Clinical Microbiology and Infection 23 (2017) 242e246

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Clinical Microbiology and Infection

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Original article

A double-blind randomized controlled trial of ibuprofen compared to

placebo for uncomplicated cellulitis of the upper or lower limb
J.S. Davis 1, 2, *, C. Mackrow 3, P. Binks 1, W. Fletcher 3, P. Dettwiller 4, C. Marshall 3, J. Day 5,
W. Pratt 5, S.Y.C. Tong 1, 6
1)
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
2)
Department of Infectious Diseases, John Hunter Hospital and the University of Newcastle, Newcastle, New South Wales, Australia
3)
Hospital in the Home Program, Royal Darwin Hospital, Darwin, Northern Territory, Australia
4)
Katherine Rural Clinical School, Flinders University, Katherine, Northern Territory, Australia
5)
Hospital in the Home Program, Shoalhaven Hospital, Nowra, New South Wales, Australia
6)
Victorian Infectious Diseases Service, The Royal Melbourne Hospital, and the University of Melbourne, at the Peter Doherty Institute for Infection and
Immunity, Melbourne, Victoria, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Cellulitis is a common skin infection resulting in inflammation that may take weeks to
Received 17 November 2016 resolve despite appropriate antibiotics. It is unclear whether the adjunctive use of nonsteroidal anti-
Received in revised form inflammatory drugs hastens the resolution of inflammation in patients with cellulitis.
26 February 2017
Methods: We conducted a double-blind, randomized controlled trial comparing ibuprofen 400 mg three
Accepted 28 February 2017
Available online 6 March 2017
times daily for 5 days with identical placebo in adults with uncomplicated cellulitis of the upper or lower
limb who were treated with intravenous cefazolin via an outpatient parenteral antibiotic treatment
Editor: L. Leibovici service at one of two Australian hospitals. Participants were assessed twice daily by a study nurse. The
primary outcome measure was the proportion of patients with regression of inflammation 48 hours after
Keywords: the first effective dose of parenteral antibiotics (trial registration ANZCTR 12611000515998).
Cellulitis Results: Fifty-one patients were enrolled; 48 had sufficient data available to be included in the modified
Ibuprofen intention-to-treat analysis. Inflammation had begun to regress at 48 hours in 20 participants (80%) in the
Randomized ibuprofen group compared to 15 (65%) in the placebo group (absolute risk difference þ15%; 95% confi-
dence interval 10 to þ40; p >0.05). There was no significant difference in any secondary outcome.
Ibuprofen appeared safe, with no patients developing renal impairment or necrotizing fasciitis.
Conclusions: This trial demonstrated no significant benefit of adjunctive ibuprofen in adults with un-
complicated cellulitis. The trial was powered to detect a large effect, and hence it is unclear whether the
15% absolute increase in the primary end point in the ibuprofen group was attributable to chance.
J.S. Davis, Clin Microbiol Infect 2017;23:242
© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction
Cellulitis is a common, painful and disabling condition, with an
estimated 14.5 million cases annually and $3.7 billion of ambula-
tory care costs annually in the United States alone [1]. The current
standard treatment of cellulitis is antibiotics to kill the responsible
bacteria [2]. This treatment is usually successful; however, most
* Corresponding author. J.S. Davis, Menzies School of Health Research, Rocklands
Drive, Tiwi, Northern Territory 0811, Australia.
E-mail address: Joshua.Davis@menzies.edu.au (J.S. Davis).
people require antibiotic treatment, rest and time off work for 10 to
14 days [3]. The majority of cases of cellulitis are caused by group A
Streptococcus and Staphylococcus aureus [4,5]. Intravenous antibi-
otics usually result in rapid bacterial killing over the first 24 to
48 hours, and ongoing signs of inflammation are likely to be due to
the patient’s inflammatory response to bacterial exotoxins rather
than the infection itself [6,7]. Hence, adjunctive treatment with
anti-inflammatory drugs may hasten the resolution of cellulitis.
A single unblinded small pseudo-randomized trial (alternating
allocation of ibuprofen or not) as adjunctive therapy has previously
shown that patients receiving ibuprofen had substantially more
rapid regression of cellulitis than those receiving antibiotics alone,

