ABSTRACT
Objectives: To evaluate the antibiotic resistance patterns in common uropathogens isolated from pediatric patients.
Methods: This was a retrospective chart review on the uropathogens causing first-time, community-acquired, symptomatic urinary tract infection (UTI). The data for this study was collected from one tertiary care hospital and 4 primary care centers in Riyadh, Saudi Arabia, with data spanning from 2017-2022. Diagnosis of UTIs was in line with the guidelines of the American Academy of Pediatrics.
Results: Isolates were gathered from 610 patients, 101 (16.6%) of whom were male and 509 (83.4%) were female. The 3 most common species isolated were Escherichia coli (E. coli; 50.5% in males and 82.7% in females), Klebsiella pneumoniae (K. pneumoniae; 28.7% males and 10.4% females), and then Proteus mirabilis (5.9% males and 2.9% in females). Escherichia coli was more prevalent in females than in males (p<0.001). Multidrugresistant E. coli was isolated more often from males than in females (39.2% versus 23.5%, p=0.014). A similar but non-significant trend was observed in multidrug-resistant K. pneumoniae (48.1% versus 30.8%, p=0.128), extended-spectrum beta-lactamase (ESBL) producing E. coli (13.7% versus 11.9%, p=0.701), and ESBL-producing K. pneumoniae (18.5% versus 7.7%, p=0.151).
Conclusion: Our study indicates that surveillance of uropathogen resistance should differentiate between isolates gathered from male and female patients. This study also indicates a possible increase in ESBL-producing E. coli isolates, and an increase in multidrug-resistant E. coli isolates.
The misuse and overuse of antibiotics has led to bacteria developing mechanisms to overcome the efficacy of antibiotics; this is known as antibiotic resistance. Antibiotic resistance is an emerging threat that is affecting public health. In 2019, infections with bacteria that were antibiotic resistant were responsible for over one million fatalities worldwide and approximately 2,500 deaths in Saudi Arabia.1,2 It is also estimated that 33,110 deaths in the European Union in 2015 can be attributed to infections with bacteria that were resistant to antimicrobials.3
Antibiotic resistance is especially dangerous for pediatric patients, as infection with multidrug-resistant (MDR) bacteria increases morbidity and mortality, and the mortality rate due to antibiotic resistant bacteria will only increase without proper intervention.4 The effect of antibiotic-resistant bacteria is even more apparent in urinary tract infections (UTIs) in children, where up to 83% of the causative uropathogens were found to be resistant to first-line treatment options. In contrast, up to 58% of the causative uropathogens in adults were resistant to first-line treatment options.5,6 It was also found that pediatric patients up to 5 years old were most susceptible to infections with multidrug-resistant bacteria out of any other age group.7
While there are some local studies on antimicrobial resistance, most of them are limited to specific pathogens (namely, Escherichia coli [E. coli]), and many more do not differentiate between adult and pediatric patients nor between isolates gathered from male and female patients. Despite some local studies on antibiotic resistance, the consumption of antibiotics continues to be higher than the international average.8,9 The importance of gathering statistics on antibiotic resistant bacteria is clear now more than ever, as infections that were once easy to treat, now require extensive testing and more complex treatment strategies.10
Studies on antibiotic resistance are insufficient in Saudi Arabia, but resistance patterns of infections in pediatric patients are especially sparse. Local studies on cases of antibiotic resistance in pediatrics are primarily focused on the resistance of a specific pathogen rather than a more comprehensive view of the resistance patterns within an infectious disease entity. This study aimed to evaluate resistance patterns of the causative pathogens of UTIs affecting pediatric patients at a hospital network in Riyadh, Saudi Arabia.
Methods
This study was a retrospective chart review that investigated the causative uropathogens and their respective resistance to antibiotics in first-time, community-acquired urinary tract infection (CAUTI). The study was carried out in 5 centers under the umbrella of the Ministry of National Guard Health Affairs, all of which were in Riyadh, Saudi Arabia. Our study focused on patients treated in the emergency department and outpatient care. The data gathered spanned over a 6-year period from 2017-2022. The data collected included patient diagnoses, medications prescribed, cultures of the organisms isolated, and testing of their respective susceptibility to antibiotics.
In accordance with the guidelines of the American Academy of Pediatrics, the following guidelines were used as the definition of UTI: growth of 1,000 colony-forming units (CFUs) per mL from suprapubic aspiration, 50,000 CFUs/mL for catheter samples, or 100,000 CFUs/mL for clean catch samples.11
Patients aged 0-15 with a first-time diagnosis of symptomatic UTI with bacteria as the causative pathogen were included. Organ transplant patients and stem cell transplant patients, along with healthcare-associated infections, were excluded.
