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Laboratory analysis of Staphylococcus aureus in Florida from January 1, 2003 to December 31, 2005 with an emphasis on me...

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Title:
Laboratory analysis of Staphylococcus aureus in Florida from January 1, 2003 to December 31, 2005 with an emphasis on methicillin resistance
Physical Description:
Book
Language:
English
Creator:
Kolar, Stephanie
Publisher:
University of South Florida
Place of Publication:
Tampa, Fla
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Subjects

Subjects / Keywords:
MRSA
Antibiotic
Resistance
Source
Percent
Oxacillin
Dissertations, Academic -- Public Health -- Masters -- USF
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bibliography   ( marcgt )
theses   ( marcgt )
non-fiction   ( marcgt )

Notes

Abstract:
ABSTRACT: The Staphylococci are gram-positive bacteria that cause infections in humans and can produce severe morbidity and mortality. Methicillin resistant S. aureus (MRSA) isolates are resistant to all beta-lactam antibiotics, such as methicillin, and cephalosporins making treatment of these infections more difficult. MRSA has become prevalent throughout the United States, spreading in the health care setting and the community.The purpose of this study is to examine methicillin resistance among S. aureus isolates in an outpatient population in the state of Florida and asses possible associations between methicillin resistance and age group, gender, and geographic area. It is important to define methicillin resistance in a population so that clinical practice can adjust to the prevalence of resistance.The dataset used for this analysis is a record of all the S. aureus isolates tested by a large lab company in the state of Florida from January 1, 2003 to December 31, 2005. This^ is the first study to asses methicillin resistance with a population based dataset and not patients from hospitals. The percent of isolates that were methicillin resistant increased as year increased. This increase in the number of methicillin resistant isolates was significant for both the crude and adjusted analysis. When treated as a continuous variable and adjusted for age category, gender, and county of residence the odds ratio for year is 1.446, 95% CI: 1.410- 1.484. In 2005, 49.7% of the isolates were methicillin resistant. Methicillin resistance also varied by age category, gender, county, and region. For age group and gender the differences were not large and may not be clinically significant. However, there was substantial variation in methicillin resistance by region and county of residence.With nearly half of the S. aureus isolates being methicillin resistant, the beta-lactam antibiotics may no longer be an ideal choice for treating S. aureus infections in Florida.^^^ The percentage of MRSA isolates that were resistant to trimethoprim-sulfamethoxazole, tetracycline, gentamycin, and rifampin was low. These antibiotics may be feasible alternatives to treat outpatient S. aureus infections in Florida.
Thesis:
Thesis (M.S.)--University of South Florida, 2006.
Bibliography:
Includes bibliographical references.
System Details:
System requirements: World Wide Web browser and PDF reader.
System Details:
Mode of access: World Wide Web.
Statement of Responsibility:
by Stephanie Kolar.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 105 pages.

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University of South Florida
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All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 001915655
oclc - 180703661
usfldc doi - E14-SFE0001784
usfldc handle - e14.1784
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SFS0026102:00001


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ABSTRACT: The Staphylococci are gram-positive bacteria that cause infections in humans and can produce severe morbidity and mortality. Methicillin resistant S. aureus (MRSA) isolates are resistant to all beta-lactam antibiotics, such as methicillin, and cephalosporins making treatment of these infections more difficult. MRSA has become prevalent throughout the United States, spreading in the health care setting and the community.The purpose of this study is to examine methicillin resistance among S. aureus isolates in an outpatient population in the state of Florida and asses possible associations between methicillin resistance and age group, gender, and geographic area. It is important to define methicillin resistance in a population so that clinical practice can adjust to the prevalence of resistance.The dataset used for this analysis is a record of all the S. aureus isolates tested by a large lab company in the state of Florida from January 1, 2003 to December 31, 2005. This^ is the first study to asses methicillin resistance with a population based dataset and not patients from hospitals. The percent of isolates that were methicillin resistant increased as year increased. This increase in the number of methicillin resistant isolates was significant for both the crude and adjusted analysis. When treated as a continuous variable and adjusted for age category, gender, and county of residence the odds ratio for year is 1.446, 95% CI: 1.410- 1.484. In 2005, 49.7% of the isolates were methicillin resistant. Methicillin resistance also varied by age category, gender, county, and region. For age group and gender the differences were not large and may not be clinically significant. However, there was substantial variation in methicillin resistance by region and county of residence.With nearly half of the S. aureus isolates being methicillin resistant, the beta-lactam antibiotics may no longer be an ideal choice for treating S. aureus infections in Florida.^^^ The percentage of MRSA isolates that were resistant to trimethoprim-sulfamethoxazole, tetracycline, gentamycin, and rifampin was low. These antibiotics may be feasible alternatives to treat outpatient S. aureus infections in Florida.
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Laboratory Analysis of Staphylococcus aureus in Florida From January 1, 2003 to December 31, 2005 with an Emphasis on Methicillin Resistance by Stephanie Kolar A thesis submitted in partial fulfillment of the requirements for the degree of Masters of Science in Public Health Department of Epidemiology and Biostatistics College of Public Health University of South Florida Major Professor: Aurora Sanchez-Anguiano, M.D., Ph.D. Skai W. Schwartz, Ph.D. Yougui Wu, Ph.D. Roger Sanderson, M.A., B.S.N. Date of Approval November 15, 2006 Keywords: MRSA, antibiotic, resist ance, source, percent, oxacillin Copyright 2006, Stephanie Kolar

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i Table of Contents List of Tables iii List of Figures v Abstract vii Introduction 1 Background 1 Antibiotic Resistance 2 Transmission 8 Types of Infections 12 Methicillin Resistance Patterns 13 Community Associated MRSA 14 High Risk Populations 21 Objectives 28 Methods 30 Database 30 Data Included and Excluded 30 Exposure 32 Outcome 34 Statistical Analysis 34 Secondary Analysis 35 Results 37 Year 37 Age Group 39 Adult and Pediatric 44 Gender 45 Region 48 County 53 Other Antibiotics 58 Source 59 USA300/USA400 63 Skin and Soft Tissue Analysis 66

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ii Discussion 80 References 92 Appendix 1 103

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iii List of Tables Table 1. Crude Odds Ratios and 95% C onfidence Interval for Age Categories When Compared to the Eleven to Twenty Age Group. 43 Table 2. Odds Ratios and 95% Confiden ce Interval for Age Categories When Compared to the Eleven to Twenty Age Group Adjusted for Gender, Year, and County. 44 Table 3. Crude Odds Ratios and 95% Conf idence Interval For the Seven Regions of Florida Compared to Region Six. 53 Table 4. Odds Ratios and 95% Confidence Interval For the Se ven Regions of Florida Compared to Region Seven, Adju sted for Gender, Age, and Year. 53 Table 5. Percent of Isolates That Were MRSA and Total Number of Isolates For Each County By Year. 54 Table 6. Crude Odds Ratio and 95% C onfidence Interval For Counties With a Significantly Higher Risk of Methicillin Resistance When Compared to Miami-Dade County. 56 Table 7. Odds Ratio and 95% Confidence Interval For Counties With a Significantly Higher Risk of MRSA When Compared to Miami-Dade County. 57 Table 8. Percent of MSSA and MRSA Isol ates Which Were Resistant to Other Antibiotics. 59 Table 9. Crude Odds Ratios and 95% C onfidence Interval For Each Age Group Compared to The Reference Group For Skin and Soft Tissue Infections. 72 Table 10. Adjusted Odds Ratios and 95% Confidence Interval For Each Age Group Compared to The Reference Group For Skin and Soft Tissue Infections. 72 Table 11. Crude Odds Ratios and 95% Conf idence Interval For Each Region For Skin and Soft Tissue Infections. 75

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iv Table 12. Adjusted Odds Ratios and 95% Confidence Interval For Each Region For Skin and Soft Tissue Infections. 75 Table 13. Percent of Isolates That Were MRSA and Total Number of Isolates For Each County By Year For Skin and Soft Tissue Infections. 76 Table 14. Crude Odds Ratios For Each County For Skin and Soft Tissue Infections. 78 Table 15. Adjusted Odds Ratios For Each County For Skin and Soft Tissue Infections. 79

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v List of Figures Figure 1. Map of the Seven Regions of Florida 33 Figure 2. Percentage of MRSA and MSSA for all S. aureus isolates from 2003 to 2005 For All Culture Sites. 38 Figure 3. Number of S. aureus Isolates for Each Age Group From 2003 To 2005 For All Culture Sites. 39 Figure 4. Percentage of S. aureus Isolates Which Were MRSA By Age Category From 2003 To 2005 For All Culture Sites. 40 Figure 5. Percentage of S. aureus Isolates Which Were MRSA By Age Category By Year From 2003 To 2005 For All Culture Sites. 41 Figure 6. Change in the Percentage of S. aureus Isolates That Were MRSA From 2003 to 2004 and from 2003 to 2005 By Age Group For All Culture Sites. 42 Figure 7. Percent of S. aureus Isolates That Were Methicillin Resistant By Adult Versus Pediatric By Year From 2004 To 2005 For All Culture Sites. 45 Figure 8. Percentage of S. aureus Isolates Which Were MRSA By Year For Males and Females From 2003 To 2005 For All Culture Sites. 46 Figure 9. Number of S. aureus Isolates For Each Age Group By Gender From 2003 To 2005 For All Culture Sites. 47 Figure 10. Percent of S. aureus Isolates That Were Methicillin Resistant By Age Group By Gender From 2003 To 2005 For All Culture Sites. 48 Figure 11. Number of Isolates For Each Region of Florida and Those That Were Missing Region From 2003 To 2005 For All Culture Sites. 49 Figure 12. Percentage of S. aureus Isolates Which Were MRSA By Region Of Florida From 2003 To 2005 For All Culture Sites. 50 Figure 13. Percentage of S. aureus Isolates Which Were MRSA By Region Of Florida By Year From 2003 To 2005 For All Culture Sites. 51

