Abstract
Objectives
Uropathogenic Escherichia coli (UPEC) is important in urinary tract infection (UTI). Quinolones and fluoroquinolones are broad-spectrum antibiotics for the treatment of UTI, although some of UPEC are resistant to these antibiotics. This study aims to investigate phenotypic and genotypic characterization of plasmid-mediated quinolone resistance UPEC isolated from patients with UTI in Bushehr. In this study, 105 isolates of UPEC were identified by standard microbiological tests and the susceptibility pattern of quinolone and fluoroquinolone were determined by the disc diffusion method. PCR was used to check the presence of plasmid-mediated quinolone resistance genes.
Results
Pattern of antibiotic susceptibility showed that more than 50% and 75% of isolates were resistant to fluoroquinolones and quinolones, respectively. The frequencies of qnrS and qnrB genes were 49.5% and 23.8%, respectively. Based on analysis, there was a significant relationship between the presence of the qnrB gene and resistance to ciprofloxacin, norfloxacin, ofloxacin and levofloxacin. There was a significant relationship between the presence of qnrS gene and resistance to the tested antibiotics. Our results showed a high level of resistance to fluoroquinolones. Therefore, it is necessary to treat and prevent UTI so that physicians can use alternative antibiotics to treatment of patients based on laboratory results.
Keywords: Quinolone resistance, Uropathogenic Escherichia coli, Urinary tract infection
Introduction
The Enterobacterales family is the largest and most heterogeneous group of Gram-negative bacteria [1]. This family includes three main groups: lactose fermenters, non-lactose fermenters and late lactose fermenters. The first group can to ferment lactose and includes Escherichia coli, Enterobacter aerogenes and Klebsiella pneumoniae [2]. In the Escherichia genus, only E. coli is important in pathogenicity and unique among other members of the natural flora because it is one of the pathogenic agents of urinary tract infection (UTI), wound infections, pneumonia, meningitis and septicemia in humans [3]. E. coli has extra and intra-intestinal pathotypes, and uropathogenic E. coli (UPEC) is the most of them in the cause of UTI. UPEC can form a specific biofilm in the form of a complex of intracellular bacterial population (IBC) between the umbrella cells of the bladder surface, which leads to urinary tract infection [4].
UTIs are considered the most prevalent bacterial infections in the clinical setting, occurring in people of all ages, which cause morbidity and significant mortality globally [5, 6]. This infection more frequently occurs between women than men because the anatomy and shorter urethra facilitate the increased susceptibility to UTIs [7]. UTIs are classified as either complicated or uncomplicated: The uncomplicated UTI (uUTI) frequently occurs in healthy, premenopausal, sexually active women whereas the complicated UTI (cUTI) is related to patients with structural abnormalities of the urinary tract or underlying diseases [7, 8]. Complications and treatment failure risk remain among the more common complications of UTIs [6].
Nowadays, resistance to antibiotics is considered an important health problem globally. According to the studies, about 50–60% of nosocomial infections are caused by resistant strains of bacteria [9]. Several antibiotics are considered for the treatment of UTI; quinolones and fluoroquinolones (FQs) including nalidixic acid and ciprofloxacin are among the one of the most frequently prescribed antibiotics for UTI treatment [10]. But some strains of UPEC are resistant to these antibiotics, and this resistance is due to mutation in the gyrA or parC genes or the acquisition of plasmids carrying resistance genes such as qnrS, qnrA, qnrB [11, 12]. Since 1998, researchers have found three mechanisms for plasmid-mediated quinolone resistance (PMQR) that are coded by qnrA, qnrB, qnrC, qnrD, qnrS, and qnrVC genes and lead to the protection of DNA gyrase and topoisomerase IV from quinolone antibiotics [13]. Identifying bacterial resistance and the genes involved in it can help to choose the appropriate antibiotic for infection treatments [14].
Due to the high horizontal gene transfer capability of UPEC and the importance of antibiotic resistance in these isolates, the monitoring of antibiotic resistance patterns and involved genes, especially in such bacteria, is essential. There have been limited published epidemiologic studies on the presence of PMQR genes in UPEC strains isolated from patients with UTI in this region; hence, in this study, we tried to investigate the phenotypic and genotypic quinolone resistance in UPEC isolated from the patients referred to Salman Farsi Hospital in Bushehr.
