Dr.  Manuel  Ramírez  Cardoce  Infectología  –  UCR  

Hospital  San  Juan  de  Dios    

menracar@gmail.com  

SEMINARIO:  ACTUALIZACIÓN  EN  INFECTOLOGÍA

INFECCIÓN DE PIEL Y TEJIDOS BLANDOS

An5bió5coterapia  •  Estrictamente   empírica   hasta   el   descubrimiento   de   las   bases  

microbiológicas  de  las  infecciones  (siglo  XIX).  

•  Estrategia  válida  ante  varias  en5dades  clínicas  infecciosas.  

INTRODUCCIÓN  

Mandell  GL  et  al.  Principles  and  prac5ce  of  infec5ous  diseases,  7th  ed.  Elsevier  2010.  Chapter  18  Principles  of  an5-­‐infec5ve  therapy.  

AnEbióEcoterapia  Empírica  

Escenarios  clínicos  

Meningi5s  

Endocardi5s  

IVRS  IVRI/Neumonía  

Infecciones  urinarias  

Infecciones  PTB  

Infección  intraabdominal  

                           

                       

               ¡IMPORTANTE!  Tomar  muestras  apropiadas  para  fro5s  y   cul5vo/PSA   previo   al   inicio   de   la  terapia  an5microbiana.  

Una  vez  iniciada  la  terapia  anEmicrobiana,  los  culEvos  suelen  ser  negaEvos  (aunque  persistan  microorganismos  viables  en  el  huésped)  

Mandell  GL  et  al.  Principles  and  prac5ce  of  infec5ous  diseases,  7th  ed.  Elsevier  2010.  Chapter  18  Principles  of  an5-­‐infec5ve  therapy.  

Escogencia  del  An5microbiano  

                       

                           AIdenEficar  al  Microorganismo  Infectante  

                                           B                                            C                

Tinción  Gram  PCR  

ELISA  o  látex  

U5lizar  la  estadís'ca  

bacteriológica  

¿Cuál  sería  el  agente  más  probable  en  este  escenario  

clínico?  

Mandell  GL  et  al.  Principles  and  prac5ce  of  infec5ous  diseases,  7th  ed.  Elsevier  2010.  Chapter  18  Principles  of  an5-­‐infec5ve  therapy.  

Escogencia  del  An5microbiano  

                       

                           A                                            BConocer  la  SuscepEbilidad  

                                           C                

MIC    

Mecanismos  de  resistencia  

Par5cularmente  importante  en:  

   S.  aureus  y  GN  

Considerar  variaciones  regionales  

Mandell  GL  et  al.  Principles  and  prac5ce  of  infec5ous  diseases,  7th  ed.  Elsevier  2010.  Chapter  18  Principles  of  an5-­‐infec5ve  therapy.  

Escogencia  del  An5microbiano  

                       

                           A                                            B                                            CFactores  del  Huésped  

               

Alergias  Edad  Trastornos  gené5cos  Embarazo  Función  renal  y  hepá5ca  

Abscesos  Hematomas  

pH  Cuerpos  extraños  

Si5o  de  Infección  

Mandell  GL  et  al.  Principles  and  prac5ce  of  infec5ous  diseases,  7th  ed.  Elsevier  2010.  Chapter  18  Principles  of  an5-­‐infec5ve  therapy.  

                           

                       

                Conocer  la  farmacocinéEca  y  farmacodinamia  

Uso  inapropiado…deletéreo  mas  que  beneficioso  

Monoterapia  vs  terapia  combinada:  indiferencia/sinergismo/antagonismo.  Espectro  anEmicrobiano.  Dosificación  y  frecuencia:  agentes  Eempo  o  concentración  dependientes.  Vía  de  administración  y  biodisponibilidad.  Metabolismo  y  excreción.  

DMandell  GL  et  al.  Principles  and  prac5ce  of  infec5ous  diseases,  7th  ed.  Elsevier  2010.  Chapter  18  Principles  of  an5-­‐infec5ve  therapy.  

                           

                       

                INFECCIONES  DE  PIEL  Y  TEJIDOS  BLANDOS  

CLAS

IFICAC

IÓN  

•  Amplio  espectro  de  presentación  clínica.  –  Complicadas:  

•  Por  compromiso  de  estructuras  profundas,  que  requieren  intervenciones   quirúrgicas   y/o   que   se   acompañan   de  comorbilidades  (p.ej.  inmunocompromiso).  

•  Infecciones  por  anaerobios  o  GN.  

NO  COMPLICADAS   COMPLICADAS  

Celuli5s   Heridas  traumá5cas  

Erisipelas   Mordeduras  

Foliculi5s  y  furunculosis   Heridas  quirúrgicas  

Impé5gos   Pie  diabé5co  

Ec5mas   Úlceras  por  presión  y  venosas  

Abscesos  simples   Perianales  

Necro5zantes  

Abrahamian  FM  et  al.  Management  of  skin  and  sol-­‐5ssue  infec5ons  in  the  emergency  department.  Infect  Dis  Clin  N  Am  2008(22);89-­‐116.  

IPTB  CLASIFICACIÓN  

61

RAJAN

early detection and prompt surgical interven-tion.15 Since necrotizing fasciitis is very dif-ficult to diagnose, clinicians must maintain a high level of suspicion and use the LRINEC score to trigger early surgical evaluation. Sur-gical exploration is the only way to definitive-ly diagnose necrotizing fasciitis.

