Open Forum Infectious Diseases

MAJOR ARTICLE

The Natural History of Antibiotic-Treated Lower Limb

Cellulitis: Analysis of Data Extracted From a Multicenter
Clinical Trial
O. Martin Williams,1,2, Fergus Hamilton,3,4, and Richard Brindle5,
1
UK Health Security Agency Microbiology Laboratory Services Bristol, Bristol Royal Infirmary, Bristol, UK, 2University Hospitals and Weston NHS Foundation Trust, Bristol Royal Infirmary, Bristol, UK,
3
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK, 4Infection Sciences, North Bristol NHS Trust, Bristol, UK, and 5School of Clinical Services, University of Bristol, Bristol, UK

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Background. Although cellulitis is a relatively common skin infection, there remains uncertainty about management,
particularly the length and route of antimicrobials required. Further information on the symptomatology and biomarker
changes associated with cellulitis over time would guide clinicians and patients as to the expected natural history.
Methods. We extracted data from a randomized clinical trial (NCT01876628) of clindamycin as adjunctive therapy in cellulitis
to illustrate the evolution of local parameters (pain, swelling, local erythema, and warmth) and the resolution of biomarkers over
time.
Results. Data from 247 individuals with mild to moderate unilateral lower limb cellulitis, who attended at least 1 face-to-face
interview following recruitment, were used to examine response dynamics. Although there was a local improvement in swelling,
warmth, erythema, and pain by day 5 compared with baseline, some individuals still had evidence of local inflammation
at 10 days. Most biomarkers demonstrated a return to normal by day 3, although the initial fall in albumin only returned to
baseline by day 10.
Conclusions. Although there was initial resolution, a significant number of individuals still had local symptoms persisting to
day 10 and beyond. Clinicians can use these data to reassure themselves and their patients that ongoing local symptoms and signs
after completion of antibiotic treatment do not indicate treatment failure or warrant extension of the initial antibiotic treatment or a
change in antibiotic class or mode of administration.
Keywords. cellulitis; leg; lower limb; natural history.

Cellulitis is a common skin infection, with an incidence ranging
from 0.2/1000 person-years to 24.6/1000 person-years [1–4].
The majority of cases are uncomplicated and can be safely
managed in the community setting, although the number of
individuals hospitalized for cellulitis has increased over time,
resulting in significant health care expenditure [5].
Published guidelines for the treatment of cellulitis [6–10] are
mostly based on evidence extrapolated from studies of skin and
soft tissue infections, which have included cellulitis, or are based
on expert opinion. Of note, a recent systematic review of treat­
ment guidelines of acute infections commonly seen in primary
care highlighted that none of the identified guidelines for the
Received 28 July 2023; editorial decision 18 September 2023; accepted 27 September 2023;
published online 29 September 2023
Correspondence: O. Martin Williams, PhD, FRCPath, FRCP, Department of Microbiology,
Level 8, Bristol Royal Infirmary, Bristol BS2 8HW, UK (martinx.williams@uhbw.nhs.uk); or
Richard Brindle, PhD, FRCPath, FRCP, School of Clinical Services, University of Bristol,
Bristol, UK (richard.brindle@bristol.ac.uk).
Open Forum Infectious Diseases®
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases
Society of America. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original
work is properly cited.
https://doi.org/10.1093/ofid/ofad488
management of cellulitis or nonpurulent skin and skin structure
infections included details on the natural history of the disease
[11]. Treatment decisions are complicated by the persistence
of the local bacterial toxin effects and resultant local inflamma­
tion [7, 12], which do not necessarily correlate with organism
load or need for prolongation of antimicrobial therapy.
Approximately 20% of individuals with cellulitis “fail” initial
antimicrobial therapy [13] and are prescribed repeat courses of
antimicrobials or re-attend health care. It is likely that a pro­
portion of these individuals simply have slowly resolving symp­
toms and that these “failures” represent the natural history of
disease. This is also complicated by guidance suggesting re-
evaluation of individuals with cellulitis at 48–72 hours, leading
to an assumption that patients should be improving at this
point [8]. The situation is further complicated as cellulitis can
be difficult to diagnose, with recognition of an increasing num­
ber of cellulitis-mimics, termed pseudo-cellulitis. Indeed, be­
tween 30% and 74% of individuals initially diagnosed and/or
treated for cellulitis have an alternative final diagnosis, such
as venous stasis dermatitis, contact dermatitis, eczema, lymph­
edema, or erythema migrans [14–16].
However, there remain limited data on the trajectory of
symptoms and biomarker responses to guide patient and

