Introduction

Urinary tract infections (UTIs) are a prevalent and significant health concern worldwide, necessitating prompt antibiotic treatment to avert potential complications, including pyelonephritis.^[1] Among extraintestinal bacterial infections, UTIs stand out as one of the most common ailments encountered in medical practice, affecting individuals of all age groups, from newborns to the elderly.^[2] Globally, more than 150 million people are diagnosed with UTIs annually,^[1], ^[3] constituting 8% and 2% of total reported infections in the United States^[4] and France,^[5] respectively. Similarly, UTIs account for approximately 10% of all infections in Saudi Arabia, ranking as the second most common reason for emergency department admissions.^[6] The annual cost of treating UTIs in a single Saudi Arabian hospital is estimated to exceed $800,000.^[7]

The primary route of infection, responsible for the majority of UTIs, involves the retrograde ascent of bacteria from the fecal flora through the urethra into the bladder and kidneys, particularly in females due to their shorter and wider urethra and the transfer of microflora.^[8] The unique anatomical features of the female urethra and vagina make it susceptible to trauma during sexual intercourse and exposure to pathogens during pregnancy and childbirth.^[9], ^[10] Approximately 60% of women will experience at least one symptomatic UTI in their lifetime, with higher rates among sexually active females.^[11] In contrast, men are less susceptible to community-associated UTIs and their complications, largely due to anatomical differences.^[11] UTI can affect either the lower or both upper and lower parts of the urinary tract. The term "cystitis" specifically refers to an infection impacting the bladder, characterized by symptoms like painful urination, frequent urges to urinate, and at times, tenderness in the lower abdomen. Although most UTIs are non-life-threatening and do not result in irreversible harm, kidney involvement poses a risk of tissue damage and an increased likelihood of bacteremia.^[12]

Bacterial infections are the leading cause of UTIs, contributing to over 80% of cases, with Escherichia coli (E. coli) responsible for approximately 75% of these infections.^[11], ^[13] Other causative agents include Klebsiella pneumoniae, Staphylococcus saprophyticus, Enterococcus faecalis, and Proteus mirabilis.^[11] Notably, antibiotic susceptibility profiles of these pathogens may vary geographically, potentially influenced by the use of different antibiotic classes recommended in various regions for UTI treatment.^[14], ^[15], ^[16], ^[17] Local surveillance for antimicrobial resistance (AMR) is crucial to ensure the rational and context-specific use of antibiotics for UTI treatment. This underscores the importance of prescribing prophylactic antibiotics based on recent surveillance studies, which can aid in eradicating the likely causative bacteria, reducing complications, and shortening treatment durations.^[6]

Understanding the prevalence and antibiotic resistance patterns of bacteria causing UTIs is crucial for healthcare providers to tailor effective treatments. However, the frequency and resistance profiles of these bacteria can vary between communities, regionally, locally, and over time, thus highlighting the need for local data to make optimal treatment decisions. Monitoring and managing antibiotic resistance rates of pathogenic bacteria is essential due to the significant public health implications and impacts associated with antibiotic resistance. Recognizing the essential role of local data in guiding treatment decisions and understanding the lack of comprehensive information on UTI prevalence in the Idlib region, our study seeks to address this gap by investigating the distribution of bacteria causing UTIs and their antibiotic susceptibility patterns. The goal of this study is also to highlight the need for ongoing local antibiotic surveillance programs to evaluate microbial resistance patterns and tailor antibiotic therapies accordingly.

Materials and Methods

Single bacterial species (pure cultures) identified from positive urine cultures collected between June 2022 and December 2023 were included in this study. Positive urine cultures were defined as those containing ≥10⁵ colony-forming units (CFU) of one specific bacterial species per milliliter of urine. Mid-stream urine samples were collected by adult patients themselves using designated sterile urine collection containers. For patients with more than one urine culture, only the first reported episode was included in this study because no guidelines were available to differentiate between multiple cultures. Cultures with polymicrobial growth (more than one species), low colony counts (<10⁵ CFU/mL), and samples belonging to patients taking antibiotics were excluded from this investigation. Patients who tested positive in their cultures were categorized as individuals with UTIs, and they were further grouped based on age and gender.

Results

A summary of the different microorganisms isolated during the study period is shown in [Table 1]. It is clear that E. coli was the predominant uropathogen 187 (58.4%) causing UTI, followed by Proteus spp. 47 (14.7%), Staphylococcus spp. 42 (13.1%), Klebsiella spp.16 (5.0%) and Enterobacter spp. 12 (3.8%).