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia, provided a complete data set from the centers, including patient diagnosis, medications prescribed, culture results, and culture sensitivity results.
Statistical analysis
OpenEpi was used to carry out Chi-square tests to assess the differences between isolates gathered from male versus female patients, and a p-value of <0.05 was considered significant.
Results
Out of the isolates gathered, 610 fit the inclusion criteria, 509 (83.4%) of which were from female patients, whereas only 101 (16.5%) were from male patients. When including both genders, 389 (63.7%) were 5 years old or younger. There were 172 patients less than one year old; and of those, 125 (72.7%) were female, whereas only 47 (27.3%) were male (p<0.001, Table 1).
- Age distribution of patients, stratified by gender.
Escherichia coli was most common, with 421 (82.7%) isolates from female and 51 (50.5%) from male patients. Second most prevalent was Klebsiella pneumoniae (K. pneumoniae) with 52 (10.2%) isolates from female patients and 27 (26.7%) from male patients, and third most common, Proteus mirabilis (P. mirabilis) with 15 (2.9%) isolates from female patients and 6 (5.9%) from male patients (Table 2).
- Distribution of uropathogen species, stratified by gender.
Table 2 includes one more Klebsiella isolate from female patients, and 2 more Klebsiella isolates from male patients, and these were Klebsiella oxytoca (K. oxytoca) isolates. Therefore, the Klebsiella isolates gathered were 52 K. pneumoniae and one K. oxytoca isolates from females, and 27 K. pneumoniae and 2 K. oxytoca specimens from males.
When comparing the ratio of E. coli to non-E. coli isolates affecting male and female individuals, it was found that males were more likely to present with non-E. coli UTI (p<0.001, Table 3).
- Escherichia coli verses non-Escherichia coli isolates, stratified by gender (p<0.001).
From the isolates collected from females, E. coli was shown to be highly sensitive to nitrofurantoin, with 392 (96.3%) tested isolates being sensitive; only 2 (0.5%) resistant and 13 (3.2%) intermediate susceptibility isolates were found. Trimethoprim/sulfamethoxazole (TMP/SMX) showed lesser efficacy, with 260 (63.1%) of the tested isolates being sensitive and 152 (36.9%) being resistant. The isolates collected showed similar susceptibility to ceftriaxone with 324 (78.6%) and ciprofloxacin with 305 (76.6%) tested isolates being sensitive to both, while 87 (21.1%) tested specimens were resistant to ceftriaxone and 62 (15.6%) were resistant to ciprofloxacin; however, where the tested isolates only included one that had intermediate susceptibility to ceftriaxone, 31 (7.8%) of the isolates tested for ciprofloxacin sensitivity showed intermediate susceptibility. A total of 324 samples were tested for ampicillin susceptibility, 199 (61.4%) were resistant, one was of intermediate susceptibility, and 124 (38.3%) isolates were sensitive (Table 4).
- Resistance patterns of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis isolates, stratified by gender.
Escherichia coli isolates from males tested for nitrofurantoin showed promising susceptibility, with 41 (97.6%) sensitive isolates and one (2.3%) isolate with intermediate susceptibility. Of the isolates tested for TMP/SMX susceptibility, 23 (52.3%) were sensitive, and 21 (47.7%) were resistant. Isolates tested for ceftriaxone susceptibility showed 29 (63%) sensitive isolates and 17 (37%) resistant isolates and ciprofloxacin susceptibility showed 20 (47.6%) sensitive isolates and 16 (38.1%) resistant isolates; although, 6 (14.3%) isolates had intermediate susceptibility to ciprofloxacin. A total of 41 isolates were tested for ampicillin susceptibility, 32 (78%) were resistant, 8 (19.5%) were sensitive, and one isolate had intermediate susceptibility to ampicillin (Table 4).
