Advertisement

Route and duration of antibiotic therapy in acute cellulitis: A systematic review and meta-analysis of the effectiveness and harms of antibiotic treatment

      Highlights

      • There is no evidence to support intravenous or prolonged antibiotic therapy (>5 days) in cellulitis.
      • Harms of intravenous and prolonged antibiotic treatment are not quantified.
      • Long-term outcomes after 30 days, including recurrence, have largely been neglected.
      • Prior episodes, comorbidities and illness severity can predict treatment outcome.
      • Research into patient-tailored antibiotic therapy for cellulitis must be a priority.

      Summary

      Objectives

      Compared with guideline recommendations, antibiotic overuse is common in treating cellulitis. We conducted a systematic review and meta-analyses on antibiotic route and duration of treatment for cellulitis in adults and children.

      Methods

      We searched MEDLINE, EMBASE and trial registries from inception to Dec 11, 2019 for interventional and observational studies of antibiotic treatment for cellulitis. Exclusions included case series/reports, pre-septal/orbital cellulitis and non-English language articles. Random-effects meta-analyses were used to produce summary relative risk (RR) estimates for our primary outcome of clinical response.

      PROSPERO

      CRD42018100602.

      Results

      We included 47/8423 articles, incorporating data from eleven trials (1855 patients) in two meta-analyses. The overall risk of bias was moderate. Only two trials compared the same antibiotic agent in each group. We found no evidence of difference in clinical response rates for antibiotic route or duration (RR(oral:IV)=1.12, 95%CI 0.98–1.27, I2=32% and RR(shorter:longer)=0.99, 95%CI 0•96–1.03, I2 = 0%, respectively). Findings were consistent in observational studies. Follow-up data beyond 30 days were sparse.

