Staphylococcal Nasal Carriage of Health Care Workers

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1 ORIGINAL ARTICLE Staphylococcal Nasal Carriage of Health Care Workers Naeem Akhtar ABSTRACT Objective: To determine the frequency of staphylococcal nasal carriage of health care workers (HCWs) and antimicrobial susceptibility profile of the isolates for appropriate decolonization therapy. Study Design: An observational study. Place and Duration of Study: The study was conducted at Holy Family Hospital, Rawalpindi, during the period from May 2007 to April Methodology: Nasal swabs from anterior nares of HCWs were cultured and identified as Staphylococcus aureus, coagulasenegative staphylococci (CoNS), methicillin-resistant S. aureus (MRSA), methicillin-resistant CoNS (MRCoNS) by using standard methods. Antimicrobial susceptibility testing was performed on Muller Hinton Agar using disc diffusion method. Results: Of the 468 HCWs, 213 (45.5%) participants were men and 255 (54.5%) were women. Eighty five (18.2%) were nasal carriers of S. aureus, 07 (1.5%) for MRSA, 343 (73.3%) for CoNS and 10 (2.1%) for MRCoNS. The highest carriage rate for S. aureus was in midwives (30%) followed by maintenance staff (28.6%), security guards (25%), technicians (23.5%), staff nurses (22.7%) and < 20% in house physicians and nursing students. Carriage rate in HCWs from different departments was: surgical ICU (40%), gynaecology (34.9%), delivery room (30%), gynaecology operation rooms (25%), medicine (22.7%) and < 20% in pediatrics and surgery. All isolates were susceptible to vancomycin, imipenem and levofloxacin and > 90% of S. aureus and CoNS were susceptible to amikacin, gentamicin and fluoroquinolones tested. Conclusion: Fluoroquinolones, preferably oral levofloxacin in combination with topical gentamicin ointment, in places like Pakistan where mupirocin is not routinely available, can be used for decolonization of nasal staphylococcal carriage. Key words: Staphylococci. Nasal carriage. Health care workers. Antibiotic susceptibility. Decolonization. INTRODUCTION Staphylococcus (S.) aureus remains one of the most important nosocomial and community acquired pathogen. Both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) have been implicated in a variety of endemic and epidemic nosocomial infections worldwide. Approximately 20% of healthy adults are persistent nasal carriers of this potential pathogen and 60% harbour the organism intermittently and appear to play a key role in the epidemiology and pathogenesis of infection. 1,2 These persistent nasal carriers are an important indigenous source and are at increased risk for surgical site infections, foreign body infections and bacteremias. 3,4 Furthermore, variable percentage ( %) about carriage rate in healthcare workers in different healthcare settings has been reported. 2 Staphylococcal nasal carriage rate, both MSSA and MRSA, in HCWs from Rawalpindi and other areas in Pakistan is also variable. 5-7 Coagulase negative staphylococci (CoNS), occurring as normal flora of skin and anterior nose are also pathogenic, when the host is compromised. CoNS are the most common pathogens Department of Pathology, Rawalpindi Medical College, Rawalpindi, Pakistan. Correspondence: Dr. Naeem Akhtar, House No. A-6, Rawalpindi Medical College, Staff Collony, Rawalpindi. naeeakh@yahoo.com Received July 08, 2009; accepted May 25, in nosocomial blood stream infections and indwelling catheters. Methicillin-resistant CoNS (MRCoNS) have also been found worldwide. 8 Persistent nasal carriers can be an important source of staphylococcal infections to patients and outbreaks of staphylococcal infections Several studies have shown that elimination of carriage in the anterior nares, reduces the incidence of S. aureus infections. 