Nasal carriage rate and molecular epidemiology of methicillin-resistant Staphylococcus aureus among. medical students in a Taiwanese university

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1 Nasal carriage rate and molecular epidemiology of methicillin-resistant Staphylococcus aureus among medical students in a Taiwanese university Chang -Sheng Chen 1, Chao-Yu Chen 1, Yhu-Chering Huang 1,2 School of Medicine 1, Chang Gung University, Kweishan, Taoyuan, Taiwan Departments of Pediatrics 2, Chang Gung Memorial Hospital at Linko, Kweishan, Taoyuan, Taiwan Short title: MRSA among medical students Correspondence: Dr. Yhu-Chering Huang, Department of Pediatrics, Chang Gung Memorial Hospital, No. 5, Fu-Shin Street, Kweishan 333, Taoyuan, Taiwan. TEL: Fax: ychuang@adm.cgmh.org.tw Key words: methicillin-resistant Staphylococcus aureus, MRSA, colonization, nasal carriage, molecular epidemiology, medical students, Taiwan 1

2 Abstract Background: Methicillin-resistant Staphylococcus aureus (MRSA) is among the important pathogens of nosocomial infections. To investigate whether clinical exposures in the hospital affect nasal MRSA carriage among medical students, we conducted this study. Methods: From June to September 2010, a total of 322 students of Chang Gung University, pre-clinical (n=167) and clinical (n=155), were recruited. Specimens from the nares of the subjects were obtained and sent for the detection of S. aureus. A questionnaire regarding demographics and potential risk factors for acquisition of S. aureus was also completed for each subject. All the MRSA isolates were further molecularly characterized. Results: Overall, the carriage rate of S. aureus was 19.3%, with a rate of 16.8% for pre-clinical students and 21.9% for clinical students (p=.26); the carriage rate of MRSA was 2.2%, with a rate of 2.4% for pre-clinical students and 1.9% for clinical students (p =.54). There was no significant difference between the pre-clinical and clinical students in terms of nasal carriage of S. aureus and MRSA. All seven MRSA isolates belonged to sequence type 59, carried staphylococcal chromosome cassette type IV or V T and were categorized as community strains in Taiwan. The risk factors for acquisition of S. aureus included male gender, age 23 years, and not taking antibiotics in the past year. Conclusions: A substantial proportion of medical students in northern Taiwan harbored MRSA, categorized as community strains, in their nares. The carriage of MRSA was not affected by the clinical exposure in the hospital for 1-2 years. 2

3 Introduction Staphylococcus aureus is considered one of the most frequently occurring community- and hospital-associated pathogens [1, 2]. Infectious diseases caused by S. aureus are in various forms, ranging from mild skin infection, endocarditis, to fulminant septicemia [3, 4]. Methicillin-resistant S. aureus (MRSA) was first reported in early 1960s and rapidly spread in 1980s [5, 6]. Nowadays, MRSA is endemic in hospitals worldwide[7]. In 2000, methicillin resistance had been identified in 53-83% of S. aureus isolates in 12 major hospitals of Taiwan [8, 9], including Chang Gung Memorial Hospital (CGMH), which is situated in northern part of Taiwan. Moreover, MRSA started to emerge in the community since 1990s and community-associated MRSA, genetically different from those of HA-MRSA, prevailed in some countries, including Taiwan. Exposure to the hospital environment of a prolonged duration may cause an increase of carriage of MRSA among the personnel [10-12]. This raised our concern of MRSA carriage among the clinical medical students, who have been exposed to the hospital environment. The reports regarding this issue have been scanty [13-20] and none was from Taiwan. Therefore, we conducted this study to figure out the prevalence and molecular epidemiology of MRSA among the medical students, stratified by pre-clinical and clinical groups, in Taiwan. 3