Natural History of Cellulitis • OFID • 1

clinician expectations. We therefore used data routinely col­
lected from a double-blinded placebo-controlled trial to illus­
trate the clinical course and response dynamics of individuals
with treated mild to moderate lower limb cellulitis.
METHODS
Data were extracted from a randomized clinical trial
(NCT01876628) of antibiotic therapy for cellulitis from 20 hos­
pitals in England. Individuals with a diagnosis of lower limb
cellulitis who attended at least 1 follow-up appointment were
included in this analysis. Those with cellulitis of the upper
limb were excluded as this site of infection was less common
variances comparing the mean of each data set was calculated
for each comparison. For comparisons of the affected and un­
affected limbs, an ordinary 2-way analysis of variance using a
main affect model only was performed. A P value <.05 was con­
sidered significant. Trend line analyses were fitted using non­
linear regression with a centered third-order polynomial
(cubic) equation. Due to small numbers (<20 data points),
data for day 1 were not included for the patient characteristics,
and data for both day 1 and day 2 were not included for blood
analytes.
RESULTS

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and less severe, and individuals were less likely to re-attend
for review [17].
Diagnosis of cellulitis was supported using criteria estab­
lished for the PATCH trial on the prevention of recurrent cel­
lulitis [18]. All adults with unilateral limb cellulitis were eligible
for recruitment, but those with obvious abscesses were exclud­
ed. In addition, those who had received antibiotic treatment for
>48 hours before recruitment were not included. All recruited
participants were given flucloxacillin orally or intravenously,
but the dose and route of administration were decided by the
clinical team treating the patient. Participants on other antibi­
otics before recruitment were switched to flucloxacillin.
The methods of assessment have been previously reported
[17]. In brief, participants had 3 face-to-face study visits sched­
uled: baseline (day of recruitment), day 5 (a median of 4 days
after baseline), day 10 (a median of 9 days after baseline). At
each visit, the affected skin area of the limb was estimated using
The baseline characteristics of 247 individuals with lower limb
cellulitis who attended at least 1 follow-up appointment are
shown in Table 1. The majority of individuals (93.1%) had an
acute presentation, with local symptoms being present for <7
days at recruitment, half of whom had been symptomatic for
<2 days. In addition, at the time of recruitment 58.3% of indi­
viduals had received <12 hours of antibiotic treatment. Where
the information was recorded, the median duration of antibiot­
ic treatment following recruitment (interquartile range [IQR])
was 7 (7–9.5) days (n = 185, 74.9%); 71.5% received only oral
therapy.
Table 1. Baseline Characteristics of 247 Patients With Lower Limb
Cellulitis
Normal
Total (n = 247) Range

a scoring system similar to the Psoriasis Area and Severity Age, mean (SD), y 52.2 (18.0) …
Index [19] from which the percentage of body skin area in­ Male, No. (%) 166 (67.2) …
Duration of local features before 3.5 (6.9) …
volved was calculated. Limb circumference was recorded at recruitment, mean (SD), d
its greatest over the affected area using a disposable tape mea­ Duration of flucloxacillin before recruitment, 0.5 (0.6) …
sure, and the highest temperature from the affected area was mean (SD), d
Affected skin area as percentage of body 6.0 (4.0–8.0) …
measured using an infrared thermometer [20]. Local observa­
surface area, median (IQR)
tions of the affected limb were compared with the unaffected Difference in circumference between 2.1 (1.1–4.1) …
limb, if available. Pain scores were measured using a visual an­ affected and unaffected limbs, median
(IQR), cm
alogue scale (0–10). In addition, at each visit blood samples
Difference in surface temperature between 2.3 (1.2–3.6) …
were taken for a full blood count, renal and liver function, affected and unaffected limbs, median
and C-reactive protein. As we have previously demonstrated (IQR), °C

