Detection of the VanA and VanB Gene in Clinical Isolates of Vancomycin-Resistant Enterococci
By Qanita Fahim, Luqman Satti, Rafia Irfan, Uzma Naeem, Warda FurqanAffiliations
doi: 10.29271/jcpsp.2026.08.1039ABSTRACT
Objective: To determine the prevalence of vancomycin-resistant enterococci (VRE) among clinical isolates and to detect the presence of the vanA and vanB genes through polymerase chain reaction (PCR).
Study Design: A descriptive cross-sectional study.
Place and Duration of the Study: Department of Microbiology, Pak Emirates Military Hospital, Rawalpindi, Pakistan, from February to July 2025.
Methodology: A total of 107 Enterococcus isolates from various clinical specimens were identified according to standard guidelines. Antimicrobial susceptibility testing was performed according to the CLSI recommendations, including the vancomycin agar dilution method. Minimum inhibitory concentration (MIC) was determined using the Vitek 2 system. Isolates identified as VRE were further analysed for the presence of vanA and vanB genes.
Results: Among the 107 isolates, 84 (78.5%) were Enterococcus faecium, 21 (19.6%) were Enterococcus faecalis, and 2 (1.9%) were classified as other Enterococcus species. Seventeen isolates were identified as VRE; hence, the observed prevalence of VRE in clinical isolates was (15.9%), all of which exhibited resistance to teicoplanin. Additionally, two VRE isolates (1.9%) were resistant to linezolid. Out of 17 VRE isolates, the vanA gene was detected in 8 (7.5%) isolates, while the vanB gene was not detected in any isolate.
Conclusion: The presence of VRE and the vanA gene among clinical isolates in a tertiary care setting underscores the need for stringent surveillance and effective infection control practices.
Key Words: Enterococcus faecium, Enterococcus faecalis, polymerase chain reaction, VanA gene, VanB gene.
INTRODUCTION
Enterococci are Gram-positive bacteria that naturally inhabit the human gastrointestinal tract.1 Despite being normal flora, they have emerged as significant pathogens in both community and hospital settings. Enterococci are notably associated with asymptomatic bacteriuria, symptomatic urinary tract infections (UTIs), cholecystitis, bacteraemia, and surgical site infections.2,3 Their increasing resistance to glycopeptides such as vancomy-cin and teicoplanin has made them one of the leading causes of hospital-acquired infections and related mortality.3
To date, six glycopeptide resistance genotypes have been des- cribed in Enterococci: three intrinsic (vanC1, vanC2, and vanC3) and six acquired types (vanA, vanB, vanC, vanD, vanE, and vanG). Of these, vanA and vanB are most commonly associated with clinical isolates in Asia.2 The vanB gene confers resistance to vancomycin but retains susceptibility to teicoplanin, whereas vanA confers high-level resistance to both the drugs.3,4
The vanA gene is particularly concerning because of its high transmissibility, including its ability to transfer to methicillin- resistant Staphylococcus aureus (MRSA), potentially resulting in vancomycin-resistant S. aureus (VRSA), which represents a major therapeutic challenge.5
Detection of vancomycin-resistant enterococci (VRE) in clini- cal settings employs conventional and molecular techniques, such as broth/agar dilution, MIC determination, E-test, and polymerase chain reaction (PCR)-based methods (including real-time and multiplex PCR).6-9
This study aimed to determine the prevalence of VRE among clinical Enterococcus isolates with a preference for the presence of vanA and vanB genes. Additional associated factors, such as patient demographics, age, gender, and clinical diseases, were also recorded. Clinical outcomes of the eight VRE isolates carrying the vanA gene were also recorded. Given the critical role of vancomycin in treating several serious infections, monitoring VRE prevalence is essential to prevent the dissemination of resistance genes through effective infec-tion control measures in a tertiary healthcare setting.
METHODOLOGY
A descriptive, cross-sectional study was conducted at the Department of Microbiology, Pak Emirates Military Hospital, Rawalpindi, Pakistan, from February to July 2025.