Of the 320 patients included in the study, the majority of the bacteria were isolated from females (68.4%), while the remaining (31.6%) were from males. The most prevalent organism found in the females and males was E. coli (42.8% and 15.6% respectively). In females, Proteus spp. was the second most prevalent organism at 10.6%, followed by Staphylococcus spp. (8.4%), Klebsiella spp. (3.8%), Enterobacter spp. (1.9%), and Pseudomonas spp. (0.9%). Among males, the second most prevalent organism was Staphylococcus spp. (4.7%) followed by Proteus spp. (4.1%), Pseudomonas spp. (4.1%), Enterobacter spp. (1.9%) and Klebsiella spp. (1.3%) ([Table 2]).

The most susceptible age group for UTI was 13–65 years (41.3%), followed by 0–13 years (35.3%), and >65 years (23.4%). The highest number of E. coli was found in the age group of 13–65 (23.4%), followed by 0–13 years (19.1%), and > 65 years (15.9%). The second most prevalent organism among the age group of 13–65 years was Staphylococcus spp. (7.5%), followed by Proteus spp. (6.6%), Klebsiella spp. (1.9%), Pseudomonas spp. (0.9%), and Enterobacter spp. (0.9%). For 0–13 years, the second most prevalent organism was Proteus spp. (5.6%), followed by Staphylococcus spp. (3.8%), Pseudomonas spp. (2.8%), Enterobacter spp. (2.2%) and Klebsiella spp. (1.9%). Likewise, for patients aged > 65 years, the second most prevalent organism was Proteus spp. (2.5%), followed by Staphylococcus spp. (1.9%), Klebsiella spp. (1.3%), Pseudomonas spp. (1.3%), and Enterobacter spp. (0.6%) ([Table 3])

Of the patients included in the study, the inpatients were (48.3%), whereas the outpatients were (51.7%). The most prevalent bacterial agent found in the inpatients group was E. coli (35%) followed by Proteus spp. (4.9%) and Pseudomonas spp. (4.2%). For outpatient group, the most prevalent bacterial agent was E. coli (30.1%) followed by Staphylococcus spp. (9.8%) and Proteus spp. (6.3%) ([Table 4]).

[Table 5] presents antimicrobial susceptibility profiling of the isolated UTI pathogens. Based on [Table 5], Cefotaxime was found to be the most resistant drug in 87.5% cases of E. coli followed by Cefadroxil (77.5%), Co-trimoxazole (75.9%) and Ampicillin/sulbactam (73.8%). However, Meropenem emerged as the most sensitive drug in 89% isolates of E. coli, followed by Imipenem (85.2%) and Amikacin (81.2%). All 47 isolates (100%) of Proteus spp. were found to be resistant to Cefotaxime followed by Co-Trimoxazole (85.3%), Cefadroxil (81.8%), Cefuroxime (76.5%). However, (86.7%) of isolates were sensitive to Meropenem followed by Amikacin (85%), Piperacillin/Tazobactam (77.8%), Gentamicin (74.2%) and Ofloxacin (70.2%). The resistance and sensitivity range of tested antimicrobial agents against Proteus spp. was 5%-100% and 0%-86.7% respectively ([Table 5]).

All 42 isolates (100%) of Staphylococcus spp. were resistant to Cefotaxime and Tobramycin followed by Cefixime (85.3%), Cefadroxil (89.5%), Cefuroxime (87.5%), Ceftriaxone (81.8%), Ampicillin/sulbactam and Co-Trimoxazole (75%). However, (77.8%) of isolates were sensitive to Piperacillin/Tazobactam followed by Amikacin (73.3%), Imipenem (73.3.8%), Nitrofurantoin (66.7%) and Meropenem (63.6%). The resistance and sensitivity range of tested antimicrobial agents against Staphylococcus spp. was 20%-100% and 0%-77.8% respectively ([Table 5]).

All 16 isolates (100%) of Klebsiella spp. were resistant to Ampicillin/sulbactam, Cefotaxime and Piperacillin/Tazobactam followed by Co-Trimoxazole (91.7%), Cefixime (88.9%), Nitrofurantoin (87.5%), Ceftriaxone (78.6%), Ceftriaxone (81.8%) and Cefuroxime (75%). However, 61.5% of isolates were sensitive to Imipenem and Norfloxacin followed by Gentamicin (58.3.%). The resistance and sensitivity range of tested antimicrobial agents against Klebsiella spp. was 0%-100% and 0%-61.5% respectively ([Table 5]).

All 16 isolates (100%) of Pseudomonas spp. were 100% resistant to Amoxicillin/clavulanic acid, Ampicillin/sulbactam, Cefadroxil, and Cefotaxime followed by highly resistant to Nitrofurantoin (91.7%), Ceftriaxone (90.9%), Cefixime (88.9%), Co-Trimoxazole (88.9%), Doxycycline (80%) and Piperacillin/Tazobactam (75%). However, 80% of isolates were sensitive to both of Cefuroxime and Imipenem followed by both of Meropenem and Ofloxacin (75%). The resistance and sensitivity range of tested antimicrobial agents against Pseudomonas spp. was 0%-100% and 0%-80% respectively ([Table 5]).

