(in the MRSA Era) Bradley Allen, MD,PhD, FACP Infectious Diseases Service Indianapolis VAMC Division of Infectious Diseases Indiana University School of.

Cellulitis and Soft Tissue Infections (in the MRSA Era) (in the MRSA Era)

Bradley Allen, MD,PhD, FACPBradley Allen, MD,PhD, FACPInfectious Diseases ServiceInfectious Diseases Service

Indianapolis VAMCIndianapolis VAMCDivision of Infectious DiseasesDivision of Infectious Diseases

Indiana University School of MedicineIndiana University School of Medicine

IU Health – Arnett Hospital IU Health – Arnett Hospital Medicine Grand RoundsMedicine Grand Rounds

October 24October 24thth, 2012, 2012

DisclosuresDisclosures

Substantial personal holdings of both Substantial personal holdings of both skin skin andand soft tissue soft tissue

Investigator; Merck clinical trialInvestigator; Merck clinical trial

Pre TestPre Test

Q1. What organisms comprise the most common cause of cellulitis?1)Streptococcus species2)Pseudomonas aeruginosa3)Aeromonas species4)Vibrio vulnificans

Pre TestPre Test

Q2. The best agent to treat streptococcal cellulitis is? 1)Trimethoprim/sulfamethoxazole2)Doxycycline3)Levofloxacin4)Cephalexin

Pre TestPre Test

Q3. Which statement is true regarding vancomycin?1)Superior to nafcillin in MSSA treatment2)Is more nephrotoxic then gentamycin3)Should be dosed at 15-20 mg/kg4)Trough goal dose should be 5-10 ug/ml

Historical perspective of Historical perspective of skin skin and soft tissue infection and soft tissue infection

(SSTI)(SSTI) ““Skin infections have been around since Skin infections have been around since

the invention of skin” the invention of skin” Brad Spellberg, UCLABrad Spellberg, UCLA

Traitement de l’erysipele par la Traitement de l’erysipele par la chlorhydrate de sulfamido-chrysoidine. chlorhydrate de sulfamido-chrysoidine. Meyer-Heine and Huguenin. Meyer-Heine and Huguenin. Presse Presse Med Med 1936: 44:454-4571936: 44:454-457 One of the first clinical trials of an One of the first clinical trials of an

antibacterial agentantibacterial agent

Review common skin and soft tissue Review common skin and soft tissue diseasedisease

treatment concepts/new agentstreatment concepts/new agents Review new IDSA Guidelines for SSTI Review new IDSA Guidelines for SSTI

and MRSA treatmentand MRSA treatment

Liu, C, A Bayer, S Cosgrove, R Daum, S Fridkin, R Gorwitz, S Kaplan, AW Karchmer, D Levine, BE Murray, MJ Rybak, D Talan, and HF Chambers. 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(3): e18-e55

Infectious Diseases Society of America Guideline websitewww.idsociety.org

ObjectivesObjectives

Skin infectionSkin infection Mild to severe in spectrumMild to severe in spectrum May reflect systemic process or be localized May reflect systemic process or be localized

to the skinto the skin Must differentiate from non-infectious etiology Must differentiate from non-infectious etiology

such as – such as – vasculitisvasculitis connective tissue disease (e.g. SLE)connective tissue disease (e.g. SLE) Neoplasm (Squamous cell ca., etc.)Neoplasm (Squamous cell ca., etc.) Allergic Dermatitis – contact or TENAllergic Dermatitis – contact or TEN Pyoderma gangrenosumPyoderma gangrenosum Non-infectiousNon-infectious venous stasis changes venous stasis changes

Skin infectionSkin infection Mild to severe in spectrumMild to severe in spectrum May reflect systemic process or be localized May reflect systemic process or be localized

to the skinto the skin Must differentiate from non-infectious etiology Must differentiate from non-infectious etiology

such as – such as –

Non-infectious venous stasis changesNon-infectious venous stasis changes

Clinical scenarioClinical scenario 34 y.o. weekend warrior34 y.o. weekend warrior Spectacular slide into 2Spectacular slide into 2ndnd base during softball base during softball

gamegame Initial abrasions on knee, washed post gameInitial abrasions on knee, washed post game Redness and warmth developed over next Redness and warmth developed over next

few days in area of the abrasionfew days in area of the abrasion Low grade fevers and red streak noticed Low grade fevers and red streak noticed

along medial thighalong medial thigh

CellulitisCellulitis Often preceded by mild skin irritation or traumaOften preceded by mild skin irritation or trauma Dermal Dermal andand subcutaneous involvement subcutaneous involvement Borders diffuse, non-elevated Borders diffuse, non-elevated ((compare to erysipelascompare to erysipelas))

May spread via lymphatics - May spread via lymphatics - lymphangitislymphangitis Overwhelming majorityOverwhelming majority due to strep/staph due to strep/staph Poor venous or lymphatic drainage are risk Poor venous or lymphatic drainage are risk

factorsfactors e.g. saphenous vein graft harvest sites, prior lymph e.g. saphenous vein graft harvest sites, prior lymph

node dissection or obstructionnode dissection or obstruction

Lymphangitic spread – Lymphangitic spread – more common with strep v. staph diseasemore common with strep v. staph disease

Diagnosis/etiology of cellulitisDiagnosis/etiology of cellulitis• History important

• pace of illness• severity of sxs

• Risk factors for resistant organisms?• MRSA history• Antibiotic exposure

• Causitive agents :• Group A streptococci• Staphylococcus aureus• Group C,G, and B strep (-hemolytic strep)

• These organisms represent 80-97% of cultured organisms associated with routine cellulitis and “non-purulent” skin and soft tissue infection

Pathogens Associated WithPathogens Associated With complicatedcomplicated * * SSTI Clinical SSTI Clinical