http://dx.doi.org/10.1016/j.cmi.2017.02.036
1198-743X/© 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
 J.S. Davis et al. / Clinical Microbiology and Infection 23 (2017) 242e246
with no increase in adverse effects [8]. Despite the dramatic results
of this study, it has never been reproduced, and this treatment has
not become the standard of care. Another trial has shown more
rapid recovery of patients with erysipelas (a similar condition to
cellulitis) who were treated with prednisolone [7].
In this randomized controlled trial, we aimed to answer the
following question: in adult outpatients with uncomplicated upper
or lower limb cellulitis that requires intravenous antibiotics, does
the addition of ibuprofen, 400 mg orally three times daily, for 5 days
to standard therapy lead to a more rapid resolution of inflammation
than does an identical oral placebo?
Methods
Trial design and participants
Between June 2011 and June 2015, we conducted a double-blind,
placebo-controlled, parallel group, 1:1, two-arm, investigator-
initiated randomized trial at two public hospitals in Australia. It was
known as the CHARIOT (Cellulitis: HAstening Resolution with
IbuprOfen Therapy) study. Participants were recruited from those
admitted to the outpatient parenteral antibiotic service of Royal
Darwin Hospital or Shoalhaven Base Hospital, Australia. Inclusion
criteria were as follows: cellulitis or erysipelas of the upper or lower
limb (defined as diagnosed by an infectious diseases specialist or
fellow); age 18 to 80 years; receiving intravenous cefazolin; and
commenced effective parenteral antibiotics <24 hours before
randomization. Exclusion criteria were as follows: complicated
cellulitis (defined as any of the following: abscess requiring surgical
intervention; postoperative wound infection; coexisting deep
venous thrombosis; necrotizing fasciitis; cellulitis extended prox-
imal to the inguinal ligament or acromion); previous allergy to or
intolerance of nonsteroidal anti-inflammatory drugs (NSAIDs);
acute (serum creatinine >120 mmol/L at the time of randomization
with no history of chronic renal disease) or chronic (estimated
glomerular filtration rate <50 mL/min for at least 3 months) renal
impairment; peptic ulcer disease; pregnancy; chicken pox or
shingles; taking regular NSAIDs or corticosteroids which cannot be
ceased or substituted; and taking therapeutic anticoagulant drugs.
Because all patients required admission to an outpatient parenteral
antibiotic service for intravenous antibiotics (as opposed to being
treated at entirely home with oral antibiotics), all patients were
considered to have moderate to severe cellulitis.
This study was registered with the Australia New Zealand
Clinical Trials Registry (registration 12611000515998), and it was
approved by the human research ethics committees of the Men-
zies School of Health Research and Northern Territory Department
of Health, and the University of Wollongong. Written informed
consent was obtained from all participants before any trial
procedures.
Interventions
Participants received their initial assessment and first dose of
antibiotics in hospital and subsequently were visited at home by a
nurse twice per day until intravenous antibiotics were ceased.
Participants attended a hospital outpatient clinic for medical re-
view between days 3 and 5. All participants were treated with
intravenous cefazolin 2 g intravenously every 12 hours for a
clinician-determined duration, followed by oral antibiotics if the
treating clinician thought them necessary. In addition, they were
randomized to receive either study drug (ibuprofen 200 mg tablets)
or placebo, two tablets three times per day orally for a total of
5 days, regardless of the duration of intravenous antibiotics. The
placebo was identical to the study drug in size, shape, colour and
243
smell, and was manufactured specifically for the study (Aspen
Pharma, Croydon, Victoria, Australia).
Outcomes
The primary end point was the proportion of patients with
regression of inflammation within 48 hours of the first effective
dose of parenteral antibiotics.
Regression of inflammation was defined as the superior edge of
inflammation having moved inferiorly rather than continuing to
expand or not changing.
The superior edge was used because it is usually the clearest and
most objectively assessable, and the inferior edge often involves the
foot and is difficult to clearly assess. The superior edge of inflam-
mation was marked with a felt-tip pen by the treating nurse at
randomization (visit 1) and then at each home visit (twice per day).
The limb was photographed, and the nurse indicated on the case
report form whether, compared to the previous visit, the superior
edge had advanced, regressed or not changed. The treating nurse
assessed the participants and filled in the case report forms at each
visit while intravenous antibiotics continued, and on days 6 and 14
after randomization. The photographs were reviewed by a blinded
investigator if there were missing or ambiguous data on the case
report forms.
The secondary end points were as follows: duration of intrave-
nous antibiotics; self-reported time to return to normal leg func-
tion; median leg pain tightness scores on day 6 (assessed using a
Likert scale where 0 is none and 10 is the worst imaginable); time to
return to work, study or usual activities; serum creatinine on day 6;
proportion with serum creatinine 120 mmol/L on day 6; need for
hospital admission (for any reason) during the first 7 days;
and proportion with epigastric discomfort, heartburn or indiges-
tion of at least moderate severity at any time from randomization
until day 6.
Randomization and blinding
A randomization list was developed and held by an independent
statistician. Randomization was in permuted blocks of sizes 4 and 6,
and was stratified by study site. Randomization numbers were
stored in sequentially numbered, sealed opaque envelopes. Study
drug bottles were prepared by an unblinded study pharmacist who
had no involvement with patient care. All investigators, treating
clinicians and participants were blinded to the treatment alloca-
tion. Data analysis was carried out without knowledge of treatment
allocation.
Statistical methods and sample size determination
The sample size was determined on the basis of the only pre-
viously published randomized controlled trial of NSAIDs in cellulitis
[8], in which the proportion with regression of inflammation at
48 hours was 80% in the intervention group and 10% in the control
group. Hence, we determined that with a power of 80% and an
alpha of 5%, we would require 23 patients in each group to detect an
absolute difference in the primary outcome of 40% (based on a
conservative estimate of regression of inflammation of 60% in the
intervention group and 20% in the placebo group). The target
sample size was thus 46 patients evaluable for the primary end
point, so we estimated that we would need 55 patients in total
(given the anticipated loss to follow-up).
The primary outcome was analysed in a modified intention-to-
treat population, which comprised all participants who received at
least one dose of study drug and who had data that could be
analysed for the primary end point (i.e. data were available at the
244 J.S. Davis et al. / Clinical Microbiology and Infection 23 (2017) 242e246