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vi Figure 14. Change in the Percent of S. aureus Isolates That Were Methicillin Resistant From 2003 to 2004 and From 2003 to 2005 By Region Of Florida. 52 Figure 15. Number of S. aureus Isolates For Each Source Site In Florida From 2003 To 2005. 60 Figure 16. Percentage of S. aureus Isolates That Were MRSA By Source of Infection From 2003 To 2005. 61 Figure 17. Percent of S. aureus Isolates That Were MRSA By Source By Year From 2003 To 2005. 62 Figure 18. Number of Isol ates That Had and Did Not Have A USA300/ USA400 Type Anti-Biogram By Year From 2003 To 2005. 63 Figure 19. Percentage of Isolates That Had a USA300/USA400 Type Anti-Biogram By Year From 2003 To 2005 For All Culture Sites. 64 Figure 20. Percentage of Isolates That Had A USA300/USA400 Type Anti-Biogram By Source By Year From 2003 To 2005 For All Culture Sites. 65 Figure 21. Percentage of Isolates That Had A USA300/USA400 Type Anti-Biogram By Source By Year From 2003 To 2005. 66 Figure 22. Number of S. aureus Isolates That Were MRSA and MSSA By Year Among Skin and Soft Tissue Infections. 67 Figure 23. Percent of S. aureus Isolates That Were Methicillin Resistant By Year Among Skin and Soft Tissue Infections. 68 Figure 24. Percent of S. aureus Isolates That Were Methicillin Resistant By Gender By Year Among Skin and Soft Tissue Infections. 69 Figure 25. Number of Isolates For Each Age Category By Year For Skin and Soft Tissue Infections. 70 Figure 26. Percent of S. aureus Isolates That Were Methicillin Resistant By Age Group By Year Among Skin and Soft Tissue Infections. 71 Figure 27. Percent of S. aureus Isolates That Were Methicillin Resistant By Region By Year Among Skin and Soft Tissue Infections. 74

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vii Laboratory Analysis of Staphylococcus aureus in Florida From January 1, 2003 to December 31, 2005 with an Emphasis on Methicillin Resistance Stephanie Kolar ABSTRACT The Staphylococci are gram-positive bacteria that cause infections in humans and can produce severe morbidity and mo rtality. Methicillin resistant S. aureus (MRSA) isolates are resistant to all -lactam antibiotics, such as methicillin, and cephalosporins making treatment of these infections more difficult. MRSA has become prevalent throughout the United States, spr eading in the health care se tting and the community. The purpose of this study is to ex amine methicillin resistance among S. aureus isolates in an outpatient populat ion in the state of Florida and asses possible associations between methicillin resistance and age gr oup, gender, and geographic area. It is important to define methicillin resistance in a population so that clinical practice can adjust to the prevalence of resistance. The dataset used for this analysis is a record of all the S. aureus isolates tested by a large lab company in the state of Florid a from January 1, 2003 to December 31, 2005. This is the first study to asse s methicillin resistance with a population based dataset and not patients from hospitals The percent of isolates that were methici llin resistant increased as year increased. This increase in the number of methicillin resistant isolates was significant for both the

PAGE 9

viii crude and adjusted analysis. When treated as a continuous variable and adjusted for age category, gender, and county of residence th e odds ratio for year is 1.446, 95% CI: 1.4101.484. In 2005, 49.7% of the isolates were methic illin resistant. Methicillin resistance also varied by age category, gender, count y, and region. For age group and gender the differences were not large and may not be cl inically significant. However, there was substantial variation in methicillin resi stance by region and county of residence. With nearly half of the S. aureus isolates being methicillin resistant, the -lactam antibiotics may no longer be an ideal choice for treating S. aureus infections in Florida. The percentage of MRSA isol ates that were resistant to trimethoprim-sulfamethoxazole, tetracycline, gentamycin, and rifampin was low. These antibiotics may be feasible alternatives to treat outpatient S. aureus infections in Florida.

PAGE 10

1 Introduction Background The Staphylococci are non-motile, gram -positive bacteria that can cause infections in humans. They have a charac teristic appearance that resembles “a bunch of grapes” (Ruben & Muder, 1998). The organism has the ability to su rvive in distressed environments such as acidic conditions high sodium concentrations, and large temperature variations. It can persist on contaminated obj ects in the environment for more than a week (Daum & Seal, 2001). The genome of S. aureus is a circular chromosome with prophages, plasmids, and transposons (Lowy, 1998). S. aureus achieves a genetic flexibility through small and large-scale horizontal transf er of genetic determinates (Buescher, 2005). The genes responsible for antibiotic re sistance are found on the chromo some or extra chromosomal elements. These genes can be tran sferred not only between different S. aureus strains, but also between other gram-positive bacterial species via the extra chromosomal elements. S. aureus also produces many surface proteins, which may play an important part in its ability to co lonize host tissue. S. aureus produces a variety of toxins, which can cause proinflammatory changes in mammalian cells, toxic shock syndrome, food poisoning, and skin erythema and separation. The organism also produces enzymes that can destroy host tissue (Lowy, 1998).

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2 Staphylococci can produce severe morbid ity and mortality. The major concern for public health is the organisms potential to cause epidemics (Ruben & Muder 1998). Once established in a hospital or long term care facility, S. aureus can be difficult to control (Gemmell et al., 2006). S. aureus is currently the most common cause of skin and soft tissue infections in the United States, wi th the mortality of serious infections at twenty to twenty five per cent (Fridkin et al., 2005). Antibiotic Resistance Before the introduction of antibiotics the mortality rate of invasive S. aureus infections was about 90% and about 70% of those who were infected developed metastatic infections (Daum & Seal, 2001; Fuda, Fisher, & Mobashery, 2005). With the introduction of penicillin in the 1940s the spread of the or ganism was initi ally checked, however the first resistant isolates were found only 1-2 years later. Penicillin resistance is conferred by a serine pr otease that hydrolyzes the -lactam ring and inactivates the antibiotic. The prevalence of penicillin resistant S. aureus rapidly increased and the organism caused widespread outbreaks in hos pitals and nurseries. Within 6 years of penicillin’s introduction the pr evalence of resistance reached 25% in hospitals and in 1520 years the prevalence reached 25% in the co mmunity. Penicillin resistance continues to be highly prevalent and le ss than 5% of isolates are currently susceptible (Ruben & Muder, 1998; Chambers, 2001; Lowy, 1998). Methicillin is a synthetic penicillin that is not susceptible to hydrolysis by staphylococcal -lactamase. Methicillin was introduced in 1961 to combat penicillin resistant S. aureus strains(Kowalski, Berbari, & Os man, 2005). The first methicillin

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3 resistant Staphylococcus aureus (MRSA) strain was reported in the United Kingdom of the same year (Chambers, 2001). Since then it has become prevalent in the Unites States and Europe and occurs worldwide. Diekema et al. (2001) used data from the SENTRY Antimicrobial Surveillance pr ogram collected from Janua ry 1997 to December 1999 to characterize the prevalence of MRSA and methicillin susceptible S. aureus (MSSA) from 52 nations across the world. They found MRSA prevalence rates of 46% (657/ 1427) in the Western Pacific region, 34.2% (2455/7169) in the United States, 34.9% (682/1956) in Latin America, 26.3% (916/3477) in Europe and 5.7% (81/1410) in Canada. The prevalence of resistance for di fferent countries varied wi thin regions. In Europe resistance rates ranged from <2% in Swit zerland and the Nether lands to 54.4% in Portugal. In the Western Pacific the prev alence ranged was from 23.6% in Australia to >70% in Japan and Hong Kong. MRSA isolates are resistant to all -lactam antibiotics: penicillins, carbapenems, and cephalosporins. The -lactams act by interfering with the enzymes required for synthesizing the peptidoglycan layer of the b acterial cell wall. Methicillin resistance is mediated by the penicillin binding prot ein PBP2a, which is encoded by the mec A gene (Daum & Seal 2001; Tenover, 2006). PBP2a confers resistance to -lactams in two ways. It sterically hinders the approach to the active site and it impedes the nucleophilic attack by the active site serine on the -lactam ring (Fuda et al., 2005). The difference in morbidity and mortality between MRSA and MSSA infections remains controversial. Studies of the a ssociation of MRSA an d mortality have had inconsistent results. Abramson and Sext on (1999) examined the difference between patients with MRSA and MSSA primary bl ood stream infections. They found that

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4 median attributable excess length of stay was longer for MRSA patients compared to MSSA patients (p= 0.23) and the median attri butable total cost wa s greater for MRSA infections (p= 0.43). When examining S. aureus bacterimia (SAB) Conterno, Wey, and Castelo (1998) found a rate of mortality for MR SA infections that was four times that of those with a MSSA infection. RomeroVi vas, Rubio, Fernandez, and Picazo (1995) found that methicillin-resistance was an indepe ndent predictor of mortality in those with SAB. In a recent study of S. aureus bacterimia, Lodise and McKinnon (2005) found that those who had a MRSA infection spent 1.5 ti mes longer in the hospital (p=0.005) and the cost of hospitalization was 2 times that (p =0.001) of patients who had MSSA, controlling for disease severity. This study did not find a significant associat ion between MRSA and mortality. Other studies have also failed to find an associa tion between MRSA infections and increased mortality (Mylotte & Ta yara, 2002; Blot, Vandewoude, Hoste, & Colardyn, 2002). In a study of methicillin resistance on th e outcome of patients with surgical site infections (SSIs) Engemann et al. (2003) f ound that when compared to patients with MSSA, MRSA patients had a significantly gr eater 90 day mortality rate (OR= 3.4, 95% CI: 1.57.2), a greater duration of hospitaliza tion (2.6 additional hospi tal days, p= 0.11), and a 1.19 fold increase in hospital charges (mean extra cost due to methicillin resistance $13,901, p= 0.03). Many MRSA strains are multi-drug resistant. Vancomycin and teicoplanin belong to the glycopeptide cla ss of antibiotics and are currently the an tibiotics of choice for treating multi-drug resistant MRSA infections, however strains of S. aureus have been found that have intermediate or full re sistance to vancomycin (Waldvogel, 2000;