2,12 Therefore, the knowledge of frequency of nasal carriage of HCWs by S. aureus, MRSA, CoNS and MRCoNS along with their current antimicrobial profile becomes necessary in the selection of appropriate treatment options for these carriers. The present study was carried out to determine the prevalence of these staphylococci in anterior nares of HCWs at a tertiary care facility in Rawalpindi, and also the susceptibility of the isolates against 24 antibiotics. METHODOLOGY The study was conducted at Holy Family Hospital, Rawalpindi, Pakistan, from May 2007 to April Four hundred and sixty eight HCWs including specialists, postgraduate trainees, house physicians, staff nurses, nursing students and sanitary staff participated in the study. HCWs having history of upper respiratory tract infection or having taken any antibiotic during the last one week were excluded from the study. After taking consent, a predesigned proforma including details about Journal of the College of Physicians and Surgeons Pakistan 2010, Vol. 20 (7):

2 Naeem Akhtar status, gender, duration of hospital stay and Units etc. was filled for each individual. Nasal specimens were obtained by using cotton swabs, (Becton Dickinson Culturette Systems, Sparks, Md.) moistened in sterile saline. The swabs were inserted into both anterior nares and rotated 5 times. Culture of the swabs and identification of the obtained growth as S. aureus or CoNS was done by using standard methods. In addition methicillin resistance for both the organisms was tested by oxacillin disc. Antimicrobial susceptibility testing was performed by Kirby-Bauer disc diffusion method according to Clinical Laboratory Standards Institute (CLSI) guidelines using Mueller-Hinton agar. 13 Zone sizes of each antimicrobial agent were recorded and interpreted as resistant, intermediate or susceptible. Intermediately susceptible isolates were considered resistant. Susceptibility was tested against following 24 antimicrobials: ampicillin, cloxacillin, co-amoxyclav, cephradine, cephalexin, cefaclor, cefotaxime, amikacin, gentamicin, lincomycin, tetracycline, chloramphenicol, co-trimoxazole, ofloxacin, ciprofloxacin, enoxacin, sparfloxacin, levofloxacin, moxifloxacin, vancomycin, imipenem, fusidic acid, fosfomycin and rifampicin. Microsoft Excel spread sheet was used to analyze the data in the form of percentages. RESULTS Out of 468 HCWs participating in the study, 213 (45.5%) were men, and 255 (54.5%) were women. Eighty five (18.2%) were nasal carriers of S. aureus, 07 (1.5%) for MRSA, 10 (2.1%) for MRCoNS and 343 (73.3%) harboured CoNS as shown in Table I. Of the 85 nasal carriers for S. aureus, 37.65% were men and 62.35% were women. Carriage rate for MRSA and MRCoNS in men and women was 1.87 and 1.17% and 1.40 and 2.74% respectively. Eleven (2.35%) of HCWs showed growth of Klebsiella spp. while one (0.21%) gave growth of Escherichia coli. The frequency of carriage rate of S. aureus, MRSA, CoNS and MRCoNS in various groups of staff members is given in Table I. Only 7 specialists and 8 dispensers participated in the study and none was carrier for S. aureus, MRSA or MRCoNS. The highest carriage rate for S. aureus was seen in midwives (30%) followed by maintenance staff (28.57%), security guards (25%), technicians (23.52%) and staff nurses (22.68%). MRSA was isolated from anterior nares of 3/97 (3.09%) staff nurses, 2/24 (8.33%) security guards, 1/91 (1.01%) postgraduate trainee and 1/17 (5.88%) technician. MRCoNS was isolated from 6/97 (6.18%) staff nurses, 2/34 (5.88%) sanitary workers, 1/37 (2.70%) nursing student and 1/17 (5.88%) technician. The frequency of S. aureus, MRSA and MRCoNS carriage also varied between different departments. For example, 40% of HCWs in surgical ICU (SICU) were carriers of Table I: Frequency of nasal carriage of healthcare workers for staphylococcus aureus, methicillin-resistant S. aureus and coagulase-negative staphylococci. Status (n) Organisms isolated S. aureus MRSA* CoNS** RCoNS*** n (%) n (%) n (%) n (%) Specialists (07) 07 (100) Postgraduate trainees (91) 12 (13.2) 01 (1.0) 75 (82.4) House physicians (83) 16 (19.3) 61 (73.5) Staff Nurses (97) 22 (22.7) 03 (3.1) 59 (60.8) 06 (6.2) Student nurses (37) 07 (18.9) 29 (78.4) 01 (2.7) Dispensers (08) 07 (87.5) Mid wives (20) 06 (30) 14 (70) Ward boys (27) 04 (14.8) 22 (81.5) Technicians (17) 04 (23.5) 01 (5.9) 08 (47.1) 01 (5.9) Sanitary workers (34) 04 (11.8) 27 (79.4) 02 (5.9) Security guards (24) 06 (25) 02 (8.3) 15 (62.5) Clerks (16) 02 (12.5) 14 (87.5) Maintenance staff (07) 02 (28.6) 05 (71.4) Total (468) 85 (18.2) 07 (1.5) 343 (73.3) 10 (2.1) *Methicillin-resistant S. aureus; **Coagulase-negative staphylococci; ***Methicillin-resistant coagulase-negative staphylococci. S. aureus, whereas only 5.55% of HCWs in the ENT department were carriers. Next higher carriage rate was in HCWs in gynaecology ward (34.92%), delivery room (30%) and gynaecology operation rooms (25%) followed by medicine department (22.68%). S. aureus carriage rate in HCWs in departments of pediatrics and surgery were 17.94% and 10.84% respectively. The highest carriage rate was seen in staff with a hospital stay from years (40%) followed by 6-10 years (20.51%) and the least (13.04%) was in staff with hospital service of years. Susceptibility profile against the antibiotics tested of all the isolates i.e. S. aureus (n=85), MRSA (n=07), CoNS (n=343) and MRCoNS (n=10) is shown in Table II and III. All the isolates were susceptible to vancomycin, imipenem and levofloxacin. All MRSA were also susceptible to amikacin and all MRCoNS were Table II: Antibiotic susceptibility profile of Staphylococcus aureus, methicillin-resistant S. aureus and coagulase-negative staphylococci isolated from nasal swabs of healthcare workers to penicillins, cephalosporins, aminoglycosides. Antibiotics Organisms isolated (total no.) S. aureus MRSA* CoNS** MRCoNS*** TOTAL (85) n (%) (07) n (%) (343) n (%) (10) n (%) (445) n (%) Ampicillin 16 (18.8) NT 52 (15.2) NT 68 (15.9)# Co-amoxyclav 70 (80.2) 03 (42.9) 288 (84.0) 07 (70) 368 (82.7) Cloxacillin 58 (68.2) NT 208 (60.6) NT 266 (62.1)# Cephradine 76 (89.4) 05 (71.4) 307 (89.5) 07 (70) 395 (88.8) Cephralexin 79 (92.9) 05 (71.4) 305 (88.9) 08 (80) 397 (89.2) Cefaclor 75 (88.2) 05 (71.4) 299 (87.2) 05 (50) 384 (78.2) Cefotaxime 83 (97.6) 03 (42.9) 327 (95.3) 05 (50) 418 (93.9) Amikacin 84 (98.8) 07 (100) 336 (98.0) 10 (100) 437 (98.2) Gentamicin 80 (94.1) 06 (85.7) 312 (91.0) 10 (100) 408 (91.7) Lincomicin 62 (72.9) 04 (57.1) 184 (53.6) 07 (70) 257 (57.8) Tetracycline 53 (62.4) 03 (42.9) 198 (57.7) 05 (50) 259 (58.2) Chloramphenicol 49 (57.6) 02 (28.6) 172 (50.2) 07 (70) 230 (51.7) Co-trimoxazole 14 (16.5) NT 57 (16.6) NT 71 (16.6)# *Methicillin-resistant S. aureus; **Coagulase-negative staphylococci, ***Methicillin-resistant coagulase-negative staphylococci; NT; Not tested: #Percentage out of total 428 isolates 440 Journal of the College of Physicians and Surgeons Pakistan 2010, Vol. 20 (7):

3 Staphylococcal nasal carriage of health care workers Table III: Antibiotic susceptibility profile of Staphylococcus aureus, methicillin-resistant S. aureus and coagulase-negative staphylococci isolated from nasal swabs of healthcare workers to fluoroquinolones, imipenem, vancomycin, fosfomycin and rifampicin. Antibiotics Organisms isolated (total nos.) S. aureus MRSA* CoNS** MRCoNS*** TOTAL (85) n (%) (07) n (%) (343) n (%) (10) n (%) (445) n (%) Ofloxacin 81 (95.3) 05 (71.4) 319 (93.0) 08 (80) 413 (92.8) Ciprofloxacin 81 (95.3) 05 (71.4) 318 (92.7) 08 (80) 412 (92.6) Enoxacin 80 (94.1) 05 (71.4) 287 (83.7) 08 (80) 380 (85.4) Sparfloxacin 82 (96.5) 06 (85.7) 341 (99.4) 10 (100) 439 (98.7) Levofloxacin 85 (100) 07 (100) 343 (100) 10 (100) 445 (100) Moxifloxacin 82 (96.5) 06 (85.7) 334 (97.4) 10 (100) 432 (97.1) Fusidic-acid 74 (87.1) 04 (57.1) 271 (79.00) 07 (70) 356 (80) Imipenem 85 (100) 07 (100) 343 (100) 10 (100) 445 (100) Vancomycin 85 (100) 07 (100) 343 (100) 10 (100) 445 (100) Fosfomycin 80 (94.1) 05 (71.4) 313 (91.3) 05 (50) 403 (90.6) Rifampicin 78 (91.8) 04 (57.1) 282 (82.2) 07 (70) 371 (83.4) *Methicillin-resistant S. aureus; **Coagulase-negative staphylococci; ***Methicillin-resistant coagulase - negative staphylococci. susceptible to gentamicin, sparfloxacin and moxifloxacin. More than 90% of S. aureus and CoNS were susceptible to amikacin, gentamicin, cefotaxime, ofloxacin, ciprofloxacin, sparfloxacin, moxifloxacin and fosfomycin. In addition > 90% of