Ethical approval was obtained from the Army Medical College Ethics Review Committee (ERC No. 446). As a tertiary care hospital, it serves the entire Rawalpindi district and a substantial portion of Punjab province. The sample size was calculated using the WHO sample size calculator.9,10 Approximately 107 participants were required to achieve a 95% confidence level with a 5% margin of error, assuming a prevalence of 5.21%. Using a non-probability convenience sampling technique, 107 clinical isolates of Enterococcus were collected from specimens received at the hospital lab department, including urine, blood, pus, cerebrospinal fluid (CSF), tissue, catheter tips, biliary stent, biliary fluid, serous fluid, nasobronchial lavage (NBL), and other specimens. Repeat samples and outbreak-associated isolates were excluded.
Specimens were cultured on appropriate media, including blood agar, chocolate agar, and MacConkey agar, and incubated at 37°C for 24–48 hours. Identification involved Gram’s staining, catalase test, motility testing, bile esculin, growth in 6.5% NaCl, PYR test, carbohydrate fermentation, pigment formation, Lancefield grouping, and vancomycin screen agar testing.11 Species-level identification and antibiotic suscep-tibility testing were performed using both conventional methods (Kirby-Bauer disk diffusion) and the Vitek 2 system (BioMérieux, France). According to Clinical and Laboratory Standards Institute (CLSI) guidelines, isolates with a minimum inhibitory concentration (MIC) of >16–32 μg/mL and growth on vancomycin agar were classified as VRE.11,12 All VRE isolates were preserved in glycerol broth at −70°C.
Susceptibility to vancomycin (30 μg), teicoplanin (30 μg), linezolid (30 μg), nitrofurantoin (300 μg), ampicillin (10 μg), tetracycline (30 μg), doxycycline (30 μg), ciprofloxacin (5 μg), erythromycin (15 μg), gentamicin (120 μg), and fosfomycin (200 μg) was evaluated as per the CLSI guidelines using Kirby Bauer disc diffusion technique. Enterococcus faecalis (E. faecalis) ATCC 29212 served as a control.11,12
Phenotypic resistance to vancomycin was assessed using brain heart infusion (BHI) agar containing 6 μg/mL of vancomycin, according to the CLSI recommendations.11,12 Isolates showing growth on this medium were considered VRE. E. faecalis ATCC 51299 (VRE) was used as the positive control.
MIC values were interpreted as per CLSI breakpoints. How-ever, all Enterococcus faecium (E. faecium) VRE isolates (VREf) demonstrated MIC >32 μg/mL for vancomycin. Manufacturer instructions for the Vitek 2 system were followed.6,11,12
All VRE isolates underwent multiplex PCR to detect vanA and vanB genes. DNA was extracted manually using a Qiagen kit. Primers were designed using Primer3Plus and validated using NCBI BLAST. The primer sequences were as follows: vanA: F 5′-GGATAGCTACTCCCGCCTTT-3′, R 5′-CCGAAACAG CCTGCTCAATT-3′ and vanB: F 5′-AGCTTGCATGGACAAATCACT-3′, R 5′-GACCTCACAGCCCGAAATC-3′.
PCR amplification was performed using a Cepheid thermocycler. Cycling conditions included an initial denaturation at 95°C for 5 minutes, followed by 35 cycles at 95°C for 30 seconds, 51°C for 30 seconds, and 72°C for 90 seconds, with a final extension at 72°C for 10 minutes. PCR products were observed in 1.5% agarose gels, stained with ethidium bromide and visualised under UV light. A 100 bp molecular ladder was used. Positive controls included E. faecalis ATCC 51299 (vanB) and E. faecium ATCC 51575 (vanA). A no-template control served as the negative control.6
Data were analysed using the Statistical Package for Social Sciences (SPSS) version 29. Frequencies and percentages were calculated for qualitative variables, while quantitative variables were summarised using mean and standard deviation (SD).
RESULTS
The prevalence of VRE in the clinical isolates was (15.9%). The VanA gene was detected in 8 VRE isolates. Its prevalence was 7.5%. Table I outlines the distribution of isolates according to sample type and corresponding frequencies. The cohort included 42 female and 65 male patients. The mean age was 40.71 ± 23.67 years.
