Research

JAMA Dermatology | Original Investigation

Assessment of Antibiotic Treatment of Cellulitis and Erysipelas

A Systematic Review and Meta-analysis
Richard Brindle, DM, FRCP; O. Martin Williams, PhD, FRCP, FRCPath; Edward Barton, BM, FRCPath;
Peter Featherstone, MPhil, FRCP

Supplemental content
IMPORTANCE The optimum antibiotic treatment for cellulitis and erysipelas lacks consensus. CME Quiz at
The available trial data do not demonstrate the superiority of any agent, and data are limited jamanetwork.com/learning
on the most appropriate route of administration or duration of therapy. and CME Questions page 1095

OBJECTIVE To assess the efficacy and safety of antibiotic therapy for non–surgically
acquired cellulitis.

DATA SOURCES The following databases were searched to June 28, 2016: Cochrane Central
Register of Controlled Trials (2016, issue 5), Medline (from 1946), Embase (from 1974), and
Latin American and Caribbean Health Sciences Information System (LILACS) (from 1982). In
addition, 5 trials databases and the reference lists of included studies were searched.
Further searches of PubMed and Google Scholar were undertaken from June 28, 2016, to
December 31, 2018.

STUDY SELECTION Randomized clinical trials comparing different antibiotics, routes of

administration, and treatment durations were included.

DATA EXTRACTION AND SYNTHESIS For data collection and analysis, the standard
methodological procedures of the Cochrane Collaboration were used. For dichotomous
outcomes, the risk ratio and its 95% CI were calculated. A summary of findings table was
created for the primary end points, adopting the GRADE approach to assess the quality of
the evidence.

MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of patients cured,
improved, recovered, or symptom-free or symptom-reduced at the end of treatment, as
reported by the trial. The secondary outcome was any adverse event.

RESULTS A total of 43 studies with a total of 5999 evaluable participants, whose age ranged
from 1 month to 96 years, were included. Cellulitis was the primary diagnosis in only 15
studies (35%), and in other studies the median (interquartile range) proportion of patients
with cellulitis was 29.7% (22.9%-50.3%). Overall, no evidence was found to support the
superiority of any 1 antibiotic over another, and antibiotics with activity against
methicillin-resistant Staphylococcus aureus did not add an advantage. Use of intravenous
antibiotics over oral antibiotics and treatment duration of longer than 5 days were not
supported by evidence.
Author Affiliations: Author
affiliations are listed at the end of this
CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis, only low-quality article.
evidence was found for the most appropriate agent, route of administration, and duration of Corresponding Authors: Owen
treatment for patients with cellulitis; future trials need to use a standardized set of outcomes, Martin Williams, PhD, FRCP, FRCPath,
Public Health England Microbiology
including severity scoring, dosing, and duration of therapy.
Services Bristol, and University
Hospitals Bristol NHS Foundation
Trust, Bristol Royal Infirmary,
Marlborough Street, Bristol,
United Kingdom, BS2 8HW
(martinx.williams@uhbristol.nhs.uk);
Richard Brindle, DM, FRCP,
Department of Clinical Sciences,
University of Bristol, Bristol,
JAMA Dermatol. 2019;155(9):1033-1040. doi:10.1001/jamadermatol.2019.0884 United Kingdom (richard.brindle@
Published online June 12, 2019. bristol.ac.uk).