Blood cultures in some casesBlood cultures have a low yield and are usually not cost-effective, but they should be obtained in patients who have lymphedema, immune deficiency, fever, pain out of proportion to the findings on examination, tachycardia, or hy-potension, as blood cultures are more likely to be positive in more serious infections and can help guide antimicrobial therapy. Blood cul-tures are also recommended in patients with infections involving specific anatomic sites, such as the mouth and eyes.19

Aspiration, swabs, incision and drainageFluid aspirated from abscesses and swabs of debrided ulcerated wounds should be sent for Gram stain and culture. Gram stain and culture have widely varying yields, from less than 5% to 40%, depending on the source and technique.19 Cultures were not routinely obtained before MRSA emerged, but knowing antimicrobial susceptibility is now important to guide antibiotic therapy. Unfortunately, in cellulitis, swabs and aspi-rates of the leading edge have a low yield of around 10%.25 One prospective study of 25 hospitalized patients did report a higher yield of positive cultures in patients with fe-ver or underlying disease,26 so aspirates may be used in selected cases. In small studies, the yield of punch biopsies was slightly bet-ter than that of needle aspirates and was as high as 20% to 30%.27

FIGURE 1. Depth of involvement in skin and soft-tissue infections..

Epidermis

Dermis

Superficial fascia

Subcutaneous tissue

Deep fascia

Muscle

Erysipelas Impetigo Folliculitis

Ecthyma Furunculosis Carbunculosis

Cellulitis

Necrotizing fasciitis

Myonecrosis (clostridial and nonclostridial)

Sabitha  R.  Skin  and  sol-­‐5ssue  infec5ons:  classifying  and  trea5ng  a  spectrum.  Clev  Clin  J  Med  2012;79(1):57-­‐66.  

Erisipelas  Impé5go  Foliculi5s  

Ec5ma  Furunculosis  Carbunculosis  

Celuli5s  

Fascii5s  necro5zante  

Mionecrosis  

IPTB  MICROBIOLOGÍA  Y  SUSCEPTIBILIDAD  

•  La  microbiología  es  dependiente  de  varios  factores:  –  Huésped.  –  Ambiente  (comunitaria  vs.  ACS).  –  Mecanismo  de  trauma.  –  Duración  y  severidad  de  la  enfermedad.  

•  En  general,  estreptococos  y  S.  aureus  originan  la  gran  mayoría  de  IPTB  no  complicadas  y  complicadas.  –  Excepción:  mordeduras.  

Abrahamian  FM  et  al.  Management  of  skin  and  sol-­‐5ssue  infec5ons  in  the  emergency  department.  Infect  Dis  Clin  N  Am  2008(22);89-­‐116.  

•  En   un   estudio   mul5céntrico   y  prospec5vo  de  IPTB  purulenta:  

–  MRSA  fue  aislado  en  15  a  74%  de  casos.  •  61%  de  abscesos.  •  53%  de  heridas  infectadas.  •  47%  de  celuli5s  purulentas.  

–  MSSA  fue  aislado  en:  •  14%  de  abscesos.  •  21%  de  heridas  infectadas.  •  34%  de  celuli5s  purulentas.  

–  Streptococcus  spp.  fue  aislado  en:  •  7%  de  abscesos.  •  9%  de  heridas  infectadas.  •  13%  de  celuli5s  purulentas.  

•  L a s   mo r d edu r a s   s u e l e n   s e r  infecciones   mixtas   (aerobios   y  anaerobios).  

•  De  animales:  –  Pasteurella  spp.:  

•  50%  en  perros  (P.  canis,  26%).  •  75%  en  gatos  (P.  multocida,  54%).  

–  Streptococcus  spp.  en  46%  (ambas).  –  MSSA  en  20%  (perros)  y  4%  (gatos).  –  Anaerobios:   Fusobacterium   spp.  

Bacteroides  spp.  Prevotella  spp.  

•  De  humanos:  –  Streptococcus  spp.  en  84%.  –  S.  aureus  en  30%.  –  Eikenella  corrodens  en  30%.  –  Prevotella  spp.  en  36%.  –  Fusobacterium  spp.  en  34%.  

Abrahamian  FM  et  al.  Management  of  skin  and  sol-­‐5ssue  infec5ons  in  the  emergency  department.  Infect  Dis  Clin  N  Am  2008(22);89-­‐116.  

Moran  GJ  et  al.  MRSA  infec5ons  among  pa5ents  in  the  emergency  department.  N  Engl  J  Med  2006;355(7):666-­‐74.  

MRSA  

Cambio  epidemiológico  más  

significa5vo  

Alta  prevalencia  aún  en  ausencia  de  FR  “clásicos”  clínicos  y  epidemiológicos  

Algunas  cepas  (MRSA-­‐CA)  se  

asocian  a  mayor  virulencia  y  

producción  de  toxinas  (p.ej.  PVL)  

Abrahamian  FM  et  al.  Management  of  skin  and  sol-­‐5ssue  infec5ons  in  the  emergency  department.  Infect  Dis  Clin  N  Am  2008(22);89-­‐116.  

IPTB  MICROBIOLOGÍA  Y  SUSCEPTIBILIDAD  

Abrahamian  FM  et  al.  Management  of  skin  and  sol-­‐5ssue  infec5ons  in  the  emergency  department.  Infect  Dis  Clin  N  Am  2008(22);89-­‐116.  

adequate serum levels with respect to the minimum inhibitory concentration(MIC) and maximizing concentration-dependent killing [74]. Although thisrecommendation seems logical and is made to prevent under-dosing, itshould be noted that there are no prospective human trials demonstratingthe superiority of a two double-strength, compared with a one double-strength, regimen. TMP/SMX has been shown to have adequate penetrationinto experimentally made human skin blisters [75,76]; however, the samemay not apply to abscesses even with an increased dosage regimen. Mostimportantly, the issue of penetration into the abscess cavity may bea moot point if they are treated with adequate incision and drainage.Dosage increases may also lead to increased side-effects and potentiallylower patient compliance with the advocated regimen.