ScenariosScenarios• • Diabetes: Diabetes: S. aureus, S. aureus, strep > anaerobes, GN bacillistrep > anaerobes, GN bacilli

• • Cirrhosis: Cirrhosis: Campylobacter fetus, Campylobacter fetus, coliforms, coliforms, Vibrio Vibrio vulnificusvulnificus, Capnocytophaga canimorsus, Capnocytophaga canimorsus

• • Neutropenia: Neutropenia: Pseudomonas aeruginosaPseudomonas aeruginosa

• • Human bite: Human bite: Eikenella corrodensEikenella corrodens

• • Cat bite: Cat bite: Pasteurella multocidaPasteurella multocida

• • Dog bite: Dog bite: P. multocida, C. canimorsusP. multocida, C. canimorsus

• • Rat bite: Rat bite: Streptobacillus moniliformisStreptobacillus moniliformis

• • Hot tub exposure: Hot tub exposure: P. aeruginosaP. aeruginosa

• • Fresh water laceration: Fresh water laceration: Aeromonas hydrophilaAeromonas hydrophila

• • Fish tank exposure: Fish tank exposure: Mycobacterium marinumMycobacterium marinum

• • IV drug use: IV drug use: MRSA, MRSA, P. aeruginosaP. aeruginosa

* Purulent process, open wound, deep collection, etc* Purulent process, open wound, deep collection, etc

Streptococcus pyogenes Streptococcus pyogenes

Streptococcus pyogenes Streptococcus pyogenes

Staphylococcus aureusStaphylococcus aureus

Staphylococcus aureusStaphylococcus aureus

Risk Factors for Skin andRisk Factors for Skin andSoft-Tissue InfectionSoft-Tissue Infection

• • Trauma (Trauma (lacerations, burns, abrasions, crush, lacerations, burns, abrasions, crush, open fxopen fx))

• • Intravenous drug useIntravenous drug use

• • Human or animal bitesHuman or animal bites

• • Conditions that predispose to infectionConditions that predispose to infection

DM, alcoholism, chronic renal disease, cirrhosis, DM, alcoholism, chronic renal disease, cirrhosis, neutropenia, hypogammaglobulinemia, arterial or neutropenia, hypogammaglobulinemia, arterial or chronic venous insufficiency, lymphedemachronic venous insufficiency, lymphedema

• • Past cellulitis (Past cellulitis (especially with tinea pedis)especially with tinea pedis)

• • Radical mastectomy with axillary LN dissectionRadical mastectomy with axillary LN dissection

• • Saphenous vein harvestingSaphenous vein harvestingCellulitis and Soft-tissue infections. American College of Physicians; In the Clinic, Annals of Internal Medicine. 2009. 150(1):ITC1-14.

Annual visits to US EDs for SSTIs during the emergence of community- associated (CA) MRSA from 1993 - 2005

Boucher H et al. Clin Infect Dis. 2010;51:S183-S197© 2010 by the Infectious Diseases Society of America

3-fold increase1.2 to 3.4 millionvisits/year

7 to 38% of abxregimens activeagainst MRSA

Clinical Outcomes of Hospitalized SSTI 2007

Jenkins T C et al. Clin Infect Dis. 2010;51:895-903

© 2010 by the Infectious Diseases Society of America

SSTI requiring hospitalization: Opportunities for antimicrobial (and resource) stewardship

Jenkins TC et al. Clin Infect Dis. 2010;51:895-903

© 2010 by the Infectious Diseases Society of America

Cellulitis Cutaneous Abscess

cSSTI

Antibiotic Duration (days)

13 14 13

Imaging (20% CT or MRI)

94% 86%

Failure < 30 days (%) 12.1 4.9 9.2

322 patients admitted to academic center IVDA, DM, alcoholism common comorbidities 150 culture positive, 97% S. aureus or

streptococci. Antibiotics with broad aerobic GNR and

anaerobic bacteria used in 83% of patients Imaging results yielded new information <4%

Treatment of cellulitisTreatment of cellulitis Non-pharmacologic interventions

Elevation is critical! decrease dependent edema Improves -

venous drainage arterial flow to soft tissue

Oxygen and nutrients antibiotic delivery WBC delivery

Address risk factors to prevent recurrencesAddress risk factors to prevent recurrences Treat tinea pedisTreat tinea pedis

Optimize skin health in generalOptimize skin health in general Moisturize, minimize trauma such as shaving, etcMoisturize, minimize trauma such as shaving, etc

Mortality rates associated with erysipelas before and after the introduction of antimicrobial agents.

Spellberg B et al. Clin Infect Dis. 2009;49:383-391

© 2009 by the Infectious Diseases Society of America

Is antimicrobial treatment of cellulitis needed at all?

16%

2%

Hoyne et al. Mortality rates in the treatment of 998 erysipelas patients. JAMA 1939;113:2279-81.Cook County Hospital

Madsen S.T. Scarlet fever and erysipelas in Norway during the last hundred years. Infection 1973;1:76-81.

10

100

0

Copyright ©2009 American Academy of Pediatrics

Elliott, D. J. et al. Pediatrics 2009;123:e959-e966

Antibiotic management and treatment failure rates for nondrained noncultured SSTIs in 2002-2007

2096 patients, 104 with failures

Note that failure rate did not change over time despite change in antibiotic choices

Copyright ©2009 American Academy of Pediatrics

Elliott, D. J. et al. Pediatrics 2009;123:e959-e966

Predicted probability of treatment failure 104 failures compared to 480 controls

- Empiric CA-MRSA coverage was not associated with improved outcomes in the outpt mgt of nondrained noncultured SSTIs. - Monotherapy with tmp-smz may increase the risk of treatment failure- β-Lactam therapy remains the preferred empiric therapy for

uncomplicated SSTI , even with high prevalence of CA-MRSA.