      Conclusions

      The evidence base for antibiotic treatment decisions in cellulitis is flawed by biased comparisons, short follow-up and lack of data around harms of antibiotic overuse. Future research should focus on developing patient-tailored antibiotic prescribing for cellulitis to reduce unnecessary antibiotic use.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Infection
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Stevens D.L.
        • Bisno A.L.
        • Chambers H.F.
        • Dellinger E.P.
        • Goldstein E.J.
        • Gorbach SL
        • et al.
        Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America.
        Clin Infect Dis. 2014; 59: 147-159
        • Raff A.B.
        • Kroshinsky D.
        Cellulitis: A Review.
        JAMA. 2016; 316: 325-337
        • Tun K.
        • Shurko J.F.
        • Ryan L.
        • Lee G.C.
        Age-based health and economic burden of skin and soft tissue infections in the United States, 2000 and 2012.
        PLoS One. 2018; 13e0206893
        • Health & Social Care Information Centre
        Hospital Episode Statistics.
        Admitted Patient Care. 2018;
        • Miller L.G.
        • Eisenberg D.F.
        • Liu H.
        • Chang C.L.
        • Wang Y.
        • Luthra R.
        • et al.
        Incidence of skin and soft tissue infections in ambulatory and inpatient settings, 2005-2010.
        BMC Infect Dis. 2015; 15: 362
        • Bruun T.
        • Oppegaard O.
        • Kittang B.R.
        • Mylvaganam H.
        • Langeland N.
        • Skrede S.
        Etiology of Cellulitis and Clinical Prediction of Streptococcal Disease: A Prospective Study.
        Open Forum Infect Dis. 2016; 3 (ofv181)
        • Hook 3rd, E.W.
        • Hooton T.M.
        • Horton C.A.
        • Coyle M.B.
        • Ramsey P.G.
        • Turck M.
        Microbiologic evaluation of cutaneous cellulitis in adults.
        Arch Intern Med. 1986; 146: 295-297
        • McGowan Jr., J.E.
        • Gerding D.N.
        Does antibiotic restriction prevent resistance?.
        New Horiz. 1996; 4: 370-376
        • Eron L.J.
        • Lipsky B.A.
        • Low D.E.
        • Nathwani D.
        • Tice A.D.
        • Volturo G.A.
        • et al.
        Managing skin and soft tissue infections: expert panel recommendations on key decision points.
        J Antimicrob Chemother. 2003; 52: i3-17
        • Quirke M.
        • Saunders J.
        • O'Sullivan R.
        • Wakai A.
        The management of cellulitis in emergency departments: Antibiotic-prescribing practices and adherence to practice guidelines in Ireland.
        Eur J Emerg Med. 2016; 23: 173-178
        • Nathwani D.
        • Eckmann C.
        • Lawson W.
        • Stephens J.M.
        • Macahilig C.
        • Solem C.T.
        • et al.
        Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections.
        Clin Microbiol and Infec. 2014; 20: 993-1000
        • Walsh T.L.
        • Chan L.
        • Konopka C.I.
        • Burkitt M.J.
        • Moffa M.A.
        • Bremmer D.N.
        • et al.
        Appropriateness of antibiotic management of uncomplicated skin and soft tissue infections in hospitalized adult patients.
        BMC Infect Dis. 2016; 16: 721
        • Kwak Y.G.
        • Choi S.H.
        • Kim T.
        • Park S.Y.
        • Seo S.H.
        • Kim M.B.
        • et al.
        Clinical Guidelines for the Antibiotic Treatment for Community-Acquired Skin and Soft Tissue Infection.
        Infect Chemother. 2017; 49: 301-325
        • Clinical Resource Efficiency Support Team
        Guidelines on the management of cellulitis in adults.
        CREST, Belfast2005
        • National Institute for Health and Care Excellence and Public Health England
        Summary of antimicrobial prescribing guidance - managing common infections.
        PHE, London2019
        • Brindle R.
        • Williams O.M.
        • Barton E.
        • Featherstone P.
        Assessment of Antibiotic Treatment of Cellulitis and Erysipelas: A Systematic Review and Meta-analysis.
        JAMA Dermatol. 2019;
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • Mulrow C.
        • Gotzsche P.C.
        • Ioannidis J.P.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339: b2700
        • Viera A.J.
        • Garrett J.M.
        Understanding interobserver agreement: the kappa statistic.
        Fam Med. 2005; 37: 360-363
        • Higgins J.P.T.
        • Altman D.G.
        • Sterne J.A.C.
        Chapter 8: Assessing risk of bias in included studies.
        in: Higgins J.P.T. Green S. Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, London2011 (Version 5.1.0)
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        J Clin Epidemiol. 2008; 61: 344-349
        • Schünemann
        Schünemann H.B.J. Guyatt G. Oxman A. GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. The GRADE Working Group, 2013 (Updated in 2013)
        • Review Manager (RevMan)
