Clinical Trial Details
— Status: Suspended
Administrative data
| NCT number |
NCT05544565 |
| Other study ID # |
APHP211043 |
| Secondary ID |
2021-005627-21 |
| Status |
Suspended |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
March 22, 2023 |
| Est. completion date |
October 2025 |
Study information
| Verified date |
February 2024 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Antibiotic therapies currently recommended for the treatment of acute pyelonephritis (AP) in
children, whether fully by the oral route or initially intravenous (IV, 3 days) followed by
the oral route, have a duration of 7 to 14 days (10 days in France).
In children with no prior urological malformation, the global clinical and microbiological
cure rate after antibiotic treatment completion is around 95%. Recurrence occurs in less than
5% of cases in the 3 months following AP. Renal scarring, when documented, concerns 15% of
children 6 months after treatment. Renal scarring can be associated with chronic renal
disease.
The investigators hypothesize that 3 days of IV treatment is equivalent to extending to 10
days with an oral therapy to prevent long-term renal scarring.
The investigators also hypothesize that while achieving equivalent clinical and
microbiological success, and prevention of re-infections in the following 3 months, 3 days of
IV treatment reduces the risk of acquisition of resistant strains of Enterobacteriaceae and
increases the gut microbotia diversity compared to extending to 10 days with an oral therapy.
Description:
1.0 Hypothesis for the study
Antibiotic therapies currently recommended for the treatment of acute pyelonephritis (AP) in
children, whether fully by the oral route or initially intravenous (IV, 3 days) followed by
the oral route, have a duration of 7 to 14 days (10 days in France).
In children with no prior urological malformation, the global clinical and microbiological
cure rate after antibiotic treatment completion is around 95%. Recurrence occurs in less than
5% of cases in the 3 months following AP. Renal scarring, when documented, concerns 15% of
children 6 months after treatment. Renal scarring can be associated with chronic renal
disease.
The investigators hypothesize that 3 days of IV treatment is equivalent to extending to 10
days with an oral therapy to prevent long-term renal scarring.
The investigators also hypothesize that while achieving equivalent clinical and
microbiological success, and prevention of re-infections in the following 3 months, 3 days of
IV treatment reduces the risk of acquisition of resistant strains of Enterobacteriaceae and
increases the gut microbotia diversity compared to extending to 10 days with an oral therapy.
2.0 Description of knowledge relating to the condition in question
Acute pyelonephritis (AP) is the most common proven bacterial infection in pediatric clinical
practice. It can lead to sepsis or renal abscess and induce long-term complications such as
renal scarring. Renal scarring during childhood can lead to hypertension or chronic renal
disease at adult age, although the link between AP and chronic renal disease has not been
firmly established.
AP is most frequently due to Enterobacteriaceae, mainly Escherichia coli. Extended-spectrum
beta-lactamase producing Enterobacteriaceae (ESBL-E) now account for 5% of AP in France and
represent a serious threat to public health, owing to limited therapeutic options.
The overall clinical success rate in children treated for AP is around 95% and is not
significantly different when ESBL-E are implicated. In children with no prior urological
malformation, recurrence in the following 3 months occurs in less than 5% of cases.
Antibiotic treatment decreases the risk of renal scarring, which remains important, around
15% (95% CI: 11-18) in the largest meta-analysis. Moreover, delay in treatment of AP is
associated with permanent renal scarring.
In children without prior urological malformation, acute complications are exceptional, even
in the presence of bacteraemia. Short courses of intravenous (IV) antibiotics (2-4 days)
followed by oral therapy have proved to be as efficient as longer courses (7-14 days) of IV
treatment. For children aged ≥ 1 month, oral treatment alone for 10 to 14 days has proved non
inferior to initial IV antibiotics (2-4 days) followed by oral therapy (total 10 to 14 days).
French Paediatric guidelines recommend a short course (up to 4 days) of IV amikacin and/or
ceftriaxone followed by oral therapy (total 10 days), with the possibility, for children aged
> 3 months of a 10-day course of oral cefixime [12]. In children initially treated IV, the
oral relay occurs once the urine culture and antibiogram are available. The American
Association of Pediatrics that focused on children aged 2 to 24 months recommends either an
oral or a sequential IV/oral treatment for a total of 7 to 14 days, while the British NICE
guidelines recommend an exclusively oral route only for children aged ≥ 3 months
In practice, most centers initiate an IV treatment in a large subset of patients (ongoing
practice analysis on the management of AP in children in France, personal data, to be
published in 2021). An initial IV treatment is particularly used in young children, with an
age cut-off varying between 3 months and 3 years according to the center. It is also used to
secure the absorption of the treatment if the child vomits, is unable to take oral
antibiotics or is severely unwell.
The excellent short-term and the good long-term clinical outcomes in children treated for AP
questions the need for a 10-day course of antibiotics.
In adults, shorter treatments, such as amikacin for 5 days, have been validated for the
treatment of uncomplicated AP. Since the publication of studies demonstrating the
non-inferiority of oral vs IV treatment, no controlled trial has been published to shorten
the duration of antibiotic treatment for AP in children, whether oral or IV.