Case-cohort trial of 2096 kids with uncomplicated skin infectionsCultures of SSTI in the community indicated MRSA in >50%

* P < .05

Risk Factors- Fever- Abscess- ED visit- Prior abx

Copyright restrictions may apply.

Hepburn, M. J. et al. Arch Intern Med 2004;164:1669-1674.

Serial composite scores for cellulitis with 5 vs 10 days of therapy, randomized, double-blind, placebo-controlled trial

in 87 military hospital cases of acute cellulitis

How long to treat simple cellulitis?

What is the management of What is the management of outpatients with “non-outpatients with “non-

purulent” cellulitispurulent” cellulitis?? Empirical therapy for infection due to β-Empirical therapy for infection due to β-

hemolytic streptococci is recommended hemolytic streptococci is recommended (A-II).(A-II).

The role of CA-MRSA is unknown. The role of CA-MRSA is unknown. Coverage for CA-MRSA is recommended in Coverage for CA-MRSA is recommended in

patients who do not respond to β-lactam patients who do not respond to β-lactam therapy and those with systemic toxicity. therapy and those with systemic toxicity.

Five - 10 days of therapy is recommended Five - 10 days of therapy is recommended

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

World leader – irritable, aggressive behavior World leader – irritable, aggressive behavior

FurunculosisFurunculosis Arises from folliculitisArises from folliculitis Pus collectionPus collection Surrounding cellulitisSurrounding cellulitis Risks – DM, obesity, Risks – DM, obesity,

steroids, poor PMN steroids, poor PMN functionfunction

S. aureus S. aureus most most commoncommon

Rx - Rx - DrainageDrainage, heat, , heat, +/- abx+/- abx

Skin v. Soft tissue infection Skin v. Soft tissue infection – –

Include combinations of skin, subcutaneous Include combinations of skin, subcutaneous tissue, fascia and/or muscle and bone.tissue, fascia and/or muscle and bone. May be localized or rapidly progressiveMay be localized or rapidly progressive

Systemic, multi-organ involvement may Systemic, multi-organ involvement may developdevelop

Higher mortality than skin infectionsHigher mortality than skin infections Higher rate of associated bacteremiaHigher rate of associated bacteremia Need more aggressive treatmentNeed more aggressive treatment May need surgical drainage/debridementMay need surgical drainage/debridement

Antibiotics Antibiotics areare recommended recommended for abscesses associated with for abscesses associated with

(A-III)(A-III):: severe or extensive severe or extensive

disease (eg, involving disease (eg, involving multiple sites of multiple sites of infection)infection)

rapid progression in rapid progression in presence of presence of associated cellulitis, associated cellulitis, signs and symptoms signs and symptoms of systemic illnessof systemic illness

associated associated comorbidities or comorbidities or immunosuppressionimmunosuppression

extremes of ageextremes of age areas difficult to drain areas difficult to drain

(eg, face, hand, and (eg, face, hand, and genitalia)genitalia)

septic phlebitisseptic phlebitis lack of response to lack of response to

incision and drainageincision and drainageLiu et al. Clin Infect Dis. (2011) 52(3): e18-e55

What is the management of What is the management of outpatientsoutpatients with purulent with purulent

cellulitiscellulitis?? Empirical therapy for CA-MRSA is Empirical therapy for CA-MRSA is

recommended pending culture results. recommended pending culture results. Empirical therapy for infection due to β-Empirical therapy for infection due to β-

hemolytic streptococci is likely to be hemolytic streptococci is likely to be unnecessary unnecessary (A-II)(A-II). .

Five - 10 days of therapy is Five - 10 days of therapy is recommended but should be recommended but should be individualized on the basis of the individualized on the basis of the patient's clinical response. patient's clinical response.

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

The Rise of MRSA and The Rise of MRSA and antibiotic resistant antibiotic resistant

Staphylococcus aureusStaphylococcus aureus

1928 to present…1928 to present…

S. aureus

Penicillin

[1950s]

Penicillin-resistant

S. aureus

Evolution of Drug Resistance in Evolution of Drug Resistance in S. S. aureusaureus

Methicillin

[1970s]

Methicillin-resistant

S. aureus (MRSA)

Vancomycin-resistant

enterococci (VRE)

Vancomycin

[1990s]

[1997]

Vancomycin

intermediate-resistantS. aureus (VISA)

Vancomycin

resistantS. aureus

http://www.cdc.gov/ncidod/hip/ARESIST/visa.htm

[2002]

Methicillin Resistant S.aureus Methicillin Resistant S.aureus (MRSA)(MRSA)

Methicillin MIC ≥ 16 mcg/ml, oxacillin ≥ 4 MR is encoded by the mecA gene

a low-affinity binding protein, PBP-2a All β-lactam agents are affected (cefazolin,

dicloxacillin, imipenem, aztreonam, etc.) Other species of Staphylococci are > 50%

Methicillin-resistant Coagulase-negative Staph group

S.epidermidis, S.haemolyticus, S.hominis, and S.saprophyticus

CA-MRSA antibiotic susceptibilityCA-MRSA antibiotic susceptibilityUSA300: nationwide vs. IowaUSA300: nationwide vs. Iowa

Agent

EMERGency

N=226

Iowa 2000-2007

N=167

Erythromycin 6 6

Clindamycin* 95 93

Levofloxacin 60 63

Tetracycline 92 95

TMP-SMX 100 100

*includes testing for inducible clindamycin resistance

Moran, et al. N Engl J Med 2006;355:666-74., Iowa data compliments Daniel Diekema

AVOID!

