Association of <i>qnr</i> Genes and OqxAB Efflux Pump in Fluoroquinolone-Resistant <i>Klebsiella pneumoniae</i> Strains

Amereh, Fereshteh; Arabestani, Mohammad Reza; Hosseini, Seyed Mostafa; Shokoohizadeh, Leili

doi:https://doi.org/10.1155/2023/9199108

International Journal of Microbiology

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Abstract Introduction Methods Results Discussion Conclusion Data Availability Ethical Approval Conflicts of Interest Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 9199108 | https://doi.org/10.1155/2023/9199108

Association of qnr Genes and OqxAB Efflux Pump in Fluoroquinolone-Resistant Klebsiella pneumoniae Strains

Fereshteh Amereh,¹Mohammad Reza Arabestani,^2,3Seyed Mostafa Hosseini,^2,3and Leili Shokoohizadeh^2,3

Academic Editor: Faham Khamesipour

Received19 Dec 2022

Revised23 Jan 2023

Accepted02 Feb 2023

Published21 Feb 2023

Abstract

Background. The aim of this study was to investigate the frequency and relationship between plasmid-mediated quinolone resistance genes and OqxAB pump genes, as well as the genetic linkage in K. pneumoniae strains isolated from Hamadan hospitals in the west of Iran. Materials and Methods. In this study, 100 K. pneumoniae clinical strains were isolated from clinical samples of inpatients at Hamadan Hospital in 2021. The antimicrobial susceptibility testing was performed using the disk diffusion method. The frequencies of genes encoding OqxAB efflux pumps and qnr were investigated by PCR. Molecular typing of qnr-positive K. pneumoniae isolates was assessed by ERIC-PCR. Results. Antibiotic susceptibility testing showed high resistance (>80%) to fluoroquinolones. The gene encoding the OqxAB efflux pump was detected in more than 90% of K. pneumomiae strains. All K. pneumoniae isolates were negative for qnrA, and 20% and 9% of the isolates were positive for qnrB and qnrS, respectively. The genes encoding oqxA and oqxB were detected in 96% of qnr-positive strains. A qnrB + /qnrS + profile was observed in 16% of qnr-positive K. pneumoniae strains. Ciprofloxacin MIC ≥ 256 μg/ml was detected in 20% of qnr-positive strains. Genetic association analysis by ERIC-PCR revealed genetic diversity among 25 different qnr-positive strains of K. pneumonia. Conclusion. However, no significant correlation was found between the qnr and the OqxAB efflux pump genes in this study. The high rate of fluoroquinolone resistance and determinants of antibiotic resistance among diverse K. pneumoniae strains increase the risk of fluoroquinolone-resistance transmission by K. pneumoniae strains in hospitals.

1. Introduction

One of the causes of pneumonia, sepsis, and urinary tract infections in hospitalized patients is known to be Klebsiella pneumoniae, a Gram-negative bacterium in the Enterobacteriaceae family. This bacterium is more likely to infect people whose immune systems are weak. The majority of antibiotics used to treat infections caused by this bacterium are beta-lactam and fluoroquinolones [1].

Controlling antibiotic resistance in multidrug-resistant K. pneumoniae (MDR-KP) is a major challenge. Optimal treatment options for MDR-KP infections are not yet well established. New antimicrobial agents against MDR-KP have been developed over the past decades and are currently in various stages of clinical research [2]. Fluoroquinolones such as ciprofloxacin are among the antibiotics used to treat infections associated with K. pneumoniae [3]. Quinolones and fluoroquinolones represent a wide range of antibiotics whose mode of action is to inhibit bacterial DNA gyrase enzymes [4]. In recent years, increasing resistance to these antibiotics has led not only to problems in the treatment procedure but also to increased treatment costs and longer hospital stays. Therefore, there is a need to assess resistance levels and mechanisms of resistance to these antibiotics in nosocomial pathogens such as K. pneumonia infections [5].

Resistance to ciprofloxacin can develop through a variety of mechanisms. Ciprofloxacin resistance is primarily associated with chromosomal mutations that alter ciprofloxacin target proteins (DNA gyrase and topoisomerase IV). Quinolone resistance can also be induced by mutations in the Efflux pump gene regulators. In addition to mutations in susceptible targets, ciprofloxacin resistance can also be mediated by plasmid-mediated quinolone resistance (PMQR) genes and efflux pumps such as OqxAB [4]. The OqxAB is expressed on plasmids in clinical isolates of E. coli and K. pneumoniae [6]. The qnr plasmid protects ciprofloxacin targets from inhibition and causes low-level resistance to quinolone. Different qnr genes have been found in bacterial strains from various regions of the world. Many qnr genes have been discovered including qnrA, qnrS, qnrB, qnrC, and qnrD and more recently qnrVC and qnrT [6, 7].