4 Material and Methods This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (CGMH). Chang Gung University (CGU) is located in a rural area of northern Taiwan; the campus itself makes a good isolated community. It houses schools of Medicine and Chinese Medicine. Students of both schools study in the same campus without extensive clinical exposure within their first three years. Starting on their fifth year, they have daily clinical exposure in CGMH until graduation. In this study, eligible subjects were medical students (from both schools) except grade fourth students. Students were divided into two groups: pre-clinical and clinical. In pre-clinical group, which included first- to third-year students (enrolled from 2007 to 2009), was considered to be representative of community; clinical group, consisting of fifth and higher grade students (enrolled before 2005), had at least one year of clinical exposure at CGMH. Eligible subjects were invited and sampled from their anterior nares for the detection of S. aureus after a written informed consent was obtained. A questionnaire was completed for each subject, including the demographics and risk factors for the acquisition of S. aureus. Specimens were collected at the end of academic year to ensure subjects in the clinical group had at least one-year-round clinical exposure. Specimens for culture were obtained with a cotton swab, placed in transport medium (Venturi Transystem, Copan Innovation Ltd, Limmerick, Ireland), and then brought to and processed in the microbiology laboratory. Isolates of S. aureus were identified according to standard methods and were categorized into methicillin-susceptible (MSSA) and methicillin-resistant (MRSA), according to the antibiotic susceptibility to oxacillin by the disk diffusion method of Clinical and Laboratory Standards Institute (CLSI) guide- 4

5 lines, 2005 [21]. The susceptibility of the MRSA isolates to additional 9 antibiotics, including doxycycline, vancomycin, teicoplanin, penicillin, co-trimoxazole, erythromycin, clindamycin, linezolid and fusidic acid were also determined using the disc diffusion method according to recommendations of the Clinical and Laboratory Standards Institute [22]. Pulsed-field gel electrophoresis (PFGE) was used to fingerprint MRSA isolates according to the procedure described previously [9, 21, 23-25]. Staphylococcal cassette chromosome mec (SCCmec) type and the presence of Panton-Valentine leucocidin (PVL) genes were determined by PCR assays according to the procedure described previously [9, 21, 23, 26, 27]. Multilocus sequence typing (MLST) was performed for selective strains of representative PFGE patterns as described elsewhere [26]. We performed statistical analyses with the Statistical Package for the Social Sciences (SPSS software for Windows, version 17.0). Appropriate χ 2 -tests and Yates correction were used for analysis. Odds ratio (OR) and 95% confidence interval (CIs) were also be calculated. We used two-sample t-test to compare means between two continuous variables. We further analyzed potential predictors of colonization with P =0.05 in uni-variate analysis with a multiple logistic regression model in SPSS. Multivariate analysis was performed by using two-tailed tests and statistical significance was based on P

6 Results A total of 322 students, including 167 pre-clinical and 155 clinical medical students, were recruited to this study. Age ranged from 18 to 41 years with a mean of 22.3 years. In pre-clinical group, the mean age was 20.3 year and in clinical group, 24.5 years. The male to female ratio was 1:0.4. Students major in medicine consisted 83.9% of the subjects, while Chinese medicine students 16.1%. (Table 1) Overall, S. aureus was identified from 62 students (19.3%), including MSSA for 55 students (17.1%) and MRSA for 7 students (2.2%). The mean ages of carrieres of S. aureus and MRSA are (SD=2.271) and 22.0 (SD=1.633), respectively. Then carriage rates of MSSA, MRSA, and S. aureus of two groups were calculated. Appropriateχ 2 -tests were used to find statistical significant differences. Nasal MSSA carriage rate was higher for clinical group (20.0%) than for pre-clinical group (14.4%), while nasal MRSA carriage rate was higher for pre-clinical group (2.4%) than for clinical group (1.9%). However, no significant difference was found between the two groups in terms of nasal carriage of MSSA and MRSA (Table 1). Table 2 illustrates comparison of the potential risk factors for acquisition of S. aureus between the carriers and the non-carriers. No significant association was found between carriers and non-carriers of MRSA. The carriers of S. aureus were significantly associated with male gender (p=.036, OR=2.098, 95%CI ), and age no less than 23 years (p=.009, OR=2.121, 95%CI ). Participants who had antibiotics usage in the past one year had a significantly lower rate of S. aureus carriage than those who had not (17.1% vs. 25.0%, p=.028). With a marginal significance, subjects who had hospitalization within the past one year had a higher S. aureus carriage rate than those who had not (40.0% vs. 18.6%, p=.091, OR=2.920, 95%CI: ). 6