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5 Appelbaum 2006a). Strains of S. aureus that are resistant to teicoplanin have been reported in France (Gemmell et al. 2006). The glycopeptides act by inhibiting the synthesis of the bacterial cell wall. Thickening of the cell wall and th e transfer of genetic materi al are hypothesized to be the cause of the development of vancomycin resi stance. Vancomycin binds to the terminal D-alanyl-D-alanine of the bacterial cell wall precursors and inhibits cell wall synthesis. Resistance in vancomycin intermediate S. aureus (VISA) strains is thought to arise by the synthesis of extra D-alanylD-alanine resi dues, which bind vancomycin molecules and sequester them in the outer cell wall. Genetic analysis suggest that the first vancomycin resistant S. aureus (VRSA) case occurred from the in-vivo transfer of the vancomycin resistant genes, van A from E. faecalis to a MRSA stain. This VRSA isolate was resistant through changing the D-alanylD-al anine termination residue to D-alanyl-Dlactate, which has a reduced affinity for vancomycin (Applebaum, 2006a). In 1995 and 1996, two isolates from Japan were found to have reduced susceptibility to vancomycin. The first fr om the sputum of a 64-year-old male who underwent lung cancer surgery and the other fr om the surgical wound of a 4-month old infant. Both had been treated unsuccessfully with vancomycin. The first isolate had a pattern of heterogeneous resistance to vancomycin, on culture it produced subpopulations of cells with varying de grees of resistance (Appelbaum, 2006a; Hiramatsu, 1998). A 1998 study of 195 non-university and 7 unive rsity hospitals in Japan, found that of the 970 isolates from the non-university hospitals 1.3% had heterogeneous resistance

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6 to vancomycin and of the 129 isolates from the university hospitals 9.3% had heterogeneous resistance to vancomycin (Hiramatsu, 1998). In June of 2002 the first VRSA isolate from the United States was identified from a 40-year-old man in Michigan with diabetes, peripheral va scular disease, and chronic renal failure. He had been treated for pr ior infection with vancomycin. Vancomycinresistance Enterococcus faecalis and Klebsiella oxytoca were also isolated from the culture of an ulcer. In September of 2002 another VRSA isolat e was reported from a 70-year-old man who was morbidly obese and hypertensive in Hershey, Pennsylvania. This patient had also had multiple courses of treatment with vancomycin and the culture was also from an ulcer. In 2004, a third VRSA isolate was obtained from the urine sample of an elderly patient in New York. Other vancomycin-resistant enterococi were also isolated from this patient. In 2005 a forth isolate was cultured from a 78-year-old man with coronary artery disease, diabetes, peripheral vascular disease, neuropathy, chronic renal insufficiency, and obstructive uropathy. This patien t had received vancomycin therapy and vancomycin-resistant E. faecalis was isolated from a surveillance culture (Appelbaum, 2006b; Appelbaum, 2006a). The in-vitro and in-vivo conjugative tr ansfer of vancomycin resistance from E. faecalis to S. aureus has been demonstrated in the la boratory setting (Noble, Virani, & Cree, 1992). Three of the four VRSA isolates from the U.S. have been cultured from patients whose cultures also grew vancomycin-resistant en terococci, only the patient from Hershey did not have vancomycin-resista nt enterococci isolates found. This could

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7 indicate the in-vivo transfer of the van A gene from the enterococcus to S. aureus (Appelbaum, 2006b; Appelbaum, 2006a). Using data from the SENTRY program Diek ema et al. (2001) found that less than 1% of S. aureus isolates had reduced susceptibility to Vancomycin and only one isolate was resistant. There were also 5 isolates with reduced susceptibility to teicoplanin. Currently there are three effective drugs on the market to treat multi-drug resistant MRSA infections other than vancomycin. Li nezolid, which blocks the assembly of the initiation complex required for protein synthe sis, and daptomycin, which promotes the efflux of potassium out of the cell, are both effective treatments for MRSA and since they have unique mechanisms of actions there is no cross-resistance to other antibiotics (Anstead & Owens, 2004). In a open-label, randomized, multinational study conducted among hospitalized patients with MRSA surgical site infections to compare vancomycin to linezolid, significantly more patients that received linezolid were microbiologically cured (87% versus 48%, p= 0.0022). Unlik e vancomycin, linezolid has an oral formulation that is completely bioavaila ble and can be used on an outpatient basis(Weigelt, Kaafarani, Itani, & Swanson, 2004). Quinupristin-dalfopristin has been approved for the treatment of S. aureus however due to high cost and adverse effect s it is has not been widely used since linezolid and dapomycin have come onto th e market. There are also three other promising drugs currently undergoi ng clinical trials that shou ld enter the market within the next couple of years. Two new glyc opeptides, oritavancin and dalbavancin, which inhibit cell-wall formation and are not affected by the van A, van B, and van C encoded alterations that impart resistance to vanc omycin. The third drug under development is

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8 tiglecycline, a glycycycline th at is an analog of tetracyclin e. These new drugs are also effective against VISA and VRSA isolates (Anstead & Owens, 2004). Transmission The major source of outbreaks is due to carriers. Carriage of S. aureus is strongly associated with subsequent infection. The ante rior nares are the major site of carriage in children and adults. The rate of nasal carri age is estimated to be from 20% to 40%. Vaginal carriage has also b een reported and is estimated to be about 10% among premenopausal women. About 20% of the population will be prolonged carriers of S. aureus 60% will be intermittent carriers, and 20 % will never be colonized. Some people may become colonized with several different strains at the same time (Waldvogel, 2000; Kuehnert et al., 2006). As part of the National Health and Nutrition Examination Survey, 20012002, Kuehnert et al. (2006) examined the nasa l colonization rates of 9,622 people. The weighted prevalence of S. aureus colonization was 32.4% (95% CI: 30.7%34.1%). Colonization was highest among those 6-11 years of age (OR= 2.7, 95% CI: 2.03.6, reference group: 1 to 5 year olds). The we ighted prevalence of MRSA colonization was 0.8% (95% CI: 0.4%1.4%). They found that MRSA colonization was associated with being female (OR= 2.0, 95% CI: 1.23.4) and age greater than 60 (O R= 4.3 95% CI: 1.214.8). No other factors inves tigated, such as poverty, educ ation, birth outside the US, military service, health-care exposure, or presence of diabetes or dermatologic conditions, were found to be statistically significant.

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9 Certain groups of people are more prone to carriage. Physicians, nurses, and hospital ward attendants may have higher nasopha ryngeal carriage rate s than the general population. Other groups at high er risk of carriage include; diabetics receiving insulin injections, those undergoing chronic hemodialys is or continuous ambulatory peritoneal dialysis, those with a variety of dermatolog ic conditions, illicit in travenous drug users, and HIV positive patients (Waldvogel, 2000). Nasal carriers are predisposed to postoperative infection (Ruben & Muder 1998). From the anterior nares carriage site, the ba cteria can be transferred to the skin. The mucous membrane and skin are an effec tive barrier to tissue infection. Trauma provides S. aureus with a portal of entry and leads to a local or generalized infection. In the case of hospitals and long te rm care facilities, the bacter ia are usually introduced into an institution via an infected or colonized pa tient or by a colonized health care worker. The bacteria are then transferred from one pa tient to another by the hands of health care workers or the inanimate environment. This has led to major epidemics in hospitals and other chronic care facilities (Waldvogel, 2000). In a study of contact transmission, McBryde, Bradley, Whiteby, and McElwain (200 4) found that 17%(925%) of contacts between a health care worker and a patient colonized with MRSA resulted in the transmission of MRSA onto the gl oves of the health care worker. Other routes of transmission have also been reported. Embil et al. (2001) investigated an outbreak of MRSA on a burn unit from September 19 to November 20, 1996. They found that a hand held shower and stretcher for showering in the hydrotherapy room were culture positive for the outbreak strain of MRSA and the most likely route of transmission. In an investigation of a MR SA outbreak on an Intensive

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10 Therapy Unit Cotterill, Evans, and Fraise ( 1996) found that the source may have been the air-exhaust component of the is olation room’s ventilation syst em. The exhaust grille for the ventilation system of the isolation room was in close proximity to a window above another patient bed. It is hypothesized that it would be possible for particles being exhausted from the ventilation system to be blown into the air a nd through the window. Kluytmans et al. (1995) studied an ou tbreak of MRSA between November 1992 and April 1993 affecting 27 patients and 14 health-care workers at the University Hospital Rotterdam, Dijkzigt, The Netherla nds. MRSA was subsequently found in a banana and the outbreak strain was detected in a culture of a dietar y workers nares that had prepared food for the hematology unit. Th is is the first reporte d incident of a food initiated MRSA outbreak. In 2002, Jones et al. (2002) reported a cluster of gastroenteritis in a community setting. Three adults became ill after consuming shredded pork and coleslaw from a convenience-market delicates sen. The likely source of contamination was determined to be a food handler who was a nasal carrier of the outbreak MRSA strain. There is also growing evidence of animal s as potential sources of infection. Potential human to animal and animal to human transmission have been reported among veterinary personal and pet owners (Weese et al., 2005; Weese et al., 2006; O’Mahoney et al., 2005; Manian, 2003). Weese et al. (2005) investigated an outbreak of MRSA among veterinary personal that had worked w ith a neonatal foal colo nized with MRSA at the Ontario Veterinary College Veterinary Teaching Hospital. MRSA skin infections were found in three of the neonatal intensive care unit personnel and 10 of 103 other veterinary personnel were found to be nasaly colonized. All of the isolates were

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11 indistinguishable by pulsed field gel electrophores is (PFGE) analysis and were classified as CMRSAA-5. While it is difficult to dete rmine the direction of transmission, it appears that there was transmission between huma ns and horses at this institution. Weese et al. (2006) investigat ed six cases of MRSA infection in 8 animals. In each case a MRSA isolate with an indistingu ishable PFGE pattern was isolated from at least one human. All of the isolates were found to be the Canadian epidemic MRSA-2 strain. Manian (2003) examined a case of MRSA in a diabetic patien t and his wife who had repeated MRSA infections and nasal colonization despite antibiotic therapy and decolonization attempts. Nares cultures of the pet dog grew MRSA with an identical PFGE pattern. The recurrent MR SA infections in the patient and his wife were resolved once MRSA had been eradicated from the pet do g. In this case it is likely that the dog served as a reservoir of MRSA, which led to repeated infections in the couple. O’Mahony et al. (2005) documented the rec overy of MRSA from 25 animals and 10 veterinary personnel from different lo cations throughout Irel and. PFGE analysis showed that most of the non-e quine isolates (14 dogs, one cat, one rabbit, and one seal) were indistinguishable from each other and from the personnel caring for the infected animals. This strain was indistinguishable by PFGE analysis from the most prevalent MRSA strain in the Irish populat ion. The eight isolates from horses and the isolates from their personnel were indistinguishable from each other and were unlike those from the other animals. Concurrent colonization with indisti nguishable PFGE patterns suggests that human to animal and animal to human tr ansmission of MRSA is possible. The