The aim of this study was to investigate the frequency and relationship between plasmid-mediated quinolone resistance (qnr) genes and OqxAB pump genes (oqxA and oqxB), as well as the genetic linkage in K. pneumoniae strains isolated from Hamadan hospitals in the west of Iran.

2. Methods

2.1. Bacterial Isolation and Identification

A total of 100 clinical isolates of K. pneumoniae were randomly collected in 2021 from patients at three major hospitals in Hamadan. K. pneumoniae isolates were identified by routine microbiological testing. Lactose-fermenting mucoid (pink-colored) colonies on MacConkey agar were selected. K. pneumoniae isolates were identified by IMVIC test (Indole production, Methyl Red (MR), Voges Proskauer (VP), and Simmons citrate), as well as by SIM, TSI, Urea Hydrolysis, and Lysine Decarboxylase tests. The results of the biochemical assay were confirmed by PCR using species-specific primers for the ureD gene responsible for urea hydrolysis in K. pneumoniae [8, 9].

2.2. Antimicrobial Susceptibility Testing

Antibiotic susceptibility testing of K. pneumoniae strains was performed according to CLSI criteria [10]. Susceptibility to piperacillin (100 μg), chloramphenicol (30 μg), nitrofurantoin (300 μg), imipenem (10 μg), gentamicin (10 μg), amikacin (30 μg), ceftazidime (30 μg), ceftriaxone (30 μg), cefotaxime (30 μg), ciprofloxacin (5 μg), levofloxacin (5 μg), and ampicillin-sulbactam (10/10 μg) were detected by the disk diffusion method, and the minimum inhibitory concentration (MIC) of ciprofloxacin (Sigma, Germany) was determined by the broth microdilution method. E. coli ATCC 25922 was used as a quality control strain.

2.3. Molecular Detection of qnr and Efflux Pump Genes

Genomic DNAs from ciprofloxacin-resistant K. pneumoniae isolates was extracted using the boiling method [11]. The presence of qnrA, qnrB, qnrS, oqxA, and oqxB genes was investigated by PCR using specific primers as previously described [12, 13]. The PCR reaction mixture contained 3 μl template DNA, 12.5 μl 2X Taq premix (Ampliqune Co, Denmark), 2 μl each primer (Metabion Co, Germany), and 3.5 μl ddH2O in a final volume of 25 μl. The PCR procedure OqxAB efflux pump genes and of qnrA, qnrB, and qnrS were performed in a thermal cycler (Bio-Rad, Inc. USA), according to the program shown in Table 1. Detection of PCR products was performed with a 100 bp DNA ladder on a 1% agarose gel. The sizes of amplified fragments for qnrA, qnrB, qnrS, oqxA, and oqxB were 571 bp, 594 bp, 388 bp, 207 bp, and 512 bp, respectively [12, 13].

2.4. ERIC-PCR

All qnr-positive K. pneumoniae strains were selected for molecular typing by ERIC-PCR. This procedure was performed using the primers as described previously [12] and the program in Table 1. The ERIC profiles were analyzed by an online database analysis service (insilico.ehu.es). A cutoff similarity of ≥95% was considered.

2.5. Data Analysis

Data were analyzed using SPSS software version 22.0 (IBM Co., Armonk, NY, USA). The relationships between different qnr genes, OqxAB efflux pump genes, antibiotic resistance, sample source, and hospital wards were analyzed using the Pearson chi-squared or fisher exact test. The relationship between qnr genes and the ciprofloxacin MIC values was analyzed by the t-test. values less than 0.05 were considered statically significant.

3. Results

3.1. Phenotypic Characteristics of K. pneumoniae Isolates

Klebsiella pneumoniae colonies were observed as pink mucoid colonies on McConkey agar. According to biochemical tests, K. pneumoniae colonies were indole and MR negative, and VP, Simmons citrate, urea hydrolysis, and lysine decarboxylase tests were positive. The presence of the ureD gene in K. pneumonia isolates were confirmed by PCR.