There are currently 2 ongoing non-inferiority controlled clinical trials
(http://clinicaltrials.gov) comparing a 5-day vs a 10-day oral treatment for urinary tract
infection in children between 2 months and 5 years (NCT04400110), or a 7-day vs a 10-day oral
treatment in children between 3 months and 7 years old (NCT03221504). A third controlled
clinical trial (NCT01595529) has ended its inclusions ad performed analysis but not yet
published in a peer-reviewed journal: it compared a 5-day vs a 10-day oral treatment for
urinary tract infection (febrile or not) in children between 2 months and 10 years old. Both
treatments resulted in high success rates (> 96%). The 5-day treatment tended to be inferior
to the 10-day one (p=0.054). However, the study allowed 4 different oral therapies
(Trimethoprim sulfamethoxazole, Cefixime, Cefdinir or Cephalexin) and results for each
subgroup are not yet available. Moreover, antibiotic treatments modify the diversity of the
gut microbiota. These disturbances, described as dysbiosis, are generally transient, but can
lead to a lasting and stable modification of the gut microbiota, and be involved in the
occurrence of chronic diseases in children as in adults.
Third-generation cephalosporins (3GC), such as ceftriaxone, rapidly reduce the richness and
diversity of the gut microbiota and also select subpopulations of resistant bacteria,
particularly by acquisition of extended spectrum beta-lactamases, a major public health
issue.
There is no data on the impact of antibiotic relays on the gut microbiota. Since each
antibiotic has its own anti-bacterial spectrum, a sequence of treatments could have an
additive or even synergistic deleterious effect on the gut microbiota. This may in particular
be the case in children treated with IV ceftriaxone for 3 days followed by cotrimoxazole for
7 days, as recommended in France in first intention.
3.0 Summary of relevant pre-clinical experiments and clinical trials
1999 Hoberman et al. Oral versus initial intravenous therapy for urinary tract infections in
young febrile children This was a non-inferiority study between oral cefixime for 14 days and
intravenous ceftriaxone for 3 days followed by oral cefixime for 11 days. One of the outcomes
was the occurrence of renal scarring. It included children aged 1 to 24 months. A total of
306 children were included. Renal scarring at 6 months was noted in 9.8% children treated
orally versus 7.2% of children treated intravenously. The study conclude that oral treatment
was safe.
The main limit of the study was the lower rate of renal scar in both arms compared to other
studies, probably linked to a female/male sex ratio of 9:1 (with a median age of 8 months),
when the sex ratio is in favour of boys before 1-year-old.
2007, Montini et al. Antibiotic treatment for pyelonephritis in children: multicentre
randomised controlled non-inferiority trial This was a multicentre, randomised controlled,
open labelled, parallel group, non-inferiority trial comparing oral co-amoxiclav for 10 days
to parenteral ceftriaxone for three days, followed by oral co-amoxiclav for 7 days. Primary
outcome was the rate of renal scarring after 12 months. A total of 502 children aged 1 month
to <7 years with clinical pyelonephritis were included. Intention to treat analysis showed no
significant differences between oral (n=244) and parenteral (n=258) treatment, both in the
primary outcome (scarring scintigraphy at 12 months 27/197 (13.7%) v 36/203 (17.7%), and
secondary outcomes: time to defervescence, white cell count at day 3, and percentage with
sterile urine at day 3 (99.5% n both arms). The results were similar in the subgroups of
children older and younger than 2 years (data not shown in the paper).
2012, Boquet et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute
pyelonephritis in children PHRC AOM 04 105; NCT00136656 This was a non-inferiority study
between oral cefixime for 10 days and IV ceftriaxone for 4 days followed by oral cefixime for
6 days on the occurrence of renal scarring. It included children aged 1 to 36 mont with a
first proven urinary tract infection and procalcitonin concentration ≥ 0.5 ng/mL s. The
primary endpoint was the proportion of renal scar measured by 99mTc-DMSA renal scintigraphy 6
to 8 months after treatment. The study included a total 171 children of the 698 expected. The
incidence of renal scarring was 30.8% in the oral treatment group and 27.3% for children who
received the sequential treatment. The trial could not demonstrate statistically the
non-inferiority due to insufficient enrolment.
Comment: The protocol was demanding for participants: each child had a first 99mTc-DMSA renal
scintigraphy upon diagnosis, and for those with abnormal scintigraphy, a second 6 to 8 months
later to evaluate renal scar. All children also had a voiding cystography. The 99mTc-DMSA
scintigraphy to measure renal scarring led to fewer than 12% lost to follow. The association
of 2 9mTc-DMSA renal scintigraphy probably limited the acceptance of the protocol, which
explains that we chose to perform only one scintigraphy at the end of the evaluation.
The higher renal scarring than in the study by Montini et al may in part be explained by the
additional inclusion criteria of a procalcitonin concentration ≥ 0.5 ng/mL, a level being
associated with renal scars