Rifampin, a highly active agent against CA-MRSA, is commonly used incombination with TMP/SMX or doxycycline. It should not be used alonebecause of its rapid tendency to select resistant strains [77]. The SanfordGuide recommends the addition of rifampin to TMP/SMX for patientswho have an abscess associated with fever, those with large or multipleabscesses, and in severe infections [74]. The only supporting data are froma retrospective study of CA-MRSA SSTIs, in which clinical resolutionwas achieved in all of six patients treated with a combination of TMP/SMX and rifampin, but in only 6 of 12 patients treated with double-strengthTMP/SMX [78]. Rifampin has numerous drug-drug interactions and an

Table 5In vitro susceptibility patterns of community-associated methicillin-resistant Staphylococcusaureus to a variety of antimicrobial agents

Antibiotic Moran et al [12] Miller et al [21] Naimi et al [23] Ruhe et al [60]

TMP/SMX 100% (n ¼ 217) 100% (n ¼ 120) 95% (n ¼ 106) 99% (n ¼ 322)Rifampin 100% (n ¼ 186) 100% (n ¼ 120) 96% (n ¼ 106) 99% (n ¼ 318)Clindamycin 95% (n ¼ 226)a 95% (n ¼ 102) 83% (n ¼ 106) 98% (n ¼ 482)b

Tetracycline 92% (n ¼ 226) 81% (n ¼ 120) 92% (n ¼ 106) 93% (n ¼ 455)Gentamicin NT 100% (n ¼ 120) 94% (n ¼ 106) 100% (n ¼ 320)Ciprofloxacin 60% (n ¼ 176) 15% (n ¼ 101) 79% (n ¼ 106) 73% (n ¼ 354)Erythromycin 6% (n ¼ 226) 7% (n ¼ 120) 44% (n ¼ 106) 5% (n ¼ 23)Vancomycin NT 100% (n ¼ 120) 100% (n ¼ 106) 100% (n ¼ 492)Linezolid NT 100% (n ¼ 19) NT NT

Susceptibility patterns are dynamic and may vary markedly by geographic regions.Physicians’ familiarity with the prevalence and susceptibility patterns of CA-MRSA in theircommunity is a crucial element in the management of CA-MRSA infections.

Abbreviations: NT, Not tested; TMP/SMX, Trimethoprim/sulfamethoxazole.a Four (approximately 2%; n ¼ 226) MRSA isolates had inducible clindamycin resistance

detected by an antimicrobial susceptibility D-zone disk diffusion test.b Two (3%; n ¼ 59) MRSA isolates had inducible clindamycin resistance detected by an

antimicrobial susceptibility D-zone disk diffusion test.Modified from Abrahamian FM, Snyder EW. Community-associated methicillin-resistant

Staphylococcus aureus: incidence, clinical presentation, and treatment decisions. Curr InfectDis Rep 2007;9(5):391–7; with permission.

104 ABRAHAMIAN et al

0 10 20 30 40 50 60 70 80 90

100

1995  (101  aislamientos)   2004  (956  aislamientos)  

Vancomicina   Oxacilina   Ciprofloxacina   TMP/SMX   Gentamicina  

Histórico de susceptibilidad de S. aureus (Hospital México)

2006-­‐08  (2410  aislamientos)  

?  

72%  

48%  

34%  

87%  

74%  66%  

72%  

87%  88%  

74%  79%  

69%  

Cortesía  Dr.  Villalobo

s  Vinda

s,  Servicio  de

 Infectología  Hosp.  M

éxico  

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

OXA CIP CLI

Susceptibilidad 2410 cepas de S. aureus, Hospital México

LEV TET GEN RIF MOX VAN LZD

66%  

SENSIBLE  

RESISTENTE  

34%   33%   34%   31%   27%   12%   11%   8%  51%  

ERI

Cortesía  Dr.  Villalobos  Vindas,  Servicio  de  Infectología  Hosp.  México  

SXT

0  

10  

20  

30  

40  

50  

60  

70  

80  

90  

100  

1995   2000   2004   2009   2014  

%  MRSA  

Cortesía  Lab.  Microbiología  HSJD  y  Dr.  Boza  Cordero  

Histórico de susceptibilidad de S. aureus (HSJD)

0%  

10%  

20%  

30%  

40%  

50%  

60%  

70%  

80%  

90%  

100%  *2014:  Todos  los  culEvos,  de  hospitalizados,  urgencias  y  consulta  externa.  

Susceptibilidad 1292 cepas de S. aureus, HSJD

68%  Oxa-­‐R  

32%  R  

0%  

10%  

20%  

30%  

40%  

50%  

60%  

70%  

80%  

90%  

100%  

CIP  

CLI  

ERY  

GEN  

LEV  

LZD  

MIN  

MOX  

OXA

 

Q/D  

RIF  

TEC  

TET  

SXT  

VAN  

2012  

2013  

*Todos  los  culEvos  de  consulta  externa.  

Susceptibilidad 144 cepas de S. aureus, HSJD

65%  Oxa-­‐R  

20-­‐30%  R  

0%  

10%  

20%  

30%  

40%  

50%  

60%  

70%  

80%  

90%  

100%  

CIP  

CLI  

ERY  

GEN  

LEV  

LZD  

MIN  

MOX  

OXA

 

Q/D  

RIF  

TEC  

TET  

SXT  

VAN  

2012  

2013  

2014  

*Todos  los  culEvos  de  urgencias.  

Susceptibilidad 462 cepas de S. aureus, HSJD

65-­‐75%  Oxa-­‐R  

20%  R  

Susceptibilidad 163 cepas de S. aureus aisladas del Servicio de Urgencias, Hospital México

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

OXA CLI SXT CIP TET LEV RIF MOX VAN LZD

53%  

SENSIBLE

RESISTENTE

24%   13%   13%   12%   11%   6%   6%   4%  35%  

ERI GEN

Cortesía  Dr.  Villalobos  Vindas,  Servicio  de  Infectología  Hosp.  México  

%  R  %  S  

Oxacilina Clindamicina Levofloxacina TMP/SMX

%  R    

%  S   %  R    

%  S   %  R    

%  S  

68    79    74    74    74  

32    21    26    26    26  

Año  

2007    2008    2009    2010    Total  

0    7    4    0    3  

100    93    96    100    97  

5    4    0    0    2  

95    96    100    100    98  

0    0    0    0    0  

100    100    100    100    100  

(n=22)  

(n=28)  

(n=27)  

(n=77)  

Cortesía  Dr.  Villalobos  Vindas,  Servicio  de  Infectología  Hosp.  México  

IPTB  ABORDAJE  Y  MANEJO  

•  Abscesos   no   complicados  (incluso  por  MRSA):  –  Incisión   y   drenaje   solamente  

(tasa  de  curación  85-­‐90%).  •  P r i n c i pa l   c au sa   de   f a l l a  

t e r a p é u 5 c a :   d r e n a j e  inadecuado.  