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12 possibility of household pets as a reservoir of MRSA should be considered in patients with recurrent Community Acquired-MRSA (CA-MRSA) infections in which no other source can be identified (Wees e et al., 2006; Manian, 2003). Types of Infections S. aureus can cause a variety of inf ections. Skin infections of S. aureus include folliculitis, furuncles (boils), impeti go, hydradenitis suppurativa, mastitis, wound infection, and spreading pyodermas. Treatment fo r these localized skin infections is the removal of hair from the area, repeated clean sing with an antiseptic solution alternating with a moist dressings, and c overing the infected area with a sterile dressing. Parenteral vancomycin and teicoplanin may also be cons idered as part of the treatment for skin infections of MRSA if there is a high risk of serious inf ection such as bacteremia or endocarditis (Gemmell et al 2006; Waldvogel, 2000). Two localized infections with diffuse skin rash are Staphylococcal Scalded Skin Syndrome (SSSS) and Toxic Shock Syndrome (T SS). SSSS is treated with parental antibiotics and supportive skin ca re. TSS treatment requires aggressive fluid replacement followed by intravenously administered antibiotics (Waldvogel, 2000). S. aureus can spread to other sites including the bones, joints, kidneys, and the lungs. In severe cases, infection can lead to septicemia and endocardi tis. Factors such as advanced age, immunosuppression, chemothera py, and invasive procedures have been found to increase the risk of sepsis (Lowy, 1998). In most instances, S. aureus bacteremia is the result of a localized in fection gaining access to the blood stream. Patients initially experience chills and occas ionally frank rigors. Patients are often obtunded and have joint pain and more rarely pleuritic chest pain. Antibiotics should be

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13 promptly administered and in some cases endocarditis warrants su rgical intervention (Waldvogel, 2000). Methicillin Resistance Patterns Diekema et al. (2004) performed a repres entative survey of 670 US hospitals, stratified by number of beds, geographic re gion, and teaching status to examine the antibiotic resistance tr ends for major pathogens, the fre quency of outbreaks, and control measures. In the 494 hospitals that responded, 36% of the S. aureus isolates were found to be MRSA. There were significant differe nces in oxacillin re sistance by region (p= 0.0001), with higher rates of MRSA in the s outh. MRSA was the most common resistant pathogen in US hospitals to cause outbreaks and was increasing in more than two thirds of the hospitals surveyed. Li et al. (2005b) used statewide, populati on-based antimicrobial susceptibility test data collected from both outpatients a nd inpatients in Hawaii to examine the epidemiologic trends of MRSA in the state. Data was collected retrospectively from the State of Hawaii Antimicrobial Resistance Pr oject from 2000 to 2002. After removal of duplicate data 31,482 isolates remained in th e analysis, of which 8,206 (26%) were found to be MRSA. They found that the proporti on of MRSA isolates during the study period was significantly higher among pediatric pa tients then among the adult population (p<0.01) and that a significantly higher pr oportion (p< 0.01) of the adult isolates were resistant to non-lactam antibiotics compared to the pediatric isolates. Most of the pediatric isolates were susceptible to the non-lactam antibiotics except for erythromycin (24% of isolates were resistan t). They also found a significant increase in

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14 the proportion of MRSA isolates, from 24% to 30% (p<0.01), among the adult population and an increasing, but not significan t trend among pediatric patients. Moran et al (2006) performed a prospec tive prevalence study of adult patients who presented to hospitals in the EMER GEncy ID Net, a network of emergency departments in 11 US cities, to examine meth icillin resistance in skin and soft tissue infections in August of 2004. Of 422 patients with skin a nd soft tissue infections, 320 were due to S. aureus Of the S. aureus isolates, 78% were methicillin resistant. Among those who received antibiotics antibiotic therapy given was not active against the infecting bacterium in 57% (100 of 175) of cas es. Only presence of abscess at enrollment was significantly associated with MRSA comp ared to MSSA. Twenty seven percent of MRSA patients had an established risk f actor for methicilli n resistance. Community Associated MRSA Initially infections of MRSA were pr imarily a problem of hospitals, nursing homes, and long term care facili ties. Traditional risk factor s for Health care AssociatedMRSA (HA-MRSA) infections include fre quent contact with the health care environment, prolonged hospitalization, recent hospitalization or surgery, living in a long-term care facility or nursing home, adva nced age, immunocompromise, dialysis, use of anti-microbial agents within the previous 60 days, and indwelling medical devices. In the early 1980s, cases of MRSA began to em erge in the community, mostly among those with a history of injection drug use and othe r patients at high risk. Recently, CA-MRSA infections have been found in adults and ch ildren who did not have exposure to hospitals or other established risk factors. These in fections acquired in th e community are referred to as community-acquired MRSA (Daum & Seal, 2001; Jones, Kellum, Porter, Bell &

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15 Schaffner, 2002; Niami et al., 2003). Certain populations in the US have been found to have an increased risk of CA-MRSA. CA-MRSA outbreaks have been reported among IV drug users, children (particularly those in daycare), soldiers, competitive sport players, the disadvantaged, native Americans and Alas kan natives, prisoners, men who have sex with men, and the urban homeless. Lack of hygiene and basic-infection control may contribute to outbreaks among these populations (Kowalski et al., 2005; Appelbaum, 2006a). There are several features that distinguish CA-MRSA from HA-MRSA strains. CA-MRSA lacks the presence of hospital-associated risk factors. CA-MRSA is generally susceptible to most antibiotics other than -lactam antimicrobial drugs, unlike HA-MRSA strains that exhibit multi-drug resistance. CA-MRSA has distinct genotypes that differ from the S. aureus strains commonly found in hospitals. CA-MRSA predominantly carries the type IV staphylococcal chromosomal cassette mec (SCCmec) whereas HAMRSA carries cassettes I, II, or III. The HA-MRSA strains typically carry a mec A gene that is positioned next to other genetic el ements, which confers resistance to other antibiotics. The type IV SCCmec is smaller and lacks the additional genetic elements, which confer multi antibiotic resistance. CA -MRSA typically carries genes encoding for toxins such as Pantone-Valentine leukocidin (PVL ),a leukocyte-killing toxin, and many other staphylococcal enterotoxins. The PVL cytotoxins can cause tissue necrosis and leukocyte destruction. Pantone-V aletine leukocidin toxin is t hought to contribute to the virulence of CA-MRSA strains (Charlebois et al., 2004; Weber, 2005; Rihn, Michaels, & Harner, 2005; Appelbaum, 2006b).

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16 The most common clinical manifestati on of CA-MRSA are furunculosis and cutaneous skin abscesses. Approximately 90% of CA-MRSA infections are non-invasive skin and soft tissue infections These skin and soft tissue infections account for most of the morbidity of CA-MRSA, with mortality very uncomm on (Kowalski, 2005; Stankovic & Mahajan, 2006). The origins of CA-MRSA are unknown and may have arisen by different pathways. Hospital strains of MRSA may be carried into the community, where they can then spread from person to person. CA-MRSA may also arise de novo when the methicillin-resistance gene complex is acquired by a methicillin-susceptible strain of S. aureus (Charlebois et al., 2004). Naimi et al. (2003) compared HA-MRSA and CA-MRSA. Twelve sentinel laboratories in Minnesota were used to id entify cases of MRSA from January 1, 2000 to December 31, 2000. A medical record review was conducted to determine whether they met the definition of health care associated or community acquired MRSA. During the study period 4612 patients were identified with an S. aureus clinical culture, of these 25% were identified as MRSA infec tions. Of the MRSA infecti ons 131 (12%) were classified as community acquired, 937 (85%) as health care associated, and 32 (3%) could not be classified due to lack of information. The CA-MRSA patients were significantly younger (p<0.001) than health care associated patients with a median age of 23 years versus 68 years. Race was documented for 72% of the CA-MRSA patients and 64% of the health care related patients. The CAMRSA patients were significantly more li kely to be nonwhite, OR= 3.13, 95% CI: 2.164.32.

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17 The distribution of the type of clinical infections was also different between the community acquired and health care associ ated cases. The CA-MRSA cases were significantly more likely to involve skin and soft tissue, OR= 4.25, 95% CI 2.975.90. The CA-MRSA cases were also significantly le ss likely to be respir atory infections, OR = 0.22, 95% CI 0.090.49 and urinary tract infections, OR = 0.04, 95% CI 00.24. The CA-MRSA isolates were signifi cantly more likely to be su sceptible to ciprofloxacin, clindamycin, gentamicin, and trimethoprim -sulfamethozazole, OR= 5.88, 95% CI 4.866.64. PFGE testing identified 119 di stinct subtypes. From th ese subtypes, five clonal groups containing 3 or more isolates were identified and accounted for 96% of the isolates. Clonal group A accounted for 62% of the CA-MRSA isolates, but only 9% of the health care related ones (OR= 4.61, 95% CI 3.825.16). Clonal group B accounted for 14% of the CA-MRSA isolates and 2% of the health care related isolates (OR= 2.43, 95% CI 1.612.93). Clonal group H was asso ciated with health care related MRSA, accounting for 80% of the isolat es in that group versus 16% of the CA-MRSA isolates (OR= 2.83, 95% CI 2.602.97). Fridkin et al. (2005) used data fr om the MRSA Activ e Bacterial Core Surveillance project which monitored all MRSA isolates from 11 Baltimore hospitals, Health District 3 in greater Atlanta, and 12 se ntinel hospitals in Minnesota to examine the incidence of endemic CA-MRSA infection, raci al disparities in incidence, patterns of anti-microbial susceptibility, and clinical outcomes. Surveillance was from February 2002 to February 2003 in Baltimore, from July 2001 to January 2003 in Atlanta, and from January 2001 to January 2003 in Minnesota.