All 12 isolates (100%) of Enterobacter spp. were resistant to Amoxicillin/clavulanic acid, Ampicillin/sulbactam, and Cefadroxil followed by Cefixime, Cefotaxime, Cefuroxime and Ceftriaxone. However, 91.7% of the isolates were sensitive to Amikacin followed by Imipenem (72.7%). The resistance and sensitivity range of tested antimicrobial agents against Enterobacter spp. was 0%-100% and 0%-91.7%, respectively ([Table 5]).

Discussion

Bacterial UTIs frequently prompt medical attention within the community. Successfully treating individuals with these infections depends on identifying the specific organisms responsible and choosing an appropriate antibiotic that targets those organisms effectively. Healthcare providers need to be aware of how often bacteria provoke UTIs and the way they resist antibiotics. This knowledge helps tailor treatments effectively. However, these bacteria's prevalence and resistance vary among different communities, so local data is crucial for optimal treatment choices. There is an urgent need to take an action to combat the spread of antimicrobial resistance^[20] as the prevalence of antibiotic resistance among causes of UTIs continues to increase.^[21], ^[22], ^[23] Accordingly, multiple steps have been recommended, each with an important role in combating antimicrobial resistance, with antibiotic surveillance programs being one of the top 10 resistance control strategies.^[24] For instance, antibiotic surveillance programs have been recommended to combat antimicrobial resistance, with such programs being recognized as one of the top 10 strategies for resistance control. Several Saudi cities, including Mecca, Jeddah, and Riyadh, have routinely conducted antibiotic surveillance programs for microorganisms associated with UTIs.^[25], ^[26], ^[27]

Amidst the conflicting research data on antibiotic susceptibility in UTIs,^[28] clinicians are compelled to evaluate local bacterial cultures for guiding targeted antibiotic therapies. This approach becomes crucial to mitigate the escalating threat of antibiotic resistance in communities and underscores the significance of local insights in making informed decisions about antibiotic treatment. This study's goal was to identify how often different agents cause UTIs and assess their current resistance to antibiotics among the outpatients visiting Idlib University hospital in Syria.

The results of our study have shown that E. coli stands out as the primary causative factor behind the UTIs, contributing to as much as 58.4% of occurrences. Within our investigation, the prevailing UTIs were primarily attributed to Gram-negative bacteria, constituting around 85% of all isolated strains ([Table 1], [Table 2]). Consistent with existing literature, our study accentuates predominant role played by E. coli in UTIs across genders. ^[29], ^[30], ^[31], ^[32]

In our research, we found that E. coli and Proteus species were the predominant organisms identified. While E. coli is widely recognized as the primary cause of UTIs in medical literature, our study revealed a different second most common pathogen (Proteus spp.) compared to previous researches. For instance, two studies from Turkey reported Klebsiella species as the second most prevalent organism, consistent with our findings.^[33], ^[34] Kidwai et al. observed S. aureus and Klebsiella species as the second most common bacteria after E. coli among Pakistani patients in low socioeconomic strata.^[35] According to a retrospective study conducted by Ağca and Toklu, the second most frequently detected bacteria in urine samples after E. coli were Pseudomonas aeruginosa (6%), Enterococcus species (5%), Klebsiella species (5%), and Staphylococcus aureus (4%).^[36] These variations elucidate the importance of considering local epidemiological factors and patient demographics when assessing UTI etiology and designing treatment strategies.

With respect to the distribution percentage of bacterial agents in different age groups ([Table 3]), the age group of 13–65 years appears to be the most susceptible to UTIs, with the highest incidence (41.3%), followed by the 0–13 years group (35.3%), and those aged >65 years (23.4%). Possible reasons for being the age group of 13–65 years to be the most susceptible to UTIs could be attributed to heightened sexual activity, increased frequency of pregnancies, and the utilization of specific contraceptives such as diaphragms or spermicides, which could be associated with UTIs in this age group.^[37] E. coli remains the primary cause of UTIs across all age groups, while the distribution of other organisms varies, highlighting potential age-related differences in susceptibility and bacterial profiles associated with UTIs.