(Reprinted) 1033
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 Research Original Investigation
C
ellulitis is a common acute skin infection.1 Published
guidelines for the management of cellulitis2-6 are mostly
based on evidence from studies of skin and soft tissue
infections, which have included cellulitis, or on expert opin-
ion. Despite the published guidance, substantial variations in
the antibiotic management of cellulitis have been identified.7,8
This systematic review and meta-analysis aimed to in-
form the production of evidence-based guidelines that cover
antibiotic choice, route of administration, duration of treat-
ment, the role of combinations of antibiotics, and gaps
in research.
Methods
We searched the following databases until June 28, 2016:
Cochrane Central Register of Controlled Trials (2016, issue 5),
Medline (from 1946), Embase (from 1974), and LILACS
(Latin American and Caribbean Health Sciences Information
System; from 1982). We also searched 5 trial databases and the
reference lists of included studies. Further searches of PubMed
and Google Scholar were undertaken from June 28, 2016, to
December 31, 2018.
We included studies of adults or children with a cellulitis
diagnosis that randomized participants to groups. We used the
term cellulitis to include erysipelas, as the 2 conditions can-
not be readily distinguished. The focus of this review was cel-
lulitis requiring acute therapy with antibiotics rather than
prophylaxis. We considered a randomized clinical trial if a com-
parison was made between different treatment regimens,
including different antibiotics, routes of administration, and
duration of therapy.
The primary outcome of the proportion cured, improved,
recovered, or symptom-free or symptom-reduced at the end
of treatment was commonly reported by patients or medical
practitioners. No standard outcome measure was used be-
cause each trial applied different time points and criteria to
assess patient recovery or improvement. The secondary out-
come was any reported adverse events.
We identified relevant randomized clinical trials pub-
lished in the English language. The databases we searched and
the search strategies we used are detailed in eAppendix 1 in the
Supplement. We checked bibliographies of included studies for
additional relevant trials. We did not perform a separate search
for adverse effects of the target interventions, but we did ex-
amine data on adverse effects in the included studies.
All studies of antibiotic therapy included in the previous
2010 systematic review9 were included in this review. Poten-
tial studies for inclusion were independently reviewed by 2 of
us (R.B. and O.M.W.) against the inclusion criteria. If both of
us agreed that the study was not relevant to the objectives of
this review, the study was excluded. If relevance was unclear
from the abstract, the 2 of us reviewed the full text. Any dis-
agreement between us was resolved by consensus and re-
ferred to a third author (P. F.) if necessary.
Among the information we recorded from each study was
the population description, interventions, treatment dura-
tion, number of participants randomized into each treatment
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Antibiotic Treatment of Cellulitis and Erysipelas
Key Points
Question What is the most appropriate antibiotic choice, route
of administration, and duration of treatment for cellulitis?
Findings In this systematic review of 43 studies that included
5999 participants, no evidence was found to support the
superiority of any 1 antibiotic over another and the use of
intravenous over oral antibiotics; short treatment courses (5 days)
appear to be as effective as longer treatment courses.
Meaning In light of low-quality evidence found for the most
appropriate agent, route of administration, and duration of
treatment for patients with cellulitis, additional research is
required to define the optimum management of cellulitis.
group, number of participants who were cured or did not re-
spond to treatment, number of participants lost to follow-up,
and duration of follow-up. For all potential studies, 2 of us (R.B.
and O.M.W.) independently extracted and analyzed the data,
and 1 (R.B.) entered the data into RevMan, version 5.3 (Nordic
Cochrane Centre).10
Six types of bias were assessed11: selection, performance,
detection, attrition, reporting, and other bias (eAppendix 2 in
the Supplement). We followed the recommendations of the
Cochrane Handbook for Systematic Reviews of Interventions12
and categorized each included study as having high, low, or
unclear risk of bias.
Statistical Analysis
For studies in which similar types of interventions were com-
pared, we performed a meta-analysis to calculate a weighted
treatment effect across trials. A Mantel-Haenszel fixed-
effects model was used to calculate a treatment effect when
heterogeneity was low and the advantages of small studies
would be overestimated by the random-effects analysis.
Because the number of included studies was low, we inter-
preted I2 values of 50% or greater as representing substantial
heterogeneity and applied a random-effects model. The
results are expressed as risk ratios (RRs) with 95% CIs for di-
chotomous outcomes.
We assessed the reporting of withdrawals, dropouts, and
protocol deviations as well as whether participants were ana-