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18 During the study period 12,553 MRSA isolat es were reported. Of these 2,107 were classified as confirmed or probable CA-MRSA. In Atlanta and Baltimore the incidence was significantly higher among those who were less than two years old, OR=1.51 (95% CI: 1.191.92). In Atlanta th e incidence was significantly higher among blacks than whites, age-adjusted re lative risk = 2.74 (95% CI 2.443.07). Groom et al. (2001) used a retrospective cohort study design to examine the occurrence of CA-MRSA and ri sk factors associated with CA-MRSA compared with MSSA among a rural American Indian comm unity during 1997. They found that of the 112 isolates 55% (62) were MRSA and 45% (50) were MSSA. Of the 62 MRSA infections 74% (46) were classified as community acquired. CA-MRSA isolates were more likely to be susceptible to other antib iotics than non-community acquired isolates, only resistance to ciprofloxacin was significant however. No significant differences in risk factors were found be tween CA-MRSA and CA-MSSA. The current approach to trea tment of community acquired S. aureus infections commonly includes the use of -lactam antibiotics. In communities where MRSA has become a significant proportion of S. aureus isolates this treatment approach may need to be reevaluated. Clinicians need to consider the possibility of MR SA infection in the community setting and obtain material for bact erial culture to determine the susceptibility of the infecting organism (Fridkin et al., 2005). Molecular typing stud ies have found that in the U.S. most of the CA-MRSA infections are caused by two clones, USA 300 and USA 400. These clones have also been associated with the Panton-Valentine leukocidin (PVL) virulence factor and the SCCmec type IV. These CA-MRSA cl ones are typically resistant to -lactams and

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19 erythromycin, but remain susceptible to cl indamycin, trimethoprin-sulfamethoxazole, and fluoroquinolones. King et al (2006) conducted active labor atory surveillance from August 1, 2003 to November 15, 2003 of S. aureus isolates from patients with skin and soft tissue infections at a 1000-bed urban hospi tal and its outpatient clinics in Atlanta, Georgia. This hospital provides for a me dically indigent inne r-city population, about 80% of which are African American. The isolates were defined as US A 300 or USA 400 based on PFGE or antimicrobial susceptibility pattern (anti-biogram) if PFGE was not available. If the isolates with no PFGE were resistant to the -lactams and erythromycin, but susceptible to clindamycin, trimethoprin-sulfamethoxazo le, vancomycin, and fluoroquinolones they were classified as USA300/USA400. There were 389 episodes of S. aureus skin and soft tissue infection among 384 patients, of which 72% (279) were found to be MRSA and 28% (100) were MSSA. Of the 389 infections, 279 were classified as CA-MRSA and of those 87% (244) were classified as the USA 300/USA 400 CA-MRSA group. When only isolates with a PFGE were considered (175 isolates), 91% (159) coul d be classified as US A 300/ USA 400. Of the CA-MRSA isolates with PFGE pattern s that matched the USA 300 or USA 400 pattern, 87% (136) met the antimicrobial sus ceptibility pattern of resistance only to the lactams and erythromycin. Of the isolates with PFGE patterns that had a pattern other than the USA 300/USA 400, 88% (14 of 16 isolat es) met the antimicr obial susceptibility pattern of HA-MRSA with resistance to the -lactams, erythromycin, and at least one additional antibiotic.

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20 It was also found that inadequate empiri cal and definitive antibiotic therapy was more common among the CA-MRSA group ( 65% inadequate empirical and 43% inadequate definitive) versus the MSSA gr oup (1% and 1%). When comparing the CAMRSA USA300/USA400 group to the MSSA group black race (prevalence ratio 1.53, 95% CI: 1.162.02), female sex (prevalence ratio 1.16, 95% CI: 1.021.32) and previous hospitalization within 12 months (prevalence ratio 0.80, 95% CI: 0.660.97) were found to be significantly associated in multivariate an alysis. In areas with a high prevalence of CA-MRSA non-lactam agents should be used as em pirical therapy (King et al., 2006). In a study of S. aureus infections at Texas Child ren’s Hospital from August 1, 2001 to July 31, 2004 Kaplan et al. (2005) f ound that the percentage of community associated S. aureus isolates that were methicillin re sistant significantly increased during the study period, from 71.5% in 2001 to 76.4% in 2004 (p=0.008). They also found that in the beginning of 2000 the percentage of CA-MRSA isolates that were the USA300 clone was 50%. In 2003 the percentage of CA-MRSA isolates that were USA300 was >90% and carried the PVL gene. This indicat es that the USA300 strain is capable of rapidly spreading in the community. The risk factors for community acquired MRSA differ from those for health-care related MRSA infections. Factors that have been associated with a higher risk for nosocomial acquisition of MRSA ( HA-MRSA) are prolonged hospitalization, care in an intensive care unit, prolonged antimicrobial therapy, surgical procedures, dialysis, presence of an indwelling catheter, use of injectable drugs, residence in a nursing home or long term care facility, and close proximity to a patient in the hospital who is infected or colonized with MRSA (Salgado, Farr, & Calfee, 2003; Li et al., 2005b).

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21 While hospital admission within the past twelve months has been identified as a risk factor for CA-MRSA in some populations there have been reports of CA-MRSA in patients with no identifiable risk factors (Ellis, Hospenthal, D ooley, Gray, & Murray, 2004). High Risk Populations There have been reports of infec tions and outbreaks of CA-MRSA among children. Hunt et al. (1998) reported four pe diatric deaths due to CA-MRSA. All four lacked traditional risk factors and were initia lly treated with a cephalosporin to which the MRSA strain was not susceptible. Delaye d use of an antibiotic to which the MRSA strain was not susceptible may have contributed to the fatal outcomes. Herold et al. (1998) cond ucted a retrospective review of medical records to examine CA-MRSA in children with no predisposing risk factors admitted to the University of Chicago Children’s Hospital. Ca ses of MRSA infection were classified as community acquired if they were obtained within 72 hours of admission, if they were obtained after 72 hours they were classified as nosocomially acquired. Children with CA-MRSA were classified as thos e without identified ri sk if they lacked a traditional risk factor and those with an iden tified risk factor if they ha d a previous hospitalization of antimicrobial therapy within the previous 6 months, history of endot racheal intubation, an underlying chronic disorder, an indwelling venous or urinary catheter, history of surgical procedure, or a notation of a household contact with an iden tified risk factor in the medical record. From 1988 to 1990 there were 32 cases of MRSA identified and from 1993 to 1995 there were 56 cases of MRSA identifi ed. For 1988 to 1990, 8 of the MRSA cases

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22 were determined to be community-acquire d and for 1993 to 1995, 35 of the MRSA cases were identified as CA-MRSA. Only one of the cases from 1988 to 1990 lacked an identified risk factor while 25 of the case s from 1993 to 1995 lacked a traditional risk factor. In this popul ation the prevalence of CA-MRSA with no identified risk factors increased from 10 per 100,000 admissions in 1988 to 1990 to 259 per 100,000 admissions in 1993 to 1995. The clinical spectrum of disease associat ed with MRSA and MSSA isolates from 1993 to 1995 was also examined. Among child ren with CA-MRSA without identified risk none of the 22 children had bacteremia without a focus of infection and 27% (6 of 22) had a diagnosis of abscess. Among children with an identified risk factor 20% (2 of 10) had bacteremia without a focus and none of the 10 had a diagnosis of an abscess. The distribution of clinical syndromes for CA-MRSA was also compared to CAMSSA. In children with CA-MRSA without id entified risk the dist ribution of clinical syndromes was similar to that of CA-MSSA. Cellulitis and abscess were the predominate clinical syndromes for both CA-MRSA and CA-MSSA. Creech et al. (2005) examined the prevalence of S. aureus colonization in healthy children attending health maintenance visits in 2004. Na sal swabs were collected from 500 children. They found that 36.4% ( 182) children were colonized with S. aureus and 9.2% (46) were colonized with MRSA. When compared to the prevalence rate of colonization in 2001, the rate in 2004 was significantly higher (p< 0.001). The only significant risk factor found was having a family member that worked in a hospital (OR= 2.0, 95% CI: 1.034.1).

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23 Infections of athletes, such as footba ll players, rugby players, wrestlers, and fencers have been reported. Among this group risk factors for infection that have been identified are skin trauma, contact with lesions of infected players, and sharing equipment or clothing (Barrett & Moran, 2004) Studies of athletes sugges t that players involved in frequent, repetitive contact are more likel y to develop an infection, supporting the hypothesis that transmission occurs via dir ect person-to-person c ontact (Rihn et al., 2005). Kazakova et al. (2005) conducted a retr ospective cohort study of 84 St. Louis Rams football players and staff members. From September 1 through December 1, 2003 8 MRSA infections were identified in 5 of 58 Rams players. All were skin abscesses and developed at turf burn sites. Only the lineman or linebacker position and body-mass index was significantly associated with MR SA infection, RR=10.6 (95% CI 1.3infinity) and p= 0.03 This may be due to the freque nt contact among linem en during play. The outbreak strain carried the SCCmec type IV and PVL genes. Comparison of PFGE patterns of the outbreak strain with those of other isolates revealed that the outbreak strain had an indistinguishab le PFGE pattern from strain s of two other professional football teams. Eighty-four nasal cultures were obtained. Of these none grew MRSA and 42% grew MSSA. MSSA was also cultu red from environmental samples and was found to have an identical PFGE pattern to is olates obtained from nasal swabs. Nguyen, Mascola, and Bancroft (2005) examined recurring MRSA infections among a college football team in Los Angeles. Using a case-control design they found that sharing bars of soap and having preexisting cuts or abrasi ons were associated with an increase risk of becoming infected. In a ‘c arrier-control’ study th ey found that having a