Empirical oral options for Empirical oral options for coverage of CA-MRSA with coverage of CA-MRSA with

SSTISSTI?? clindamycin clindamycin (A-II)(A-II)

Poorly tolerated, 4 x Poorly tolerated, 4 x dailydaily

TMP-SMX TMP-SMX (A-II)(A-II) tetracycline (doxy or tetracycline (doxy or

minocycline) minocycline) (A-II)(A-II) linezolid linezolid (A-II)(A-II) Use of rifampin as single Use of rifampin as single

agent or SSTI adjunctive agent or SSTI adjunctive therapy is therapy is notnot recommended recommended (A-III)(A-III)

To cover To cover bothboth β- β-hemolytic streptococci hemolytic streptococci and CA-MRSA:and CA-MRSA:

clinda alone clinda alone (A-II)(A-II) TMP-SMX or tet in TMP-SMX or tet in

combination combination withwith a β- a β-lactam (e.g. amoxicillin, lactam (e.g. amoxicillin, cephalexin) cephalexin) (A-II)(A-II)

linezolid alone linezolid alone (A-II)(A-II) > $1000 per 10 day > $1000 per 10 day

coursecourse

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

TMP/SMX & TMP/SMX & doxycyclinedoxycycline Both agents maintain activity against CA MRSA Both agents are second-line for streptococci Both increase sun sensitivity Both agents are bacteriostatic, not bacteriocidal Both are to be avoided in infants

TMP/SMX can be bacteriocidal at higher doses, but is inferior to vanco in head-to-head trials

DS tablet twice daily may be as effective as two tabs bid

Cautious use in elderly and with renal insufficiency

Doxycyline is overall well tolerated

Does MRSA v. MSSA impact infection outcomes?Meta-analysis of 40 studies: mortality associated with

nosocomial MRSA with MSSA.

Boucher H et al. Clin Infect Dis. 2010;51:S183-S197

© 2010 by the Infectious Diseases Society of America

Hospitalized patients with Hospitalized patients with complicated SSTIcomplicated SSTI??

cSSTI; defined as patients with deeper cSSTI; defined as patients with deeper soft-tissue infections, surgical/traumatic soft-tissue infections, surgical/traumatic wound infection, major abscesses, and wound infection, major abscesses, and infected ulcers and burnsinfected ulcers and burns

in addition to surgical debridement and in addition to surgical debridement and broad-spectrum antibiotics, empirical broad-spectrum antibiotics, empirical therapy for MRSA therapy for MRSA shouldshould be considered be considered pending culture data. pending culture data.

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

Options for MRSA coverage in Options for MRSA coverage in complicated SSTI?complicated SSTI?

IV vancomycin IV vancomycin (A-I)(A-I) linezolid 600 mg bid, oral linezolid 600 mg bid, oral

or IV or IV (A-I)(A-I),, daptomycin 4 mg/kg/ IV daptomycin 4 mg/kg/ IV

daily daily (A-I)(A-I) telavancin 10 mg/kg/dose telavancin 10 mg/kg/dose

IV once daily IV once daily (A-I)(A-I) clindamycin 600 mg IV or clindamycin 600 mg IV or

PO 3 times a day PO 3 times a day (A-III)(A-III) 7 - 14 days of therapy 7 - 14 days of therapy

Cultures from Cultures from abscesses and other abscesses and other

purulent SSTIspurulent SSTIs severe local infectionsevere local infection signs of systemic illnesssigns of systemic illness inadequate responseinadequate response concern for a cluster or concern for a cluster or

outbreak outbreak (A-III).(A-III).

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

VancomycinVancomycin IV formulation, E.C. Kornfeld, Lilly 1958 Bacteriocidal activity equivocal

Poor head-head comparisons to nafcillin or cefazolin in clinical trials of MSSA treatment

Red-man syndrome and true allergies Renal and ototoxicity

Amycolatopsis orientalis

Borneo

VancomycinVancomycin Therapeutic levels initially correlated

to toxicity in early formulations of the drug – Mississippi Mud! Newer formulations lack high risk of renal

or ototoxicity, so aggressive dosing is possible

Trough levels 15-20 needed insteadof previously recommended5-10 ug/ml.

Heteroresistance in MRSA Heteroresistance in MRSA strainsstrains

Point: Vancomycin Is Not Obsolete for the Treatment of Infection Caused by Methicillin-Resistant Staphylococcus aureus Mohr and Murray, 2007 Clin Inf Dis, 44:1536

• MRSA contain subpopulations with reduced in vitro killing by vancomycin

• MIC is still in susceptible range (<4 mcg/ml)– Tend to be in the MIC = 2 range

• Human and animal data indicate higher level of clinical failures when infected with hVISA strains

Mohr and Murray, 2007 Clin Inf Dis, 44:1536

HeterotypicVISA are increasing

Vancomycin Therapeutic Guidelines: Vancomycin Therapeutic Guidelines: Rybak, Rybak, et al. 2009. Clin Infect Dis; et al. 2009. Clin Infect Dis;

49:325–27 49:325–27 Trough serum vancomycin concentrations of

15 – 20 mg/L are recommended This trough level generates AUC/MIC of >400

if the MIC of the MRSA isolate is <1 mg/L Vancomycin dosages of 15–20 mg/kg (actual

body weight) given every 8–12 h for most patients with normal renal function.

For rapid target concentrations, a loading dose of 25–30 mg/kg (actual body weight) can be considered.

Vancomycin Therapeutic Guidelines: Vancomycin Therapeutic Guidelines: Rybak, Rybak, et al. 2009. Clin Infect Dis; et al. 2009. Clin Infect Dis;

49:325–27 49:325–27

AUC/MIC of >400 is not achievable if the vancomycin MIC is 2 mcg/ml. Therefore, alternative therapies should be considered.