As presented in Table I, a total of 107 enterococcal isolates were analysed over six months, of which 17 (15.9%) were identified as VRE. The predominant species isolated was E. faecium (n = 84, 78.5%), followed by E. faecalis (n = 21, 19.6%), and other Enterococcus species (n = 2, 1.9%). All 17 isolates identified as VRE (15.89%) were E. faecium (VREf) and exhibited a vancomycin MIC >32 μg/mL. As shown in Table I, the highest number of VRE isolates were recovered from urine samples (n = 6, 5.4%), followed by pus swabs (n = 3, 2.7%), blood (n = 2, 1.8%), double lumen catheter (DLC) tips (n = 2, 1.8%), NBL (n = 1, 0.9%), tissue sample (n = 1, 0.9%), CSF (n = 1, 0.9%) and a biliary stent (n = 1, 0.9%).
Most isolates demonstrated multidrug resistance. However, a considerable proportion remained susceptible to linezolid, tigecycline, teicoplanin, vancomycin, and tetracycline. Fosfomycin showed promising sensitivity in urinary isolates. High-level gentamicin resistance was checked in 65 urinary isolates, of which 13 were resistant.
All VREf isolates demonstrated resistance to ampicillin, quinolones, vancomycin, and teicoplanin. Five out of the 17 isolates were susceptible to tetracycline. All urinary VREf isolates were susceptible to fosfomycin but showed complete resistance to nitrofurantoin and norfloxacin (Figure 1).
Table I: Frequency and percentage distribution of Enterococcus isolates and VRE/GRE recovered from specimens submitted for bacterial culture.
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| NBL: Non-directed nasobronchial lavage; DLC: Double lumen catheter; UVC: Umbilical venous catheter; CSF: Cerebrospinal fluid. Isolates are linezolid resistant. The chi-square test was used to assess the significance of the prevalence of the VanA gene. *Isolates showing linezolid resistance. | ||||||
Table II: Demographic and clinical characteristics of patients with VRE infection.
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Hysterectomy with ureteric stenting |
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| Neonatal sepsis | ||||||
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Repeated admissions due to renal dialysis |
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Figure 1: Antibiogram of vancomycin-resistant Enterococcus (VRE) isolates.
AMP: Ampicillin; VAN: Vancomycin; TEC: Teicoplanin; LNZ: Linezolid; CIP: Ciprofloxacin; TET: Tetracycline; NOR: Norfloxacin; NIT: Nitrofurantoin; FOS: Fosfomycin; TIG: Tigecycline.
All VREf cases occurred in patients either admitted to critical care units (n = 7) or with a history of prolonged hospitalisation (n = 10); thus, the chances of nosocomial infection are predominant.
As demonstrated in Figure 1, all 17 VREf isolates had also shown teicoplanin resistance (MIC >32 μg/mL); therefore, they were glycopeptide-resistant enterococci (GRE).
Figure 2: Agarose gel electrophoresis showing amplification of a 204 bp fragment of the vanA gene from 17 clinical VRE isolates. Lanes 1, 5, 7, 8, 10, 11, 13, and 14 show VRE strains with an amplified 204 bp vanA product. A 100 bp is a ladder marker. The arrow indicates the negative control. Isolates in lanes 1, 2, 7, 10, 11, and 14 were recovered from urine; lanes 3 and 6 from blood; lane 4 from NBL; lanes 5, 12, and 17 from pus swabs; lanes 8 and 16 from umbilical vein catheters; lane 9 from a biliary stent; lane 13 from fluid; and lane 15 from tissue. Lanes 12 and 13 LRVRE isolates.
Two GRE isolates showed resistance to linezolid (MIC >8 μg/mL), qualifying them as linezolid-resistant VRE (LRVRE). One was isolated from fluid collected via right percutaneous nephrostomy (PCN) in a patient from the nephrology ward, with a history of multiple hospitalisations. The second was from a patient with purulent postoperative wound discharge who also had a prolonged hospital stay (Table II). Both isolates demonstrated multidrug resistance except for susceptibility to tigecycline (MIC <0.12).
PCR analysis confirmed the presence of the vanA gene in eight of the 17 VREf isolates (7.5%), with a 204 bp amplicon observed in agarose gel electrophoresis (Figure 2). In contrast, no vanB gene was detected, as evident by the absence of a 262 bp band in agarose gel electrophoresis. One of the two LRVRE isolates also harboured the vanA gene.