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24 locker near a teammate with an infection, sharing towels and living on campus were associated with nasal carriage. In another study of college football players, Begier et al. (200 4) investigated an outbreak of MRSA in Connecticut, which had resulted in 2 hospita lizations. Ten case patients were identified from the 100 players on the team. Of the six isolates available for PFGE, all had the pattern of USA 300 and carried the PVL gene. Analysis revealed an increased risk among those who had cosmetically shaved the groin area (RR 9.3, 95% CI: 2.337.6) or shared the whirlpool greater than or equal to 2 times a week (RR 12.2, 95% CI: 1.4109.2). Those who had sustaine d turf burns had a RR of 7.2, 95% CI: 1.054.4. In a retrospective cohort study of a MRSA outbreak among a high school wrestling team and the surrounding commun ity Lindenmayer, Schoenfeld, O’Grady, and Carney (1998) found that none of the risk f actors investigated (demographics, wrestling history, use of Jacuzzi, sharing towels or clothing, and contac t with health care facilities) was associated with a significant increase in risk for developing a MRSA infection. Eleven non-wrestlers also developed MRSA infections, six had a connection with the high school while the other five had no known c onnection with the wrestling team or the high school. The authors can only speculate that MRSA may be transmitted by less direct contact than that which occurs am ong wrestlers or that some unknown mode of transmission was responsible for the community cases. Military recruits are another high risk group. Ellis et al. (2004) examined the prevalence and risk factors for CA-MRSA among 812 U.S. Army recruits. Recruits had a nasal swab at the beginning of their trai ning and 810 weeks later. At the first

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25 sampling 3% (24) of the recruits were colonized with MRSA and 28% (229) were colonized with MSSA. Antibiotic use within the previous 6 mont hs was the only risk factor for CA-MRSA coloniza tion that was significant (p =0.03). Colonization with MRSA at the initial sampling was a significan t risk factor for developing a soft-tissue infection. During the study period 38% (9) of MRSA carri ers developed soft-tissue infections while only 3%(8) of MSSA carri ers developed infections (RR= 10.7, 95% CI 4.625.2, p< 0.001). Zinderman et al. (2004) investigated an outbreak of MRSA among military recruits at a training facility in the Southern U.S.. From August to December 2002 there were 235 cases of MRSA identified. Most of the infections (73%,) occurred on an extremity. Nasal swabs of 874 workers who ha d direct contact with recruits found that 2.7% (24) were colonized with MRSA. Once control measures were implemented such as placing antibacterial soaps at all recruit sinks, enforci ng daily showers of adequate duration, and prohibiting sh aring of personal items the outbreak subsided. Outbreaks of MRSA have also been reported among inmates in correctional facilities. A case-control study from a mini mum-security detention center in Georgia identified prolonged incarceration (>36 days) and outdoor work duty as risk factors for MRSA acquisition. Another case-control study from a maximum-security prison identified previous antimicrobial use, self -draining of boils, skin laceration, washing clothes by hand, sharing soap, and recent arrival at the prison as risk factors for MRSA infection. A case-control study from the Texas Department of Criminal Justice’s (TDCJ) largest intake facility identified previous sk in infections and recen t close contact with a MRSA-infected inmate as risk factors. In 1998 TDCJ began requiri ng the culturing of all

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26 draining skin lesions. The proportion of S. aureus infections that were found to be MRSA increased from 24% in 1998 to 66% in 2002. The investigators of these st udies identified four factor s that contribute to the spread of MRSA in jails and prisons. Th ere are barriers to inmate hygiene such as limited access to soap due to security reasons. Access to medical care can be held up due to co-payments required for care and insuffici ent supplies and staff. Frequent medical staff turnover make providing education on prope r infection-control procedures difficult and MRSA may not be recognized as the cau se of skin infections (Tobin-D’Angelo, 2003). There have also been reports of outbreaks of CA-MRSA among Native Americans, Alaskan natives, and Pacific is landers. Baggett et al. (2003) conducted a retrospective cohort study in ru ral southwestern Alaska to in vestigate a large outbreak of community-onset MRSA infections and to de termine the extent of the infections and whether the isolates were CA-MRSA. This area of Alaska has a population of 25,000, of which about 85% are Alaskan Natives. Many live in isolated villages with no running water. Isolates from the microbiology laborat ory records were identified from March 1, 1999 to August 10, 2000. The percentage of isol ates that were MRSA was 82.2% (412 of 501) for the study period. Through chart review there were 240 isolates recovered from 229 patients. Of the 240 isolates 75% (180) were MR SA, and skin infections acc ounted for 73% (175) of the isolates. Of the 175 skin in fection isolates, 86% (151) we re MRSA and 14% (24) were MSSA (p< 0.01). When comparing CA-MRSA with non-CA-MRSA, sex was found to be significantly different, OR= 2.5, 95% CI: 1.15.8.

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27 All of the 143 cases of MRSA skin in fections during the study period were community onset. There were 109 that met the definition of CA-MRSA infections. Seventy-six percent of the MRSA isolat es from this population were community acquired, suggesting widespread acquisition and transmissi on in the community. The high prevalence of methicillin resistan ce supports the recommendation that the -lactams should not be used as first line therapy in this population. The authors recommend that trimethoprim-sulfamethoxazole be used as fi rst line therapy, with vancomycin only used in patients with severe infections. Melish et al. (2004) conducte d a retrospective study of CA-MRSA infections in Hawaii from July 2001 to June 2003. Duri ng the study period 1,389 patients from the four study facilities were identified as ha ving MRSA, of which 389 (28%) had an illness that was consistent with CA-MRSA. Racial /ethnic data was available for 346 (89%) of these patients. Pacific Islanders accounted for 51% (178) of the CA-MRSA patients, but they made up only 24% of the population of Hawaii in 2001 (p<0.01). In the pediatric and women’s center that was included in th e study Pacific Islanders accounted for 76%(90 of 118) of the CA-MRSA patients, but only 35% of the patients served by these centers are Pacific Is landers (p< 0.01).

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28 Objectives The purpose of this study is to examin e whether or not me thicillin and the -lactam class of antibiotics should continue to be used to treat Staphylococcal infections in Florida. The study will examine the proporti on of MRSA versus MSSA infections in Florida and who is becoming infect ed with methicillin resistant S aureus strains. The lactam antibiotics are ine ffective against MRSA isolates. If the percent of S. aureus isolates that are methicillin resistant is high then -lactam antibiotics may not be the ideal choice for initial treatment of S. aureus infections in this popula tion. In clinical practice antibiotic use needs to adjust to changes in the prevalence of resistance (Gemmell et al. 2006). Knowing the prevalence of resistance in Florida will allow cl inicians to adapt treatment of S. aureus infections based on the likelihood that the strain is resistant. The study will also examine potential associ ations between gender, age, county, and region with regard to methic illin resistance to examine whether any subgroup of the population has a higher risk of having infecti ons with methicillin resistance. Secondary descriptive analysis will include examining any association between MRSA and site of infection (ear, eye, nasal, other, respiratory, skin and soft tissue, sinus, and sterile site) and how many of the isolates in the datase t have the USA300/USA400 type anti-biogram (the most common CA-MRSA clones in the U.S.). The hypothesis is that the proportion of S. aureus isolates that are methicillin resistant have increased from January 1, 2003 to December, 31 2005 and that there are differences

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29 in those who contract methicillin-resistant versus methicillin susceptible S. aureus infections.

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30 Methods Database The dataset is a record of all the S. aureus isolates tested by a large lab company in the state of Florida from January 1, 2003 to December 31, 2005. This is the first statewide surveillance of both methicillin resistant and methicillin susceptible S. aureus and was conducted over a three year time peri od. The dataset contained a large number of isolates. Before exclusi ons there were 67,790 isolates. Th is dataset consists almost entirely of cultures from outpatient facilities Only 275 of the tota l 67,790 isolates, 0.4%, were from a provider with hospital in the name. This is in contrast to previous studies of MRSA that have been based on S. aureus isolates taken from em ergency room visits or hospitalized patients. Data Included and Excluded The study design of this investigation is cross-sectional since information on both the outcome (Methicillin resistance) and expos ure (age, gender, county) was collected at the same point in time. The original datase t was cleaned at the Florida Department of Health. In the initial dataset the antibiotic susceptibilities that were tested for each person were listed down in approximately fifteen rows. The antibiotics and the resistance variables were transposed in order to make each observation into one row. First and last name and date of birth were used to determ ine if two isolates we re duplicates. If two observations had the same first and last name a nd date of birth then they were considered

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31 to be the same person. Address was not use to categorize observati ons as duplicates due to large variation in the manner in which street addresses were record ed and there is also the possibility that a person could have moved during the study period, which would cause them to be counted more than once. The dataset was examined manually to look for potential errors in first and last name and date of birth. If it was determined th at there was an error in the first and last name or date of birth then it was changed ma nually. For all three years there were 298 observations that were changed. Some patients had more than one isolat e taken for testing on the same day. A majority of these had the same antibiotic su sceptibility profile. For patients who had different susceptibilities for an antibiotic th e most resistant isolate was used for the analysis. Some observations that had two isolates taken on the same day had two different sources. For these observations the isolate fr om the more serious infection was used. In nearly all of those who had two sources, one of them was a nasal swab or unknown. The other source recorded was used because a nasa l swab may be a test for colonization with MRSA and not infection. There were only two observations that had two sources in which one of them was not nasal or unknown. As per National Committee for Clinic al Laboratory Standards (NCCLS) guidelines, only the first isolate per person pe r analysis period of 365 days was used in the analysis. This approach has been valid ated by several studies evaluating isolate removal methods (Horvat, Klutman, Lacy, Graver, & Wilson, 2003; Lee et al., 2004; Li et al., 2005; Magee, 2004; Shannon & French, 2 002). It is believed that patients with a

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32 methicillin resistant isolate may have repeat cultures taken more often than patients who have susceptible S. aureus isolates, leading to a biased re sistance estimate (Magee, 2004). Horvat et al. (2003) found that there was a significant diffe rence between de-duplicated methicillin resistance estimates and estimates including all isolates and that 91% of patients tested did not switch between MRSA and MSSA during the 6-year analysis period. Lee et al. (2004) and Li et al. (2005) found that t hose with MRSA isolates had more duplicates then those with MSSA a nd including all isolates produced lower susceptibility estimates. Lee et al. (2004) conc luded that, “These resu lts suggest that the method of calculating results fo r the first isolate per patien t may remove the effect of duplication, allowing the simple and unambiguou s analysis of cumulative susceptibility rates” (p. 4776). Exposure The exposures used in the analysis were gender, age, and county and region of residence. Age was put into 10-year inte rvals of <1, 1-10, 1120, 2130, 31-40, 4150, 5160, 6170, 7180, 8190, and >90. Those w ho were less than one year of age were put into a separate category because they may ha ve different risks than older children. In the analysis age was treated as a nominal vari able. Of those who were 11 to 40, the 11 to 20, 21 to 30, and 31 to 40 age groups, the group w ith the lowest resistance was selected. This age range was chosen because these age categories contain young healthy people. The 11 to 20 age group had a large number of isolates and had the lo west resistance of those who were 11 to 40 and was selected as the reference category. Ten dummy variables were created for the eleven age cat egories. In a separate analysis age was

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33 divided into those who were le ss than 18 and those gr eater then or equal to 18 in order to compare adult and pediatric patients. Counties were numbered 1 to 67 and also treated as a nominal variable. For selection of the reference cat egory, of the five counties th at had the highest number of isolates the one with the lowest resistance was chosen. Of the five counties with the most isolates, Miami-Dade County ha d the lowest percentage of methicillin-resistance and was used as the reference category. The state was also divided into 7 regions for analysis (Figure 1). Region 6 was made the reference category because it ha d the lowest resistance percentage. Figure 1. Map of the Seven Regions of Florida.