lyzed in the group to which they were originally randomized
(intention-to-treat population).
Results
The study selection process is summarized in Figure 1. A sum-
mary of findings, using the GRADE approach13 to assess the qual-
ity of evidence, is included in eTable 1 in the Supplement.
Of the 41 studies included, 2 consisted of 2 sets of com-
parisons and were then treated as separate studies (Bucko et al
200214 and Daniel 199115), increasing the number of studies
to 43. One study was treated as 2 and thus is presented as 2
papers (Corey et al 201016 and Wilcox et al 201017).
The 43 studies included 5999 evaluable participants,
whose age ranged from 1 month to 96 years. Details of the stud-
ies are summarized in eTable 2 in the Supplement. Cellulitis
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 Antibiotic Treatment of Cellulitis and Erysipelas
Figure 1. Flowchart of Article Selection
21 Full-text articles included 908 Records identified through
in 2010 review database search
926 Records screened
147 Full-text articles assessed
for eligibility
19 Studies included in qualitative
synthesis
1 Study added
43 Studies included in meta-analysis
was the primary diagnosis in only 15 studies (35%), and in other
studies the proportion of patients with cellulitis ranged from
8.9%18 to 90.9%,19 with a median (interquartile range) of 29.7%
(22.9%-50.3%).
Most studies compared different antibiotics or treatment du-
rations. No studies compared antibiotics with placebos. For most
studies, the duration was allowed to vary, depending on clini-
cal need. Some trials had different durations but not with the
same antibiotic. Because of the wide range of antibiotics used,
we could not analyze variations in antibiotic doses and outcomes.
Because every study reported outcomes in different ways,
we accepted the proportion cured as equivalent to the propor-
tion with improved or reduced symptoms. The criteria for de-
termining improvement and the time points for assessment of
cure or improvement varied widely. The quality of follow-up
ranged from the assessment of all participants to the assump-
tion that cure had occurred unless the participant returned.
The reason for the exclusion of most trials was they did not
present results for the population with cellulitis, they were
quasi–randomized clinical trials,20 or they had no obvious ran-
domization process.21,22 The type of risk of bias for each study
is shown in Figure 2 and eAppendix 2 in the Supplement.
Effects of Interventions
Penicillin vs Cephalosporins
Three studies23-25 (n = 86) compared a penicillin with a cepha-
losporin. In 2 studies,23,24 intravenous (IV) ampicillin and sul-
bactam was compared with IV cefazolin, and a third study25 com-
pared IV ceftriaxone with IV flucloxacillin. We found no differ-
ence between the 2 treatments. This outcome had high levels of
heterogeneity (RR = 0.98; 95% CI, 0.68-1.42; I2 = 70%) (eFigure 1.1
in the Supplement). Two studies reported on adverse events.23,25
No difference was found between the groups (RR = 0.48; 95%
CI, 0.14-1.69; n = 68) (eFigure 1.2 in the Supplement).
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Original Investigation Research
18 Records identified through
other sources
779 Records discarded
25 Full-text articles discarded
103 Full-text articles excluded
Of the original 21 articles, 2 were
treated as 2 separate studies and thus
are presented as 2 for the total of 43.
Older vs Newer Cephalosporins
We identified 6 studies14,18,19,26,27 (n = 527) that were orga-
nized into 4 subgroups. No single cephalosporin was
accepted as a standard for comparison. We defined the
newer cephalosporin as cephalosporin A and the older as
cephalosporin B. We found no difference between the 2
treatments (RR = 1.02; 95% CI, 0.96-1.09) (eFigure 2.1 in the
Supplement). Only 1 study 26 reported data for adverse
events for the cellulitis subgroup; the cefazolin-probenecid
group experienced more adverse events compared with the
IV ceftriaxone group (21% vs 10%), but this was not statisti-
cally different (RR = 0.50; 95% CI, 0.22-1.16; n = 134) (eFig-
ure 2.2 in the Supplement).
β-lactam vs Macrolide, Lincosamide, or Streptogramin
Two studies28,29 compared IV benzylpenicillin with an oral
macrolide (roxithromycin) and a streptogramin (pristinamy-
cin). Participants in both studies had uncomplicated erysip-
elas, presumed streptococcal, and were therefore penicillin
sensitive. Another study compared oral cloxacillin with
azithromycin,15 and a community study30 compared oral
flucloxacillin with oral erythromycin. A small study, which
included participants with cellulitis, compared cefalexin
with azithromycin.31
A further study compared oral clindamycin with
sequential IV and oral flucloxacillin.32 In total, 6 studies
(n = 596) were found. We found no difference between the 2
treatments (RR = 0.94; 95% CI, 0.85-1.04; I2 = 44%) (eFig-
ure 3.1 in the Supplement). This has been independently
published,33 including more studies but with similar find-
ings. Three studies reported adverse events.28,29,32 No sig-
nificant differences were observed between the groups
(RR = 0.70; 95% CI, 0.45-1.08; n = 397) (eFigure 3.2 in the
Supplement).
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 Research Original Investigation Antibiotic Treatment of Cellulitis and Erysipelas

