Randomized trial of oral versus sequential IV/oral antibiotic for acute
pyelonephritis in children.
Bocquet N, Sergent Alaoui A, Jais JP, Gajdos V, Guigonis V, Lacour B, Chéron G.
Background questions: short answer, list resource
1. What is a urinary tract infection (UTI)?
 Infection of the urinary tract caused by bacteria, viruses and fungi (bacteria is
most common source), worsens the higher it goes up the urinary tract
http://kidney.niddk.nih.gov/kudiseases/pubs/utiadult/#uti
2. What is a bladder infection versus pyelonephritis?
 Bladder infection (Cystitis): inflammation of the urinary bladder; symptoms
include: dysuria, frequency, urgency, malodorous urine, enuresis,
hematuria, and suprapubic pain
 Kidney infection (Pyelonephritis): pyogenic (pus-producins) infection of the
kidney; symptoms include: fever (100 F or greater), chills, along with
costovertebral angle or flank pain and tenderness
http://www.medscape.com/viewarticle/507162_6
3. What are the top three microorganisms responsible in causing a UTI?
1. Escherichia coli
2. Staphylococcus saprophyticus
3. Klebsiella
(others include Proteus, Pseudomonas, and Enterobacter)
4. What categories of antibiotics are considered to treat UTI’s? Of these antibiotics which
cannot be used in children?
For Adults:
Generic Name
Brand Name
ciprofloxacin
Cipro
levofloxacin
Levaquin
nitrofurantoin
Furadantin, Macrobid, Macrodantin
sulfamethoxazole with trimethoprim
Bactrim, Septra
For Children:
Generic Name
Brand Name
amoxicillin
Dispermox, Larotid
amoxicillin and clavulanate
Augmentin
cefixime
Suprax
nitrofurantoin
Furadantin, Macrobid, Macrodantin
sulfamethoxazole and trimethoprim
Bactrim, Septra
5. What are the long term complications of untreated pyelonephritis in pediatrics?
Untreated pyelonephritis can lead to permanent kidney damage or loss of the
kidney, scarring of the kidney sepsis, or blood poisoning and death.
MAARIE Analysis:
Method:
•
clearly defined study question or hypothesis:
To confirm whether oral antibiotic treatment is as efficacious as sequential
intravenous/oral antibiotic treatment in the prevention of renal scarring in children with
acute pyelonephritis and scintigraphy-documented acute lesions.
•
Is what they wanted to study, what they actually studied?
Yes, they had two treatment groups: one group received oral antibiotics for 10
days and the other group received IV antibiotics for 4 days and oral antibiotics for the
following 6 days. They measured their results by comparing the number of children
who developed renal scarring. This is the appropriate method of study to answer this
question. However, they chose one particular antibiotic to study so their results only
reflect the comparison of treatment method for that antibiotic.
•
must be specific, clear & appropriate to study type
Assignment:
•
method of assignment?
This was a prospective randomized trial comparing the effects of oral sequential
antibiotic regimens. A Sample population of 1-36 months with their first case of
pyelonephritis. Inclusion criteria is that participants must have a serum procalcitonin
concentration ≥0.5 ng/mL, no known uropathy, and a normal ultrasound exam.
Exclusion criteria is patients that are not in the age range of 1-36 months, patients with
initial ultrasound exam revealing obstructive uropathy, renal hypoplasia, or signs of
renal abscess, those with an allergy to the study drugs, who received antibiotic
treatment in the 5 days before inclusion, patients judged as severally ill or had vomiting
and diarrhea, patients whose parents refused or those with Medicaid insurance.
Furthermore, patients with cultures of more than one type of bacteria, patients with
serum PCT concentration <0.5 ng/mL, patients with normal initial DMSA scintigraphy, or
if they have recurrence of pyelonephritis before the second DMSA scintigraphy, were
excluded. 171 infants were studied and randomly placed into two groups with no
significant difference between the two groups.
•
confounding variables?
A confounding variable may be that the patients were recruited form patients
that presented to the ER with febrile UTI. This means that those patients that have a UTI
may go to their pediatrician for care rather than the ER and would be excluded from the
study.
•
masking or blinding?
No, the kids were given either oral medications or IV. The parents were given
the oral medications.
Assessment:
•
appropriate measurement to address question?
Incidence of renal scarring

Precise and accurate measurement?
Precise: produces nearly identical results when repeated under the same conditions. It
has minimum variation as a result of the effects of chance; there is minimal random
error. --- I didn’t see any places in the article where they repeated any tests to double
check for errors made.
Accurate: on average, it has the same numerical value as the phenomenon being
investigated. It is free of systematic error or bias. ---- All patients had an ultrasound
exam before randomization to make sure no patients had no signs of obstructive
uropathy, renal hypoplasia, or renal abscess.