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34 Outcome The outcome was whether or not the S. aureus isolate tested was methicillin resistant. Resistance for all antibiotics wa s determined based on NCCLS standards. Oxacillin is used as a surrogate for methicillin resistance and was used for this purpose in this dataset. If the minimum inhibitory c oncentration (MIC) for ox acillin of an isolate was less than or equal to two then the isolat e was coded as susceptible, if the MIC was between two and four then it was coded as in termediate, and if the MIC was greater than or equal to 4 then it was code d as resistant. Those that were methicillin resistant were considered to have the outcome. For the analysis, antibiotic susceptibilities were coded as one if the isolate was resistant or had an intermediate resistance to oxacillin (a surrogate for methicillin resistance) and zero if the isolate was susceptible. Statistical Analysis Logistic regression was used to calculat e odds ratios and statistical significance of potential risk factors for meth icillin resistance to examine the association between the independent variables and the dependent variab le. For cross sectional studies, odds ratios may be calculated to evaluate statistical signi ficance of exposure variables. The resulting odds ratio is the odds of having the dis ease, not developing incident disease For the logistic regression analysis crude odds ratios were calculated for each variable. A model that in cluded gender, age category, year, and county was used to obtain adjusted odds ratios and 95% confidence intervals for these exposures. In logistic regression any observation that has a missing variable is excl uded from the analysis, so a crude odds ratio and 95% confidence interval were calculated for each variable including only those who were not missing any of the e xposure variables and were included in the

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35 full model. A second model was used to calcu late adjusted odds ratios for region, which also included gender, age category, and y ear to adjust for these factors. A second analysis of only patients with a skin and soft tissue infection was also conducted. The data from this subset of patie nts was analyzed in the same manner as the complete dataset. To examine whether the proportion of MRSA has changed over time, the data was analyzed in two ways. Year was treated as a nominal variable and two dummy variables were created. The year 2003 was made the reference category because it had the lowest resistance percentage. The s econd method was to treat year as a ordinal variable and put it directly into the model. The Year 2003 was coded as 0, 2004 was coded as 1, and 2005 was coded as 2. This analysis was performe d only including year and in a model with gender, age category, and county. Secondary Analysis The site from which the culture was taken, the source of the infection, was divided into nine categories. Isolates which were reported to be taken from the ear were categorized as ear. Isolates which were reco rded as eye, cornea, conjunctiva, etc. were categorized as eye. Isolates with a reporte d source of nasal, nose, and nostrils were categorized as nasal. Isolates were categorized as other is they were from bone, urine, vaginal/cervical, breast fluid, seme n, urethra, etc. Isolates that were cultured from throat, oral, nasopharynx, and sputum were categorized as respiratory. Is olates that were recorded as sinus or ethmoid were categorized as sinus. An y isolate that had a reported source of arm, leg, finger, toe, etc. or ulcer abscess, or wound were categorized as skin and soft tissue. Isolates were categorized as sterile site if they were cultured from blood,

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36 bursa fluid, synovial fluid, etc. If the source was missing or the recorded data was not interpretable then it was categorized as unknown. This study also examined how many of the isolates in the dataset have the USA300/USA400 type anti-biogram. If the is olate was resistant to methicillin and erythromycin, but susceptible to clin damycin, trimethoprim-sulfamethoxazole, ciprofloxacin and levofloxacin then it was considered to have the USA300/USA400 type anti-biogram (King et al 2006). SAS version 9 statistical software was used for cleaning the raw dataset and to perfor m statistical analyses.

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37 Results Year After removal of duplicates there were 8299 isolates for 2003, 17,309 for 2004 and 35,986 for 2005. There were two is olates that were missing th e date of service. The total number of isolates after excl usions for all three years was 61,596. There were 8,286 isolates for 2003, 16,980 isolates for 2004, and 35,946 isolates for 2005 with a reported susceptibility or resi stance to oxacillin and 384 observations that were missing a MIC for oxacillin for all thr ee years. These observations were not included in any of the analys is because they were missing the outcome variable. The percentage of MRSA for all S. aureus isolates increased as ye ar increased (Figure 2). The percentage of MRSA in creased from 35.1% of all S. aureus isolates in 2003 to 41.5% of isolates in 2004 to 49.7% of isolates in 2005.

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38 Percentage of MRSA and MSSA By Year (All Culture Sites)0 20 40 60 80 100 200320042005 YearPercentage MRSA MSSA Figure 2. Percentage of MRSA and MSSA for all S. aureus isolates from 2003 to 2005 For All Culture Sites. The increase was significant for both met hods of analysis. The crude odds ratio, when treated as a categori cal variable, is 1.31, 95% CI: 1.241.38 for 2004 compared to 2003 and the odds ratio for 2005 compared to 2003 is 1.82, 95% CI: 1.731.91. When analyzed as a continuous va riable, the crude odds ratio for year is 1.36, 95% CI: 1.331.39. All of these confidence intervals do not include one and are significant at the = 0.05 level. The crude odds ratios excluding observations that were missing any variable were 1.31, 95% CI: 1.241.39 when compari ng 2004 to 2003 and 1.84, 95% CI: 1.741.95 when comparing 2005 to 2003. When treated as a continuous variable the odds ratio was 1.37, 95% CI: 1.341.40. For the full logistic regression model year was included as a continuous variable and put directly into th e model. When included with age, gender, and county the odds ratio for year becomes 1.45, 95% CI: 1.411.48.

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39 Age Group There were 11 age categories, <1, 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, and >90, which were numbered 0 to 10 in the anal ysis. The 51-60 age group, category 5, had the highest number is isolates, followed by the 11-20 age group, category 3. There were 901 obs ervations that were missing patient age (Figure 3). Number of Isolates For Each Age Group From 2003 To 2005 (All Culture Sites) 0 2000 4000 6000 8000 10000M issing <1 1 to 10 11 to 20 21 t o 30 31 to 40 41 to 50 5 1 to 60 61 to 70 71 to 80 81 to 90 > 90Age GroupNumber of Isolates Figure 3. Number of S. aureus Isolates for Each Age Group From 2003 To 2005 For All Culture Sites. When the percentage of MRSA is cal culated for each age group, the missing category had the highest percen tage of MRSA (61% in 2005). Of all the age groups, the

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40 2130 age group has the highest percentage of MRSA (51% in 2005). This group is followed by the >90 age group (50% in 2005) and the 31-40 age group (49% in 2005) (Figure 4). Methicillin resistance for all the age groups and the missing group increased from year to year, except for the >1 age group which had a slight decrease from 2003 to 2004, then an increase from 2004 to 2005 (Figure 5). Percentage of Isolates That Were MRSA By Age Category (All Culture Sites)0 20 40 60 80 100<1 1 t o 1 0 11 to 2 0 21 to 30 31 to 40 41 to 5 0 51 to 60 61 to 70 71 to 8 0 81 to 9 0 >90Age CategoryPercentage of MRSA Figure 4. Percentage of S. aureus Isolates That Were MR SA By Age Category From 2003 To 2005 For All Culture Sites.

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41 Percentage of Isolates That Were MRSA By Age Group By Year (All Culture Sites)0 20 40 60 80 100>1 1 to 1 0 1 1 t o 20 2 1 t o 30 3 1 t o 40 4 1 t o 50 5 1 to 60 6 1 to 70 7 1 to 80 8 1 to 90 > 9 0 Miss i ngAge GroupPercentage 2003 2004 2005 Figure 5. Percentage of S. aureus Isolates That Were MRSA By Age Category By Year From 2003 to 2005 For All Culture Sites. The missing group had the largest change in the percent of is olates that were resistant. Of the age groups, the 21 to 30 year olds had the largest change in the percent of isolates that were resistant. The yo unger age groups had a great er increase in the percent of isolates that were methicillin resistant (Figure 6).

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42 Change In Percent of Isolates That Were MRSA From 2003 to 2004 and 2003 to 2005 By Age Group-5 0 5 10 15 20 25 30>1 1 t o 10 11 to 20 21 to 3 0 31 to 40 41 to 5 0 51 to 60 61 to 7 0 71 to 80 81 to 9 0 >90 Mi s si n gAge GroupDifference In Percent 2003 to 2004 2003 to 2005 Figure 6. Change in the Percentage of S. aureus Isolates That Were MRSA From 2003 to 2004 and from 2003 to 2005 By Age Group For All Culture Sites. For the crude odds ratios, the less than 1, 1 to 10, and 61 to 70 age groups have a significantly lower risk of being methicillin resistant and the 21 to 30, 31 to 40, 41 to 50, and the greater than 90 age groups have a sign ificantly higher risk of being methicillin resistant when compared to the 11 to 20 year old reference category. For the crude odds ratios excluding those missing any variable the 61 to 70 age group had significantly lower risk of having methicillin re sistance and the 21 to 30, 31 to 40, 41 to 50, and greater than 90 age groups have a significantly higher ri sk of being methicillin resistant when compared to the reference group (Table 3).