There were 52 K. pneumoniae isolates collected from female patients, 49 of which were tested for ampicillin susceptibility; all 49 tested isolates were resistant to ampicillin. A total of 44 K. pneumoniae isolates were tested for nitrofurantoin susceptibility, 17 (38.6%) isolates were sensitive, 5 (11.4%) were resistant, and 22 (50%) were of intermediate susceptibility to nitrofurantoin. A total of 44 isolates were also tested for TMP/SMX susceptibility, 35 (79.6%) of which were sensitive, whereas 9 (20.4%) isolates were resistant to TMP/SMX. Of the isolates tested for ceftriaxone susceptibility, 38 (80.8%) were sensitive, and 9 (19.1%) were resistant. 30 (69.7%) of isolates tested for ciprofloxacin susceptibility were sensitive, 6 (13.9%) were resistant, and an additional 7 (16.3%) were of intermediate susceptibility, unlike ceftriaxone (Table 4)
In the case of K. pneumoniae, only 27 specimens were gathered from males, 25 of which were tested for ampicillin susceptibility and were all resistant. Of the 20 isolates tested for nitrofurantoin susceptibility, 7 (35%) were sensitive, one was resistant, and 12 (60%) were of intermediate susceptibility to nitrofurantoin. A total of 19 isolates were tested for TMP/SMX susceptibility, 5 (26.3%) isolates were sensitive, whereas 14 (73.7%) were resistant. All but one isolate were tested for ceftriaxone susceptibility, 16 (61.5%) isolates were sensitive, but 10 (38.4%) were resistant. A total of 19 isolates were tested for ciprofloxacin susceptibility, 9 (47.3%) isolates were sensitive, 6 (31.5%) were resistant, and 4 (21%) were of intermediate susceptibility to ciprofloxacin. Gentamicin susceptibility was also tested, 20 (95.2%) isolates were sensitive, and one isolate was resistant (Table 4).
A total of 15 isolates of P. mirabilis were collected from females, all of which were tested for nitrofurantoin susceptibility, all 15 were resistant to nitrofurantoin. All 15 isolates were also tested for TMP/SMX susceptibility, 11 (73.3%) were sensitive, and 4 (26.6%) were resistant. The isolates were also tested for ceftriaxone and ciprofloxacin; the isolates had the same susceptibility to both, with 13 (86.6%) isolates sensitive and 2 (13.3%) isolates resistant to ceftriaxone and ciprofloxacin (Table 4).
A multidrug-resistant isolate was defined as an isolate with non-susceptibility (whether resistance or intermediate susceptibility) to at least one antibiotic agent within 3 or more separate antibiotic categories.12 With that in mind 99 (23.5%) of the 421 E. coli isolates gathered from females were MDR, compared to the 20 (39.2%) out of a total of 51 E. coli isolates gathered from males (p=0.014). Klebsiella pneumoniae isolates gathered from females had 16 (30.8%) MDR isolates out of the 52 total isolates collected, whereas K. pneumoniae isolates from males had 13 (48.1%) MDR isolates out of the 27 total isolates (p=0.128, Figure 1).
- Multidrug-resistant and extended-spectrum beta lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates, stratified by gender. MDR: multidrug-resistant, E. coli: Escherichia coli, K. pnemoniae: Klebsiella pneumoniae, ESBL: extended-spectrum beta lactamase
Extended spectrum beta-lactamase (ESBL)-producing isolates were found among the E. coli and K. pneumoniae specimens collected from both males and females. From the 421 E. coli isolates gathered from females, 50 (11.9%) of them were found to be ESBL-producing E. coli isolates, whereas of the 51 E. coli isolates gathered from males, 7 (13.7%) of them were ESBL-producing isolates (p=0.701). On the other hand, of the 52 K. pneumoniae isolates collected from females, 4 (7.7%) were ESBL-producing, compared to the K. pneumoniae isolates gathered from males which contained 5 (18.5%) ESBL-producing isolates out of the 27 isolates in total (p=0.151, Figure 1).
A statistically significant difference was found between the amount of non-E. coli isolates causing UTI in males compared to females, with males being more likely to have a non-E. coli UTI (p<0.001). When comparing the E. coli isolates gathered from males and females, specimens from males were more likely to be resistant/intermediate susceptibility to ampicillin (p=0.018), ceftriaxone (p=0.016), and ciprofloxacin (p<0.001).
When comparing the ESBL-producing E. coli isolates gathered from males and females, no statistically significant difference was found (p=0.701). However, it was found that MDR E. coli isolates affected males more (p=0.014).
Regarding K. pnemoniae isolates, a proportionally larger number of isolates gathered from male patients were non-susceptible to ceftriaxone (p=0.071) and ciprofloxacin (p=0.092) compared to isolates gathered from females. However, the results are not statistically significant, which may change if the sample size for K. pneumoniae isolates increases. Interestingly, TMP/SMX resistant K. pnemoniae isolates were more commonly isolated from male patients (p<0.001) which must be validated and studied. Again, no difference was found between the susceptibility of K. pnemoniae isolates gathered from males compared to females when it came to imipenem, meropenem, nitrofurantoin, piperacillin-tazobactam (TZP), gentamicin, or amoxicillin/clavulanate. However, it is important to note that these results may change with a larger sample size of K. pnemoniae isolates.