S. aureus were susceptible to enoxacin and rifampicin. In general CoNS were less susceptible to the antibiotics than S. aureus. In contrast susceptibility profile of MRSA and MRCoNS was otherway round i.e. resistance rate in MRSA isolates was more than that of MRCoNS. Cumulative susceptibility profile of all the staphylococci is presented in Figure 1. Figure 1: Cumulative percentage susceptibility profile of the staphylococci isolated from nasal swabs of health-care workers. DISCUSSION Significant work has been done on the subject of nasal carriage of S. aureus by patients, HCWs and its association with increased relative risk of infections in patients. 4 Screening for carriage of staphylococci is fundamental to nosocomial infection control practices. Eradication of staphylococcal nasal carriage reduces the infection rate in patients. 2,12 In the present study, 18.2% of HCWs were nasal carriers of S. aureus. Higher nasal carriage rate (33% and 48%) for S. aureus of HCWs has been reported in two Pakistani studies. 5,6 Prevalence of nasal carriage of S. aureus in other countries is also different ( %). 2 This difference may be due, in part, to differences in geographical distribution, differences in the quality and size of samples and the culture methods used to detect S. aureus. Out of 468 HCWs, carriage rate for MRSA was 1.49%. Out of total 92 isolates of S. aureus, 07 (7.6%) were MRSA. Varying rates for MRSA carriage by HCWs are reported in Pakistan (14%) and neighbouring country like India (39.7%). 6,14 Low MRSA nasal carriage in our study is in contrast to these reports, however, it correlates with a previous study in another hospital in Rawalpinidi (1.78%). 7 Also lower isolation rate of MRSA from clinical specimens from our patients indicate lower isolation rate of the germ. Similarly, lower colonization (2.13%) by MRCoNS in contrast to other studies including community skilled nursing facility nursing personnel (60%), 15 HCWs 25-62%, 16,17 may be attributed to differences in geographical distribution, techniques and use of different antibiotic discs like oxacillin, methicillin or cefoxitin for the detection of methicillin resistance. Eleven HCWs (2.35%) showed growth of Klebsiella spp. while only one (0.21%) gave growth of Escherichia coli. This simply could be associated with poor hygienic practices. Higher carriage rate for S. aureus seen in midwives (30%), maintenance staff (28.57%) and security guards (25%) may have some association with their personal hygiene or longer hospital stay as on day to day basis they are not in direct patient contact. HCWs having direct patient contact have higher carriage rate than those who have lesser contact. 16 Carriage rate in HCWs like technicians (23.52%), staff nurses (22.68%), house officers and nursing students (16-20%) is also high and can partially be related to direct patient contact. The low rate of MRSA and MRCoNS carriage may be due to variable contact of HCWs with patient infected with these microbes. There was a remarkable difference in S. aureus carriage rate in HCWs of SICU (40%) and MICU (5.88%). In our hospital, staff for SICU and MICU is specified and not rotating. Higher carriage rate in HCWs in wards, operation rooms and delivery rooms is of great concern as they can be a source of transmission to neonates particularly. Some relationship can be inferred from duration of hospital service. Highest carriage rate (40%) seen in staff with a hospital service of years (40%) is self explanatory. This was followed by 6-10 years (20.51%) and the least carriage rate (13.04%) in staff with hospital service of years is explained on the basis that many of the workers in this group were those who have least direct patient contact. Journal of the College of Physicians and Surgeons Pakistan 2010, Vol. 20 (7):