Methods
Study population
In this study, 105 UPEC were isolated from the urine samples of patients referred to Salman Farsi Hospital in Bushehr (south of Iran) and transferred to the microbiology laboratory. Consent to participate was obtained from all patients. The study was approved by the Ethics Committee of Kherad Institute of Higher Education (Approval No. IR.BPUMS.REC.1402.293). Samples were collected from March 2023 to June 2023 from patients who presented with symptomatic UTI. The samples were collected as clean-catch midstream urine and UTI was defined as the presence of a positive culture (≥ 105 colony-forming units CFU/mL) and pyuria (≥ 104 leukocyte/mL of urine) [5]. Identification of bacteria was done based on conventional microbiological methods (specific colony form, Gram staining and differential biochemical tests) [15]. Finally, all samples were stored in tryptic soy broth (Merck Co., Germany) containing 20% glycerol (Merck KGaA, Germany) at −70 °C for further work.
Quinolone susceptibility testing
Antibiotic susceptibility of all isolates to nalidixic acid (30 µg), ciprofloxacin (5 µg), levofloxacin (5 µg), norfloxacin (10 µg), and ofloxacin (5 µg) was investigated using the disk diffusion method. The bacteria were cultured with the help of swab in three different directions on the solid medium of Mueller Hinton agar, with the antibiotic disks one by one placed on the medium and the plate incubated in the incubator at 37 °C for 24 h. After this period, the diameter of the zone around each disc was measured in millimeters with a ruler. Interpretation of zone diameter was done according to the Clinical and Laboratory Standards Institute(CLSI) standard [16]. The standard strain E. coli ATCC 25,922 was used as a control.
Detection of Qnr genes
First, DNA extraction was performed using the boiling method based on the standard protocol [17]. PCR was performed with specific primers [18] to investigate qnrB and qnrS genes in UPEC isolates. We prepare a total volume of 25 µL containing 3 µL DNA template, 2.5 µL PCR buffer (1X), 1 µL deoxyribonucleotide triphosphates solution (dNTPs, 200 µM), 1.5 µL MgCl2 (1.5 mM), 0.25 µL Taq DNA polymerase (1 Unit) and 1 µL of each specific primer (1 µM).
To perform PCR, it was placed in the thermal cycler 5530 (Eppendorf master, Germany) and cycle program as follows: Initial denaturation (1 cycle, 5 min, 94 °C), denaturation (30 cycles, 30 s, 94 °C), annealing (30 cycles, 45 s, 45–60 °C), extension (30 cycles, 1 min, 72 °C) and final extension (1 cycle, 7 min, 72 °C). DNA ladder was 100 bp. The amplifications were separated on 1.5% agarose gel prepared in 1X TAE (Tris/Acetate/EDTA) buffer. The obtained product was qualitatively evaluated by electrophoresis and then visualized using ultraviolet light. As positive control for qnr genes, we used qnr- positive clinical strains which Rastegar et al. previously found [19].
Statistical analysis
SPSS (version 22) was used for data analysis and data were reported as relative frequency. Chi-square and Fisher’s exact tests were used to determine the statistical relations between qnr genes, antibiotic resistance and different wards, and the P- value level ≤ 0.05 was considered significant.
Results
Demographic results
In this study, 105 UPEC isolates were collected. UPEC isolates from outpatient and different wards were as follows: Outpatient (n = 45, 42.8%), emergency (n = 41, 39%), Internal wards (n = 15, 14.3%), Intensive Care Unit (ICU) and surgery wards both (n = 2, 2%). The highest frequency of isolates was observed in outpatients. The mean age of patients in our study was 45.85 ± 18.69 years. Moreover, 39% of the study population were males and 61% were females.
Quinolone resistance among UPEC isolates
The antibiotic susceptibility testing results of 105 UPEC isolates are shown in Table 1. Based on these results, the highest and lowest resistance were observed against nalidixic acid 79 (75.2%) and levofloxacin 61 (58.1%), respectively.
Table 1.