7 There was no significant difference between the carriers and non-carriers of S. aurues in terms of different departments, different year grades, clinical exposure years, having family members as HCWs or not, having dates as HCWs or not, having previous S. aureus infection history or not, having physical contact to S. aureus-infected patients or not; neither was the exposures in specific hospital departments (data not shown in Table). All seven MRSA isolates were further characterized molecularly. Table 3 illustrates the detailed molecular characteristics of these strains. Two PFGE patterns with one major type (type C) were identified. All six isolates with PGFE type C carried SCCmec IV, and none had PVL genes. The only one isolate with PFGE type D SCCmec V T and had PVL genes. Three isolate were selected for MLST analysis and only one sequence type (ST59) was identified. All 7 isolates were susceptible to teicoplanin, vancomycin, doxycycline, fusidic acid, linezolid, and co-trimoxazole. In contrast, only two of them were susceptible to erythromycin and clindamycin; the others were resistant to both. 7

8 Discussion Results from the present study indicated that 2.2% of the medical students, preclinical (2.4%) and clinical (1.9%), in northern Taiwan harbored MRSA in their nares. One-to-two years clinical exposure did not affect the carriage rate of MRSA. These results were compatible with previous studies from the US and Australia [14, 20]. We also found that the years (1 or 2) of clinical exposure did not affect the carriage rate of MRSA among the medical students. However, the carriage rate of MRSA among medical student was less than that among general population (3.8% ~ 4.8 %) [28, 29] and that among health care workers (6.6% ~ 7.8%) in northern Taiwan[28]. In the current study, six of seven MRSA isolates shared common molecular characteristics, as ST 59/PGFE C/ SCCmec IV/ PVL-negative, which is the most common clone of the colonizing strains among general population in Taiwan. The remaining one isolate, characterized as ST 59/PGFE D/ SCCmec V T / PVL-positive, was among the most common clone of clinical CA-MRSA isolates in Taiwan[3, 9, 28]. Both clones belonged to community clones in Taiwan. The results suggested that these medical students might acquire MRSA colonization in the community rather than in the hospital. This could be explained by their limited clinical exposure and fewer chances to enter intensive care units, where MRSA prevailed. Due to limited case number, we failed to identify any risk factor for the acquisition of MRSA among the medical student in the current study. For the carriage of S. aureus, neither clinical exposure years nor year grade of the medical students were associated with difference of the carriage rates. However, we found that students age 23 years were significantly more likely to carry S. aureus than those age < 23 years, which were consistent with previous report [30]. This study also found that male gender was significant as- 8

9 sociated with S. aureus colonization than female, as many studies showed [30-33]. Personal hygiene and genetic aspects may explain this finding. Furthermore, medical students who took antibiotics in the past year were significantly less likely to be colonized by S. aureus, compared with those who did not. This finding also correlated to Bischoff et al s study [30]. There were several limitations for the current study. We obtained the sampling during the end of academic year. Grade seven medical students, who had 3 years of clinical exposure, graduated one month earlier before we started this project, and therefore were not recruited in. Thus, we had no data from those who had 3 years of clinical exposure. The total number of subjects was not large enough to draw any definite conclusion. A longitudinal study may be performed to confirm the relationship between MRSA/S. aurues carriage and age, and clinical exposures. 9

10 Acknowledgment This research work was supported by grants from Chang Gung Memorial Hospital (CMRPG ) and Medical Foundation in Memory of Dr. Deh-Lin Cheng. Special thanks to Shu-Er Chow (Center of General Education, Chang Gung University (CGU)) and Shu-Yuan Hsu (Department of Anatomy, CGU) for their assistance of helping collect nasal samples; to Jun-Bin Chen (MD), Chun-Hao Liu (School of Medicine, CGU), and Chih-Wei Yang (Department of Nephrology, Chang Gung Memorial Hospital) for idea contribution. 10