DISCUSSION
The observed prevalence of VRE in these clinical enterococcal isolates was 15.9% (95% CI: 10.16%–23.98%), higher than previously reported prevalence rates from Pakistan (10.5%) and India (12.5%).13,14 In the present study, the prevalence of the VanA gene amongst the clinical VRE isolates was 7.5%.9
The predominant species isolated was E. faecium (n = 84, 78.5%), followed by E. faecalis (n = 21, 19.6%), and other Enterococcus species (n = 2, 1.9%). Although traditionally E. faecalis has been considered more prevalent than E. faecium, many recent studies have shown a shift towards E. faecium dominance among nosocomial isolates because of antimicrobial selection pressure and adaptation to the hospital environment.15
The predominant specimens yielding Enterococcus isolates were urine and blood (Table I), and the predominant species was E. faecium. All the VRE isolates in this study originated from hospitalised patients, reinforcing the hospital environment’s role in propagating multidrug-resistant Enterococci.15
In this study, UTIs predominantly affect two age groups: children under 10 years and adults over 60 years of age, largely due to anatomical anomalies in one and long-term catheterisation in the other.16 However, the majority of patients in the study were over 50, with a mean age of 40.71 years.
Enterococci are among the top three causative agents of complicated and uncomplicated UTIs. While E. faecalis remains the predominant isolated species, showing vancomycin resistance. However, in this study, it is more frequently associated with E. faecium, probably because it is often linked to medical instrumentation and prolonged catheterisation.17-19 Although E. faecium was the most resistant and frequently isolated species in this study, its resistance profile was consistent with global findings.17-19
Among the 34 urine samples analysed, 24 yielded E. faecium, and 6 (5.4%) of these were identified as VREf, with 5 (4.5%) carrying the vanA gene. The gender distribution in urinary isolates was nearly equal. However, accurate collection of midstream urine in females presents challenges, including contamination from poor hygiene, improper technique, and insufficient patient preparation.18,19 Among the 34 urine samples, 16 were from females and 18 from males. In males, E. faecalis and E. faecium were isolated in 5 (4.5%) and 11 (9.9%) cases, respectively, while in females, these figures were 3 (2.7%) and 13 (11.7%). Two male samples yielded E. spp. Overall, E. faecium was more prevalent than E. faecalis (24 [21.6%] vs. 8 [7.4%]), consistent with other studies.17-19
Contamination cannot be entirely excluded, especially because four of the six urine samples yielding VRE were obtained from female patients, and only two of these were collected as midstream samples. All six patients were over 45 years old and had underlying health conditions. Four patients (two males, two females) had long-term indwelling catheters.18 Approximately 14.8% of the 34 urine samples were catheter-derived.
Biofilm formation on catheters, once thought to be unique to E. faecalis, has now been observed in other enterococcal strains. These findings suggest that the VREf isolates in this study may possess biofilm-forming capabilities; however, this cannot be confirmed because biofilm-forming ability was not assessed in the present study, although it has been reported in previous studies.19,20
Antibiotic susceptibility testing revealed that most E. faecium and approximately half of E. faecalis isolates were resistant to norfloxacin. These findings support a meta-analysis from Poland recommending against empirical use of fluoroquinolones and beta-lactams for UTIs, given resistance in common enterococcal strains.20 However, the universal susceptibility of the isolates to fosfomycin aligns with the findings of previous studies.
Complete resistance to glycopeptides among the clinical VREf isolates mirrors findings from Peng et al., who attri-buted this to concurrent use of vancomycin with teico- planin.21 Teicoplanin should be avoided when vancomycin is administered to preserve teicoplanin and linezolid as a last- line option.