The antibiotic susceptibility testing results of 105 UPEC isolates
| Antibiotics | Resistance, No. (%) | |||
|---|---|---|---|---|
| I | R | S | ||
| CP | 13 (12.38%) | 67 (63.81%) | 25 (23.81%) | |
| NOR | 0 (0%) | 67 (63.81%) | 38 (36.19%) | |
| OFX | 0 (0%) | 66 (62.86%) | 39 (37.14%) | |
| NA | 4 (3.81%) | 79 (75.24%) | 22 (20.95%) | |
| LEV | 1 (0.95%) | 61 (58.1%) | 43 (40.95%) | |
CP ciprofloxacin, NOR norfloxacin, OFX ofloxacin, NA nalidixic acid, LEV levofloxacin, R resistant, S sensitive, I intermediate
Frequency of QnrS and QnrB genes
The frequency of qnrS and qnrB among UPEC isolates was 52 (49.5%) and 25 (23.8%), respectively.
QnrB gene and resistance to quinolone antibiotics
As shown in Table 2 there is no significant relationship between the presence of the qnrB gene and resistance to all of quinolone antibiotics. (P-value > 0.001)
Table 2.
Distribution of antibiotic resistant UPEC isolates according to QnrB gene
| qnrB | |||||
|---|---|---|---|---|---|
| N | P | Total | P-value | ||
| CP | 13 (100%) | 0 (0%) | 13 (100%) | > 0.001 | |
| R | 43 (64.18%) | 24 (35.82%) | 67 (100%) | ||
| S | 24 (96%) | 1 (4%) | 25 (100%) | ||
| Total | 80 (76.19%) | 25 (23.81%) | 105 (100%) | ||
| NOR | I | 0 (0%) | 0 (0%) | 0 (0%) | > 0.001 |
| R | 44 (65.67%) | 23 (34.33%) | 67 (100%) | ||
| S | 36 (94.74%) | 2 (5.26%) | 38 (100%) | ||
| Total | 80 (76.19%) | 25 (23.81%) | 105 (100%) | ||
| OFX | I | 0 (0%) | 0 (0%) | 0 (0%) | > 0.001 |
| R | 41 (62.12%) | 25 (37.88%) | 66 (100%) | ||
| S | 39 (100%) | 0 (0%) | 39 (100%) | ||
| Total | 80 (76.19%) | 25 (23.81%) | 105 (100%) | ||
| NA | I | 4 (100%) | 0 (0%) | 4 (100%) | 0.121 |
| R | 56 (70.89%) | 23 (29.11%) | 79 (100%) | ||
| S | 20 (90.91%) | 2 (9.09%) | 22 (100%) | ||
| Total | 80 (76.19%) | 25 (23.81%) | 105 (100%) | ||
| LEV | I | 1 (100%) | 0 (0%) | 1 (100%) | > 0.001 |
| R | 36 (59.02%) | 25 (40.98%) | 61 (100%) | ||
| S | 43 (100%) | 0 (0%) | 43 (100%) | ||
| Total | 80 (76.19%) | 25 (23.81%) | 105 (100%) | ||
CP ciprofloxacin, NOR norfloxacin, OFX ofloxacin, NA nalidixic acid, LEV levofloxacin, N Negative, P Positive, R: resistant, S: sensitive, I: intermediate
QnrS gene and resistance to quinolone antibiotics
As shown in Table 3, there is a significant relationship between the presence of the qnrS gene and resistance to the all of quinolone antibiotics (P-value ≤ 0.05).
Table 3.