Quinolone or Vancomycin vs Other Antibiotic

Figure 2. Type of Risk of Bias for Each Study
We found 3 studies (n = 160) comparing a quinolone with other
antibiotics: 1 compared a novel fluoroquinolone with

Random Sequence Generation

linezolid,34 1 compared moxifloxacin with a penicillin/beta-

Incomplete Outcome Data

Allocation Concealment
lactamase inhibitor combination,35 and 1 compared delafloxa-

Selective Reporting
cin with tigecycline.36 We found no difference between the
treatments (RR = 1.04; 95% CI, 0.94-1.16) (eFigure 4.1 in the

Other Bias
Supplement). Data on adverse events could not be extracted.

Blinding
We identified 10 studies (n = 2275), organized into 3 sub-
Study
Aboltins et al,58 2015 + + – + + +
groups comparing vancomycin with other antibiotics. We
Baig et al,30 1988 ? ? – + + ? found no difference between the 2 treatments (RR = 1.00; 95%
Bernard et al,29 1992 ? ? – + + ? CI, 0.98-1.02) (eFigure 5.1 in the Supplement).
Bernard et al,28 2002 + ? – + + ?
Boucher et al,37 2014 + + + + + ? Vancomycin Plus Gram-Positive, Plus Gram-Negative, or Alone
Brindle et al,53 2017 + + + + + + vs Other Antibiotic
Bucko et al,14 (1+2) 2002 + + + + + ?
One study37 (n = 625) compared vancomycin followed by oral li-
Chan,23 1995 ? ? + + + ?
nezolid with dalbavancin. No difference was observed between
Corey et al,16 2010 + + + + + ?
vancomycin alone or in combination and other antibiotics
Corey et al,38 2015 + + ? + + ?
Covington et al,34 2011 + + + + + ?
(RR = 0.99; 95% CI, 0.94-1.04) (eFigure 5.1.1 in the Supplement).
Daniel,15 (1) 1991 ? ? – – + ? Four studies (n = 853) compared vancomycin combined
Daniel,15 (2) 1991 ? ? – – ? ? with a gram-negative antibiotic: vancomycin with oritavan-
DiMattia et al,50 1981 + ? – – + ? cin (aztreonam allowed in both arms),38 vancomycin plus aztre-
Fabian et al,51 2005 + + + + + ? onam with ceftaroline fosamil,16,17 and vancomycin plus cefta-
Giordano et al,35 2005 ? ? + – + ? zidime with ceftobiprole medocaril.39 No difference was found
Grayson et al,26 2002 + + + + + +
between vancomycin alone or in combination and other
Hepburn et al,57 2004 + + ? – + ?
antibiotics (RR = 1.00; 95% CI, 0.96-1.05) (eFigure 5.1.2 in the
Iannini et al,27 1985 ? ? – – + ?
Supplement).
Kauf et al,40 2015 + ? – + + ?
Kiani,31 1991 ? ? + – + ?
We found 5 trials (n = 797) that compared vancomycin
Leman et al,52 2005 + + ? ? ? ? alone with other antibiotics: daptomycin,40,41 ceftobiprole,42
Miller et al,47 2015 + + + + + + a new pleuromutilin,43 and linezolid.44 We found no evi-
Moran et al,45 2014 + + + + ? ? dence of a difference between the 2 treatments (RR = 1.00; 95%
Moran et al,49 2017 + ? + + ? + CI, 0.97-1.03) (eFigure 5.1.3 in the Supplement).
Noel et al,42 2008 + + + ? ? ? The only study (n = 101) with cellulitis-specific adverse
Noel et al,39 2008 + ? + ? ? ?
events41 did not demonstrate a difference between the 2 treat-
O'Riordan et al,36 2015 + + + + + ?
ments (RR = 1.02; 95% CI, 0.42-2.51) (eFigure 5.2 in the Supple-
Pallin et al,48 2013 + + + ? + +
ment).
Pertel et al,41 2009 + ? – + + ?
Prince et al,43 2013 ? ? ? ? ? ?
Prokocimer et al,46 2013 + + + + + ? Linezolid vs Other Antibiotic
Rao et al,54 1985 + + – ? ? ? Four studies (n = 1024) compared linezolid with a variety of
Sachs and Pilgrim,24 1990 + ? – – ? ? other antibiotics: a novel fluoroquinolone, 34 tedizolid
Schwartz et al,19 1996 ? ? – – ? ? phosphate,45,46 and vancomycin.44 No difference was ob-
Tack et al,18 1998 ? ? + – ? ? served between linezolid and other antibiotics (RR = 1.00; 95%
Tarshis et al,55 2001 + + + – ? ?
CI, 0.95-1.05) (eFigure 6.1 in the Supplement). Data on
Thomas,32 2014 + + + ? ? +
adverse events could not be extracted.
Vinen et al,25 1996 ? ? – – ? ?
Weigelt et al,44 2005 ? ? – + ? ?
Wilcox et al,17 2010 + ? ? ? + ? Clindamycin vs Trimethoprim Sulfamethoxazole
Zeglaoui et al,56 2004 + + +– + ? ? One study47 (n = 248) compared clindamycin with trimethoprim-
sulfamethoxazole. This study was of uncomplicated skin infec-
Random sequence generation and allocation concealment are selection biases. tions and included participants with cellulitis in an area of high
Blinding is categorized as a performance bias and a detection bias. Incomplete community prevalence of methicillin-resistant Staphylococcus
outcome data are an attrition bias, and selective reporting is a reporting bias. aureus (MRSA). No difference was found between clindamycin
Black positive indicates low risk of bias; blue question mark, unclear risk of bias;
and orange negative, high risk of bias. Bucko et al14 (1 + 2) is a single study and trimethoprim-sulfamethoxazole (RR = 1.05; 95% CI, 0.96-
regarded in the analysis as 2 studies because the risk of bias for both arms is the 1.15) (eFigure 7.1 in the Supplement). Data on adverse events
same. Daniel15 (1) and (2) is also 1 study regarded as 2 separate studies because could not be extracted.
the risk of bias for the separate arms is different.

MRSA-Active vs Non–MRSA-Active Antibiotics

Two studies48,49 (n = 557) examined whether the addition of
antibiotics active against MRSA affected outcome. The MRSA-