        [Computer program]. Version 5.3.
        The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen2014
        • Aboltins C.A.
        • Hutchinson A.F.
        • Sinnappu R.N.
        • Cresp D.
        • Risteski C.
        • Kathirgamanathan R.
        • et al.
        Oral versus parenteral antimicrobials for the treatment of cellulitis: a randomized non-inferiority trial.
        J Antimicrob Chemother. 2015; 70: 581-586
        • Bernard P.
        • Plantin P.
        • Roger H.
        • Sassolas B.
        • Villaret E.
        • Legrain V.
        • et al.
        Roxithromycin versus penicillin in the treatment of erysipelas in adults: a comparative study.
        Br J Dermatol. 1992; 127: 155-159
        • Bernard P.
        • Chosidow O.
        • Vaillant L.
        • French Erysipelas Study G
        Oral pristinamycin versus standard penicillin regimen to treat erysipelas in adults: randomised, non-inferiority, open trial.
        BMJ. 2002; 325: 864
        • Thomas M.G.
        Oral Clindamycin Compared With Sequential Intravenous and Oral Flucloxacillin in the Treatment of Cellulitis in Adults.
        Infect Dis Clin Prac. 2014;
        • Jorup-Ronstrom C.
        • Britton S.
        • Gavlevik A.
        • Gunnarsson K.
        • Redman AC.
        The course, costs and complications of oral versus intravenous penicillin therapy of erysipelas.
        Infection. 1984; 12: 390-394
        • Clarke M.C.
        • Cheng A.C.
        • Pollard J.G.
        • Birch M.
        • Cowan R.U.
        • Linke J.A.
        • et al.
        Lessons Learned From a Randomized Controlled Trial of Short-Course Intravenous Antibiotic Therapy for Erysipelas and Cellulitis of the Lower Limb (Switch Trial).
        Open Forum Infect Dis. 2019; 6 (ofz335)
        • Daniel R.
        Azithromycin, erythromycin and cloxacillin in the treatment of infections of skin and associated soft tissues. European Azithromycin Study Group.
        J Int Med Res. 1991; 19: 433-445
        • Kiani R.
        Double-blind, double-dummy comparison of azithromycin and cephalexin in the treatment of skin and skin structure infections.
        European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 1991; 10: 880-884
        • Hepburn M.J.
        • Dooley D.P.
        • Skidmore P.J.
        • Ellis M.W.
        • Starnes W.F.
        • Hasewinkle W.C.
        Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis.
        Arch Intern Med. 2004; 164: 1669-1674
        • Prokocimer P.
        • De Anda C.
        • Fang E.
        • Mehra P.
        • Das A.
        Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial.
        JAMA. 2013; 309: 559-569
        • Moran G.J.
        • Fang E.
        • Corey G.R.
        • Das A.F.
        • De Anda C.
        • Prokocimer P.
        Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial.
        The Lancet Infectious diseases. 2014; 14: 696-705
        • Lv X.
        • Alder J.
        • Li L.
        • O'Riordan W.
        • Rybak M.J.
        • Ye H.
        • et al.
        Efficacy and Safety of Tedizolid Phosphate versus Linezolid in a Randomized Phase 3 Trial in Patients with Acute Bacterial Skin and Skin Structure Infection.
        Antimicrob Agents Chemother. 2019; 63: e02218-e02252
        • Cranendonk D.R.
        • Opmeer BC.
        • van Agtmael M.A.
        • Branger J.
        • Brinkman K.
        • Hoepelman A.I.M.
        • et al.
        Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomised, double-blind, placebo-controlled, non-inferiority trial.
        CMI. 2019;
        • Rodriguez-Solares A.
        • Pérez-Gutiérrez F.
        • Prosperi J.
        • Milgram E.
        • Martin A.
        A comparative study of the efficacy, safety and tolerance of azithromycin, dicloxacillin and flucloxacillin in the treatment of children with acute skin and skin-structure infections.
        J Antimicrob Chemother [Internet]. 1993; 31: 103-109
        • Montero L.
        A comparative study of the efficacy, safety and tolerability of azithromycin and cefaclor in the treatment of children with acute skin and/or soft tissue infections.
        J Antimicrob Chemother. 1996; 37: 125-131
        • Jenkins T.C.
        • Knepper B.C.
        • Sabel A.L.
        • Sarcone E.E.
        • Long J.A.
        • Haukoos J.S.
        • et al.
        Decreased antibiotic utilization after implementation of a guideline for inpatient cellulitis and cutaneous abscess.
        Arch Intern Med. 2011; 171: 1072-1079
        • Seaton R.A.
        • Bell E.
        • Gourlay Y.
        • Semple L.
        Nurse-led management of uncomplicated cellulitis in the community: Evaluation of a protocol incorporating intravenous ceftriaxone.
        J Antimicrob Chemother. 2005; 55: 764-767
        • Bogner J.R.
        • Kutaiman A.
        • Esguerra-Alcalen M.
        • Heldner S.
        • Arvis P.
        Moxifloxacin in complicated skin and skin structure infections (cSSSIs): A prospective, international, non-interventional, observational study.
