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Received: 17 September 2024 | Accepted: 11 November 2024
DOI: 10.1002/jpn3.12430
OR I G I NA L ART I C L E
G a s t r o e n t e r o l o g y : I n f l amm a t o r y B ow e l D i s e a s e
A decade of real‐world clinical experience with 8‐week
azithromycin–metronidazole combined therapy in
paediatric Crohn's disease
Maria Teresa Fioretti1 | Laura Gianolio1 | Katherine Armstrong1 |
Rosalind M. Rabone1 | Paul Henderson1,2 | David C. Wilson1,2 |
Richard K. Russell1,2
1Department of Paediatric Gastroenterology
and Nutrition, Royal Hospital for Children and
Young People, Edinburgh, UK
2Child Life and Health, University of
Edinburgh, Royal Hospital for Children and
Young People, Edinburgh, UK
Correspondence
Richard K. Russell, Royal Hospital for
Children and Young People, 50 Little France
Crescent, Edinburgh EH16 4TJ, UK.
Email: richard.russell@nhs.scot
Abstract
Objectives: The aim of our study was to assess the effectiveness and side‐
effect profile of a combination of azithromycin and metronidazole (CD AZCRO)
as alternative induction therapy for 8 weeks in mild to moderately active pae-
diatric Crohn's disease (CD).
Methods: We performed a retrospective cohort study (November 2012 to
July 2023) of a regional paediatric inflammatory bowel disease service.
Disease activity, faecal calprotectin (FC), C‐reactive protein (CRP), ery-
throcyte sedimentation rate (ESR), haematological parameters and albu-
min were collected at baseline, 8 and 16 weeks. At Week 8, patients were
divided based on (paediatric Crohn's disease activity index) score and
inflammatory markers (blood and stool) into: Group 1 clinical remission and
Group 2 non‐remission.
Results: A total of 48 patients were initially identified of whom 44 were included
in the intention‐to‐treat analysis. After 8 weeks, the overall remission rate was
64%. Of the 38 patients who completed the CD AZCRO course, 28 patients
(74%) entered remission (Group 1) and 10 (26%) did not (Group 2). At baseline
a shorter disease duration, low weight z score and higher inflammatory burden
(ESR, platelets and FC levels) were observed in Group 2. After 8 weeks, Group
1 showed improved CRP levels and higher albumin and haemoglobin levels
than Group 2. Median FC declined significantly from 650mcg/g at baseline to
190mcg/g at Week 8 in Group 1 (p 12.5 points, was not statistically dif-
ferent between the groups (66% vs. 45%; p = 0.07).
Faecal calprotectin (FC) declined significantly in the
combination group but not in the metronidazole group,
with high levels in both groups at the end of 8 weeks.17
Before this RCT, a retrospective uncontrolled experi-
ence conducted by Levine and Turner showed clinical
remission in 21/32 (66%) children with active CD
treated with a combination of metronidazole and azi-
thromycin over 8 weeks.18 This is reflected in the latest
European Crohn's and Colitis Organisation–European
Society for Paediatric Gastroenterology, Hepatology
and Nutrition (ECCO‐ESPGHAN) guidance on the
management of CD in children, which advises the use
of combination antibiotics for the induction of remission
in mild‐to‐moderate paediatric CD where nutritional
therapy is not an option.19 Given the limited evidence
presented above, the aim of this study was to review
our experience with azithromycin and metronidazole
in CD (CD AZCRO) in terms of effectiveness, tolerance
and safety in a real‐world clinical setting.
2 | METHODS
Our Edinburgh‐based, south‐east Scotland, regional
paediatric IBD (PIBD) service manages all children and
young people in the region before transition to adult
services, with very few 16 years old but the majority of
17 years old diagnosed in adult IBD services. We
performed a retrospective cohort study of all paediatric
patients with CD who were treated with a CD AZCRO
course between 1 November 2012 and 30 July 2023.
Data were gathered from electronic medical records.
The diagnosis of CD was aligned with the revised
Porto Criteria for the diagnosis of PIBD20 and disease
phenotype assigned using the Paris classification.21
The inclusion criteria were (i) a confirmed diagnosis
of CD, (ii) age at diagnosis of 17 years or younger, (iii)
clinical follow‐up of at least 3 months after CD‐AZCRO,
(iv) symptoms and/or investigations in keeping with
active luminal disease, (v) commencement of a CD‐
AZCRO course at any point since diagnosis and ability
to take or tolerate the antibiotics for more than
a week.20 All patients were given metronidazole
(15–20mg/kg/day two times daily, maximum of
1000mg/day) administered daily for 8 weeks and azi-
thromycin (7.5 mg/kg to a maximum of 500mg/once
a day) administered 5 days per week for the first
4 weeks, followed by 3 days per week for the final
What is Known
• The gut microbiome represents a key factor
in the pathogenesis of inflammatory bowel
disease.