•  Cul5vos  de  heridas,  sólo  en:  –  Admisión  hospitalaria.  –  Infecciones  complicadas.  –  Inmunocompromiso.  –  Enfermedad  severa.  –  Recurrencia  o  refractariedad.  

Abrahamian  FM  et  al.  Management  of  skin  and  sol-­‐5ssue  infec5ons  in  the  emergency  department.  Infect  Dis  Clin  N  Am  2008(22);89-­‐116.  

•  Se   recomienda   el   uso   de  t e r a p i a   a n 5m i c r o b i a n a  (asociada  al  manejo  quirúrgico  de   incisión   y   drenaje)   en  aquellos  abscesos  cutáneos:  

–  Complicados.  –  Múl5ples.  –  Con  gangrena.  –  Por  mordeduras.  –  En  inmunocomprome5dos.  –  Con  celuli5s  extensa.  –  Con  toxicidad  sistémica.  

IPTB  TERAPIA  ANTIMICROBIANA  TIPO   ESCENARIO   AGENTES  

ImpéEgo  

Ambulatorio  x  5-­‐10  d  

Mupirocina  al  2%  ungüento  tópico  

CeluliEs  No  purulenta  

Cefalexina  VO  500  mg  qid                                                                +/-­‐  TMP-­‐SMX  160/800  mg  VO  1-­‐2  tab  bid  

CeluliEs  Purulenta  

TMP-­‐SMX  160/800  mg  VO  1-­‐2  tab  bid                      ó  Clindamicina  VO  300  mg  qid                                                        ó  Doxiciclina  VO  100  mg  bid  

Absceso  con  celuliEs  leve   Incisión  y  drenaje  

Pie  diabéEco  

Clindamicina  VO  300  mg  qid                                                          +  Ciprofloxacina  VO  500  bid                                                                                                                                                                ó  Amox-­‐clav  875/125  mg  VO  1  tab  bid                            +/-­‐  TMP-­‐SMX  160/800  mg  VO  1-­‐2  tab  bid  

Mordeduras  

Amox-­‐clav  875/125  mg  VO  1  tab  bid                                                                                                                                                                ó  Clindamicina  VO  300  mg  qid                                                          +  Ciprofloxacina  VO  500  mg  bid  

Abrahamian  FM  et  al.  Management  of  skin  and  sol-­‐5ssue  infec5ons  in  the  emergency  department.  Infect  Dis  Clin  N  Am  2008(22);89-­‐116.  

M A J O R A R T I C L E

Clinical Trial: Comparative Effectiveness ofCephalexin Plus Trimethoprim-Sulfamethoxazole Versus Cephalexin Alone forTreatment of Uncomplicated Cellulitis: ARandomized Controlled Trial

Daniel J. Pallin,1,2 William D. Binder,3 Matthew B. Allen,1,4 Molly Lederman,1,5 Siddharth Parmar,1 Michael R. Filbin,3

David C. Hooper,6 and Carlos A. Camargo Jr31Department of Emergency Medicine, Brigham and Women’s Hospital, 2Division of Emergency Medicine, Boston Children’s Hospital, and 3Department ofEmergency Medicine, Massachusetts General Hospital, Boston; 4Perelman School of Medicine at the University of Pennsylvania, Philadelphia;5Department of Pediatrics, and 6Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston

(See the Editorial Commentary by Chambers on pages 1763–4.)

Background. Community-associated methicillin-resistant S. aureus (CA-MRSA) is the most common organismisolated from purulent skin infections. Antibiotics are usually not beneficial for skin abscess, and national guidelinesdo not recommend CA-MRSA coverage for cellulitis, except purulent cellulitis, which is uncommon. Despite this,antibiotics targeting CA-MRSA are prescribed commonly and increasingly for skin infections, perhaps due, in part,to lack of experimental evidence among cellulitis patients. We test the hypothesis that antibiotics targeting CA-MRSA are beneficial in the treatment of cellulitis.

Methods. We performed a randomized, multicenter, double-blind, placebo-controlled trial from 2007 to 2011.We enrolled patients with cellulitis, no abscesses, symptoms for <1 week, and no diabetes, immunosuppression, pe-ripheral vascular disease, or hospitalization (clinicaltrials.gov NCT00676130). All participants received cephalexin.Additionally, each was randomized to trimethoprim-sulfamethoxazole or placebo. We provided 14 days of antibiot-ics and instructed participants to continue therapy for ≥1 week, then stop 3 days after they felt the infection to becured. Our main outcome measure was the risk difference for treatment success, determined in person at 2 weeks,with telephone and medical record confirmation at 1 month.

Results. We enrolled 153 participants, and 146 had outcome data for intent-to-treat analysis. Median age was29, range 3–74. Of intervention participants, 62/73 (85%) were cured versus 60/73 controls (82%), a risk differenceof 2.7% (95% confidence interval, −9.3% to 15%; P = .66). No covariates predicted treatment response, includingnasal MRSA colonization and purulence at enrollment.

Conclusions. Among patients diagnosed with cellulitis without abscess, the addition of trimethoprim-sulfame-thoxazole to cephalexin did not improve outcomes overall or by subgroup.

Clinical Trials Registration. NCT00676130.