Proportionally speaking, more of the K. pneumoniae isolates gathered from males were ESBL-producing (p=0.151) and MDR (p=0.128) than isolates gathered from females, but a larger sample size of K. pneumoniae is needed to validate these claims.
Discussion
When comparing the species gathered, UTI due to E. coli was most common, with 77.4% of isolates being E. coli, close to the 75.7% that a comparable study found.6 An interesting finding brought up by Hameed et al5 was that non-E. coli isolates were proportionally more common in male patients; our study reinforces this finding; 49.5% of the isolates gathered from males were non-E. coli species, compared to 17.3% of non-E. coli isolates from females (p<0.001, Table 3).
Comparing the number of MDR isolates found in our study to those found in other studies proved somewhat difficult due to the differences in defining MDR. Nevertheless, Alanazi et al6 using the same definition for MDR that our study used, found that from January to March of 2008, 22.7% of the E. coli isolates gathered were MDR, compared to 25.2% that we found in this study, possibly indicating a 2.5% increase in MDR CAUTIs in pediatric patients over a decade.
Alqasim et al13 observed that 67% of E. coli specimens gathered from inpatients (most of whom were adults) hospitalized in a tertiary hospital were MDR, compared to the 25.2% that our study found in the outpatient/emergency department setting in pediatric patients. This highlights the need for a study to provide insight into the resistance patterns of antibiotics to uropathogens in pediatric inpatients possibly with hospital-acquired infection.
While our study found that 57 (12.1%) of the E. coli samples were ESBL-producing, Alanazi et al6 found that only 3.2% of the E. coli isolates gathered from pediatric patients from January to March 2008 were ESBL-producing. The previously mentioned study was carried out at King Abdullah Medical City, Riyadh, Saudi Arabia (one of the centers we studied), suggesting that there may have been a significant increase in the amount of ESBL-producing E. coli isolates. However, it is important to consider the possibility that changes in surveillance intensity and infection control policies over the decade between the studied periods could have led to this increase.
Study limitations
Since this study was carried out in a limited number of centers in one city, our data may not be representative of the entire pediatric population of Saudi Arabia. The fact that the study was carried out in one city also limited the total number of cases and therefore the number of non-E. coli isolates and thus limited our ability to infer on non-E. coli isolates. The retrospective study design was also a limiting factor as we found that not all specimens were tested for the susceptibility of all possible antibiotics.
In conclusion, the possibility of a 9% increase in ESBL-producing E. coli isolates over a decade is alarming when comparing what our study found to the findings of Alanazi et al6 and requires further investigation and monitoring. The same can be said on the possible 2.5% increase in MDR E. coli isolates.
We found that the susceptibility of an isolate often depended on the gender of the individual from whom the isolate was collected. In the case of K. pneumoniae, isolates gathered from males were significantly less susceptible to TMP/SMX (p<0.001); the same could be said for the susceptibility of E. coli isolates to ampicillin (p=0.018), ceftriaxone (p=0.016), and ciprofloxacin (p<0.001). This finding indicates that routine surveillance of uropathogens should distinguish between susceptibility of isolates gathered from males versus those gathered from females, as the susceptibility of an isolate to antibiotics may differ depending on the patient’s gender.
Nitrofurantoin, TZP, and gentamicin remain excellent choices for E. coli UTI with >95% sensitivity to each. Susceptibility to TMP/SMX is not ideal, with 62.1% of the E. coli isolates being sensitive. On the other hand, only 36.2% of the E. coli isolates were sensitive to ampicillin.
While our study’s sample size regarding E. coli isolates was enough to draw inferences and judgements to compare isolates collected from males to those gathered from females, the same could not be said for K. pneumoniae isolates or P. mirabilis isolates. Future studies on the antibiotic resistance patterns of uropathogens must include a much larger sample size, preferably one from multiple hospitals within an area (as opposed to a single city), or ideally, all the hospitals within a region. This would enable the comparison to other regions in Saudi Arabia and would also allow for a large enough sample size of each of the uropathogens to draw significant inferences.
Acknowledgment
The authors gratefully acknowledge Sofia Fields Author Services (www.sofiafields.com) for their English language editing.
Footnotes
Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.
- Received December 25, 2024.
- Accepted March 17, 2025.
- Copyright: © Saudi Medical Journal
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