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 Antibiotic Treatment of Cellulitis and Erysipelas
active arm (cephalosporin plus trimethoprim-sulfamethoxa-
zole) was compared with cephalosporin plus placebo. There
was no difference between MRSA-active and non–MRSA-
active antibiotics (RR = 0.99; 95% CI, 0.92-1.06) (eFigure 8.1
in the Supplement). One study49 actively excluded patients
with purulent cellulitis, whereas another48 included those with
pustules less than 3 mm in maximal diameter. Although their
numbers were small (n = 19), purulent cellulitis was not a fac-
tor in response to therapy.48 Both studies included data on ad-
verse events. We found no difference between the 2 treat-
ments (RR = 1.03; 95% CI, 0.92-1.14; n = 642) (eFigure 8.2 in
the Supplement).
Other Studies Not Already Included
One study50 (n = 19) compared cefalexin 500 mg twice a day
with 250 mg 4 times a day. No difference was observed be-
tween the groups (RR = 1.00; 95% CI, 0.81-1.23) (eFigure 9.1
in the Supplement).
One study 51 compared meropenem with imipenem-
cilastatin for skin and skin-structure infection. No statisti-
cally significant differences were found within the cellulitis
subgroup (RR = 0.88; 95% CI, 0.68-1.15; n = 81) (eFigure 9.2 in
the Supplement).
One study52 (n = 81) examined the addition of benzylpeni-
cillin to the regimen of those who receive flucloxacillin (tem-
perature, pain, or diameter of infected area were assessed on
days 1 and 2 of treatment). No statistically significant effect on
symptoms (RR = 0.98; 95% CI, 0.87-1.09) (eFigure 9.3 in the
Supplement) was found. No adverse effects were reported in
either arm of the study.
One study53 (n = 410) compared flucloxacillin plus clinda-
mycin with flucloxacillin plus placebo and found no statisti-
cally significant difference between the 2 allocations at day 5
follow-up (RR = 1.07; 95% CI, 0.98-1.18) (eFigure 9.4.1 in the
Supplement). A statistically significant difference in adverse
events was observed, specifically diarrhea, occurring twice as
frequently in the clindamycin group (RR = 1.87; 95% CI, 1.23-
2.86; P = .004) (eFigure 9.4.2 in the Supplement).
One study54 (n = 18) compared ticarcillin and clavulanic
acid with moxalactam. No difference between the groups was
found (RR = 1.00; 95% CI, 0.82-1.22) (eFigure 9.5 in the Supple-
ment).
One study55 compared oral gatifloxacin with oral levo-
floxacin as part of a skin and skin-structure infection trial.
A small but statistically significant difference was found, fa-
voring gatifloxacin (RR = 1.17; 95% CI, 1.01-1.35; n = 82; P = .03;
low-quality evidence) (eFigure 9.6 in the Supplement).
One study56 (n = 112) compared IV benzylpenicillin with
intramuscular penicillin (benzylpenicillin and procaine peni-
cillin) for 10 days. No difference in outcome was observed
(RR = 0.93; 95% CI, 0.79-1.10) (eFigure 9.7.1 in the Supple-
ment), but more adverse events occurred in the IV group
(RR = 7.25; 95% CI, 1.73-30.45; P = .007) (eFigure 9.7.2 in the
Supplement).
Shorter vs Longer Courses of Antibiotics
We identified 5 studies (n = 916) that compared a shorter with
a longer duration of treatment. Only 1 study57 compared the
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Original Investigation Research