in this population that the addition of short-course clindamy­ Pain score (0–10), median (IQR) 5 (3–7) …
Hemoglobin, median (IQR), g/L 136 (122–145) 130–170
cin to flucloxacillin did not alter the clinical outcome [17]
Neutrophil, median (IQR), ×109/L 6.7 (4.5–9.4) 1.5–8.0
and that the route of administration (oral vs intravenous) and Lymphocyte, median (IQR), ×109/L 1.5 (1.2–2.0) 1.0–4.0
duration of treatment (5 days or >5 days) were not associated Neutrophil/lymphocyte ratio, median (IQR) 4.2 (2.5–7.3) …
with recovery [21], we have combined the data from all of the Platelets, median (IQR), ×109/L 222 (179–269) 150–400
individuals into 1 data set. Urea, median (IQR), mmol/L 5.1 (4.2–6.6) 2.5–7.8
Creatinine, median (IQR), μmol/L 79 (67–96) 59–104
Statistical analysis was done using GraphPad Prism, version
Albumin, median (IQR), g/L 38 (34–42) 35–50
9.5.0, for Windows (GraphPad Software, San Diego, CA, USA). C-reactive protein, median (IQR), mg/L 43.5 (13.2–115.8) <6.0
For comparisons of variables at the 3 assessment time points, a Alkaline phosphatase, median (IQR), U/L 78 (63–97) 30–130
mixed-effects analysis with Geisser-Greenhouse correction was Alanine transaminase, median (IQR), U/L 23 (18–35) 10–50
performed. Tukey’s multiple comparison test with individual Abbreviation: IQR, interquartile range.

2 • OFID • Williams et al
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Figure 1. Box plots showing median, IQR, and maximum/minimum values. A and B, The circumference of the affected and unaffected lower limbs at baseline and at the day
5 and day 10 assessments, respectively. D and E, The local temperature of the affected and unaffected lower limbs at baseline and at the day 5 and day 10 assessments,
respectively. ****P < .0001; ***P < .001; **P < .01; *P < .05. C and F Trend lines of the median and IQR of the circumference (C) and the local temperature (F ) of the
affected and unaffected limbs from baseline to day 10. The numbers above and below the lines represent the number of observations included at each time point. Data
from day 1 have been omitted due to small numbers (n < 20). Abbreviation: IQR, interquartile range; ns, non-signficant.

Overall, there was a reduction in mean limb circumference of
the affected limb between baseline and day 5 (mean reduction,
0.5 cm; 95% CI, 0.17–0.81; P = .001), baseline and day 10 (mean
reduction, 0.85 cm; 95% CI, 0.45–1.25; P < .001), and between
the day 5 and day 10 assessments (mean reduction, 0.36 cm;
95% CI, 0.08–0.63; P = .0072) (Figure 1A–C). Despite the re­
duction in edema by day 10, there remained a difference
in the mean circumference between the affected and unaffected
limbs (mean difference, 1.94 cm; 95% CI, 1.60–2.28; P < .0001),
with more than a third (36.4%) of individuals having a ≥2-cm
difference in circumference between the affected and unaffect­
ed limbs. There was a similar reduction in the mean tempera­
ture of the affected limb between baseline and day 5 (mean
reduction, 1.4°C; 95% CI, 1.0–1.8; P < .001) and between base­
line and day 10 (mean reduction, 1.8°C; 95% CI, 1.4–2.2;
P < .0001) (Figure 1D–F). Despite the reduction in local
warmth by day 10, there remained a significant difference in
the mean local temperature between the affected and unaffect­
ed limbs (mean difference, 1.1°C; 95% CI, 0.9–1.3; P < .0001).
Again, approximately one-third of individuals (29.5%) had
≥1°C greater difference in local skin temperature between the
affected and unaffected limbs at day 10.
There was a 34% reduction in the mean percentage of affect­
ed surface area between baseline and day 5 (P < .0001), and
a further reduction of 31.1% between day 5 and day 10
(P < .0001), with an overall reduction in the mean percentage
of affected skin area of 54.8% (P < .0001) (Figure 2A and B).
In addition to a reduction in local swelling, warmth, and the
area of affected skin, there was also a significant reduction in
local pain between baseline and day 5 (mean reduction, 2.0;
95% CI, 1.6–2.4; P < .0001), baseline and day 10 (mean reduc­
tion, 2.9; 95% CI, 2.5–3.3; P < .0001), and day 5 and day 10
(mean reduction, 0.9; 95% CI, 0.6–1.2; P < .0001), although
more than half of individuals (54.3%) continued to report a
pain score of ≥1, and 13.9% reported a pain score of ≥5 on
day 10 (Figure 2C and D).
When comparing the various hematological and biochemical
parameters, there was a reduction in the total neutrophil count be­
tween baseline and day 5, as well as baseline and day 10
(Figure 3A), appearing to stabilize by day 3 (Figure 3C), with an
associated recovery in the total lymphocyte count between base­
line and day 5, and between day 5 and day 10 (Figure 3B and C).
In parallel, there was a significant reduction in the neutrophil/lym­
phocyte ratio (NLR) between baseline and day 5, and baseline and