3.2. Antimicrobial Susceptibility Testing

Disk diffusion results showed a high level of resistance (89%) to ciprofloxacin. According to the CLSI 2021 criteria, ciprofloxacin breakpoints of ≥0.25 μg/ml, 0.5 μg/ml, and ≥1 μg/ml were considered susceptible, intermediate, and resistant strains. In this study, the MIC values of ciprofloxacin ranged from ≥0.5 μg/ml to ≥256 μg/ml. Ciprofloxacin MIC ≥ 256 μg/ml was detected in 26% and 20% of ciprofloxacin-resistant and qnr-positive strains, respectively. A multidrug resistance (MDR) phenotype was found in 96% (24 isolates) of the qnr-positive strains (Table 2). The non-MDR strain with a ciprofloxacin MIC > 2 μg/ml was negative for the efflux pump genes (Table 2).

3.3. Prevalence of qnr and Efflux Pump Genes

The results of qnr-genes detection by PCR showed that all K. pneumoniae isolates were negative for qnrA, and 20% and 9% of the isolates were positive for qnrB and qnrS, respectively (Figure 1). A qnrB+/qnrS + profile was observed in 16% of qnr-positive K. pneumomiae strains. The oqxA and oqxB genes were detected at 95% and 98% of K. pneumoniae isolates, respectively (Figure 2). According to the results, the gene encoding oqxA and oqxB were detected in 24 (96%) of qnr-positive strains. Table 2 provides information on isolates containing the qnr genes. Static analysis of the results showed that there were no significant correlations between qnr genes, efflux pumps, ciprofloxacin resistance, hospital wards, sample sources, ciprofloxacin MICs, or patterns of antibiotic resistance ( value ≥0.05). However, efflux pump genes and ciprofloxacin resistance were found to be significantly correlated ( value ≤0.04).

(a)

(b)

(c)

(d)

ERIC-PCR analysis of genetic linkage revealed genetic diversity among 25 different K. pneumonia qnr-positive strains. The results of the ERIC-PCR revealed the presence of 18 different ERIC profiles, including 5 common types and 13 unique types (including one isolate). There were two to three isolates in the common types (Figure 3). Our findings revealed the distribution of MDR and fluoroquinolone-resistant K. pneumoniae strains in some Hamadan hospital wards, as well as the distribution of related K. pneumoniae clones (ERIC type) in some hospital wards (ERIC types A, B, and E in the intensive care units). Strains of a common type showed different patterns of antibiotic resistance and different profiles of efflux pumps and qnr genes, and no significant relationship was observed between them (Table 2). There were no significant correlations between qnr genes and ERIC types.

4. Discussion

Fluoroquinolone resistance is an important problem associated with K. pneumoniae. Fluoroquinolone resistance has been suggested to play an important role in the successful evolution of K. pneumoniae strains [14]. This study showed a high level (≥80%) of resistance to ciprofloxacin in K. pneumoniae strains. Most fluoroquinolone-resistant strains also display the MDR phenotype. This finding highlights the problem of management of K. pneumoniae infections in hospitals and poses significant challenges for clinicians. Many of the isolates in this study were isolated from patients admitted to the ICU, which may be one of the main reasons for the high resistance to ciprofloxacin in this study. The rate of fluoroquinolone resistance in our study is higher than that in the study in Iran and some other regions [15–20]. However, a recent study of Hamadan reported a high rate of resistance (≥80%) to fluoroquinolones [21]. In total, our findings indicate that the qnr genes were present in 25% of K. pneumoniae isolates. None of the isolates contained qnrA, and qnrB was identified as the most prevalent qnr gene. The prevalence of qnrB and qnrS was 20% and 9%, respectively, in the isolates. On the distribution of the qnr gene in K. pneumoniae, there are various reports, including those from Iran. Nourozi et al. reported that qnrB (43% of isolates) was the most frequently detected qnr gene, followed by qnrS (34% of isolates) and qnrA (23% of isolates) in K. pneumoniae isolates from hospitals in Tehran [22]. The study results of Salimbahrami et al. showed that 47 (52%), 22 (25%), and 21 (23%) K. pneumoniae isolated from hospitals in Sari (northern Iran) contains the qnrB, qnrA, and qnrS genes, respectively [16]. In another study from southwestern of Iran by jomehzadeh et al., ciprofloxacin resistance was lower than our results while qnrA, qnrB, and qnrS were detected in (12%), (24%), and 17% of K. pneumonia isolates [23]. In the following, studies that reported results similar to ours are reviewed. In a study conducted by Malek Jamshidi et al., at Yazd central laboratory, the qnrA gene was not detected in any of the K. pneumoniae strains, and the qnrB gene (25%) was identified as dominant [23]. In a study from India, 22% of isolates possessed both qnrB and qnrS genes, while the qnrA gene was not detected in any strains [19]. Studies in China, Singapore, and Malaysia have demonstrated that qnrB is the major qnr gene, which is consistent with our findings and the majority of Iranian studies [24–26].