When individual doses exceed 1 g (e.g., 1.5 and 2 g), the infusion period

should be extended to 1.5–2 h. Cost ~ $13/day

Most SSTI is due to staph and strepMost SSTI is due to staph and strep Non-purulent SSTIs do Non-purulent SSTIs do notnot need initial need initial

MRSA coverageMRSA coverage Gram-negative coverageGram-negative coverage Imaging (Imaging (unlessunless suspicion of foreign body, fluid) suspicion of foreign body, fluid)

β-hemolytic streptococci are still a major β-hemolytic streptococci are still a major cause of cellulitis and respond best to β-cause of cellulitis and respond best to β-lactam agentslactam agents

β-hemolytic streptococci respond slowly to β-hemolytic streptococci respond slowly to TMP/SMX and doxyTMP/SMX and doxy

SSTI in the MRSA Era SSTI in the MRSA Era ConclusionsConclusions

Guidelines: start with β-lactam agent Guidelines: start with β-lactam agent and change to MRSA agents and change to MRSA agents ifif no no response response

Duration of treatment for cellulitis and Duration of treatment for cellulitis and SSTI should be short, 5-10 days SSTI should be short, 5-10 days

Quinolones are Quinolones are notnot good agents for SSTI good agents for SSTI CA-MRSA infections are commonCA-MRSA infections are common

Majority are relatively minor SSTIsMajority are relatively minor SSTIs Most can be managed with I&D, & oral TMP/SMX Most can be managed with I&D, & oral TMP/SMX

or doxycycline IF NEEDEDor doxycycline IF NEEDED

SSTI in the MRSA Era SSTI in the MRSA Era ConclusionsConclusions

Vancomycin is a less potent cell-wall Vancomycin is a less potent cell-wall active drug compared to β-lactam active drug compared to β-lactam agentsagents

Vancomycin trough levels need to be Vancomycin trough levels need to be pushed to the 15-20 mcg/ml range to pushed to the 15-20 mcg/ml range to be effectivebe effective

Dose vanco aggressively, 15-25 mg/kg MRSA with vancomycin MICs of MRSA with vancomycin MICs of 2 2

are likely to fail vancomycin therapyare likely to fail vancomycin therapy

cSSTI in the MRSA Era cSSTI in the MRSA Era ConclusionsConclusions

SSTI in the MRSA Era SSTI in the MRSA Era ConclusionsConclusions

Nafcillin or 1st cephalosporin are still superior drug choices for methicillin-sensitive S.aureus

Empiric vanco is reasonable – but change asap if sensitivities show MSSA

Consider alternatives pathogens if clinical failure

Surgical co-management is critical for Surgical co-management is critical for abscess drainage or suspected tissue abscess drainage or suspected tissue necrosisnecrosis

Bonus SlidesBonus Slides

Linezolid Linezolid Q 12 hr or BID; IV and PO oxazolidinone,

bacteriostatic Novel class, some resistance in MRSA and VRE Adverse events – post marketing

Thrombocytopenia – after 14 days, reversible Serotonin syndrome – do not use with SSRIs

Fever, tachycardia, blood pressure, CNS sxs, etc.

Need 14 day wash-out of SSRI to avoid Peripheral/Optic neuropathy – long courses >4

weeks, irreversible in some cases Metabolic acidosis – case reports with longer

treatment courses (osteomyelitis, mycobacterial diseases, etc.)

Cost ~ $100/day

Daptomycin : OverviewDaptomycin : Overview Lipopeptide Activity in Gram-positive organisms Leads to membrane disruption Bactericidal in vitro and in vivo Most common side effect - myopathy

Baseline and weekly CPK Once-daily IV dosing, 4-6 mg/kg Ineffective in pneumonia due to interaction with

surfactant Some resistance in MRSA arising, even during therapy

Cost ~ $130/day

Telavancin – not currently being produced bactericidal lipoglycopeptide, IV onlybactericidal lipoglycopeptide, IV only

active against MRSA, VISA and VRSAactive against MRSA, VISA and VRSA Industry-spons, randomized, double-blind Industry-spons, randomized, double-blind

phase II study compared i.v. telavancin (10 phase II study compared i.v. telavancin (10 mg/kg daily) against vancomycin or mg/kg daily) against vancomycin or antistaphylococcal penicillin in 195 SSTI ptsantistaphylococcal penicillin in 195 SSTI pts

Clinical cure rate overall 82% for telavancin Clinical cure rate overall 82% for telavancin v. 85% ; and 83% and 82% in the 108 v. 85% ; and 83% and 82% in the 108 S. S. aureusaureus-infected patients -infected patients

Severe AEs similar (6% and 4%)Severe AEs similar (6% and 4%) Nausea, hypokalemia, creatinine rise, QTc Nausea, hypokalemia, creatinine rise, QTc

prolongedprolongedStryjewski ME et al. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study. Antimicrob Agents Chemother 2006 Mar; 50:862-7.

Cost ~ $130/day

Ceftaroline Ceftaroline New cephalosporin with high affinity for PBP 2a New cephalosporin with high affinity for PBP 2a

(mecA gene product)(mecA gene product) MRSA MICMRSA MIC9090 - 1 µg/mL, also gram-negative activity - 1 µg/mL, also gram-negative activity Randomized, double-blind trial of 1378 pts with Randomized, double-blind trial of 1378 pts with

cSSSI, ceftaroline (600 mg every 12 hrs for 5–14 cSSSI, ceftaroline (600 mg every 12 hrs for 5–14 days) was similar with ITT rates (85.9 v. 85.5%) days) was similar with ITT rates (85.9 v. 85.5%) compared to vancomycin plus aztreonam (1000 mg compared to vancomycin plus aztreonam (1000 mg every 12 hours). every 12 hours).