48-hour time point). A per-protocol population was also defined,
which comprised all participants who received at least nine doses
of study drug within the first 5 days after randomization and who
had data that could be analysed for the primary end point. The
assessment of doses received was based on a pill count at the end of
the study. There were no interim analyses. Prespecified subgroups
for analysis were as follows: time from symptom onset to presen-
tation >48 hours vs. 48 hours; received NSAIDs in 24 hours before
randomization vs. those who did not; and baseline C-reactive
protein 50th percentile or more for analysis population vs. <50th
percentile.
The primary outcome in the two groups was compared by the
chi-square test. Other dichotomous outcomes were compared by
chi-square test, or by Fisher’s exact test if the expected number in
any cell was <5. Continuous outcomes were summarized and
compared by median and Mann-Whitney U test (for nonnormally
distributed data) and mean and Student’s t test (for normally
distributed data); p values of <0.05 were considered significant. All
analyses were carried out by Stata 12 (StataCorp, College Station,
TX, USA).
Results
Fifty-one patients were enrolled, of whom 25 were randomly
allocated to ibuprofen and 26 to placebo. The two groups were well
matched in terms of baseline characteristics (Table 1). In the study
overall, 38 patients (75%) had lower limb cellulitis and 13 (25%)
upper limb; the mean (SD) age was 42.9 (13.6) years, and 35 par-
ticipants (69%) were male. Three of the placebo group were lost to
follow-up before the primary end point assessment; hence, 48
patients were included in the modified intention-to-treat popula-
tion (Fig. 1). The primary end point was met in 20 participants (80%)
in the ibuprofen group compared to 15 (65%) in the placebo group
(p >0.05) (Table 2). This nonsignificant 15% absolute increase in the
primary end point (95% confidence interval 10 to þ40) was very
similar to that found in the per-protocol population: 61% in the
placebo group and 75% in the ibuprofen group met the primary
outcome (Table 2).
There was no significant difference in any of the secondary end
points (Table 3). Patients received a median of 3 days of intravenous
antibiotics and 10 days of total antibiotics (intravenous and oral
antibiotics combined). The median time to return to normal leg
function was 7 days in both groups (in the subgroup with lower
limb cellulitis). The proportion who had returned to usual activities
by day 14 (e.g. had returned to work or studies) was 71% in the
placebo group and 95% in the ibuprofen group (p 0.06). There were
also no significant between-group differences in the prespecified
subgroups (Table 4).
There were no safety signals of concern in the ibuprofen group.
No patient in either group developed acute renal failure. One pa-
tient in each group was admitted to hospital, both because of
worsening cellulitis. Two patients in the ibuprofen group reported
epigastric pain at least once during the first 6 days, but both of
these patients continued the study drug, and the symptoms
resolved.
Discussion
Main findings
In this double-blind, placebo-controlled trial, we found no sig-
nificant benefit of 5 days of adjunctive ibuprofen in the treatment of
cellulitis. Although a numerically higher proportion of participants
had resolution of inflammation at the 48-hour mark in the
ibuprofen group than in the placebo group, the difference was not
statistically significant. The secondary outcomes also did not differ
between groups, with the exception of the patient-centred
outcome of return to usual activities by day 14, in which there
was a trend towards benefit in the ibuprofen group. Adjunctive
ibuprofen therapy appeared safe, with no difference in renal
function or adverse events between groups.
Comparison with other studies and implications of findings
Our findings differ in magnitude but not direction from those of
Dall et al. [8], who nonrandomly allocated 64 patients to receive
5 days of open-label ibuprofen 400 mg 4 times daily in addition to
antibiotics. They found a significant difference (83 vs. 9%) in the
proportion showing any regression of inflammation within 1 to
2 days in the ibuprofen group. The absolute difference of 74% was