Natural History of Cellulitis • OFID • 3

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Figure 2. Box plots showing median, IQR, and maximum/minimum values. A, The percentage of affected skin area at baseline and at the day 5 and day 10 assessments,
respectively. C, Pain scores at baseline and at the day 5 and day 10 assessments, respectively. ****P < .0001; ***P < .001; **P < .01; *P < .05. B and D, Trend lines of the
median and IQR of the percentage of affected skin area (B) and the local temperature (D) of the affected limb from baseline to day 10. The numbers above the lines represent
the number of observations included at each time point. Data from day 1 have been omitted due to small numbers (n < 20). Abbreviation: IQR, interquartile range.

day 10 (Figure 3D), appearing to stabilize from day 3 (Figure 3E).
In addition, there was a significant increase in the platelet count
between baseline and day 5, and day 5 and day 10 (Figure 3F
and G). Data on other hematological and biochemical parameters
are included in the Supplementary Figures (hemoglobin,
Supplementary Figure 1; urea and creatinine, Supplementary
Figure 2; alkaline phosphatase and alanine transaminase,
Supplementary Figure 3). There was a small but significant drop
in albumin between the baseline measurement and day 5, with a
trend toward recovery by day 10 (Figure 4A and B). Finally, base­
line C-reactive protein (CRP) was significantly elevated, with
significant falls at day 5 and a return toward normal levels by
day 10 (Figure 4C and D).
DISCUSSION
Lower limb cellulitis remains a common infection syndrome,
with the greatest numbers occurring predominantly in the
summer months [4, 5, 22]. It causes a significant drain on
health resources [23, 24], but there remains uncertainty about
the most appropriate form of therapy, and little in the literature
documents the natural history of antibiotic-treated disease.

4 • OFID • Williams et al
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Figure 3. Box plots showing median, IQR, and maximum/minimum values. A, B, D, and F, The neutrophil count, lymphocyte count, NLR, and platelet count at baseline and at
the day 5 and day 10 assessments, respectively. ****P < .0001; ***P < .001; **P < .01; *P < .05. C, The daily trend of the median and IQR of the neutrophil and lymphocyte
counts. E and G, Trends for NLR and platelet count, respectively, to day 10. The numbers above and below the lines represent the number of observations included at each time
point. Data from day 1 and day 2 have been omitted due to small numbers (n < 20). Abbreviations: IQR, interquartile range; NLR, neutrophil/lymphocyte ratio; ns, non-significant.

The data presented here, derived from a clinical trial on the
antibiotic management of mild to moderate lower limb celluli­
tis, demonstrate that although there are early responses in lab­
oratory parameters, there is a delay in the resolution of local
symptoms and signs. This has a number of implications for cli­
nicians and patients. First, clinicians and patients should expect
prolonged symptomatology, and early re-assessment should be
considered only in light of worsening, not ongoing, symptoms.
Second, the use of “rescue” antimicrobials should again be lim­
ited to those with worsening symptoms. Finally, these data
should inform the conduct and outcome of randomized trials
of therapies to alleviate cellulitis. There have been a number
of randomized controlled trials on the antibiotic treatment of
cellulitis (see a recent meta-analysis and systematic review