Complete assessment and unaffected by observation?
Complete: outcomes or endpoints of all participants have been measured.
--- 6 to 8 months after the infection, all children were checked for renal scarring.
Unaffected by the observation: neither the participants’ nor the investigators’
knowledge of the study group or control group assignment affects the measurement of
outcome. Also, the process of observation itself doesn’t affect the outcome.
---- All renal scars were viewed secondarily by 2 independent nuclear medicine experts who
were unaware of the treatment that had been assigned to the patients.
Results
•
Estimation? what methods for magnitude or strength of association?
 Categorical data between study groups (oral treatment vs. sequential treatment) was
compared with the chi square test
 Quantitative data was compared using the Wilcoxon rank test
Inference: how statistically significant?
•
95% confidence interval used for incidence of renal scarring (p < 0.05 is significant)
•
Found no significant difference in renal scarring between oral treatment group and the
sequential treatment group.
•
adjustment: what methods used to account for differences between study & control
group that may affect results?
The researchers looked at the incidence of renal scarring of the two groups as a whole, as well
as in sub groups. For instance, they looked at the IV and PO groups as a whole, as well as those
groups for children 1 year or young, and aged 1-3 years. They then could compare sub groups
to one another to account for difference due to age.
•
The researchers also followed a very strict selection process of the participants (such as it
had to be the first occurrence of APN, had to undergo US and other testing to rule out other
common possible causes, to assure antibiotic sensitivity, not allowing children who had sick
parents, etc.). They also occluded participants who, after further investigation, were not
sensitive to the antibiotic or had other underlying conditions.
•
After initial assessment of patient, there were 171 participants. That number went down
to 119 due to a range of reasons: Problem with urine culture, violation of protocol, consent
withdrawal, absence of initial scintigraphy, normal initial scintigraphy, and problems with PCT
measurement. These help to account for differences.
•
Only used pts with UTIs caused by E. coli.
•
They also made sure the demographics of both the PO and IV treatment were very similar
(can be seen in Table 1), such as age, gender, initial fever, etc.
Interpretation
•
association? cause with effect more often than chance?
No cause and effect reported. The main finding of this experiment is that PO vs IV
antibiotic treatment did not have an effect on renal scarring after having APN. The article
states that there is “no currently available antibiotic therapy … able to prevent renal scarring
after pyelonephritis”. The researchers were unable “to conclude whether the oral treatment is
noninferior because our data study lack sufficient power”
•
prior association? cause before effect? Does the investigation establish that the “cause”
precedes the “effect”?
Cause – Treatment (Oral or Sequential); Effect – (presence or absence of) renal scarring
The objective of the study was to determine if the amount of risk of developing scarring
was dependent upon the type of treatment given. Participants were only included in the
study if they had not already received treatment, has Serum PCT levels ≥ 0.5 ng/ml, and
if they showed lesions on the initial DMSA scintigraphy (there were also other
qualifications). This ensured that that the treatment provided by the researchers was
the only treatment given, and also made sure that all of the participants were at risk for
developing the scarring. The cause did indeed precede the effect.
•
altering the cause alters the effect?
Does the investigation establish that altering or modifying the frequency or severity of
the “cause” alters the frequency or severity of the disease or other effect”?
1. Strength of Association: Both treatments produced the same outcome, so they have
a strong association with the effect. The only treatment that was not tested was to
not treat the condition at all and see what the effects were. This is unethical, so it
would not be performed.
2. Consistency of Association: The study identified participants that were at risk for the
effect, and so the population was homogenous. The different characteristics that
were present, such as age and gender, did not have an impact on the effect.
3. Biological Plausibility: Even though the treatments were administered differently,
but both produced the same pharmacological effects and were excreted the same
way, and so it makes sense that the incidences of renal scarring for each were
comparable.
4. Dose-Response Relationship: To under-medicate or over-medicate are unethical, so
these effects were not observed.
Extrapolation
•
What assumptions needed to extrapolate beyond the data? to groups similar to study
group?
•
to outside the study population?
This trial does not statistically demonstrate non-inferiority (Non-inferiority clinical trial: A clinical
trial that shows that a new treatment is equivalent to standard treatment) of clinical treatment
compared with sequential treatment.
The outside study population must take into consideration why certain groups were not eligible for the
study.
The study excluded infants and children with the following characteristics:

Aged <1 month, prematurely born with a corrected age of <1 month, or aged >36
months

Initial ultrasound exam revealing obstructive uropathy, renal hypoplasia, or signs of
renal abscess

Allergy to the study drugs

Received antibiotic treatment in the 5 days before inclusion

Patients judged as severally ill (prolonged capillary refill; high or low blood pressure)

Vomiting or diarrhea that could have precluded administration of oral antibiotics

Refusal from 1 or both parents

Parental misunderstanding or unsure adherence

No Medicaid
Secondarily, infants and children excluded with the following:

Urinary culture with no bacteria, more than 1 type of bacteria, or bacteria resistant to
the study antibiotics

Serum PCT concentration <0.5 ng/mL after quantitative measurement

Normal initial DMSA scintigraphy

Recurrence of pyelonephritis before the second DMSA scintigraphy
1- What assumptions are needed to extrapolate beyond the data?
You must assume that patients will be compliant with oral antibiotic therapy and/or available for
close follow-up. You also must assume that the side effects of therapy will be worth the risk
based on patient prognosis. You also must assume the availability of specialized imaging
equipment, specifically dimercaptosuccinic acid scintigraphy, ultrasound, and voiding cystography
to detect the presence of vesicoureteral reflux. You must assume that the therapy will be
available to you patient (affordable, insurance coverage, etc.).
2- What assumptions are needed to extrapolate to groups similar to the study group?
You must assume that the group is at risk for renal scarring, for there to even be a disparity
between different treatment options. You must also assume that their etiology of infection is
similar in that it involves gram negative bacteria (that is not 3 rd generation cephalosporin
resistant) and elicits renal involvement. You would have to assume that this is their first
infection, and that they have no previous renal scarring. Again you would have to assume that
the therapy would be worth the risk of side effects in patients with a less severe prognosis.