Table 1
Baseline characteristics according to treatment allocation

Characteristic Placebo group (n ¼ 26) Ibuprofen group (n ¼ 25)

Male 15 (58%) 20 (80%)

Age, years, mean (SD) 40.2 (14.1) 45.6 (12.9)
Diabetes mellitus 2 (8%) 2 (8%)
Peripheral vascular disease 1 (4%) 1 (4%)
Obesity (BMI >30 kg/m2) 3 (12%) 7 (30%)
Lymphoedema 1 (4%) 1 (4%)
Previous cellulitis 3 (12%) 6 (25%)
Sepsis (2 SIRS criteria)a 4 (15%) 0
C-reactive protein, mg/dL, mean (SD) 102 (79) 75 (73)
White blood cell count, 109/L, mean (SD) 11.9 (3.5) 11.6 (2.9)
Use of NSAIDs between symptom onset and randomization 14 (54%) 12 (48%)
Use of paracetamol between symptom onset and randomization 17 (68%) 16 (67%)
Received antibiotics for this episode before randomization 20 (77%) 16 (64%)
Presentation >48 hours after symptom onset 16 (62%) 10 (40%)
Lower limb cellulitis 21 (81%) 17 (68%)
Upper limb cellulitis 5 (19%) 8 (32%)
Grew GAS from skin swabs 5 (19%) 3 (12%)
Grew MSSA from skin swabs 6 (24%) 3 (12%)
Grew MRSA from skin swabs 2 (8%) 2 (8%)

A total of 51 patients were randomized; data from three patients were not able to be analyzed for primary end point but are included here.
BMI, body mass index; GAS, group A Streptococcus; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; NSAID,
nonsteroidal anti-inflammatory drug; SIRS, systemic inflammatory response syndrome.
a
SIRS criteria as published [9].
 J.S. Davis et al. / Clinical Microbiology and Infection 23 (2017) 242e246 245

Fig. 1. Recruitment flowchart.

Table 2 The data from our trial quantify the anecdotal impression that
Primary outcome measure by treatment allocation the signs of cellulitis take a long time to resolve: over 30% of pa-
Characteristic Placebo Ibuprofen p tients still had symptoms or signs of cellulitis 14 days after
Intention-to-treat population, n (%) 15/23 (65%) 20/25 (80%) 0.25
randomization. The median time to regression of inflammation in
Per-protocol population 11/18 (61%) 15/20 (75%) 0.36 our study was similar to that of several previously published
studies, increasing the confidence in our findings. Pertel et al.
found the median time to the cessation of margin advancement
much larger than that of 15% found in the present study. Possible was 22.0 hours in 50 patients treated with vancomycin [10];
explanations for this finding in the Dall study include an exagger- Leman and Mukherjee [11] found the total number of doses of
ated benefit due to lack of blinding, and imprecise definitions of the flucloxacillin until the diameter of inflammation was <100 mm
primary end point.

