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Indian Pediatr 2016;53: 519-522 |
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Can We Predict Antibiotic-resistance in
Urinary Tract Infection?
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Source Citation: Marin M, Marti M, Kambhampati A,
Jeram SM, Seward JF. Global varicella vaccine effectiveness: A
meta-analysis. Pediatrics. 2016;137:1-10.
Section Editor: Abhijeet Saha
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Summary
In this study, 769 children (age 2-71 mo) enrolled in
the Randomized Intervention for Children with Vesicoureteral Reflux
(RIVUR) or Careful Urinary Tract Infection Evaluation (CUTIE) studies
were included to determine the risk factors of having pathogens
resistant to narrow spectrum antimicrobials in urinary tract infection
(UTI). The authors used logistic regression models to test the
associations between demographic and clinical characteristics and
resistance to narrow spectrum antimicrobials. Of the included patients,
91% were females, and 76% had vesicoureteral reflux. The odds of
resistance to narrow-spectrum antibiotics in uncircumcised males were
approximately 3 times that of females (OR 3.1; 95% CI 1.4, 6.7); in
children with bladder bowel dysfunction, the odds were 2 times that of
children with normal function (OR 2.2; 95% CI 1.2, 4.1). Children who
had received one course of antibiotics during the past 6 months also had
higher odds of harboring resistant organisms (OR 1.6; 95% CI 1.1, 2.3).
Hispanic children had higher odds of harbouring pathogens resistant to
some narrow-spectrum antimicrobials. The authors concluded that
uncircumcised males, hispanic children, children with bladder bowel
dysfunction, and children who received a course of antibiotics in the
past 6 months were more likely to have a urinary tract infection caused
by pathogens resistant to one or more narrow-spectrum antimicrobials.
Commentaries
Evidence-based Medicine Viewpoint
Relevance: Urinary tract infection (UTI) is a
fairly common clinical problem, occurring in upto 10% female and 3% male
infants and toddlers [1]. Children with vesico-ureteric reflux (VUR)
have greater risk of recurrent episodes and potentially serious
consequences, including renal scarring [2]. Appropriate administration
of antibiotic therapy is therefore vital, and guidance for choice of
initial empiric antibiotics is important.
Critical appraisal: In a sense, this report
represents analysis of data obtained from the primary studies. The
commendable aspects include clear definitions of UTI and VUR. The
primary studies included infants and children with their first or second
episode of UTI, yet none were receiving antibiotic prophylaxis. This is
somewhat unusual considering that the bulk of evidence and clinical
guidelines recommend VUR screening and antibiotic prophylaxis following
the first episode of (confirmed) UTI [3].
In this analysis, antibiotics were appropriately
grouped according to class, taking care to exclude cephalothin from the
first generation cephalosporins, on account of its inconsistent
association of resistance with the other agents in the same class. As
data were pooled from sites participating in the primary studies, and
antibiogram protocols were not uniform across sites, it is difficult to
assess whether some of the geographic differences could be explained by
this. The investigators examined data separately for E. coli and
other organisms; although their type and frequency are not described.
The investigators examined the effect of presence,
and grade of VUR on antibiotic resistance, but the results are presented
only for the grade of VUR. Analysis of patterns among those with (and
without VUR) would have helped to understand differences in the pattern
of pathogens, antibiotic sensitivity pattern(s), and clinical
implications for corresponding episodes of UTI in those without VUR. It
is unclear whether the data of the relatively few boys in this analysis
could be representative of the whole sex, especially considering that
boys often have other underlying conditions predisposing to UTI
episodes.
What can we learn from this data analysis? It is
difficult to confirm whether the differences are mere statistical
artifacts, or clinically meaningful. This is because none of the
‘predictors’ showed consistency across all antibiotics studied.
Similarly some differences are difficult to explain, such as why one
prior course of antibiotic increases the likelihood of resistance;
whereas two or more courses (within the same time frame) have no
apparent effect. Some observations could have a genetic basis; for
example Hispanic children could have different pharmacokinetics for
trimethoprim-sulphamethoxazole, compared to other groups. But in the
absence of further information, no meaningful conclusions can be drawn.
Similarly, the observation of more frequent resistance in one geographic
region is unhelpful without additional data.
Therefore, it is pertinent to examine the data from
this analysis [4] against the backdrop of other available data. In this
analysis, E. coli was the most prevalent organism, and it showed
variable degrees of resistance to different antibiotics, but especially
high resistance to amoxicillin. This is in consonance with data from
various developing countries, including India [5-13].
Prior antibiotic therapy has been associated with
subsequent infection by resistant organisms in diverse settings. This is
a pattern consistent with UTI as well as other infections [14-19]. The
pattern seems consistent irrespective of age, site of initial infection,
or whether the subsequent infection is with the same or a different
organism. In this light, this analysis [4] does not provide new
information. There is ample evidence that antibiotic therapy results in
selection of organisms that are resistant (or can develop resistance).
Recent hypotheses suggest that the gap between the minimum inhibitory
concentration (MIC) of antibiotic and the mutant prevention
concentration (MPC) called the ‘mutant selection window’ creates a range
wherein resistant mutants are more likely to thrive [20]. Against this
backdrop, the investigators’ recommendation [4] that children having
characteristics associated with greater resistance to specific
narrow-spectrum antibiotics should be treated with broader spectrum
agents or another antibiotic, appears too simplistic. Although this may
work in the short-term reducing the risk of treatment failure in
individual children, it would likely create greater problems with
resistant organisms in the long term.