        Adv Ther. 2013; 30: 630-643
        • Lipsky B.A.
        • Moran G.J.
        • Napolitano L.M.
        • Vo L.
        • Nicholson S.
        • Kim M.
        A prospective, multicenter, observational study of complicated skin and soft tissue infections in hospitalized patients: clinical characteristics, medical treatment, and outcomes.
        BMC Infect Dis. 2012; 12: 227
        • Morpeth S.C.
        • Chambers S.T.
        • Gallagher K.
        • Frampton C.
        • Pithie A.D.
        Lower limb cellulitis: features associated with length of hospital stay.
        J Infect. 2006; 52: 23-29
        • McNamara D.R.
        • Tleyjeh I.M.
        • Berbari E.F.
        • Lahr B.D.
        • Martinez J.
        • Mirzoyev S.A.
        • et al.
        A predictive model of recurrent lower extremity cellulitis in a population-based cohort.
        Arch Intern Med. 2007; 167: 709-715
        • Gouin S.
        • Chevalier I.
        • Gauthier M.
        • Lamarre V.
        Prospective evaluation of the management of moderate to severe cellulitis with parenteral antibiotics at a paediatric day treatment centre.
        J Paediatr Child Health. 2008; 44: 214-218
        • Ibrahim L.F.
        • Hopper S.M.
        • Connell T.G.
        • Daley A.J.
        • Bryant P.A.
        • Babl F.E.
        Evaluating an admission avoidance pathway for children in the emergency department: Outpatient intravenous antibiotics for moderate/severe cellulitis.
        Emerg Med J. 2017; 34: 780-785
        • Aly A.A.
        • Roberts N.M.
        • Seipol K.S.
        • MacLellan D.G.
        Case survey of management of cellulitis in a tertiary teaching hospital.
        Med J Aust. 1996; 165: 553-556
        • Kam A.J.
        • Leal J.
        • Freedman S.B.
        Pediatric cellulitis: Success of emergency department short-course intravenous antibiotics.
        Pediatr Emerg Care. 2010; 26: 171-176
        • Collazos J.
        • de la Fuente B.
        • Garcia A.
        • Gomez H.
        • Menendez C.
        • Enriquez H.
        • et al.
        Cellulitis in adult patients: A large, multicenter, observational, prospective study of 606 episodes and analysis of the factors related to the response to treatment.
        PLoS One. 2018; 13e0204036
        • LeFrock J.L.
        • Johnson E.S.
        • Smith L.G.
        • Rosenberg E.
        Noncomparative trial of ticarcillin plus clavulanic acid in skin and soft tissue infections.
        Am J Med. 1985; 79: 122-125
        • Carratala J.
        • Roson B.
        • Fernandez-Sabe N.
        • Shaw E.
        • del Rio O.
        • Rivera A.
        • et al.
        Factors associated with complications and mortality in adult patients hospitalized for infectious cellulitis.
        European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 2003; 22: 151-157
        • Davies M.S.
        • Robertson M.B.
        • Brown S.H.A.
        • Saunders B.
        • Waring W.S.
        Variability of antimicrobial prescribing in patients with acute cellulitis.
        Eur J Clin Pharmacol. 2012; 68: 1303-1307
        • Figtree M.
        • Konecny P.
        • Jennings Z.
        • Goh C.
        • Krilis S.A.
        • Miyakis S.
        Risk stratification and outcome of cellulitis admitted to hospital.
        J Infect. 2010; 60: 431-439
        • Jenkins T.C.
        • Sabel A.L.
        • Sarcone E.E.
        • Price C.S.
        • Mehler P.S.
        • Burman W.J.
        Skin and soft-tissue infections requiring hospitalization at an academic medical center: opportunities for antimicrobial stewardship.
        Clin Infect Dis. 2010; 51: 895-903
        • Lazzarini L.
        • Conti E.
        • Tositti G.
        • de Lalla F.
        Erysipelas and cellulitis: Clinical and microbiological spectrum in an Italian tertiary care hospital.
        J Infect. 2005; 51: 383-389
        • Lee C.Y.
        • Tsai H.C.
        • Kunin C.M.
        • Lee S.S.J.
        • Chen Y.S.
        Clinical and microbiological characteristics of purulent and non-purulent cellulitis in hospitalized Taiwanese adults in the era of community-associated methicillin-resistant Staphylococcus aureus.
        BMC Infect Dis. 2015; 15
        • Solomon M.
        • Barzilai A.
        • Elphasy H.
        • Trau H.
        • Baum S.
        Corticosteroid therapy in combination with antibiotics for erysipelas.
        Isr Med Assoc J. 2018; 20: 137-140
        • Vanlangen K.M.
        • Dumkow L.E.
        • Axford K.L.
        • Havlichek D.H.
        • Baker J.J.
        • Drobish I.C.
        • et al.
        Evaluation of a multifaceted approach to antimicrobial stewardship education methods for medical residents.
        Infect Control Hosp Epidemiol. 2019; 40: 1236-1241
        • Moore S.J.
        • O'Leary S.T.
        • Caldwell B.
        • Knepper B.C.
        • Pawlowski S.W.
        • Burman W.J.
        • et al.