Distribution of antibiotic resistant UPEC isolates according to QnrS gene
| qnrS | |||||
|---|---|---|---|---|---|
| N | P | Total | P-value | ||
| CP | I | 13 (100%) | 0 (0%) | 13 (100%) | < 0.001* |
| R | 21 (31.34%) | 46 (68.66%) | 67 (100%) | ||
| S | 19 (76%) | 6 (24%) | 25 (100%) | ||
| Total | 53 (50.48%) | 52 (49.52%) | 105 (100%) | ||
| NOR | I | 0 (0%) | 0 (0%) | 0 (0%) | < 0.001** |
| R | 19 (28.36%) | 48 (71.64%) | 67 (100%) | ||
| S | 34 (89.47%) | 4 (10.53%) | 38 (100%) | ||
| Total | 53 (50.48%) | 52 (49.52%) | 105 (100%) | ||
| OFX | I | 0 (0%) | 0 (0%) | 0 (0%) | < 0.001** |
| R | 18 (27.27%) | 48 (72.73%) | 66 (100%) | ||
| S | 35 (89.74%) | 4 (10.26%) | 39 (100%) | ||
| Total | 53 (50.48%) | 52 (49.52%) | 105 (100%) | ||
| NA | I | 3 (75%) | 1 (25%) | 4 (100%) | 0.001** |
| R | 32 (40.51%) | 47 (59.49%) | 79 (100%) | ||
| S | 18 (81.82%) | 4 (18.18%) | 22 (100%) | ||
| Total | 53 (50.48%) | 52 (49.52%) | 105 (100%) | ||
| LEV | I | 1 (100%) | 0 (0%) | 1 (100%) | < 0.001** |
| R | 17 (27.87%) | 44 (72.13%) | 61 (100%) | ||
| S | 35 (81.4%) | 8 (18.6%) | 43 (100%) | ||
| Total | 53 (50.48%) | 52 (49.52%) | 105 (100%) | ||
CP ciprofloxacin, NOR norfloxacin, OFX ofloxacin, NA nalidixic acid, LEV levofloxacin, N negative, P positive, R resistant, S sensitive, I intermediate
*Chi-Square Test. **Fisher Exact Test
Frequency of resistance to quinolone antibiotics and qnrB, QnrS genes in different wards
The results showed that the most antibiotic resistance was against nalidixic acid, which was isolated from outpatients, followed by the ER ward. In addition, the most antibiotic susceptibility was against norfloxacin in the outpatient. The most frequency of the qnrB gene was related to emergency ward followed by outpatient while this gene did not exist between ICU and surgery wards. All isolates recovered from ICU and surgery wards harbored qnrS gene. (Table 4)
Table 4.
Distribution of Qnr genes according to wards
| qnr genes | ||||
|---|---|---|---|---|
| qnrB | qnrS | |||
| Ward | N | P | N | P |
| ICU | 2 (100%) | 0 (0%) | 0 (0%) | 2 (100%) |
| Emergency (ER) | 31 (75.61%) | 10 (24.39%) | 20 (48.78%) | 21 (51.22%) |
| Surgery | 2 (100%) | 0 (0%) | 0 (0%) | 2 (100%) |
| Internal | 10 (66.67%) | 5 (33.33%) | 9 (60%) | 6 (40%) |
| Outpatient | 35 (77.78%) | 10 (22.22%) | 24 (53.33%) | 21 (46.67%) |
| Total | 80 (76.19%) | 25 (23.81%) | 53 (50.48%) | 52 (49.52%) |
P positive, N negative
Discussion
E. coli is the digestive tract’s normal flora; however, some strains get virulence factors and show pathologic potential [20, 21]. Urinary tract infection is one of the most common infections and many bacteria are capable of causing infection in the urinary system UPEC is the most common of them [22, 23]. In the pathogenesis of UPEC, multiple virulence factors are involved including toxins, adhesions, secretion, and iron acquisition systems that lead to urinary flow resistance, bacterial cell signaling pathways activation, and infection [24].
Quinolones and fluoroquinolones are broad spectrum antibiotics widely used in the treatment for urinary tract infections; however, it seems that overconsumption of these antibiotics is related to antibiotic resistance [25]. In the present study, the most resistant antibiotic was nalidixic acid 79 (75.24%), and resistance to ciprofloxacin and norfloxacin was high (63.81%). In line with our study, the resistance rate to ciprofloxacin among E. coli isolates was reported to be around 60% in China [26], however, in the USA resistance to quinolone and fluoroquinolones were low and reported at 21% and 12% respectively [27]. Another study also conducted in Iran reported a high resistance percentage to ciprofloxacin and nalidixic acid [28–30]. The explanation for the increase in resistance to quinolone antibiotics in this region and some parts of Iran may be due to the indiscriminate use of antibiotics in clinical settings, for example, the empirical treatment of uncomplicated urinary tract infections with fluoroquinolones and the use of these drugs as first-line drugs in the treatment of urinary tract infections. In Pakistan, the resistance of UPEC isolates to ciprofloxacin and nalidixic acid was reported as 36.45% and 84.16%, respectively [31]. The results of last studies are in line with the present study that show the resistance to quinolone and fluoroquinolone antibiotics, especially nalidixic acid and ciprofloxacin was high and as a warning and concern for the treatment of resistant strains. As a result, physicians as much as possible should not use these antibiotics for the first line of UTI treatment.