• Antibiotics reduce luminal bacterial concen-
trations and may alter the composition of gut
microflora, controlling luminal inflammation.• The latest European Crohn's and Colitis
Organisation–European Society for Paediat-
ric Gastroenterology, Hepatology and Nutri-
tion guidance on the management of Crohn's
disease (CD) in children advises the use of
combination antibiotics for the induction of
remission in mild‐to‐moderate paediatric CD
where nutritional therapy is not an option.
What is New
• Our real‐world data demonstrate that
azithromycin‐based therapy in combination
with metronidazole would represent an alter-
native induction therapy for mild to moderate
paediatric CD offering benefits in terms of
cost and practicalities compared to exclusive
enteral nutrition and side effects compared to
steroids.
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4 weeks as per the initial publications.17,18 The anti-
biotic course was considered completed if patients took
8 weeks of antibiotics. Patients who were intolerant to
the medications (significant nausea, abdominal pain or
diarrhoea) were instructed to reduce the dose of met-
ronidazole by at least 25%. The introduction of any
other induction medication for CD after starting anti-
biotics and before 8 weeks was considered a treatment
failure. Patients on CD maintenance therapy with im-
munomodulators were allowed to continue it.
Baseline demographics, disease characteristics
before and after treatment, concurrent medications and
treatment adverse events (AEs) were obtained from
electronic health records. C‐reactive protein (CRP),
erythrocyte sedimentation rate (ESR), haemoglobin
(Hb), platelets (PLT), albumin and FC were collected at
baseline, at 8 weeks (the end of CD AZCRO) and
16 weeks (the first outpatient visit after the start of the
treatment). Disease activity was monitored at the same
timepoints using (PCDAI) score and defined as mild
(10–27.5), moderate (27.5–37.5) or severe (>37.5).22
When PCDAI score was not reported in electronic
records, it was calculated retrospectively from clinical
details and blood tests at the clinic attendance.
Therefore, based on PCDAI score and inflammatory
markers in blood and stool, at Week 8 patients were
divided into two groups: Group 1 remission and
Group 2 non‐remission. The Week 16 was focused only
on the remission group to evaluate changes in therapy,
as well as in disease activity and inflammatory markers
in blood and stool after treatment discontinuation.
2.1 | Outcome
Our primary aim was to assess the rate of remission in
patients treated with CD AZCRO at 8 weeks. Remis-
sion was defined as clinically quiescent, with PCDAI
score oftreatment of azithromycin
and metronidazole for induction of remission in mild
to moderate paediatric CD. According to the latest
F IGURE 1 Flow of CD patients treated with CD AZCRO. Group 1: remission group; Group 2: non‐remission group. AE, adverse events; CD,
Crohn's disease; CD AZCRO, azithromycin and metronidazole; EEN, exclusive enteral nutrition; ITT, intention‐to‐treat.
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ECCO‐ESPGHAN guidance on the management of CD
in children, a combination of antibiotics may be con-
sidered for induction of remission in mild‐to‐moderate
paediatric CD where nutritional therapy is not an
option.19 EEN is a well‐established first‐line induction
treatment for active luminal CD,19 characterised by
equal efficacy to steroids, a favourable side effect
profile and higher rates of mucosal healing.19 Based on
what we know about the key role of microbiome in CD
pathophysiology, it may be possible to achieve remis-
sion by addressing the initial trigger of bacterial
adherence or invasion, instead of targeting the end
result of the inflammatory process.14,24 However, the
effect of antibiotics may depend on the type of the mi-
crobiota involved and on its susceptibility to antibiotics,
such that patients with resistant bacteria either go into
remission or do not respond, recognising the so called
‘all or none’ phenomenon. Metronidazole is one of the
most commonly prescribed antibiotics in the treatment
of paediatric CD, but superior outcomes for the
combination of metronidazole and azithromycin have
been reported compared with metronidazole alone.17,18
Azithromycin is especially promising in the treatment of
IBD, as it covers a wide variety of bacteria that colonise
the small and large intestine, due to its effect in
inducing apoptosis and efficacy against biofilms and
TABLE 1 Baseline characteristics of the 44 included children treated with CD AZCRO.