Success rates similar among patients with MRSA Success rates similar among patients with MRSA infections (93.4 vs. 94.3%). infections (93.4 vs. 94.3%).

Corey GR, et al. Integrated analysis of CANVAS 1 and 2: Phase 3, Multicenter, Randomized, double-blind studies to evlautate the saftey and efficacy of Ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010 ; 51:641-650.

Cost ~ $85/day

DalbavancinDalbavancin bactericidal lipoglycopeptide, IV onlybactericidal lipoglycopeptide, IV only

active against MRSA, VISA and VRSAactive against MRSA, VISA and VRSA Once Once weeklyweekly dosing based on pharmacokinetics dosing based on pharmacokinetics

Industry-spons, randomized, double-blind Industry-spons, randomized, double-blind phase II study, i.v. dalbavancin showed phase II study, i.v. dalbavancin showed equivalence with vancomycin in catheter equivalence with vancomycin in catheter infectionsinfections

Phase III trial indicated equivalence to Phase III trial indicated equivalence to linezolid in SSSI.linezolid in SSSI.

New phase III trial in progress. New phase III trial in progress. Not FDA-Not FDA-approvedapproved

Severe AEs minimal so far - Severe AEs minimal so far - Fever, headache, nauseaFever, headache, nauseaJauregui LE, Babazadeh S, Seltzer E. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis 2005; 41: 1407-1415.

Cost ~ $priceless

References/ResourcesReferences/Resources Liu, C, A Bayer, S Cosgrove, R Daum, S Fridkin, R Gorwitz, S Kaplan, AW Karchmer, D Levine, BE Murray, MJ

Rybak, D Talan, and HF Chambers. 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(3): e18-e55

Hayashi, Y, and DL Paterson. Strategies for Reduction in Duration of Antibiotic Use in Hospitalized Patients. Clin Infect Dis. (2011) 52(10): 1232-1240

Jenkins, TC, AL Sabel, EE Sarcone, CS Price, P Mehler, and WJ Burman. Skin and Soft-Tissue Infections Requiring Hospitalization at an Academic Medical Center: Opportunities for Antimicrobial Stewardship Clin Infect Dis. (2010) 51(8): 895-903

Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004;164:1669-74.

Elliot, DJ, et al. Empiric Antimicrobial Therapy for Pediatric Skin and Soft-Tissue Infections in the Era of Methicillin-Resistant Staphylococcus aureus. (2009) PEDIATRICS 23 (6): e959-e966

Boucher, H., L. Miller, and R. Razonable. Serious Infections Caused by Methicillin-Resistant Staphylococcus aureus Clin Infect Dis. (2010) 51(Supplement 2): S183-S197

van Rijen M, Bonten M, Wenzel R, Kluytmans J. Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers. Cochrane Database of Systematic Reviews 2008, Issue 4.

Cellulitis and Soft-tissue infections. American College of Physicians; In the Clinic, Annals of Internal Medicine. 2009. 150(1):ITC1-14.

Stevens DL, Bisno AL, Chambers HF, et al. Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections.Clin Infect Dis. 2005;41:1373-406.

Mandell, G.L. Atlas of Infectious Diseases, Volume II. Dennis Stevens ed., Current Medicine. http://dermatlas.med.jhmi.edu/derm/index.cfm

Super Bonus SlidesSuper Bonus Slides

Recurrent MRSA: Prevention – Recurrent MRSA: Prevention – favored initial approachfavored initial approach

Consistent hand hygiene antibacterial soap (e.g., Dial®) Chlorhexidine (Hibiclens®) showers

twice weekly Avoid cosmetic body shaving Optimize treatment of skin conditions

(e.g., eczema and tinea) Clean cuts & abrasions with soap &

water Cover wounds with clean, dry dressings

RecurrentRecurrent skin infections – skin infections – possible steps to eradicatepossible steps to eradicate

MRSA carrier state eradication difficult Consider only if multiple infections, evidence of

contact spread, or before major surgeries Mupiricin 2% ointment, twice daily, 5-10 days

Resistant strains arise with frequent use Use of chlorhexidine soaps Meticulous cleaning of contact surfaces in the

home, school, workplace with detergent or dilute bleach

Laundering of all clothes, outerwear, bedding “Modified head lice approach”

van Rijen M, Bonten M, Wenzel R, Kluytmans J. Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers. Cochrane Database of Systematic Reviews 2008, Issue 4.

Management of recurrent MRSA Management of recurrent MRSA SSTIsSSTIs

Preventive educational messages: Preventive educational messages: i. Keep draining wounds covered with i. Keep draining wounds covered with

clean, dry bandages clean, dry bandages (A-III)(A-III). . ii. Maintain good personal hygiene with ii. Maintain good personal hygiene with

bathing and hand cleaning with soap bathing and hand cleaning with soap and water or an alcohol-based hand gel and water or an alcohol-based hand gel (A-III)(A-III)

iii. Avoid reusing or sharing personal iii. Avoid reusing or sharing personal items (eg, razors, towels) items (eg, razors, towels) (A-III)(A-III)

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

Environmental hygiene Environmental hygiene recurrent recurrent MRSA SSTIsMRSA SSTIs

i. Cleaning efforts on high-touch i. Cleaning efforts on high-touch surfaces (ie, counters, door knobs, bath surfaces (ie, counters, door knobs, bath tubs, and toilet seats) tubs, and toilet seats) (C-III)(C-III)

ii. Commercially available cleaners or ii. Commercially available cleaners or detergents appropriate for the surface detergents appropriate for the surface being cleaned should be used according being cleaned should be used according to label instructions for routine cleaning to label instructions for routine cleaning of surfaces of surfaces (C-III)(C-III)

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

Decolonization with recurrent MRSA Decolonization with recurrent MRSA SSTIsSSTIs

MayMay be considered in selected cases if: be considered in selected cases if:i. A patient develops a recurrent SSTI despite i. A patient develops a recurrent SSTI despite

optimizing wound care and hygiene optimizing wound care and hygiene (C-III)(C-III). .

ii. Ongoing transmission is occurring among ii. Ongoing transmission is occurring among household members or close contacts household members or close contacts despite optimizing wound care and hygiene despite optimizing wound care and hygiene (C-III)(C-III). .