Natural History of Cellulitis • OFID • 5

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Figure 4. Box plots showing median, IQR, and maximum/minimum values. A and C, Albumin and C-reactive protein measurements at baseline and at the day 5 and day 10
assessments, respectively. ****P < .0001; ***P < .001; **P < .01; *P < .05. B and D, The trends of the median and IQR of albumin and C-reactive protein, respectively, from
baseline to day 10. The numbers above the lines represent the number of observations included at each time point. Data from day 1 and 2 have been omitted due to small
numbers (n < 20). Abbreviation: IQR, interquartile range; ns, non-significant.

[25]). The outcomes of these clinical trials have been the subject
of a systematic review [26], which demonstrated the lack of
consensus on the description of outcomes, with most trials us­
ing the terms “cure, improvement, success, failure.” There was
also a lack of consensus for the time point for assessment of
clinical response, with some trials measuring outcomes at sev­
eral time points ranging from 48 hours to 42 days.
In 2013, the US Food and Drug Administration (FDA)
recommended that the primary efficacy end point for antibi­
otic clinical trials of acute bacterial skin and skin structure
infections (ABSSSIs) be based on a percent reduction
(≥20%) in lesion size at 48–72 hours compared with baseline,
with complete resolution at 7–14 days after completion of
therapy as a secondary end point [27]. This was based in
part on the observations by Snodgrass and Anderson [28].
Early assessment of clinical response was tentatively support­
ed by a recent meta-analysis [29], although it has been criti­
cized by others [30] as early responses to treatment are not
the primary aim of treatment. In contrast, recently updated
European guidelines continue to support the assessment of
the primary end point at the test of cure visit, after comple­
tion of therapy [31].