A previous retrospective analysis [14] in infants and
pre-school children showed a significantly higher risk of UTI with a
resistant organism among those who had received amoxicillin in the
preceding 30 as well as 60 days, but not those who received it earlier
than 60 days. Based on this information, it would have been very helpful
if this analysis [4] had provided more detailed description of the
relationship with time. This may be especially important, because
another analysis of data from the RIVUR trial (on which the current
report also is based) suggested that, even though
trimethoprim-sulphamethoxazole resistance increased with prior usage, it
decreased over time, and there was no significant difference in
recurrence of UTI episodes between those children whose first episode
was with resistant organisms, versus those with sensitive
organisms [21].
Previous studies have shown that circumcision of
infants with antenatally detected hydronephrosis [22] and posterior
urethral valves [23], can help to prevent frequent UTI episodes. Data
from systematic reviews also suggest that circumcision is associated
with lower frequency of first [24] and subsequent [25] UTI episodes,
although the number-needed-to-treat for the latter benefit is very high.
Against this backdrop, the data from this analysis [4] showing higher
frequency of UTI with resistant organisms among uncircumcised boys is
interesting. However, it would have been more helpful if the data were
compared with uncircumcised boys rather than girls, and more information
on underlying conditions in both sets of boys were presented. Of course,
it must be emphasized that circumcision under consideration, is that
performed by qualified personnel using aseptic techniques, as UTI
appears to be more frequent following ritualistic/traditional
circumcision procedures [26].
Extendibility: What lesson can be learnt
from this analysis, for the Indian context? Considering the rampant,
relatively unregulated, and often inappropriate use of (prescribed and
unprescribed) antibiotics in our country, selection of resistant clones
of almost every pathogen is inevitable. Further, many of these
‘antibiotic courses’ are not completed, thereby further encouraging
selection of resistant organisms. Perhaps the most important lesson from
this analysis [4] relates to antibiotic stewardship and restraint
policies, which are otherwise outside the scope of this discussion. The
other conclusions from the authors [4] are not very useful for
application in the Indian context.
Conclusion: This analysis of data from two
prospective studies suggests that prior antibiotic usage could result in
(first or subsequent) UTI with resistant organisms in infants and
toddlers. However there are limitations that preclude drawing specific
conclusions for evidence-based management and/or prophylaxis decisions.
Funding: None; Competing interest: None
stated.
Joseph L Mathew
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email: [email protected]
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Pediatric Nephrologist’s Viewpoint
Delayed treatment of urinary tract infection (UTI)
may aggravate renal damage [1]. Hence early initiation of a sensitive
antibiotic is important, but this should be balanced by avoiding
inappropriate use of broad spectrum antibiotic [2]. Keeping this in
perspective, the study by Shaikh, et al. [3] analyzing the
antibiotic resistance pattern among children with UTI assumes
importance.
In a sub-analysis of data gained from the large RIVUR
and the parallel run CUTIE studies, the authors found that none of the
narrow spectrum antibiotics [first generation cephalosporin (1 stGenC),
trimethoprim-sulfamethoxazole, nitrofurantoin and amoxicillin] covered
significantly both E Coli and non-E Coli pathogens. It
recommended the use of 2nd/3rdGenC
for UTI with suspected kidney involvement whereas in an afebrile child 1stGenC
may suffice. As this has potential to change practice, it is important
to assess its applicability in Indian scenario.
Indian studies although few in numbers have also
demonstrated high incidence of resistance even in community-acquired UTI
[4]. Although resistance to most of the narrow spectrum antibiotics are
similar, organisms have been found to be resistant to even broader
spectrum antibiotics, including 2 nd/3rdGenC
[4,5]. The findings by Shaikh, et al. [3] that certain group of
children are more prone to have antibiotic resistance can be a useful
guide while selecting antibiotic, but local antibiotic sensitivity
patterns are to be considered. Lastly, we have to remember that even the
RIVUR’s cohort has been questioned regarding its true representativeness
for the population we commonly encounter [6].
In summary, the publication by Shaikh, et al.
[3], though interesting, has to be interpreted in light of local
practice/population, and may not be completely reproducible in the
practice of an Indian paediatric nephrologist.
Funding: None; Competing interest: None
stated.
Rajiv Sinha
Department of Pediatrics,
Institute of Child Health, Kolkata, India.
Email: [email protected]
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3. Shaikh N, Hoberman A, Keren R, Ivanova A,
Gotman N, Chesney RW, et al. Predictors of antimicrobial
resistance among pathogens causing urinary tract infection in
children. J Pediatr. 2016; 171:116-21.
4. Sharan R, Kumar D, Mukherjee B. Bacteriology
and antibiotic resistance pattern in community acquired urinary
tract infection. Indian Pediatr. 2013;50:707.
5. Gupta P, Mandal J, Krishnamurthy S, Barathi D,
Pandit N. Profile of urinary tract infections in paediatric
patients. Indian J Med Res. 2015;141:473-7.
6. Ingelfinger JR, Stapleton FB. Antibiotic prophylaxis for
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