duration for the same antibiotic. One study38 compared a single
dose of oritavancin, a glycopeptide with a long half-life, with 7
to 10 days of vancomycin. The 2 studies by Daniel15 compared
5 days of azithromycin with 7 days of either cloxacillin or eryth-
romycin. One study57 compared 5 days of oral levofloxacin with
a 10-day regimen. Another study45 compared 6 days of tedi-
zolid with 10 days of linezolid. No difference was found be-
tween short and long antibiotic courses (RR = 0.99; 95% CI, 0.94-
1.04) (eFigure 10.1 in the Supplement). Only 1 study57 (n = 87)
reported adverse events that led to participant withdrawal,
which was not statistically significant (RR = 0.33; 95% CI, 0.01-
7.79) (eFigure 10.2 in the Supplement).
Intravenous vs Oral Antibiotics
We identified 4 studies (n = 550), although the only study58
designed specifically to compare oral with IV antibiotics was
small (n = 47) and showed no statistical difference in out-
comes. Two studies (n = 357) investigated an oral macrolide28
or an oral streptogramin29 against IV benzylpenicillin. The oral
agents were shown to be more effective than the IV benzyl-
penicillin. Pallin et al48 included data on route of administra-
tion, although the study was not designed to examine
this route.
For this outcome, we found low-quality evidence that IV
administration was inferior compared with oral administra-
tion (RR = 0.83; 95% CI, 0.75-0.93; P < .001) (eFigure 11.1 in the
Supplement). Although more adverse events occurred in the
oral administration group, no statistically significant differ-
ence was observed between the groups (RR = 1.11; 95% CI, 0.73-
1.68; n = 549; I2 = 46%) (eFigure 11.2 in the Supplement).
Discussion
From the data presented, defining the most effective antibi-
otic treatment for cellulitis was not possible, given that no
1 antibiotic was superior over another. The use of a cephalo-
sporin rather than a penicillin was not supported despite trials
that showed equivalence.23-25,54 Similarly, glycopeptide,37,38
oxazolidinone,44 and daptomycin41 did not show superiority
to the other antibiotics. The use of combination therapy was
not supported, as the trials with combination therapy did not
demonstrate better outcomes.48,49,52,53
The use of oral therapy was supported by the limited data
for oral vs IV antibiotics and by trials in which only oral anti-
biotics were used with good outcome. The earliest studies of
antimicrobials for erysipelas administered the drugs orally with
good outcomes.21,22 In this review, when oral antibiotics were
compared with IV treatments, the oral treatments appeared
more effective.28,29,48,58
Identifying the optimum duration of antibiotic therapy was
not possible, with only 1 trial designed to look specifically at
duration,57 but no supporting evidence was found for antibi-
otic therapy longer than 5 days.15 The trial by Hepburn et al57
only randomized to longer treatment at day 5, which did not
clarify whether prolonged antibiotic treatment for those pa-
tients who were slow to improve made any difference to the
rate of improvement or final outcome. An antibiotic with
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 Research Original Investigation Antibiotic Treatment of Cellulitis and Erysipelas