4 Naeem Akhtar Various topical agents including; mupirocin, bacitracin and fusidic acid ointments and oral agents like; trimethoprim-sulfmethoxazole, ciprofloxacin, doxycycline, rifampicin and clarythromycin have been used separately or in combination in different settings for eradication of S. aureus and MRSA nasal carriage in HCWs. This has been recently reviewed in detail by Ammerlaan et al. 18 One important limitation of present study is that mupirocin, the agent recommended for eradication of staphylococcal nasal carriage, 18 was not tested. This is due to the non-availability of mupirocin discs for susceptibility testing. However, intranasal application of mupirocin has limited effectiveness in eradicating colonization in patients who carry the organism at multiple body sites. Therefore, a broader range of antibiotics were tested for suitable therapy. Antimicrobial susceptibility for CoNS was also tested as CoNS nasal carriers can disperse these organisms in the environment, 19 and have shown association with increased rate of infection in haemodialysis patients. 20 In present study all the isolates including S. aureus, MRSA, CoNS and MRCoNS were susceptible to vancomycin, imipenem and levofloxacin. Due to the fear of development of resistance, being injectable and expensive, vancomycin has not been used for nasal decolonization. Imipenem, a broad-spectrum antibacterial agent, also injectable and expensive, is mostly kept as a reserve drug for life threatening infections, 21 and has not been used in staphylococcal decolonization. Levofloxacin, a respiratory fluoroquinolone, remains the option that can be used for eradication of any of staphylococcal nasal carriage as it has a very good nasal penetration and its activity better than ciprofloxacin. 22,23 All the other fluoroquinolones tested had > 90% activity against staphylococci and can be a second option. Whenever required in special settings like hemodialysis units to eradicate CoNS nasal carriage most of the fluoroquinolones can be used. Rifampicin, a first line antituberclous drug also, has been used in various studies for eradication of staphylococcal nasal carriage and has shown variable activity against S. aureus and MRSA. 24 However, due to the reason that S. aureus quickly develops resistance to rifampicin monotherapy, 25 and secondly being reserved as anti-tuberculosis drug in Pakistan with high prevalence of tuberculosis cannot be opted for decolonization. CONCLUSION Nasal carriage rate in HCWs for S. aureus, MRSA, CoNS and MRCoNS was 18.2%, 1.5%, 73.3% and 2.1% respectively. Fluoroquinolones, preferably oral levofloxacin can be used for decolonization of staphylococcal nasal carriage in HCWs. This may be used in combination with topical gentamicin ointment in S. aureus and CoNS but not in methicillin-resistant staphylococci, as an alternate option in places like Pakistan where mupirocin is not routinely available. Acknowledgements: This study is a part of research project funded by Higher Education Commission of Pakistan, Islamabad. I would like to thank my colleagues; Mr. Yusuf Rajput, Dr. Umair Mahmood, Dr. Amber Habib, Dr. Abubakr, Dr. Waqas, Mr. Tariq Baig, Mr. Arthur Manzoor, Mr. Muhammad Mushtaq and Mr. Sajjad for their facilitation in this study in their capacity. REFERENCES 1. Boyce JM. Epidemiology and prevention of nosocomial infections. In: Crossley KB, Archer GL, editors. The staphylococci in human disease. New York: Churchill Livingstone; 1997.p Kluytmans J, Von Belkum A, Verburgh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 1997; 10: Weems JJ, Beck LB. Nasal carriage of Staphylococcus aureus as a risk factor for skin and soft tissue infections. Curr Infect Dis Rep 2002; 4: von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a source of staphylococcus aureus bacteremia. N Engl J Med 2001, 344: Naheed A, Saima S, Mobina D, Hayat A. Nasal carriage of Staphylococcus aureus in health care workers in Rawalpindi General Hospital. J Rawal Med Coll 2002; 6: Kalsoom F, Zermina R, Akhtar N, Abdul Sattar, Khan JA, Bushra N. Nasal carriage of staphylococci in healthcare workers: antimicrobial susceptibility profile. Pak J Pharm Sci 2008; 21: Ashiq B. The carrier state: methicillin-resistant Staphylococcus aureus. A hospital study "screening of hospital personnel" for nasal carriage of Staph. aureus. J Pak Med Assoc 1989; 