Keywords. cellulitis; community-associated methicillin-resistant Staphylococcus aureus; comparative effectiveness;trimethoprim-sulfamethoxazole; cephalexin.

Community-associated methicillin-resistant Staphylo-coccus aureus (CA-MRSA) is the most common

identifiable cause of purulent skin infections, that is,abscess and purulent cellulitis [1, 2]. The frequency of

Received 5 December 2012; accepted 22 January 2013; electronically published1 March 2013.

Correspondence: Daniel J. Pallin, 75 Francis St, Neville House 304-D, Boston,MA 02115 (dpallin@partners.org).

Clinical Infectious Diseases 2013;56(12):1754–62© The Author 2013. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:journals.permissions@oup.com.DOI: 10.1093/cid/cit122

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M A J O R A R T I C L E

Clinical Trial: Comparative Effectiveness ofCephalexin Plus Trimethoprim-Sulfamethoxazole Versus Cephalexin Alone forTreatment of Uncomplicated Cellulitis: ARandomized Controlled Trial

Daniel J. Pallin,1,2 William D. Binder,3 Matthew B. Allen,1,4 Molly Lederman,1,5 Siddharth Parmar,1 Michael R. Filbin,3

David C. Hooper,6 and Carlos A. Camargo Jr31Department of Emergency Medicine, Brigham and Women’s Hospital, 2Division of Emergency Medicine, Boston Children’s Hospital, and 3Department ofEmergency Medicine, Massachusetts General Hospital, Boston; 4Perelman School of Medicine at the University of Pennsylvania, Philadelphia;5Department of Pediatrics, and 6Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston

(See the Editorial Commentary by Chambers on pages 1763–4.)

Background. Community-associated methicillin-resistant S. aureus (CA-MRSA) is the most common organismisolated from purulent skin infections. Antibiotics are usually not beneficial for skin abscess, and national guidelinesdo not recommend CA-MRSA coverage for cellulitis, except purulent cellulitis, which is uncommon. Despite this,antibiotics targeting CA-MRSA are prescribed commonly and increasingly for skin infections, perhaps due, in part,to lack of experimental evidence among cellulitis patients. We test the hypothesis that antibiotics targeting CA-MRSA are beneficial in the treatment of cellulitis.

Methods. We performed a randomized, multicenter, double-blind, placebo-controlled trial from 2007 to 2011.We enrolled patients with cellulitis, no abscesses, symptoms for <1 week, and no diabetes, immunosuppression, pe-ripheral vascular disease, or hospitalization (clinicaltrials.gov NCT00676130). All participants received cephalexin.Additionally, each was randomized to trimethoprim-sulfamethoxazole or placebo. We provided 14 days of antibiot-ics and instructed participants to continue therapy for ≥1 week, then stop 3 days after they felt the infection to becured. Our main outcome measure was the risk difference for treatment success, determined in person at 2 weeks,with telephone and medical record confirmation at 1 month.

Results. We enrolled 153 participants, and 146 had outcome data for intent-to-treat analysis. Median age was29, range 3–74. Of intervention participants, 62/73 (85%) were cured versus 60/73 controls (82%), a risk differenceof 2.7% (95% confidence interval, −9.3% to 15%; P = .66). No covariates predicted treatment response, includingnasal MRSA colonization and purulence at enrollment.

Conclusions. Among patients diagnosed with cellulitis without abscess, the addition of trimethoprim-sulfame-thoxazole to cephalexin did not improve outcomes overall or by subgroup.

Clinical Trials Registration. NCT00676130.

Keywords. cellulitis; community-associated methicillin-resistant Staphylococcus aureus; comparative effectiveness;trimethoprim-sulfamethoxazole; cephalexin.

Community-associated methicillin-resistant Staphylo-coccus aureus (CA-MRSA) is the most common

identifiable cause of purulent skin infections, that is,abscess and purulent cellulitis [1, 2]. The frequency of

Received 5 December 2012; accepted 22 January 2013; electronically published1 March 2013.

Correspondence: Daniel J. Pallin, 75 Francis St, Neville House 304-D, Boston,MA 02115 (dpallin@partners.org).

Clinical Infectious Diseases 2013;56(12):1754–62© The Author 2013. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:journals.permissions@oup.com.DOI: 10.1093/cid/cit122

1754 • CID 2013:56 (15 June) • Pallin et al

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ber on July 11, 2013http://cid.oxfordjournals.org/

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M A J O R A R T I C L E

Clinical Trial: Comparative Effectiveness ofCephalexin Plus Trimethoprim-Sulfamethoxazole Versus Cephalexin Alone forTreatment of Uncomplicated Cellulitis: ARandomized Controlled Trial

Daniel J. Pallin,1,2 William D. Binder,3 Matthew B. Allen,1,4 Molly Lederman,1,5 Siddharth Parmar,1 Michael R. Filbin,3

David C. Hooper,6 and Carlos A. Camargo Jr31Department of Emergency Medicine, Brigham and Women’s Hospital, 2Division of Emergency Medicine, Boston Children’s Hospital, and 3Department ofEmergency Medicine, Massachusetts General Hospital, Boston; 4Perelman School of Medicine at the University of Pennsylvania, Philadelphia;5Department of Pediatrics, and 6Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston

(See the Editorial Commentary by Chambers on pages 1763–4.)

Background. Community-associated methicillin-resistant S. aureus (CA-MRSA) is the most common organismisolated from purulent skin infections. Antibiotics are usually not beneficial for skin abscess, and national guidelinesdo not recommend CA-MRSA coverage for cellulitis, except purulent cellulitis, which is uncommon. Despite this,antibiotics targeting CA-MRSA are prescribed commonly and increasingly for skin infections, perhaps due, in part,to lack of experimental evidence among cellulitis patients. We test the hypothesis that antibiotics targeting CA-MRSA are beneficial in the treatment of cellulitis.

