60. Adjunctive Therapies in Treatment of MRSA Infections
Protein synthesis inhibitors (e.g. clindamycin and linezolid) and IVIG are not routinely recommended as adjunctive therapy (AIII).
Limited in vitro data, animal model data (some conflicting)
Some experts may consider these agents in selected scenarios (e.g. necrotizing pneumonia or severe sepsis.) (CIII).
Protein synthesis inhibitors (e.g. clindamycin and linezolid) and IVIG are not routinely recommended as adjunctive therapy for the management of invasive MRSA diseases. Some experts may consider these agents in selected scenarios such as necrotizing pneumonia or severe sepsis. Limited in vitro data suggest that clindamycin and linezolid inhibit production of staphylococcal toxic shock syndrome toxin type 1 and PVL and that linezolid suppresses alpha- and beta-hemolysins, staphylococcal enterotoxin A and B, and protein A. However, clindamycin or linezolid in combination with vancomycin can be antagonistic in vitro, and vancomycin alone was more effective than vancomycin plus linezolid in a rabbit endocarditis model. Existing clinical data are limited to case reports for patients with staphylococcal toxic shock syndrome and necrotizing/ cavitary pneumonia, and additional studies are needed.
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61. Performance Measures
The management of all MRSA infections should include identification, elimination, and/or debridement of the primary source and other sites of infection when possible
In patients with MRSA bacteremia, document clearance of bacteremia (follow-up blood cultures 2-4 days after initial positive cx and as needed thereafter)
Vancomycin should be dosed according to actual body weight (15-20 mg/kg/dose every 8-12h), not to exceed 2 gram per dose. Target trough of g/mL in patients with serious infections
Document in vitro susceptibility when an alternative to vancomycin is being considered
For MSSA infections, a -lactam antibiotic is the drug of choice
Performance measures are included at the end of the guidelines:
The management of all MRSA infections should include identification, elimination, and/or debridement of the primary source and other sites of infection when possible.
In patients with MRSA bacteremia, clearance of bacteremia should be documented with follow-up blood cultures performed 2-4 days after the initial positive culture and as needed thereafter.
Vancomycin should be dosed according to actual body weight (15-20 mg/kg/dose every 8-12 hours), not to exceed 2 grams per dose. Trough monitoring is recommended to achieve target concentrations of µg/mL in patients with serious MRSA infections and to ensure target concentrations in those who are morbidly obese, have renal dysfunction, or have fluctuating volumes of distribution.
When an alternative to vancomycin is being considered, in vitro susceptibility should be confirmed and documented in the medical record.
For MSSA infections, a -lactam antibiotic is the drug of choice in the absence of allergy.
Copyright Infectious Diseases Society of America (IDSA) 2011

62. The full text of the guideline can be found at:
Conclusion
It is important to realize that guidelines cannot always account for individual variation among patients.  They are not intended to supplant physician judgment with respect to particular  patients or special clinical situation. IDSA considers adherence to its guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.  
The full text of the guideline can be found at:
Copyright Infectious Diseases Society of America (IDSA) 2011