activity against MRSA in cellulitis was investigated in
2 trials.48,49 Neither trial showed the advantage of this antibi-
otic, however, supporting the view that cellulitis is primarily
a streptococcal infection.
Limitations
This study has several limitations. Most of the included stud-
ies lacked consistent, clear, and precise end points for cellu-
litis therapies, making comparison between treatments
difficult.59 Standard end points are needed with which assess-
ment is made and to which subsequent trials should all ad-
here. These end points must be objective (eg, no further swell-
ing, neutrophil level within the normal range) and not
subjective (eg, discharge from hospital, IV to oral switch). Ac-
cording to interviews with participants, the outcomes of in-
terest to them were time to resolution of unpleasant symp-
toms, such as pain,60 yet only 6 studies41,45,48,52,53,58 gave
information on symptom reduction. A more common out-
come was the proportion of patients cured or improved, an as-
sessment often timed at the end of treatment or up to 2 weeks
after treatment and defined as the reduction or absence of the
original signs or symptoms. This timing or definition does not
allow discrimination between treatments, which may affect the
duration of symptoms or the length of hospital stay.
Older studies either did not specify or did not exclude par-
ticipants who had received previous antibiotic therapy and in-
cluded people who did not respond to community treatment.
In contrast, 17 studies excluded participants who had re-
ceived antibiotics before enrollment, although the exclusion
period varied between studies.
Many trials included mixed populations with a range of skin
and skin-structure infections; unless they presented sub-
group data for those with cellulitis, we were unable to in-
clude these studies. The decision to show these data may be
biased, because researchers may prefer to show data for spe-
cific disease groups if the response to the treatments varied.
In most trials, the causative organisms were not isolated.
Many studies with mixed-disease populations reported sub-
group data for causal organisms but not the type of tissue in-
volvement. Isolation rates for causal organisms were gener-
ally low for cellulitis,27,51 rarely higher than 25%. This rate
means that, in some studies, 75% of participants with celluli-
tis would be excluded.
A number of studies did not adequately explain the pro-
cess of allocation concealment or blinding (Figure 2), and only
more recent studies provided sample size calculations. Eleven
studies15,19,24,29-31,40,44,54,58 were described as open, with 5 ad-
ditional studies presumed to be not blinded (their design was
not specified).25,27,28,50,56 This lack of blinding, in combina-
tion with a lack of objective outcome measures, could
increase the risk of bias.11
Implications for Research
In light of the low quality of evidence we identified, addi-
tional research is required to define the optimum manage-
ment of cellulitis. Future clinical trials should only include par-
ticipants with cellulitis and address specific issues associated
with therapy. Trials need to clarify the duration of therapy and
whether longer durations are necessary with more severe dis-
ease. None of the trials included dose comparisons, and the
tendency may be to increase the dose to resolve treatment fail-
ures without testing this hypothesis. Future trials need to
clarify dosing and whether dosing should be based on actual
or ideal body weight.
Randomized clinical trials should be conducted compar-
ing IV with oral antibiotics for participants within a commu-
nity setting; the results of such trials would have implica-
tions for the delivery and cost-effectiveness of home therapy,
minimizing the involvement of home IV services or frequent
outpatient hospital visits. In addition, trials need to have stan-
dardized criteria for severity scoring (eg, Systemic Inflamma-
tory Response Syndrome criteria, renal function, and area of
erythema) to allow the examination of treatment route, dos-
ing, and duration. A standardized set of outcomes needs to be
established for these trials. These outcomes should include sys-
temic features (eg, heart rate, blood pressure) as well as local
(eg, inflammation, swelling), blood (eg, neutrophils, urea), and
patient-focused (eg, nausea, pain, mobility) measures. Trial ex-
clusions (eg, duration of antibiotics prior to trial entry) and
times of follow-up (eg, early, late, and back-to-normal activi-
ties) should be standardized whenever possible.
Conclusions
Current evidence does not support the superiority of any
1 antibiotic over another, and the use of a combination of
antibiotics is not supported by clinical trial data. There is a lack
of evidence favoring the use of intravenous over oral antibi-
otics or for treatment durations longer than 5 days.