Methods. We performed a randomized, multicenter, double-blind, placebo-controlled trial from 2007 to 2011.We enrolled patients with cellulitis, no abscesses, symptoms for <1 week, and no diabetes, immunosuppression, pe-ripheral vascular disease, or hospitalization (clinicaltrials.gov NCT00676130). All participants received cephalexin.Additionally, each was randomized to trimethoprim-sulfamethoxazole or placebo. We provided 14 days of antibiot-ics and instructed participants to continue therapy for ≥1 week, then stop 3 days after they felt the infection to becured. Our main outcome measure was the risk difference for treatment success, determined in person at 2 weeks,with telephone and medical record confirmation at 1 month.

Results. We enrolled 153 participants, and 146 had outcome data for intent-to-treat analysis. Median age was29, range 3–74. Of intervention participants, 62/73 (85%) were cured versus 60/73 controls (82%), a risk differenceof 2.7% (95% confidence interval, −9.3% to 15%; P = .66). No covariates predicted treatment response, includingnasal MRSA colonization and purulence at enrollment.

Conclusions. Among patients diagnosed with cellulitis without abscess, the addition of trimethoprim-sulfame-thoxazole to cephalexin did not improve outcomes overall or by subgroup.

Clinical Trials Registration. NCT00676130.

Keywords. cellulitis; community-associated methicillin-resistant Staphylococcus aureus; comparative effectiveness;trimethoprim-sulfamethoxazole; cephalexin.

Community-associated methicillin-resistant Staphylo-coccus aureus (CA-MRSA) is the most common

identifiable cause of purulent skin infections, that is,abscess and purulent cellulitis [1, 2]. The frequency of

Received 5 December 2012; accepted 22 January 2013; electronically published1 March 2013.

Correspondence: Daniel J. Pallin, 75 Francis St, Neville House 304-D, Boston,MA 02115 (dpallin@partners.org).

Clinical Infectious Diseases 2013;56(12):1754–62© The Author 2013. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:journals.permissions@oup.com.DOI: 10.1093/cid/cit122

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that antibiotics be used in such settings was based solely onexpert opinion [7].

The present study is typical of pragmatic trials [11]. Onefeature of comparative effectiveness research is that its pragmat-ic approach can produce results that contradict what would belogically predictable from biological knowledge. We are in themidst of an epidemic of skin infections caused by CA-MRSA,but antibiotics targeting this organism have not been foundhelpful in pragmatic studies.

LimitationsThe chief limitation of our study is intrinsic to most cases ofcellulitis: there is no objective way to make an etiologic diagno-sis. Our study was also limited to outpatients, including, forexample, no patients with cellulitis complicating lymphede-ma, for whom blood cultures and intravenous antibiotics arerecommended [10]. Our study provides no direct informationabout the management of such complicated skin infections inhospitalized patients, though it does provide support for thegeneral concept that CA-MRSA is not important in cellulitis.Treatment of patients with life-threatening infections such asnecrotizing fasciitis is not informed by this study. In this context,it bears mentioning that we avoided the common term “skin andsoft-tissue infections,” in favor of simply, “skin infections.” “Softtissue infections,” which are not “skin infections,” include suchsyndromes as pyomyositis and fasciitis and are rare. This studydoes not inform the treatment of such conditions.

We excluded diabetics. We are aware of no evidence that dia-betics are at higher risk for CA-MRSA–associated skin infec-tions, and thus our results may be generalizable to them.Most episodes of cellulitis in diabetics are treated as in nondia-betics [7]. While diabetic foot infections do require broadercoverage, whether they require coverage for CA-MRSA remainsunknown [10]. We assessed MRSA colonization nasally. Only67% of MRSA-colonized skin infection patients have positivenasal swabs, with other common sites of colonization being theaxillae, groin, and perineum [30]. Had we also swabbed theaxillae and groin, we might have observed an interaction of col-onization and treatment response. While CA-MRSA is almostuniversally susceptible to trimethoprim-sulfamethoxazole invitro, it is possible that other agents, such as clindamycin andtetracyclines, might be more effective in vivo. Using diaries,participants indicated whether they took all of their medica-tions each day until self-reported cure, and this is analyzedabove. However, we did not record the total duration of therapy(ie, we cannot distinguish stopped therapy from a day of partialadherence). This reflects the study’s nature as an effectivenessstudy, rather than an efficacy study, in that the practicing clini-cian controls only the prescription, not subsequent adherence.We did not record lesion area, which would have required

photography and parsing of each lesion into measurable geo-metric shapes.

Though it achieved its target, our study was modest in size.This was not an equivalence study, and when we designed thetrial, we expected to find a benefit from the intervention. Thevalue of the result is that it is the first evidentiary support forthe relevant national guidelines [7]. We know of only 2 otherrelevant trials: NCT00729937 and NCT00730028. If the IDSAguidelines are correct, those trials and meta-analyses combin-ing their results with ours will narrow the confidence interval.However, those studies have posted no results on ClinicalTrials.gov (as of 30 November 2012), and thus we do not know whenthey will contribute relevant data from cellulitis patients or howlarge their samples of cellulitis patients will be.

As clinical trial evidence accumulates, antibiotic prescribingfor skin infection patients might even be a reasonable target forantibiotic stewardship interventions, especially given howcommon skin infections are. Regarding abscesses, the evidencemay already be sufficient to consider use of antibiotics for un-complicated abscesses as a good target for antibiotic steward-ship efforts. Regarding cellulitis, we feel that the present trialalone is not sufficient to motivate a stewardship campaign forcellulitis. If the results of the other studies mentioned aboveecho our own findings, reduction in the use of antibiotics thattarget CA-MRSA for uncomplicated cellulitis may become areasonable target.