Plasmid-mediated quinolone resistance genes (PMQR) including qnr genes show a high capacity for fast development of resistance among UPEC species due to their placement on plasmid [32]. In the present study, the frequency of qnrS and qnrB genes were reported 52 (49.5%) and 25 (23.8%) respectively. There are two mechanisms for resistance to quinolone in bacteria that one of them is plasmid-mediated resistance or resistance related to the presence of qnr gene. In addition, a significant difference was reported between qnrS gene and resistance to fluoroquinolones antibiotics (P < 0.001); Then this result indicates that the one of the most common resistant mechanisms among UPEC isolates in this study probably related to plasmed- mediated resistace.
Yousefi et al. in northern Iran, in accordance with our study showed high prevalence of qnrB (71.3%) and qnrS (62.8%) genes that had a significant relationship with resistance to quinolones [33]. Moreover, Sediqhi et al. reported qnrB in 6.7% and qnrS in 5% of UPEC strains and also confirmed a significant relationship between resistance to quinolones antibiotics and qnr genes [34]. However, Rezazadeh et al. reported a low level of qnrS gene among quinolone-resistant UPEC isolates while qnrA and qnrB were not found among isolates [35]. Another study conducted by Abbasi et al. showed that the prevalence of qnrS and qnrB genes among UPEC isolated from urinary tract infections were 36% and 25%, respectively [36]. In the study of Rastegar et al. frequency of qnrS and qnrB genes was 22% and 13.5%, respectively [19], and the results of this study were slightly different from the present study. In addition, other studies from Asian countries such as Iraq [37], Pakistan [38], Saudi Arabia [39], Korea [40] and Taiwan [41] were in line with Rastegar et al. report. Despite the high prevalence of qnrS and qnrB genes among UPEC in some areas, the distribution of these genes varies in different regions. The observed differences in resistance to different antibiotics as well as the frequency of antibiotic resistance genes can be caused by the varying treatment and medical programs of each country and region, using different antibiotic prescriptions, arbitrary use of antibiotics, and the geographical conditions of each region.
Conclusion
In this study, a high level of quinolone and fluoroquinolone resistance was observed among UPEC isolates in Bushehr, Iran. Rational use of infection control programs as well as inhibiting unnecessary prescription or over-the-counter sale of antibiotics might be a strategy to prevent the spread of antibiotic resistance. As a preliminary study in the region, we investigated the prevalence of quinolone resistance genes among UPEC isolated from different wards of the hospital. It was determined that there is a significant association between the frequency of resistance to quinolone antibiotics and one of the resistance gene including qnrS.
Limitation
Our isolates separated from patients in different wards of hospital in varies periods of time; Some UPEC bacteria isolated from outpatients who were not hospitalized but it might that some of isolates have same origin. For this purpose, we need to more investigation for molecular typing of isolates. In addition, more studies are needed to investigate other possible chromosomal and plasmid-mediated quinolone resistance mechanisms mediated by gyrA, parC and qnrA genes and use larger sample size.
Author contributions
Study concept and design: YM, JF, BJ. Analysis and interpretation of the data: BJ, MA, JA. Drafting of the manuscript: JF, MA. Critical revision of the manuscript for important intellectual content: YM, JF. Statistical analysis: YM, BJ. Final revise and editing: PGh, YM and JF.All authors Approval of the final manuscript.
Funding
Not applicable.
Data availability
All data is provided in this article.
Declarations
Ethics approval and consent to participate
This study was in accordance with the declaration of Helsinki and an ethical permission was sought from the institutional Ethics Committee of Kherad Institute of Higher Education (Approval No. IR.BPUMS.REC.1402.293). However, because we only used leftovers from clinical specimens, the institutional ethics committee waived the need for informed consent.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Yalda Malekzadegan, Email: malekzadeganyalda@gmail.com, Email: y.malekzadegan@bpums.ac.ir.
Behdokht Jamali, Email: behdokhtjamali@gmail.com.
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