Should be offered Should be offered in conjunction within conjunction with ongoing reinforcement of hygiene ongoing reinforcement of hygiene measures ;measures ;

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

Decolonization with recurrent MRSA Decolonization with recurrent MRSA SSTIsSSTIsi. Nasal decolonization with mupirocin twice daily i. Nasal decolonization with mupirocin twice daily

for 5–10 days for 5–10 days (C-III)(C-III). .

ii. Nasal decolonization with mupirocin twice daily ii. Nasal decolonization with mupirocin twice daily for 5–10 days for 5–10 days andand topical body decolonization topical body decolonization regimens with a skin antiseptic solution (eg, regimens with a skin antiseptic solution (eg, chlorhexidine) for 5–14 days or dilute bleach baths. chlorhexidine) for 5–14 days or dilute bleach baths. (1 tsp/gal water for 15 min twice weekly for ∼3 (1 tsp/gal water for 15 min twice weekly for ∼3 months) months) (C-III)(C-III)

Oral antimicrobial therapy NOT routinely Oral antimicrobial therapy NOT routinely recommended for decolonization recommended for decolonization (A-III)(A-III). .

Rifampin , if the strain is susceptible, may be Rifampin , if the strain is susceptible, may be considered for decolonization if infections recur considered for decolonization if infections recur despite above measures despite above measures (CIII)(CIII). .

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

Decolonization with suspected Decolonization with suspected household or household or interpersonal interpersonal

transmission transmission i. Personal and environmental hygiene i. Personal and environmental hygiene measures in the patient and contacts measures in the patient and contacts (A-III)(A-III)

ii. Evaluate contacts for ii. Evaluate contacts for S. aureusS. aureus infection: infection: a. Symptomatic contacts should be a. Symptomatic contacts should be

evaluated and treated evaluated and treated (A-III)(A-III); nasal and ; nasal and topical body decolonization strategies may topical body decolonization strategies may be considered be considered followingfollowing treatment of active treatment of active infection infection (C-III)(C-III). .

b. Nasal and topical body decolonization of b. Nasal and topical body decolonization of asymptomatic household contacts asymptomatic household contacts maymay be be considered considered (C-III)(C-III). .

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

Role of cultures in the management of Role of cultures in the management of recurrent SSTI is limitedrecurrent SSTI is limited

i. Screening cultures prior to i. Screening cultures prior to decolonization are not routinely decolonization are not routinely recommended if at least 1 of the prior recommended if at least 1 of the prior infections was documented as due to infections was documented as due to MRSA MRSA (B-III)(B-III)

ii. Surveillance cultures following a ii. Surveillance cultures following a decolonization regimen are NOT decolonization regimen are NOT routinely recommended in the absence routinely recommended in the absence of an active infection of an active infection (B-III)(B-III)

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55

Precautions for Resistant Precautions for Resistant Organisms - MRSAOrganisms - MRSA

Readmit known MRSA carriers to Readmit known MRSA carriers to appropriate level of isolationappropriate level of isolation

If newly cultured, move to private If newly cultured, move to private roomroom

Notify Infection Control to facilitateNotify Infection Control to facilitateTo remove patient from isolation - To remove patient from isolation - Needs 2 sets of negative cxs from Needs 2 sets of negative cxs from

previously positive sites AND anterior previously positive sites AND anterior naresnares Done > 3 days apartDone > 3 days apart Obtained more than 48 hrs off antibioticsObtained more than 48 hrs off antibiotics

Ceftobiprole Ceftobiprole A new cephalosporin with high affinity for PBP 2aA new cephalosporin with high affinity for PBP 2a MRSA MICMRSA MIC9090 - 2 µg/mL - 2 µg/mL Randomized, double-blind trial of 828 pts with Randomized, double-blind trial of 828 pts with

complicated skin and soft-tissue infections, complicated skin and soft-tissue infections, ceftobiprole (500 mg every 8 hrs for 7–14 days) was ceftobiprole (500 mg every 8 hrs for 7–14 days) was similar with ITT rates over 80% compared to similar with ITT rates over 80% compared to vancomycin (1000 mg every 12 hours) plus vancomycin (1000 mg every 12 hours) plus ceftazidime (1000 mg every 8 hours). ceftazidime (1000 mg every 8 hours).

Rates also similar among patients with MRSA Rates also similar among patients with MRSA infections (90% vs. 86%)infections (90% vs. 86%)

FDA approval is lagging, may not succeed FDA approval is lagging, may not succeed Noel GJ et al. A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections. Clin Infect Dis 2008 Mar 1; 46:647.

Case PresentationCase Presentation11 a.m. -36 healthy man turned his ankle 11 a.m. -36 healthy man turned his ankle

at work, mild painat work, mild painHour 5 - Onset of nausea, fever, and leg pain.Hour 5 - Onset of nausea, fever, and leg pain.

Developed chills.Developed chills.DAY 2DAY 2Hour 18 - Evaluated in ER for Hour 18 - Evaluated in ER for severesevere ankle ankle

pain, Xray (-). Thought to have “flu”pain, Xray (-). Thought to have “flu”WBC 12,900WBC 12,900 (94% neutrophils).(94% neutrophils).

