3-day IV Antibiotic Treatment Versus 3-day IV Followed by 7-day Oral Antibiotic Treatment for AP in Children

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.

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

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 1 month and \< 3 years
* For children younger than 3 months, gestational age \> 34 WA
* First episode of urinary tract infection
* AP defined by temperature ≥ 38°C on day of diagnosis AND positive urinalysis (white cell counts ≥ 10\^4/mL)
* Initial treatment by either ceftriaxone AND/OR amikacin
* Outpatient or hospitalised

Non-inclusion Criteria:

* Urine collected by bag
* Urine culture growing more than one dominant bacterium (cf section 6.2 of the protocol)
* Catheter-associated AP
* Known congenital anomalies of the kidney and genitourinary tract (other than vesicoureteral reflux and pyelocaliceal dilatation \< 10 mm)
* Previous surgery of the genitourinary tract (except circumcision in male children)
* Abnormal renal function for age and weight (defined by a serum creatinine \>40µmol/L before 1 year and \>75µmol between 1 year et 3 years)
* Known immunocompromising condition (e.g., HIV, primary immunodeficiency, sickle cell disease, use of chronic corticosteroids or other immunosuppressive agents)
* Antibiotic prophylaxis for any reason OR antibiotic treatment in the last 7 days (except treatment administered for the AP)
* Known hypersensitivity to at least one of the active substances /excipients: ceftriaxone (include cephalosporin et beta-lactams) and amikacin (include aminoside)
* Known hypersensitivity to at least one of the active substances /excipients: cotrimoxazole (=sulfamethoxazole/trimethoprim) (include sulfonamide) and cefixime (include cephalosporin)
* Known hypersensitivity to 99mTc-DMSA (medicinal product used for renal scintigraphy)
* Known severe hepatic insufficiency
* Known G6PD deficiency
* No written consent from holders of parental authority
* Non-affiliation to a social security system (as beneficiary or entitled person)
* Children whose follow-up is not carried out in the centre
* Participation in another interventional or minimal risk trial

Randomization criteria :

* Three days of taking antibiotics (IV or IM) (no interruption or discontinuation)
* Positive urine culture with Gram negative bacillus ≥ 10\^4 UFC/mL
* Favorable clinical outcome at day of randomization (D2 or D3) defined by temperature \< 38°C at day of randomization and absence of fever measured \> 38°C for at least 12 hours AND no abdominal pain AND no feeding problem AND investigator agreement
* No renal abscess AND congenital anomalies of the kidney and genitourinary tract (other than vesicoureteral reflux and pyelocaliceal dilatation \< 10 mm) on the renal ultrasound performed between D0 and day of randomization
* No more than 1 type of dominant bacteria on the urine culture
* Sensitivity to the initial antibiotic treatment
* Sensitivity to cefixime OR cotrimoxazole