        Clinical characteristics and antibiotic utilization in pediatric patients hospitalized with acute bacterial skin and skin structure infection.
        Pediatr Infect Dis J. 2014; 33: 825-828
        • Leder K.
        • Turnidge J.D.
        • Grayson M.L.
        Home-based treatment of cellulitis with twice-daily cefazolin.
        Med J Aust. 1998; 169: 519-522
        • Ong B.S.
        • Ngian V.J.J.
        • Yeong C.
        • Keighley C.
        Out Of Hospital And In Hospital Management Of Cellulitis Requiring Intravenous Therapy.
        Int J Gen Med. 2019; 12: 447-453
        • Bader M.S.
        • Twells L.
        • Hawboldt J.
        Risk factors of cellulitis treatment failure with once-daily intravenous cefazolin plus oral probenecid.
        South Med J. 2011; 104: 789-793
        • Chan M.
        • Ooi C.K.
        • Wong J.
        • Zhong L.
        • Lye D.
        Role of outpatient parenteral antibiotic therapy in the treatment of community acquired skin and soft tissue infections in Singapore.
        BMC Infect Dis. 2017; 17: 474
        • Donald M.
        • Marlow N.
        • Swinburn E.
        • Wu M.
        Emergency department management of home intravenous antibiotic therapy for cellulitis.
        Emergency medicine journal: EMJ. 2005; 22: 715-717
        • Hurley H.J.
        • Knepper B.C.
        • Price C.S.
        • Mehler P.S.
        • Burman W.J.
        • Jenkins T.C.
        Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.
        Am J Med. 2013; 126: 1099-1106
        • Landry D.
        • Eltonsy S.
        • Jalbert L.P.
        • Girouard G.
        • Couture J.
        • Belanger M.
        Continuous cefazolin infusion versus cefazolin plus probenecid for the ambulatory treatment of uncomplicated cellulitis: A retrospective cohort study.
        Pharmacoepidemiol Drug Saf. 2019; 28: 129
        • Lillie P.J.
        • Andrews D.
        • Eaves K.
        • Darton T.C.
        • Chapman A.L.
        Baseline factors predicting the duration of intravenous antibiotic therapy for cellulitis in an outpatient setting.
        European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 2010; 29: 347-349
        • Rentala M.
        • Andrews S.
        • Tiberio A.
        • Alagappan K.
        • Tavdy T.
        • Sheppard P.
        • et al.
        Intravenous Home Infusion Therapy Instituted from a 24-Hour Clinical Decision Unit for Patients with Cellulitis.
        Am J Emerg Med. 2016; 34: 1273-1275
        • Ibrahim L.F.
        • Hopper S.M.
        • Babl F.E.
        • Bryant P.A.
        Who can have parenteral antibiotics at home? A prospective observational study in children with moderate/severe cellulitis.
        Pediatr Infect Dis J. 2016; 35: 269-274
        • Zhang J.
        • Moore E.
        • Bousfield R.
        OPAT for cellulitis: its benefits and the factors that predispose to longer treatment.
        European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 2016; 35: 1013-1015
        • Smith E.
        • Patel M.
        • Thomas K.S.
        Which outcomes are reported in cellulitis trials? Results of a review of outcomes included in cellulitis trials and a patient priority setting survey.
        Br J Dermatol. 2018; 178: 1028-1034
        • Hirschmann J.V.
        • Raugi G.J.
        Lower limb cellulitis and its mimics: part I. Lower limb cellulitis.
        J Am Acad Dermatol. 2012; 67 (163 e1-12; quiz 75-6)
        • Levell N.J.
        • Wingfield C.G.
        • Garioch J.J.
        Severe lower limb cellulitis is best diagnosed by dermatologists and managed with shared care between primary and secondary care.
        Br J Dermatol. 2011; 164: 1326-1328
        • Weng Q.Y.
        • Raff A.B.
        • Cohen J.M.
        • Gunasekera N.
        • Okhovat J.P.
        • Vedak P.
        • et al.
        Costs and Consequences Associated With Misdiagnosed Lower Extremity Cellulitis.
        JAMA Dermatol. 2017; 153: 141-146
        • Schweitzer V.A.
        • van Heijl I.
        • van Werkhoven C.H.
        • Islam J.
        • Hendriks-Spoor K.D.
        • Bielicki J.
        • et al.
        The quality of studies evaluating antimicrobial stewardship interventions: a systematic review.
        Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2019; 25: 555-561
        • Seide S.E.
        • Rover C.
        • Friede T.
        Likelihood-based random-effects meta-analysis with few studies: empirical and simulation studies.
        BMC Med Res Methodol. 2019; 19: 16
        • Sanderson S.
        • Tatt I.D.
        • Higgins J.P.
        Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography.
        Int J Epidemiol. 2007; 36: 666-676
        • Snodgrass W.R.
        • Anderson T.
        Prontosil in Erysipelas: a controlled series of 312 cases.
        Bmj. 1937; 2: 101-104
        • Snodgrass W.R.
        • Anderson T.
        Sulphanilamide in the Treatment of Erysipelas.
        Br Med J. 1937; 2: 1156-1159