CONCLUSIONS

In the first study to provide experimental support for IDSA rec-ommendations against antibiotics targeting CA-MRSA for mostcases of cellulitis, we found that adding trimethoprim-sulfame-thoxazole to cephalexin conferred no benefit relative to therapywith cephalexin alone in the outpatient treatment of cellulitis.Concerns about polypharmacy and antibiotic stewardship maylead us to rely on beta lactams when treating uncomplicated cel-lulitis.

Notes

Acknowledgments. We thank Patricia Kelly, RPh, of Brigham andWomen’s Hospital, for her invaluable help in developing placebos andplanning and executing the study. We are grateful to Shannon Manzi, RPh,of Boston Children’s Hospital, for her help in implementation at that site.John T. Nagurney, MD, provided invaluable support, as did Blair Parry,both of Massachusetts General Hospital. We acknowledge gratefully thework of many research assistants, attending physicians, resident physicians,and nurses who made the study happen. None of these contributors werecompensated for their help. We are very grateful to the participants.Financial support. This work was supported by a grant from the

Eleanor and Miles Shore Fellowship Program of the Brigham and Women’sHospital Department of Emergency Medicine; by the Milton Fund ofHarvard University, Boston, MA; and by seed funding from the Depart-ment of Emergency Medicine of Massachusetts General Hospital.Potential conflicts of interest. All authors: No reported conflicts.

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The new england journal of medicine

n engl j med 372;12 nejm.org March 19, 2015 1093

established in 1812 March 19, 2015 vol. 372 no. 12

From the Los Angeles Biomedical Research Institute (L.G.M., S.J.E.) and Division of Infectious Diseases, Harbor–UCLA (Uni-versity of California, Los Angeles) Medi-cal Center (L.G.M., S.J.E.), Torrance, Da-vid Geffen School of Medicine at UCLA, Los Angeles (L.G.M., S.J.E.), Division of Plastic and Reconstructive Surgery, Uni-versity of California, San Francisco (UCSF) (D.Y.), and Division of Infectious Diseas-es, San Francisco General Hospital and UCSF (M.D.D., H.F.C.), San Francisco — all in California; Division of Pediatric In-fectious Diseases, University of Chicago, Chicago (R.S.D.); Division of Pediatric Infectious Diseases, Vanderbilt Universi-ty, Nashville (C.B.C.); the EMMES Corpo-ration, Rockville, MD (S.P.); and Cota En-terprises, Meriden, KS (R.J.H.). Address reprint requests to Dr. Miller at the Divi-sion of Infectious Diseases, Harbor–UCLA Medical Center, 1000 W. Carson St., Box 466, Torrance, CA 90509, or at lgmiller@ ucla . edu.

*A list of additional members of the Divi-sion of Microbiology and Infectious Dis-eases (DMID) 07-0051 Team is provided in the Supplementary Appendix, available at NEJM.org.

N Engl J Med 2015;372:1093-103.DOI: 10.1056/NEJMoa1403789Copyright © 2015 Massachusetts Medical Society.

BACKGROUNDSkin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear.

METHODSWe enrolled outpatients with uncomplicated skin infections who had cellulitis, ab-scesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim–sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The pri-mary outcome was clinical cure 7 to 10 days after the end of treatment.

RESULTSA total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, de-fined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, −2.6 percentage points; 95% confidence interval [CI], −10.2 to 4.9; P = 0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, −1.2 percentage points; 95% CI, −7.6 to 5.1; P = 0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups.

CONCLUSIONSWe found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infec-tions, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.)

a bs tr ac t

Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections

Loren G. Miller, M.D., M.P.H., Robert S. Daum, M.D., C.M., C. Buddy Creech, M.D., M.P.H., David Young, M.D., Michele D. Downing, R.N., M.S.N., Samantha J. Eells, M.P.H., Stephanie Pettibone, B.S., Rebecca J. Hoagland, M.S., and Henry F. Chambers, M.D., for the DMID 07-0051 Team*

The New England Journal of Medicine Downloaded from nejm.org at Hinari Phase 1 sites -- comp on May 14, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

The new england journal of medicine

n engl j med 372;12 nejm.org March 19, 2015 1093

established in 1812 March 19, 2015 vol. 372 no. 12

From the Los Angeles Biomedical Research Institute (L.G.M., S.J.E.) and Division of Infectious Diseases, Harbor–UCLA (Uni-versity of California, Los Angeles) Medi-cal Center (L.G.M., S.J.E.), Torrance, Da-vid Geffen School of Medicine at UCLA, Los Angeles (L.G.M., S.J.E.), Division of Plastic and Reconstructive Surgery, Uni-versity of California, San Francisco (UCSF) (D.Y.), and Division of Infectious Diseas-es, San Francisco General Hospital and UCSF (M.D.D., H.F.C.), San Francisco — all in California; Division of Pediatric In-fectious Diseases, University of Chicago, Chicago (R.S.D.); Division of Pediatric Infectious Diseases, Vanderbilt Universi-ty, Nashville (C.B.C.); the EMMES Corpo-ration, Rockville, MD (S.P.); and Cota En-terprises, Meriden, KS (R.J.H.). Address reprint requests to Dr. Miller at the Divi-sion of Infectious Diseases, Harbor–UCLA Medical Center, 1000 W. Carson St., Box 466, Torrance, CA 90509, or at lgmiller@ ucla . edu.

*A list of additional members of the Divi-sion of Microbiology and Infectious Dis-eases (DMID) 07-0051 Team is provided in the Supplementary Appendix, available at NEJM.org.

N Engl J Med 2015;372:1093-103.DOI: 10.1056/NEJMoa1403789Copyright © 2015 Massachusetts Medical Society.

BACKGROUNDSkin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear.

METHODSWe enrolled outpatients with uncomplicated skin infections who had cellulitis, ab-scesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim–sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The pri-mary outcome was clinical cure 7 to 10 days after the end of treatment.

RESULTSA total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, de-fined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, −2.6 percentage points; 95% confidence interval [CI], −10.2 to 4.9; P = 0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, −1.2 percentage points; 95% CI, −7.6 to 5.1; P = 0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups.