In our current study, the overall percentage revealed a more balanced distribution of uropathogens between inpatients and outpatients. Unlike the higher prevalence of uropathogens among inpatients reported in previous studies, ^[38], ^[39] we observed a similar occurrence rate among inpatients and outpatients in our study. This discrepancy suggests potential variations in the patient population as well as healthcare practices in conflict areas such as Idlib. However, overall the gram-negative isolates were more common among the inpatients as compared to the outpatients which could be explained in terms of hospitalization, underlying health conditions, prolonged antibiotic usage, and compromised immune systems of the inpatients. ^[40]

The issue of antimicrobial resistance poses a significant challenge in effectively treating infections instigated by various bacterial pathogens and has exhibited a rising trend across time. The comprehensive analysis of antimicrobial susceptibility pattern of isolated UTI pathogens ([Table 5]) sheds light onto the resistance patterns of various bacterial isolates. E. coli demonstrated heightened resistance to Cefotaxime (87.5%), while exhibiting considerable sensitivity to Meropenem (89%). Moreover, E. coli exhibited elevated resistance to ampicillin/sulbactam (73.8%) but showed considerable sensitivity to piperacillin/tazobactam. Resistance to ampicillin in many E. coli strains is mediated by plasmid-mediated TEM-1 β-lactamase.^[41] Hence, the efficacy of ampicillin-sulbactam in treating E. coli infections heavily relies on the inhibitory action of sulbactam. However, sulbactam's potency as a TEM-1 inhibitor is relatively limited,^[41] and E. coli resistance can arise through various mechanisms. Therefore, as seen in our data, Piperacillin-tazobactam may offer protection against the emergence of E. coli strains resistant to ampicillin-sulbactam, likely due to relatively high susceptibility of E. coli to piperacillin-tazobactam.^[41], ^[42] Piperacillin is less favored as a substrate for TEM-1 compared to ampicillin, and tazobactam demonstrates stronger inhibition of TEM-1 β-lactamase than sulbactam. Consequently, piperacillin-tazobactam exhibits superior activity against E. coli strains producing TEM-1. ^[41], ^[43], ^[44]

Proteus spp. showcased complete resistance to Cefotaxime but exhibited significant sensitivity to Meropenem (86.7%). Staphylococcus spp., on the other hand, displayed universal resistance to Cefotaxime and Tobramycin, with Piperacillin/Tazobactam emerging as the most effective agent (77.8%). Klebsiella spp. and Pseudomonas spp. both exhibited widespread resistance to multiple agents, emphasizing the challenges in selecting effective treatments. Carbapenems seem to serve as the final line of defense against Klebsiella spp. and Pseudomonas spp. as it has been reported in the literature.^[45], ^[46] Likewise, Enterobacter spp. revealed high resistance to several agents, with notable sensitivity to Amikacin (91.7%). The uropathogens isolated showed elevated resistance levels to ampicillin/sulbactam, cefotaxime, ceftriaxone, and co-trimoxazole. The notable resistance seen with these antibiotics could stem from the community's tendency toward self-medication and indiscriminate use of drugs to treat various bacterial infections.^[39] In contrast, minimal resistance was found across nearly all pathogens analyzed against antibiotics like Meropenem, Imipenem, Gentamicin, and Levofloxacin. The limited resistance noted for these medications may be attributed to their comparatively higher cost. Consequently, these antibiotics might serve as viable alternatives for empirically treating UTIs in our community. These findings accentuate the variability in antimicrobial susceptibility across different pathogens, emphasizing the importance of targeted and informed antibiotic therapy, thereby suggesting that a tailored approach is crucial for effective treatment based on the specific susceptibility patterns observed in each pathogen.

Conclusion

In summary, the identification of bacterial strains in UTIs displaying elevated resistance to frequently prescribed antimicrobials pose a significant challenge for clinicians, limiting available treatment options and emphasizing the need for a reevaluation of empirical treatment approaches. Given the evolving nature of drug resistance among pathogens, enhancing the efficacy of comprehensive infection control initiatives is imperative to mitigate and manage nosocomial infections stemming from highly resistant organisms. The findings from this current study shed light on the intricate landscape of antimicrobial resistance among diverse bacterial strains, necessitating a nuanced approach to treatment selection in the area of Northwest Syria. The observed patterns serve as a valuable resource for clinicians, aiding in the optimization of antibiotic therapies based on the prevalent bacterial species and their respective resistance profiles. Future research should delve into the molecular mechanisms driving resistance, facilitating the development of targeted interventions for improved treatment outcomes.

Conflicts of Interest

The authors declare that there is no conflict of interest.

Ethical Approval

This study was approved by the Ethics Committee of the University of Idlib. Patient privacy and data confidentiality were maintained in accordance with the Declaration of Helsinki.

Source of Funding

None.

Author Contributions

Writing original draft, Fouad Al-Daoud; Conceptualization, Fouad Al-Daoud and Gohar Mushtaq; Data Curation, Fouad Al-Daoud; Methodology, Fouad Al-Daoud and Gohar Mushtaq; Review & editing, Gohar Mushtaq.

Data Availability Statement

Raw data were generated at Idlib University Hospital. Derived data supporting the findings of this study are available from the corresponding author GM on request.