Total cohort (44) Group 1 (28) Group 2 (10)
p Value (Group
1 vs. Group 2)
Median age at diagnosis (years, range) 11.8 (3.3–17.9) 11.3 (3.3‐17.9) 12.1 (4–14.9) 0.952
Median age at the start of CD AZCRO
(years, range)
14 (5.2–17.9) 14.2 (6.6–17.9) 13.6 (5.2–15.4) 0.177
Duration from diagnosis to start CD AZCRO
(months median, range)
14 (0–99) 20 (0–99) 7 (0–31) 0.039
Previous treatment, n (%) 32 (73) 22 (78) 8 (80) 0.924
Maintenance therapy, n (%) 23 (52) 16 (57) 5 (50) 0.697
Sex (n, %)
Male 21 (48) 15 (53) 6 (60) 0.461
Female 23 (52) 13 (47) 4 (40)
Disease extent (Paris classification), n (%)
Terminal ileal L1 7 (14) 5 (18) 1 (10) 0.950
Colonic L2 18 (41) 13 (46) 3 (30) 0.182
Ileocolonic L3 19 (43) 10 (36) 6 (60) 0.366
Perianal disease p 4 (9) 3 (11) 1 (10) 0.559
Anthropometrics
Z score weight (median, range) −0.8 (−2.2 to 3.1) −0.7 (−2.2 to 3.1) −1.1 (−2.2 + 0.6) 0.014
Z score height (median, range) −0.4 (−1.9 to 2.8) −0.3 (−1.9 to 2.8) −0.4 (−0.9 + 1.5) 0.726
Z score BMI (median, range) −0.5 (−3.4 to 2.5) −0.5 (−1.1 to 2.5) −0.7 (−3.4 + 0.2) 0.098
PCDAI (median, range) 15 (5–45) 15 (5–22.5) 10 (5–22.5) 0.851
Laboratory values (median, range)
ESR (mm/h) 16 (2–86) 13 (1–36) 20 (7–86) 0.042
CRP (mg/L) 4 (1–62) 1 (1–62) 1 (1–30) 0.88
Hb (g/L) 128 (102–154) 130 (102–154) 122 (113–145) 0.115
PLT (10/mm3) (normal 150–400) 290 (198–575) 281 (198–432) 301 (251–575) 0.048
Albumin (g/L) 37 (28–43) 38 (30–43) 36 (28–39) 0.071
Faecal calprotectin (mcg/g) 716 (200–1250) 650 (200–1250) 916 (410–1250) 0.021
Note: Anthropometrics and laboratory data are reported as median (range). Statistically signficant results are highlighted in bold.
Abbreviations: BMI, body mass index; CD AZCRO, azithromycin and metronidazole; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate;
Hb, haemoglobin; PCDAI, paediatric Crohn's disease activity index; PLT, platelets.
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intracellular bacteria hypothesised to be critical for CD‐
related inflammation (like Escherichia coli).14,25,26 It
could be speculated theoretically that Azithromycin
could be effective without the need for co‐treatment
with Metronidazole at all however Metronidazole did
have some effect alone in the RCT and Azithromycin
monotherapy should really be tested against combined
treatment before the theory translates into clinical
practice. In our retrospective study, the enroled cohort
showed an improvement in all blood tests and a sig-
nificant decreased FC, with 28/44 (64%) entering clin-
ical and biochemical remission, replicating the previous
remission rate of 66% described in 2011 by Levine
et al. and later in 2018.17,18
At baseline, patients who did not enter into remis-
sion had a shorter duration of disease and a lower
weight z score than the remission group, aligning with
the observation that disease duration is related to the
nutritional status in paediatric CD.27 Patients who
failed to enter into remission, had a higher inflamma-
tory burden (ESR, PLT and FC levels), but no signifi-
cant difference at baseline was found between groups
for PCDAI score or disease location. Conversely,
Levine and Turner reported that patients who did not
enter remission tended to have more extensive dis-
ease (small bowel and colonic and upper GI involve-
ment) than those who entered remission, but this did
not reach significance, likely due to the small sample
size.18
After 8 weeks of CD AZCRO, our cohort of patients
showed a significant improvement in the median PCDAI
plus CRP and ESR levels decreased. These data are in
line with the previous studies on CD AZCRO.17,18 How-
ever, the significant drop of FC in our overall cohort and,
in particular, in patients who did enter clinical remission
(median FC from 650mcg/g at baseline to 190mcg/g
at Week 8) (p0.013
Faecal calprotectin (mcg/g) 353 (20–1245) 190 (20–960) 1049 (270–1245)can be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Fioretti MT, Gianolio L,
Armstrong K, et al. A decade of real‐world clinical
experience with 8‐week azithromycin–metronidazole
combined therapy in paediatric Crohn's disease.
J Pediatr Gastroenterol Nutr. 2025;80:300‐307.
doi:10.1002/jpn3.12430
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https://doi.org/10.1002/jpn3.12430
	A decade of real-world clinical experience with 8-week azithromycin-metronidazole combined therapy in paediatric Crohn's disease
	1 INTRODUCTION
	2 METHODS
	2.1 Outcome
	2.2 Statistical analyses
	2.3 Ethical statement
	3 RESULTS
	3.1 AEs
	4 DISCUSSION
	5 CONCLUSION
	CONFLICTS OF INTEREST STATEMENT
	ORCID
	REFERENCES
	SUPPORTING INFORMATION