The differences in qnr genes frequency distribution of the of K. pneumoniae strains in different studies may be due to differences in geographical distribution of fluoroquinolone-resistant strains, sampling locations, and infection control strategies in the hospitals. Most qnr-positive strains had increased MICs for ciprofloxacin (28% and 20% of qnr-positive strains, MIC ≥ 128, and MIC ≥ 256, respectively). These results indicate that the presence of the qnr gene may play a role in reducing susceptibility to fluoroquinolones. It has also been shown that the qnr genes products can protect fluoroquinolone targets from antibiotic action. These genes are widely distributed in Enterobacteriaceae. The qnr gene is thought to induce low to moderate resistance to quinolones. Factors other than PMQR, such as gyrA and gyrB mutations and efflux pumps, may also play a role in the emergence of fluoroquinolone resistance. Plasmid-mediated qnr gene transfer between nosocomial pathogens increases the risk of transmitting resistance to fluoroquinolones and reduces the susceptibility of these pathogens to these antibiotics.

Another important factor in resistance to fluoroquinolones is the efflux pump. In this study, we investigated the association of the OqxAB efflux pump with resistance to fluoroquinolones. In this study, >95% of the isolates carried the OqxAB efflux pump genes. The OqxAB gene has been repeatedly reported in quinolone-resistant Enterobacteriaceae [27]. Expression of OqxAB has been shown to be associated with reduced susceptibility to quinolones in K. pneumonia [28, 29]. The present study found a significant relationship between ciprofloxacin resistance and the presence of OqxAB efflux pumps. The percentage of the OqxAB genes in our study is higher than that in other Iranian studies [22, 30, 31]. In our study, 96% of the qnr-positive strains harbored the efflux pump genes and exhibited the MDR phenotype. High ciprofloxacin resistance may be related to the coexistence of the efflux pump OqxAB and the qnr genes.

For molecular typing of K. pneumoniae isolates, our study used ERIC-PCR, which is a simple, inexpensive, and accessible method with sufficient reliability and reproducibility. Such as many studies, genetic diversity has been distinguished among K. pneumoniae strains [12, 32–34]. Our results demonstrated the prevalence of related K. pneumoniae strains (ERIC type) in some hospital wards, as well as the distribution of MDR and fluoroquinolone-resistant K. pneumoniae strains in some hospital wards, suggesting that these strains need further investigation. In this study, antibiotic resistance profiles and qnr gene profiles of strains belonging to the same ERIC class were different. To learn more about resistant strains, we recommend further investigation of the different mechanisms that influence the genetic differentiation of K. pneumoniae. OqxAB efflux pump genes and antibiotic resistance patterns were not significantly correlated with the ERIC groups, as shown in our results. Our results also show that widespread K. pneumoniae colons with different antibiotic resistance patterns and high proportions of antibiotic resistance determinants such as oqxAB and qnr genes can interfere with the control of nosocomial infections. In addition, high-risk fluoroquinolone-resistant K. pneumoniae clones have been shown to maintain fitness, facilitating their spread in hospital settings [35].

5. Conclusion

However, the results of this study suggested that there is no significance association between PMQR and OqxAB efflux pump genes but the alarming prevalence of MDR phenotypes, presence of OqxAB efflux pump, and PMQR determinants in heterogeneous fluoroquinolone-resistant K. pneumoniae strains in hospitals increase the risk of fluoroquinolone-resistance transmission among hospital-adapted pathogens and cause challenges for clinicians in hospitals. More bacterial strains should be tested and a wider area sampled for more accurate and better results. All of this requires research funding and more collaboration between hospitals, research centers, and universities.

Data Availability

The data used to support the findings of this study are included in the article.

Ethical Approval

This study was approved by the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1400.185).

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors would like to express their gratitude to everyone all those working in the microbiology laboratory of the Hamadan University of Medical Science, as well as the staff of Sina, Beheshti, and Be’sat hospitals in Hamadan. This research was supported by the Vice-Chancellor for Research and Technology of Hamadan University of Medical Sciences, Hamadan, IRAN (grant no: 140003182068).

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Copyright © 2023 Fereshteh Amereh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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