Table 3
Secondary outcome measures

Outcome measure Placebo Ibuprofen p

Duration of intravenous antibiotics, days, median (IQR) 3 (3e4) 3 (2e4) 0.43

Time to return to normal leg function, days, median (IQR)a 7 (4e10) 7.5 (6e9) 0.52
Return to usual activities at day 14 10/14 (71%) 19/20 (95%) 0.06
Cellulitis completely resolved at day 6 7/20 (35%) 5/19 (26%) 0.56
Cellulitis completely resolved at day 14 10/14 (71%) 13/20 (65%) 0.69
Leg pain score on day 6, median (range) 0 (0e1) 0 (0e1) 0.94
Decrease in leg pain score from baseline to day 6, mean (SD) 3.6 (3.6) 3.4 (2.2) 0.86
Leg tightness score on day 6, median (range) 0 (0e2) 1 (0e2) 0.63
Decrease in leg tightness score from baseline to day 6, mean (SD) 3.8 (3.8) 3.3 (2.1) 0.73
Safety end points
Need for hospital admission in first 14 days 1 (4%) 1 (4%) 0.73
Serum creatinine at day 6, mmol/L, mean (SD) 71 (11.8) 75 (12) 0.25
Proportion with serum creatinine >120 mmol/L at day 6 0 0 NA
Proportion with at least moderate epigastric pain or heartburn at any time during days 1e6 0 2 (8%) 0.16

NA, not applicable.

a
Limited to those with lower limb cellulitis.

Table 4
Proportion meeting primary outcome in prespecified subgroups

Characteristic Placebo Ibuprofen p

Delayed presentation (>48 hours) 8/14 (57%) 9/10 (90%) 0.08

Received NSAIDs in 24 hours before randomization 7/12 (58%) 8/10 (80%) 0.23
Baseline CRP 50th percentile or greater 5/9 (56%) 5/8 (62%) 0.77

CRP, C-reactive protein; NSAID, nonsteroidal anti-inflammatory drug.

246 J.S. Davis et al. / Clinical Microbiology and Infection 23 (2017) 242e246
and until fever had resolved was 8.47 doses (i.e. 2.1 days); and
Corwin et al. [12] found that mean days to no advancement of
cellulitis was 1.50 days in 98 patients treated at home with
intravenous cefazolin.
Also of note, over half of patients had taken NSAIDs for their
episode of cellulitis before randomization. This could potentially
have diluted the effect of NSAIDs on the primary outcome measure,
but the subgroup analysis does not support this. It also shows that
NSAID use is common among those with cellulitis, which adds to
the safety data from this trial in reassuring those concerned about
the supposed dangers of using NSAIDs in cellulitis.
Although some case reports have raised concerns of a possible
association of anti-inflammatory drugs with necrotizing fasciitis
[13e15], this has not been shown to be the case in prospective
studies or animal studies [16], and several reviews have concluded
that there is no established causal relationship [17e20]. The case
reports generally included patients who self-prescribed large doses
of NSAIDs before effective antibiotic therapy was begun, thus
possibly masking their symptoms and delaying diagnosis and
effective treatment.
Study strengths and limitations
The present study is to our knowledge the only double-blind
randomized trial of this intervention in cellulitis or erysipelas,
and we used clear end point definitions. The relatively small sample
size is a limitation of this study. On the basis of the data of Dall et al.
[8], we powered the study to find a 40% absolute difference in the
primary end point, but we actually found a 15% absolute difference.
If this were a true effect, we would need 400 patients (200 in each
group) to detect it, and the number needed to treat to benefit one
patient would be 6.7. The choice of primary outcome of this study
was limited by the achievable sample size. Any potential subse-
quent larger randomized controlled trials should use more patient-
centred end points such as time to return to work/usual activities.
Conclusions
Adjunctive ibuprofen appears safe in moderate to severe cellulitis,
and may hasten resolution of inflammation. To clarify these findings,
a larger trial including at least 400 patients would be needed.
Acknowledgements
We thank B. Maley, B. Radecki, C. Gordon, C. Jeremiah, K. Kaj-
kowicz, R. Commons, G. Leung, U. Paremaswaran, J. Davies and S.
Majumdar, as well as the nursing staff of the Royal Darwin Hospital
in the Home program for help with recruiting patients; N. Anstey
for advice regarding study design; and M. Chatfield for assistance
with statistical aspects of the study.
Transparency Declaration
Supported in part by a grant from the Northern Territory Gov-
ernment Research Innovation Board. Salary support was provided
by Australia’s National Health and Medical Research Council
(Career Development fellowships to JSD (#1083105) and SYCT
(#1065736)). All authors report no conflicts of interest relevant to
this article.
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