11 References 1. Chambers H. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. 2001; 7: Gerberding JL, McGowan JE, Jr., Tenover FC. Emerging nosocomial infections and antimicrobial resistance. Curr Clin Top Infect Dis. 1999; 19: Chen CJ, Huang YC. Community-acquired methicillin-resistant Staphylococcus aureus in Taiwan. J Microbiol Immunol Infect. 2005; 38: Lowy F. Staphylococcus aureus infections. N Engl J Med. 1998; 339: Ayliffe G. The progressive intercontinental spread of methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 1997: Jevons M. " Celbenin"-resistant staphylococci. Br Med J. 1961; 1: Albrich WC, Harbarth S. Health-care workers: source, vector, or victim of MRSA? The Lancet Infectious Diseases. 2008; 8: Hsueh P, Liu C, Luh K. Current status of antimicrobial resistance in Taiwan. Emerg Infect Dis. 2002; 8: Huang YC, Ho CF, Chen CJ, Su LH, Lin TY. Comparative molecular analysis of community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus isolates from children in northern Taiwan. Clin Microbiol Infect. 2008; 14: Al-Anazi A. Prevalence of Methicillin-Resistant Staphylococcus aureus in a teaching hospital in Riyadh, Saudi Arabia. Biomedical Research. 2009; 20:

12 11. El-Jalil H, Jallad M, Thwaini A. Nasal Carriage of Methicillin Resistant Staphylococcus aureus in Individuals Exposed and Not Exposed to Hospital Environments. Euro J Scient Res 2008; 22: Eveillard M, Martin Y, Hidri N, Boussougant Y, Joly-Guillou M. Carriage of methicillin-resistant Staphylococcus aureus among hospital employees: prevalence, duration, and transmission to households. Infect Control Hosp Epidemiol. 2004; 25: Ma XX, Sun DD, Wang S, Wang ML, Li M, Shang H, et al. Nasal carriage of methicillin-resistant Staphylococcus aureus among preclinical medical students: epidemiologic and molecular characteristics of methicillin-resistant S. aureus clones. Diagn Microbiol Infect Dis. 2011; 70: Slifka KJ, Nettleman MD, Dybas L, Stein GE. Is acquisition of methicillin-resistant Staphylococcus aureus an occupational hazard for medical students? Clin Infect Dis. 2009; 49: Baliga S, Bansil R, Suchitra U, Bharati B, Vidyalakshmi K, Shenoy S. Nasal carriage of meticillin-resistant Staphylococcus aureus in medical students. J Hosp Infect. 2008; 68: Adesida S, Abioye O, Bamiro B, Brai B, Smith S, Amisu K, et al. Associated risk factors and pulsed field gel electrophoresis of nasal isolates of Staphylococcus aureus from medical students in a tertiary hospital in Lagos, Nigeria. Braz J Infect Dis. 2007; 11: Guclu E, Yavuz T, Tokmak A, Behcet M, Karali E, Ozturk O, et al. Nasal carriage of pathogenic bacteria in medical students: effects of clinic exposure on prevalence and antibiotic susceptibility. Eur Arch Otorhinolaryngol. 2007; 264: Higuchi W, Isobe H, Iwao Y, Dohmae S, Saito K, Takano T, et al. Extensive multidrug resistance of coagulase-negative staphylococci in medical students. J Infect Chemother. 2007; 13:

13 19. Berthelot P, Grattard F, Fascia P, Martin I, Mallaval FO, Ros A, et al. Is nasal carriage of methicillin-resistant Staphylococcus aureus more prevalent among student healthcare workers? Infect Control Hosp Epidemiol. 2004; 25: Stubbs E, Pegler M, Vickery A, Harbour C. Nasal carriage of Staphylococcus aureus in Australian (pre-clinical and clinical) medical students. J Hosp Infect. 1994; 27: Huang YC, Chou YH, Su LH, Lien RI, Lin TY. Methicillin-resistant Staphylococcus aureus colonization and its association with infection among infants hospitalized in neonatal intensive care units. Pediatrics. 2006; 118: Ferraro M, Craig W, Dudley M, Eliopoulos G, Hecht D, Hindler J. Performance standards for antimicrobial susceptibility testing: CLSI; Huang YC, Su LH, Wu TL, Lin TY. Changing molecular epidemiology of methicillin-resistant Staphylococcus aureus bloodstream isolates from a teaching hospital in Northern Taiwan. J Clin Microbiol. 2006; 44: Huang YC, Su LH, Wu TL, Liu CE, Young TG, Chen PY, et al. Molecular epidemiology of clinical isolates of methicillin-resistant Staphylococcus aureus in Taiwan. J Clin Microbiol. 2004; 42: Tenover F, Arbeit R, Goering R, Mickelsen P, Murray B, Persing D, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol. 1995; 33: Enright MC, Day NP, Davies CE, Peacock SJ, Spratt BG. Multilocus sequence typing for characterization of methicillin-resistant and methicillin-susceptible clones of Staphylococcus aureus. J Clin 13