39: Stefani S, Varaldo PE. Epidemiology of methicillin-resistant staphylococci in Europe. Clin Microbiol Infect 2003; 9: Cespedes C, Miller M, Quagliarello B, Vavagiakis P, Klein RS, Lowy FD. Differences between Staphylococcus aureus isolates from medical and non-medical hospital personnel. J Clin Microbiol 2002; 40: 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: Vonberg RP, Stamm-Balderjahn S, Hansen S, Zuschneid I, Ruden H, Behnke M, et al. How often do asymptomatic healthcare workers cause methicillin-resistant Staphylococcus aureus outbreaks? A systematic evaluation. Infect Control Hosp Epidemiol 2006; 27: Epub 2006 Sep Boelaert JR, Van Landuyt HW, Godard CA, Daneels RF, Schurgers ML, Matthys EG, et al. Nasal mupirocin ointment decreases the incidence of Staphylococcus aureus bacteraemias in haemodialysis patients. Nephrol Dial Transplant 1993; 8: Clinical and Laboratory Standards Institute. Performance standards for antimicrobial disk susceptibility tests: approved standard. 9th ed. Wayne (PA): Clinical and Laboratory Standards Institute; Journal of the College of Physicians and Surgeons Pakistan 2010, Vol. 20 (7):

5 Staphylococcal nasal carriage of health care workers 14. Rajaduraipandi K, Mani KR, Panneerselvam K, Mani M, Bhaskar M, Manikandan P. Prevalence and antimicrobial susceptibility pattern of methicillin resistant Staphylococcus aureus: a multicentre study. Indian J Med Microbiol 2006; 24:34-8. Comment in: Indian J Med Microbiol 2006; 24(4): Lee YL, Cesario T, Tran C, Stone G, Thrupp L. Nasal colonization by methicillin-resistant coagulase-negative Staphylococcus in community skilled nursing facility patients. Am J Infect Control 2000; 28: John JF Jr, Grieshop TJ, Atkins LM, Platt CG. Widespread colonization of personnel at a Veterans Affairs Medical Center by methicillin-resistant coagulase-negative Staphylococcus. Clin Infect Dis 1993; 17: Silva FR, Mattos EM, Coimbra MVS, Ferreira-Carvalho BT, Figueiredo AM. Isolation and molecular characterization of methicillin-resistant coagulase-negative staphylococci from nasal flora of healthy humans at three community institutions in Rio de Janeiro city. Epidemiol Infect 2001; 127: Ammerlaan HS, Kluytmans JA, Wertheim HF, Nouwen JL, Bonten MJ. Eradication of methicillin-resistant staphylococcus aureus carriage: a systematic review. Clin Infect Dis 2009; 48: Bischoff W, Bassetti S, Bassetti-Wyss BA, Wallis M, Tucker BK, Reboussin BA, et al. Airborne dispersal as a novel transmission route of coagulase-negative staphylococci: interaction between coagulase-negative staphylococci and rhinovirus infection. Infect Control Hosp Epidemiol 2004; 25: Liakopoulos V, Petinaki E, Efthimiadi G, Klapsa D, Giannopoulou M, Dovas S, et al. Clonal relatedness of methicillin-resistant coagulase-negative staphylococci in the haemodialysis unit of a single university centre in Greece. Nephrol Dial Transplant 2008; 23: Epub 2008 Feb Mitsuhashi S. In-vitro and in-vivo antibacterial activity of imipenem against clinical isolates of bacteria. J Antimicrob Chemother 1983; 12: Pea F, Marioni G, Pavan F, Staffieri C, Bottin R, Staffieri A, et al. Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose. Pharmacol Res 2007; 55: Epub 2006 Oct Takahashi H, Hayakawa I, Akimoto T. [The history of the development and changes of quinolone antibacterial agents]. Yakushigaku Zasshi 2003; 38: Japanese. 24. Simor AE, Phillips E, McGeer A, Konvalinka A, Loeb M, Devlin HR, et al. Randomized controlled trial of chlorhexidine gluconate for washing, intranasal mupirocin, and rifampin and doxycycline versus no treatment for the eradication of methicillin-resistant Staphylococcus aureus colonization. Clin Infect Dis 2007; 44: Epub 2006 Dec 14. Comment in: Curr Infect Dis Rep 2008; 10: Mandell GL, Moorman DR. Treatment of experimental staphylococcal infections: effect of rifampin alone and in combination on development of rifampin resistance. Antimicrob Agents Chemother 1980; 17: Journal of the College of Physicians and Surgeons Pakistan 2010, Vol. 20 (7):

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