ARTICLE INFORMATION
Accepted for Publication: March 22, 2019.
Published Online: June 12, 2019.
doi:10.1001/jamadermatol.2019.0884
Author Affiliations: Department of Clinical
Sciences, University of Bristol, Bristol, United
Kingdom (Brindle); Public Health England
Microbiology Services Bristol, Bristol, United
Kingdom (Williams); University Hospitals Bristol
NHS Foundation Trust, Bristol Royal Infirmary,
Bristol, United Kingdom (Williams); North Cumbria
University Hospitals NHS Trust, Carlisle, United
Kingdom (Barton); Acute Medicine Unit, Queen
Alexandra Hospital, Portsmouth Hospitals,
Portsmouth, United Kingdom (Featherstone).
Author Contributions: Drs Brindle and Williams
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Brindle, Williams,
Featherstone.
Acquisition, analysis, or interpretation of data:
Brindle, Williams, Barton.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Brindle.
Administrative, technical, or material support:
Brindle, Williams, Featherstone.
Supervision: Brindle, Williams.
Conflict of Interest Disclosures: None reported.
Meeting Presentation: The results of this study
were presented at the ASM Microbe 2018, June 8,
2018, Atlanta, Georgia.
Additional Contributions: The authors wish to
thank the Cochrane Skin Group for assistance with
the initial searches. No compensation outside of
usual salary was received.

1038 JAMA Dermatology September 2019 Volume 155, Number 9 (Reprinted) jamadermatology.com

© 2019 American Medical Association. All rights reserved.

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 Antibiotic Treatment of Cellulitis and Erysipelas
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