6 • OFID • Williams et al
 Our data support a more nuanced assessment of outcomes in
cellulitis, which should include patient-reported outcomes (eg,
pain and symptomatology), as these extend for longer than pre­
viously reported. The need for the use of more patient-focused
and patient-reported outcomes in clinical trials on cellulitis
has been identified in a recent systematic review [26], as they re­
flect the real day-to-day impact on patients’ lives. Additionally,
given the extended symptomatology, these data support consid­
eration of adjunctive therapies to reduce inflammation (such as
corticosteroids [32] or nonsteroidal anti-inflammatory drugs
[33]), as antimicrobial therapy will be ineffective at improving
symptoms. Further trials on the effectiveness, cost-effectiveness,
and safety of adjunctive therapies in cellulitis are required.
Our data are in line with the previous literature, although we
generally identified greater and longer symptomatology. A recent
study of 216 hospitalized patients with cellulitis examined both
early and late clinical responses after initiation of antibacterial
treatment, including both clinical and biochemical parameters
[34]. Of note, ∼11% of recruited patients had an associated wound
or ulcer. At day 1 of treatment, it was reported that 55% of cases
had cessation of local spread, and 52% had improvement of local
inflammation (defined as the intensity of erythema, warmth, and
tenderness), with a combination of the 2 occurring in 39%.
Defervescence (defined as a body temperature ≤37.5°C in ≥2 sep­
arate measurements among cases with temperature >37.5°C the
day before) was recorded in <40% of cases. By day 2, ∼90% of cases
had cessation of local spread, with 88% having improvement in lo­
cal inflammation, with the combination of the 2 occurring in 85%.
Despite the local improvement, nearly 40% had failed to defer­
vesce. Finally, by day 3 nearly all cases (>95%) had a cessation
of local spread and improvement of local inflammation, but
15% had failed to defervesce. Of note, a lack of clinical response
at day 3 was not predictive of clinical failure post-treatment. In
contrast, Cranendonk and colleagues in the DANCE trail de­
scribed ongoing patient-reported local symptoms (pain) and
investigator-assessed signs (edema and cellulitis severity score)
up until day 14 and beyond, with only an estimated 75% reduction
in symptom scores at day 14 compared with day 1 [35].
Yadav and colleagues undertook a systematic review and
meta-analysis of randomized controlled trials on antibiotic
treatment of uncomplicated cellulitis where data on the time
to clinical response of a variety of clinical parameters were in­
cluded [29]. Although outcomes were inconsistently defined,
the overall pooled median time to clinical response was 1.68
days (95% CI, 1.48–1.88; 4 studies). A 50% reduction in pain
(4 studies) and severity (3 studies) scores was identified by
day 5 of treatment, with a gradual resolution in pain and se­
verity reported over 2–4 weeks. There was an approximately
one-third reduction in redness diameter by day 2–3 of treat­
ment, and a further one-third reduction by day 7–14 (2 stud­
ies). Finally, there was a 30%–50% reduction in local edema
by day 2–4 of treatment (3 studies), and 50%–85% by day 7–10.
Our analysis has a number of strengths. First, data were
collected prospectively within a randomized trial, with minimal
loss to follow-up and detailed assessment of a number of pa­
rameters for a prolonged period of time. Second, the inclusion
criteria of our trial were pragmatic, unlike many other trials in
skin and soft tissue infection. Limitations of our post hoc sec­
ondary data analysis include those of the original randomized
trial; it is likely that loss to follow-up was not random and pa­
tients with greater (or fewer) symptoms may have been more
likely to have follow-up. Additionally, trial populations are
known to be “healthier” on average than the reference popula­
tion in which the trial is run. This would suggest, however, that
our reported results are an underestimate of the burden of
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symptoms of cellulitis, although they do highlight that even
those considered to have mild infection can still suffer with
prolonged symptoms. Finally, given the recognized difficulty
in clinically diagnosing cellulitis, it is possible that individuals
with pseudocellulitis may have been recruited. Although this
could bias the overall duration of symptoms, it is likely that
the number of individuals with cellulitis mimics was small.
The pragmatic design of the trial reflects the experiences of
real life, and clinicians and patients need to understand that on­
going symptoms beyond the period of active antibiotic treat­
ment are not unusual and do not indicate treatment failure.
CONCLUSIONS
The natural history of cellulitis is long, with symptoms present
in many patients more than a week after diagnosis. Clinicians
should inform patients of this natural history and should limit
repeat assessment and antimicrobial therapy to those with
worsening, not continuing, symptoms. Additional research is
required to investigate the benefits of adjunctive therapies,
but any future trials on cellulitis need to include patient-
focused outcomes with an extended duration of follow-up be­
yond 10 days to better understand the natural history of the
disease.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases
online. Consisting of data provided by the authors to benefit the reader,
the posted materials are not copyedited and are the sole responsibility of the
authors, so questions or comments should be addressed to the corresponding
author.
Acknowledgments
The authors would particularly like to thank the coordinating research
nurses Chiaki Shioi and Louise Wright and our trial administrator Lucy
Dixon.
Author contributions. R.B. conceived the original study design, and R.B.
and O.M.W. both were involved with the acquisition of data. All authors
were involved with the analysis and interpretation of the data and the draft­
ing of the article. They all gave final approval of this version to be
submitted.
Financial support. This original trial was supported by the National
Institute for Health Research (NIHR) under its Research for Patient Benefit
Natural History of Cellulitis • OFID • 7
(RfPB) Programme (Grant Reference Number PB-PG-0212-27015) and re­
ceived approval from the Medicines and Health Regulatory Authority
(MHRA). F.H.’s time was funded by the Wellcome Trust (222894/Z/21/Z).
No additional funding was received for the production of this manuscript.
Disclaimer. The views expressed are those of the authors and not neces­
sarily those of the NHS, the NIHR, or the UK Department of Health.
Data sharing. Anonymized patient-level data are available from the
Dryad Digital Repository: http://dx.doi.org/10.5061/dryad.5q1j0.
Patient consent and ethical approval. The original clinical trial
(NCT01876628) was approved by the UK National Research Ethics
Service (reference number: 13/SC/0211), and written informed consent
was obtained from all participants.
Transparency. The authors affirm that the manuscript is an honest, ac­
curate, and transparent account of the study being reported, that no impor­
tant aspects of the study have been omitted, and that any discrepancies
from the study as planned have been explained.
Prior presentation. An earlier version of this work was presented at ID
Week 2016, New Orleans, abstract number 1159.
Potential conflicts of interest. All authors: no reported conflicts.
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