Hour 24 -No relief of pain, redness starts Hour 24 -No relief of pain, redness starts over ankle, wife thinks he looks “blue”over ankle, wife thinks he looks “blue”

Temp 103.4, WBC Temp 103.4, WBC 1,8001,800; creatinine ; creatinine 2.42.4

Case Presentation – Case Presentation – cont’d cont’d day 2day 2

Hour 26 - Admitted for antibiotics, low BP Hour 26 - Admitted for antibiotics, low BP (82/50). (82/50). Hemoglobin Hemoglobin from 15.4 to 18.5, redness to from 15.4 to 18.5, redness to kneeknee

Day 3-5Day 3-5Creatinine Creatinine 4.24.2; WBC 4,600 (73% bands); ; WBC 4,600 (73% bands);

abnormal liver testsabnormal liver tests- Redness to thigh- Redness to thigh

No improvement despite multiple antibioticsNo improvement despite multiple antibiotics

Weight increased from 205 to 237 lbsWeight increased from 205 to 237 lbs

Day 5Day 5

Hospital CourseHospital Course Evaluated by Infectious Disease and SurgeryEvaluated by Infectious Disease and Surgery Antibiotics to cover Group A streptococci and Antibiotics to cover Group A streptococci and

Staphylococcus aureusStaphylococcus aureus Debridement of non-viable skin and Debridement of non-viable skin and

subcutaneous fat to the muscle. No pus or subcutaneous fat to the muscle. No pus or pockets of infection. Cultures and stains (-).pockets of infection. Cultures and stains (-).

Split-thickness skin grafting done a week laterSplit-thickness skin grafting done a week later Anti-streptococcal antibody (ASO titer) Anti-streptococcal antibody (ASO titer)

elevatedelevated Dx – streptococcal necrotizing fasciitis and Dx – streptococcal necrotizing fasciitis and

toxic streptococcal shock syndrometoxic streptococcal shock syndrome

Post op picsPost op pics

Pre debridement

Post-debridement & graft

Serious infections of deeper skin structuresSerious infections of deeper skin structures

Aggressive soft tissue Aggressive soft tissue infectionsinfections

Necrotizing Fasciitis type 2 - Group A StrepNecrotizing Fasciitis type 2 - Group A Strep severe painsevere pain often often outout of context of context with with

initial superficial appearanceinitial superficial appearance treatment is treatment is surgical surgical andand medical medical

prompt debridementprompt debridement penicillin G plus clindamycin (stop toxin penicillin G plus clindamycin (stop toxin

production)production) Pooled IVIG if severe or progressivePooled IVIG if severe or progressive

Toxin-mediated disease – goal to neutralize Toxin-mediated disease – goal to neutralize toxintoxin

Antibiotic or Antibiotic Group

Clinical Failures/Patients Treated (% Failure)

All β-lactams 93/631 (14.7)

Cephalexin 54/359 (15.1)

All other β-lactams 39/272 (14.3)

Dicloxicillin 25/169 (14.8)

Amoxicillin/clavulanate 13/88 (14.8)

Other β-lactams 1/15 (6.7)

Non-β-lactams 39/230 (17.0)

Clindamycin 14/86 (16.3)

Trimethoprim/sulfamehoxazole 8/43 (18.6)

Fluoroquinolones 8/33 (24.2)

Macrolides 3/16 (18.8)

Tetracyclines 1/11 (9.1)

Combinations 5/41 (12.2)

Clinical Failure Rates of Antibiotic Treatments for Uncomplicated Cellulitis

Madaras-Kelly KJ - Am J Med - 01-MAY-2008; 121(5): 419-25

Vancomycin Intermediate- or Resistant Vancomycin Intermediate- or Resistant SASA

Mainly see in patients with extensive Mainly see in patients with extensive vanco exposure (dialysis, etc) …vanco exposure (dialysis, etc) …

Vancomycin-intermediate SA (VISA)Vancomycin-intermediate SA (VISA) MIC = 8-16MIC = 8-16 Altered cell wall limits drug penetration into bacteriumAltered cell wall limits drug penetration into bacterium Reduced response to vancomycinReduced response to vancomycin

Vancomycin-resistant SA (VRSA)Vancomycin-resistant SA (VRSA) MIC MIC ≥≥ 32 32

Initial case in 2002, only a few worldwideInitial case in 2002, only a few worldwide Resistance acquired from VRE Resistance acquired from VRE

7 gene cluster transfer7 gene cluster transfer

Pediatric considerations in Pediatric considerations in SSTISSTI For children with minor skin infections (such as For children with minor skin infections (such as

impetigo) and secondarily infected skin lesionsimpetigo) and secondarily infected skin lesions mupirocin 2% topical ointment mupirocin 2% topical ointment (A-III)(A-III)

Tetracyclines should not be used in children <8 years Tetracyclines should not be used in children <8 years of age of age (A-II)(A-II)

Hospitalized children, vancomycin is recommended Hospitalized children, vancomycin is recommended (A-II).(A-II).

If patient stable, empiric clindamycin is an option if If patient stable, empiric clindamycin is an option if the clindamycin resistance rate is low (eg, <10%) with the clindamycin resistance rate is low (eg, <10%) with transition to oral if strain is susceptible transition to oral if strain is susceptible (A-II)(A-II)

Linezolid 600 mg PO/IV twice/d for children ≥12 years, Linezolid 600 mg PO/IV twice/d for children ≥12 years, 10 mg/kg/dose PO/IV every 8 h for children <12 10 mg/kg/dose PO/IV every 8 h for children <12 (A-II)(A-II)

Liu et al. Clin Infect Dis. (2011) 52(3): e18-e55