CONCLUSIONSWe found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infec-tions, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.)

a bs tr ac t

Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections

Loren G. Miller, M.D., M.P.H., Robert S. Daum, M.D., C.M., C. Buddy Creech, M.D., M.P.H., David Young, M.D., Michele D. Downing, R.N., M.S.N., Samantha J. Eells, M.P.H., Stephanie Pettibone, B.S., Rebecca J. Hoagland, M.S., and Henry F. Chambers, M.D., for the DMID 07-0051 Team*

The New England Journal of Medicine Downloaded from nejm.org at Hinari Phase 1 sites -- comp on May 14, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

The new england journal of medicine

n engl j med 372;12 nejm.org March 19, 2015 1093

established in 1812 March 19, 2015 vol. 372 no. 12

From the Los Angeles Biomedical Research Institute (L.G.M., S.J.E.) and Division of Infectious Diseases, Harbor–UCLA (Uni-versity of California, Los Angeles) Medi-cal Center (L.G.M., S.J.E.), Torrance, Da-vid Geffen School of Medicine at UCLA, Los Angeles (L.G.M., S.J.E.), Division of Plastic and Reconstructive Surgery, Uni-versity of California, San Francisco (UCSF) (D.Y.), and Division of Infectious Diseas-es, San Francisco General Hospital and UCSF (M.D.D., H.F.C.), San Francisco — all in California; Division of Pediatric In-fectious Diseases, University of Chicago, Chicago (R.S.D.); Division of Pediatric Infectious Diseases, Vanderbilt Universi-ty, Nashville (C.B.C.); the EMMES Corpo-ration, Rockville, MD (S.P.); and Cota En-terprises, Meriden, KS (R.J.H.). Address reprint requests to Dr. Miller at the Divi-sion of Infectious Diseases, Harbor–UCLA Medical Center, 1000 W. Carson St., Box 466, Torrance, CA 90509, or at lgmiller@ ucla . edu.

*A list of additional members of the Divi-sion of Microbiology and Infectious Dis-eases (DMID) 07-0051 Team is provided in the Supplementary Appendix, available at NEJM.org.

N Engl J Med 2015;372:1093-103.DOI: 10.1056/NEJMoa1403789Copyright © 2015 Massachusetts Medical Society.

BACKGROUNDSkin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear.

METHODSWe enrolled outpatients with uncomplicated skin infections who had cellulitis, ab-scesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim–sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The pri-mary outcome was clinical cure 7 to 10 days after the end of treatment.

RESULTSA total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, de-fined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, −2.6 percentage points; 95% confidence interval [CI], −10.2 to 4.9; P = 0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, −1.2 percentage points; 95% CI, −7.6 to 5.1; P = 0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups.

CONCLUSIONSWe found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infec-tions, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.)

a bs tr ac t

Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections

Loren G. Miller, M.D., M.P.H., Robert S. Daum, M.D., C.M., C. Buddy Creech, M.D., M.P.H., David Young, M.D., Michele D. Downing, R.N., M.S.N., Samantha J. Eells, M.P.H., Stephanie Pettibone, B.S., Rebecca J. Hoagland, M.S., and Henry F. Chambers, M.D., for the DMID 07-0051 Team*

The New England Journal of Medicine Downloaded from nejm.org at Hinari Phase 1 sites -- comp on May 14, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

The new england journal of medicine

n engl j med 372;12 nejm.org March 19, 2015 1093

established in 1812 March 19, 2015 vol. 372 no. 12

From the Los Angeles Biomedical Research Institute (L.G.M., S.J.E.) and Division of Infectious Diseases, Harbor–UCLA (Uni-versity of California, Los Angeles) Medi-cal Center (L.G.M., S.J.E.), Torrance, Da-vid Geffen School of Medicine at UCLA, Los Angeles (L.G.M., S.J.E.), Division of Plastic and Reconstructive Surgery, Uni-versity of California, San Francisco (UCSF) (D.Y.), and Division of Infectious Diseas-es, San Francisco General Hospital and UCSF (M.D.D., H.F.C.), San Francisco — all in California; Division of Pediatric In-fectious Diseases, University of Chicago, Chicago (R.S.D.); Division of Pediatric Infectious Diseases, Vanderbilt Universi-ty, Nashville (C.B.C.); the EMMES Corpo-ration, Rockville, MD (S.P.); and Cota En-terprises, Meriden, KS (R.J.H.). Address reprint requests to Dr. Miller at the Divi-sion of Infectious Diseases, Harbor–UCLA Medical Center, 1000 W. Carson St., Box 466, Torrance, CA 90509, or at lgmiller@ ucla . edu.

*A list of additional members of the Divi-sion of Microbiology and Infectious Dis-eases (DMID) 07-0051 Team is provided in the Supplementary Appendix, available at NEJM.org.

N Engl J Med 2015;372:1093-103.DOI: 10.1056/NEJMoa1403789Copyright © 2015 Massachusetts Medical Society.

BACKGROUNDSkin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear.

METHODSWe enrolled outpatients with uncomplicated skin infections who had cellulitis, ab-scesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim–sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The pri-mary outcome was clinical cure 7 to 10 days after the end of treatment.

RESULTSA total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, de-fined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, −2.6 percentage points; 95% confidence interval [CI], −10.2 to 4.9; P = 0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, −1.2 percentage points; 95% CI, −7.6 to 5.1; P = 0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups.

CONCLUSIONSWe found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infec-tions, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.)

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Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections

Loren G. Miller, M.D., M.P.H., Robert S. Daum, M.D., C.M., C. Buddy Creech, M.D., M.P.H., David Young, M.D., Michele D. Downing, R.N., M.S.N., Samantha J. Eells, M.P.H., Stephanie Pettibone, B.S., Rebecca J. Hoagland, M.S., and Henry F. Chambers, M.D., for the DMID 07-0051 Team*

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