Among the 44 blood culture samples received, 15 were from females and 29 from males, spanning all age groups. E. faecalis was isolated in 9 (8.1%) and E. faecium in 35 (31.5%) cases. Two blood isolates were VREf. One patient had hepatitis B, decompensated liver disease, chronic kidney disease, and colon cancer, and expired during hospitalisation (Table II). Literature supports a high mortality risk in patients with VREf bloodstream infections (BSI), with aHR of 2.18.22 Studies from Australia and Pakistan corroborate the association of E. faecium BSI with increased 30-day mortality.22,23 VREf BSI is associated with higher mortality compared to VRE (E. faecalis).24,25
All VREf isolates, except two LRVREf strains, were treated with linezolid. This agent remains the primary treatment option for VRE BSI due to its superior efficacy compared to daptomycin and tedizolid.25,26 However, linezolid has known adverse effects, but none of these effects had been obser-ved in this case.25,26
Teicoplanin was not recommended, given resistance in all VREf isolates and its inactivity against vanA-type VREf.24 Notably, 5 of the 17 VREf isolates were susceptible to tetracycline, but in vivo response had not been tested.
On the other hand, the two LRVREf cases received tigecycline. One, a 63-year-old man with obstructive uropathy, recovered after PCN and was shifted to the urology ward (Table II). The second, a 48-year woman with diabetes and progressive limb amputation, succumbed despite tigecycline therapy. This finding supports existing concerns regarding the efficacy of tigecycline monotherapy.26
This study emphasises that future strategies should include molecular research and alternative therapeutics to address the growing challenge of antimicrobial resistance in VRE isolates.
Although E. faecalis is traditionally reported as the predominant Enterococcus species in clinical infections, this study demonstrated a higher prevalence of E. faecium. This may reflect increasing hospital adaptation of E. faecium, selective antibiotic pressure, emergence of multidrug-resistant hospital-associated clonal lineages, and the predominance of healthcare-associated infections in the study population.15,22
The 15.9% VRE prevalence and the detection of vanA gene in Enterococcal isolates highlight the ongoing threat of vancomycin resistance in tertiary care settings. The vanA genotype is the most commonly reported mechanism of acquired vancomycin resistance among clinical Enterococcal isolates worldwide and is usually associated with high-level resistance to both vancomycin and teicoplanin. The vanA operon is commonly carried on the transposon Tn1546, which facilitates horizontal transfer of resistance genes among Enterococci and contributes to nosocomial dissemination.8
The prevalence of vanA observed in this study is comparable to findings from several regional and international studies where vanA predominates over other vancomycin resistance genotypes. The predominance of vanA may reflect selective antibiotic pressure resulting from extensive glycopeptide use and the clonal spread of resistant strains within the health- care setting. Since vanA-positive isolates are frequently multidrug resistant, their emergence poses a significant thera- peutic challenge and limits treatment options to agents such as linezolid and daptomycin. The absence of the vanB gene is consistent with regional data from Pakistan, Iran, and India.2,8,15
Unlike vanA, the vanB genotype confers variable levels of resistance to vancomycin while generally retaining susceptibility to teicoplanin. The lack of vanB detection may indicate limited circulation of vanB-harbouring strains in the studied population or differences in local epidemiological patterns.2
Interestingly, 9 out of the 17 VRE isolates were negative for both vanA and vanB genes, suggesting the possible involvement of other resistance determinants such as vanC, vanD, or less common vanE and vanG genotypes.2 Further molecular characterisation of these isolates would therefore be valuable in understanding the complete genetic basis of vancomycin resistance in this region. Clinicians must adopt individualised treatment strategies, considering infection type, resistance patterns, and patient-specific factors to optimise therapy while minimising toxicity.
CONCLUSION
Addressing the challenge of VRE necessitates a comprehensive, multidisciplinary approach that integrates timely diagnosis, appropriate antimicrobial therapy, infection control measures, and continued research.
ETHICAL APPROVAL:
Ethical approval was obtained from the Institutional Ethical Review Board of Army Medical College, Rawalpindi, Pakistan (ERC No. 02/2025/446; dated: 24 February 2025).
PATIENTS’ CONSENT:
Written informed consent was obtained from the patients for participation and publication.
COMPETING INTEREST:
The authors declared no conflict of interest.
AUTHORS’ CONTRIBUTIONS:
QF: Drafting the manuscript, editing clinical images, analysing the results, and preparing the tables.
LS: Critical revision of the manuscript.
RI: Revision of the draft and interpretation of the data.
UN: Conducting chemical pathology tests and revising the draft.
WF: Interpretation of sensitive reports and revision of the draft.
All authors approved the final version of the manuscript to be published.
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