14 Microbiol. 2000; 38: Oliveira D, Lencastre H. Multiplex PCR strategy for rapid identification of structural types and variants of the mec element in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2002; 46: Huang YC, Chen CJ. Community-associated meticillin-resistant Staphylococcus aureus in children in Taiwan, 2000s. Int J Antimicrob Agents 2011; 38: Wang JT, Liao CH, Fang CT, Chie WC, Lai MS, Lauderdale TL, et al. Prevalence of and Risk Factors for Colonization by Methicillin-Resistant Staphylococcus aureus among Adults in Community Settings in Taiwan. J Clin Microbiol. 2009; 47: Bischoff W, Wallis M, Tucker K, Reboussin B, Sherertz R. Staphylococcus aureus nasal carriage in a student community: prevalence, clonal relationships, and risk factors. Infect Control Hosp Epidemiol. 2004; 25: Graham PL, 3rd, Lin SX, Larson EL. A U.S. population-based survey of Staphylococcus aureus colonization. Ann Intern Med. 2006; 144: Wertheim HF, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, et al. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis. 2005; 5: Halablab MA, Hijazi SM, Fawzi MA, Araj GF. Staphylococcus aureus nasal carriage rate and associated risk factors in individuals in the community. Epidemiol Infect. 2010; 138:

15 Table 1: Comparison of demographics and nasal carriage of Staphylococcus aureus among pre-clinical and clinical medical students Characteristics Total (n=322) Preclinical Clinical p OR [95%CI] (n=167) (n=155) Age (years, mean± SD) ± ± ± Median Male Gender 230 (71.4%) 122 (73.1%) 108 (69.7%) Major in Medicine 270 (83.9%) 140 (92.8%) 130 (74.2%) Nasal Carriage of MSSA 55 (17.1%) 24 (14.4%) 31 (20.0%) [ ] Nasal Carriage of MRSA 7 (2.2%) 4 (2.4%) 3 (1.9%) [ ] Nasal Carriage of S. aureus 62 (19.3%) 28 (16.8%) 34 (21.9%) [ ] OR, odds ratio; CI, confidence interval; MSSA, methicillin-sensitive S. aureus; MRSA, methicillin-resistant S. sureus 15

16 Table 2: Comparison of characteristics between medical students with and without methicillin-resistant Staphylococcus aureus (MRSA) or S. aureus nasal carriage Characteristics Nasal carriage of MRSA Nasal carriage of S. aureus No.(%) p OR 95% CI No. (%) p OR 95% CI Age Groups Gender Major in Age 23 (n=160) Age<23 (n=162) Male (n=230) Female (n=92) Medicine (n=270) Chinese Medicine (n=52) 3(1.9%) (25.0%) (2.5%) 22(13.6%) 6(2.6%) (22.2%) (1.1%) 11(12.0%) 6(2.2%) (20.0%) (1.9%) 8(15.4%) Year grade 1 (n=96) 1(.1.0%).470 N/A N/A 14(14.6%).486 N/A N/A 2 (n=3) 0(0%) 0(0%) 3 (n=68) 3(4.4%) 14(20.6%) 5 (n=106) 3(2.8%) 25(23.6%) 6 (n=49) 0(0%) 9(18.4%) Duration of clinical exposure (years) 0 (n=167) 4(2.4%).511 N/A N/A 28(16.8%).374 N/A N/A 1 (n=106) 3(2.8%) 25(23.6%) 2 (n=49) 0(0%) 9(18.4%) Yes (n=81) 3(3.7%) (22.2%) Any family members as HCWs No (n=241) 4(1.7%) 44(18.3%) Any dates as HCWs Yes (n=32) 1(3.1%) (21.9%) No 6(2.1%) 55(19.0%) (n=290) 16

17 Yes (n=10) 0(0%) (40.0%) Prior hospitalization in past one year Use of antibiotics in past one year No (n=312) Yes (n=105) No (n=148) N/K (n=69) 7(2.2%) 58(18.6%) 4(3.8%).375 N/A N/A 18(17.1%).028 N/A N/A 2(1.4%) 37(25.0%) 1(1.4%) 7(10.1%) Physical contact to S. aureus-infected Yes (n=79) 2(2.5%).943 N/A N/A 17(21.5%).625 N/A N/A No (n=85) 2(2.4%) 18(21.2%) patient N/K (n=158) 3(1.9%) 27(17.1%) History of S. Yes (n=12) 1(8.3%).306 N/A N/A 4(33.3%).282 N/A N/A aureus infection No (n=180) N/K (n=130) 3(1.7%) 37(20.6%) 3(2.3%) 21(16.2%) OR, odds ratio; CI, confidence interval; N/A, not applicable; N/K, not-knowing; HCW, health care worker 17

18 Table 3: Molecular characteristics and antibiotic susceptibility of seven methicillin-resistant Staphylococcus aureus isolates from medical students Isolate Molecular Characteristic Antibiotics a No. PGFE pattern SCCmec type PVL genes MLST type Erythromycin Clindamycin 1 C IV Negative 59 R R 2 D V T Positive 59 R R 3 C IV Negative 59 S S 4 C IV Negative N/A S S 5 C IV Negative N/A R R 6 C IV Negative N/A R R 7 C IV Negative N/A R R PFGE, pulsed-field gel electrophoresis; SCCmec, staphylococcal chromosomal cassette; PVL, Panton-Valentine leukocidin; MLST, multilocus sequence type; N/A, not applicable; R, resistant; S, sensitive Three representative isolates (No. 1~3) were selected to undergo MLST type identification. a All isolates were sensitive to teicoplanin, vancomycin, doxycycline, fusidic acid, linezolid, and co-trimoxazole and resistant to penicillin. 18

19 Table 4: Data comparison of this study and current published articles dealt with medical students MRSA colonization Total Published Author Country subject Year number Colonization of MRSA No.(%) Colonization of S. aureus No.(%) Pre-clinical group Clinical group Total Pre-clinical group Clinical group Total Chen CS -- Taiwan (2.4%) 3(1.9%) 7 (2.2%) 28 (16.8%) 34 (21.9%) 62 (19.3%) Ma XX [13] Slifka KJ [14] Baliga S [15] Adesida S [16] Guclu E [17] Higuchi W [18] Berthelot P [19] 2011 China (1.0%) N/A 22(1.0%) 234(11.1%) N/A 234(11.1%) 2009 USA 182 2(2.1%) 3(3.4%) 5(2.7%) N/A N/A 62(34%) 2008 India 50 N/A 12(24.0) 12(24.0%) N/A 44(88.0%) 44(88.0%) 2007 Nigeria 182 N/A N/A 0(0%) N/A N/A 26(14.3%) 2007 Turkey 179 N/A N/A 5(2.8%) 12(15.4%) 38(37.6%) 50(27.9%) 2007 Japan 98 0(0%) N/A 0(0%) 36 (36.7%) N/A 36 (36.7%) 2004 France 124 N/A 1(0.8%) 1(0.8%) N/A 34(27.4%) 34(27.4%) Stubbs E 1994 Australia 808 0(0%) 0(0%) 0(0%) 68(35.2%) 252(40.9%) 320(39.6%) [20] N/A, not applicable. Data were re-grouped into pre-clinical and clinical groups according to the information original articles provided. 19

Hong-Kai Wang 1, Chun-Yen Huang 1 and Yhu-Chering Huang 1,2*

Hong-Kai Wang 1, Chun-Yen Huang 1 and Yhu-Chering Huang 1,2* Wang et al. BMC Infectious Diseases (2017) 17:470 DOI 10.1186/s12879-017-2560-0 RESEARCH ARTICLE Open Access Clinical features and molecular characteristics of childhood communityassociated methicillin-resistant