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43 Table 3. Crude Odds Ratios and 95% Confidence Interval for Age Categories When Compared to the Eleven to Twenty Age Group. Age Category OR 95% CI <1 0.81 0.700.93 1 to 10 0.92 0.960.98 11 to 20 Reference 21 to 30 1.27 1.191.37 31 to 40 1.19 1.121.27 41 to 50 1.11 1.051.18 51 to 60 0.97 0.911.04 61 to 70 0.82 0.760.88 71 to 80 0.93 0.861.0 81 to 90 0.98 0.901.06 >90 1.22 1.041.44 When included in the logistic regres sion model with year, gender, and county, age, those who were 1 to 10, 51 to 60, and 61 to 70 did not have a significantly higher risk of having methicillin resistant S. aureus compared to methicillin susceptible S. aureus than those in the 11 to 20 age group. The odds ratios and 95% confidence intervals for the 21 to 30, 31 to 40, 41 to 50, 71 to 80, 81 to 90, and >90 age groups all do not include one and have a significantly high er risk of having a methicillin resistant infection than the reference group at the = 0.05 level. The <1 age group has a significantly decreased risk of methicillin re sistance. The odds ratio and 95% confidence interval for the <1 category was less than one, this group has a si gnificantly decreased risk of methicillin resistance compar ed to the reference group (Table 4).

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44 Table 4. Odds Ratios and 95% Confidence In terval for Age Categories When Compared to the Eleven to Twenty Age Group Adjusted for Gender, Year, and County. Age Category OR 95% CI <1 0.76 0.650.88 1 to 10 1 0.941.07 11 to 20 Reference 21 to 30 1.19 1.101.29 31 to 40 1.21 1.131.30 41 to 50 1.14 1.061.22 51 to 60 1.04 0.941.11 61 to 70 0.93 0.861.00 71 to 80 1.1 1.011.19 81 to 90 1.13 1.041.24 >90 1.46 1.231.74 Adult and Pediatric Adults had a higher percentage of isolates that were methicillin resistant for all three years. When adults were compared to pediatric patients (those less than 18), the crude odds ratio was 1.17, 95% CI: 1.131.22. The crude odds ratios excluding those missing any variable was 1.12, 95% CI: 1.081.16. The adjusted odds ratio was 1.17, 95% CI: 1.121.22. In this dataset adults ha d a significantly higher risk of methicillin resistance than those wh o were under 18 (Figure 7).

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45 Percent of Isolates That Were MRSA By Adult By Year (All Culture Sites)0 10 20 30 40 50 60 200320042005 YearPercent Adult (18+) Pediatric (>18) Figure 7. Percent of S. aureus Isolates That Were Methicillin Resistant By Adult Versus Pediatric By Year From 2004 To 2005 For All Culture Sites. Gender For the gender variable there were 3 4,536 males and 28,898 females. There were 790 observations that were missing gender. Th e overall percentage of MRSA for males was 45.2% and the overall percentage for fema les was 45.7%. When the percentage of MRSA for gender is divided into year, th e percentage for both males and females increases from year to year. However, the increase is slightly faster for females than for males. In 2003, the percentage for males is s lightly higher than females (35.2% for males and 34.9% for females), then the percentage for males and females are approximately even in 2004 (41.5% for males and 41.4% fo r females), then the percentage becomes slightly higher for females in 2005 (49.0% for ma les and 50.2% for females) (Figure 8).

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46 Percentage of Isolates That Were MRSA By Year For Gender (All Culture Sites)0 20 40 60 80 100 200320042005 YearPercentage of MRSA Males Females Figure 8. Percentage of S. aureus Isolates That Were MRSA By Year For Males and Females From 2003 To 2005 For All Culture Sites. The crude odds ratio is 1.022 95% CI: 0.991.06. The crude odds ratio excluding observations with any missing variables is 1.05, 95% CI: 1.021.09. When adjusted for age, county, and year, females have a slig ht, but significantly hi gher risk of having methicillin resistant S. aureus versus methicillin susceptible S. aureus compared to males. The odds ratio for females compared to males is 1.05, 95% CI: 1.011.08. When methicillin resistance is plotted by gender fo r each age group the number and percent of isolates that were resistant are similar for each age group and the missing group (Figure 9 and Figure 10).

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47 Number of Isolates For Each Age Group By Gender (All Culture Sites)0 1000 2000 3000 4000 5000 6000> 1 1 to 10 11 to 20 21 to 30 31 to 40 41 to 50 51 to 60 61 to 70 71 to 80 81 to 90 > 90 Mis si ngAge GroupNumber of Isolate s Male Female Figure 9. Number of S. aureus Isolates For Each Age Group By Gender From 2003 To 2005 For All Culture Sites.

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48 Percentage of Isolates That Were Methicillin Resistant By Age Group By Gender (All Culture Sites)0 20 40 60 80 100>1 1 t o 10 11 to 20 21 t o 30 31 to 40 41 t o 50 51 to 60 61 t o 70 71 to 80 81 t o 90 > 90 M is singAge GroupPercentage Male Female Figure 10. Percent of S. aureus Isolates That Were Methicillin Resistant By Age Group By Gender From 2003 To 2005 For All Culture Sites. Region The state of Florida was divided in to seven regions. There were 1,531 observations for region one (western panhandle), 6,339 for region two (central panhandle), 5,992 for region three (north eas t), 13,980 for region four (west central, including Tampa), 11,297 for region five (eas tern central, includi ng Orlando), 3,358 for region six (southwest, including Ft. Myers), 10,305 for region seven (southeast, including Miami), and there were 8,794 observations wh ich were missing information on region (Figure 11).

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49 Number of Isolates For Each Region of Florida (All Culture Sites)0 2000 4000 6000 8000 10000 12000 14000 16000W es ter n P anhan dl e C e ntr al P a nhadl e N o r th eas t W e s t C entr al E as t er n C en t r a l S out h w e s t S o ut hea s t M i s s i n g Figure 11. Number of Isolates For Each Region of Florid a and Those That Were Missing Region From 2003 To 2005 For All Culture Sites. Region 1, the western panhandle, had the hi ghest percentage of MRSA (59.9%), followed by the northeast, region 3 (50.5%), west central, region 4 (46.4%), eastern central, region 5 (44.1%), the southeast, re gion 7 (39.8%), central panhandle, region 2, (38.3%), and the southwest, region 6 (37.4%). For the observations missing region, the percentage of MRSA was 54.2% (Figure 12). The percenta ge of MRSA increased as year increased for all seven regions and the group that were missing data on region (Figure 13).

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50 Percentage of Isolates That Were MRSA By Region of Florida (All Culture Sites)0 20 40 60 80 100W estern Panhandle C e n t ral P a n h ad l e N ortheast Wes t C e n t ra l E a stern Ce ntr a l Southwest Sou the a st M issingPercentage Figure 12. Percentage of S. aureus Isolates That Were MRSA By Region of Florida From 2003 To 2005 For All Culture Sites.

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51 Percent of Isolates That Were MRSA By Region By Year (All Culture Sites)0 20 40 60 80 100Wes t ern Pa n hand l e Central P an hadle N ortheast Wes t Ce n tral East e r n C en t ral Southw e st S outhea s t Miss i ngPercentage 2003 2004 2005 Figure 13. Percentage of S. aureus Isolates That Were MRSA By Region Of Florida By Year From 2003 To 2005 For All Culture Sites. The change in the percent of isolates that were methicillin resistant was the highest for the southeast. The central panhandl e had the smallest cha nge in the percent of isolates that were resistant (Figure 14).

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52 Change In Percent of Isolates That Were MRSA From 2003 to 2004 and 2003 to 2005 (All Culture Sites)0 5 10 15 20 25 30Western Panhandle Ce n tral P an ha dl e N o rtheast West C en tra l Eastern C entral S o ut hwe s t Sout h east M i ss i n gDifference In Percen t 2003 to 2004 2003 to 2005 Figure 14. Change in the Percent of S. aureus Isolates That Were Methicillin Resistant From 2003 to 2004 and From 2003 to 2005 By Region Of Florida. For the logistic regression analysis, the crude odds ratios for the western panhandle, the northeast, West central, Eastern central, and the Southeast have a significantly higher risk of having methicillin resistant S. aureus strains than isolates from region the Southwest. The crude odds ratios excluding those who were missing any variable were the same as the crude odds ratios (Table 5).

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53 Table 5. Crude Odds Ratios and 95% Confidence Interval For the Seven Regions of Florida Compared to Region Six. Region OR 95% CI Western Panhandle 2.50 2.212.83 Central Panhandle 1.04 0.951.13 Northeast 1.70 1.561.86 West Central 1.45 1.341.56 Eastern Central 1.32 1.221.43 Southwest Reference Southeast 1.11 1.021.20 When adjusted for gender, age, and year the western panhandle, the Northeast, West central, and the Eastern central have a significantly higher risk of having methicillin resistant S. aureus versus methicillin susceptible S. aureus when compared to the Southwest (Table 6). The risk of methicil lin resistance for the Central panhandle and the Southeast were not significantly differ ent than the reference category. Table 6. Odds Ratios and 95% Confidence Inte rval For the Seven Regions of Florida Compared to Region Six, Adjusted for Gender, Age, and Year. Region OR 95% CI Western Panhandle 2.50 2.202.83 Central Panhandle 0.97 0.891.06 Northeast 1.68 1.541.84 West Central 1.51 1.401.64 Eastern Central 1.35 1.251.47 Southwest Reference Southeast 1.00 0.921.09 County The number of isolates and the percent of isolates that were MRSA varied by county. The number of isolates from each county, for each year, ranged from 0 to 3,654 and the percent of isolates that were MRSA ranged from 0% to 75% (Table 7)

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54 Table 7. Percent of Isolates That Were MR SA and Total Number of Isolates For Each County By Year. County Percent of Isolates Which Were MRSA (Total Number of Isolates) 2003 2004 2005 Alachua 51.1% (45) 57.5% (80) 62.6% (246) Baker 0% (7) 50% (20) 68.8% (64) Bay 39.7% (63) 64.9% (37) 62.4% (117) Bradford 33.3% (3) 40% (10) 72.2% (36) Brevard 25.9% (343) 43. 1% (445) 49.5% (865) Broward 20% (5) 33.9% (1520) 42.5% (2981) Calhoun 40% (15) 46.7% (15) 66.7% (15) Charlotte 45.9% (61) 34.4% (64) 46.8% (158) Citrus 30% (36) 50.5% (91) 53.8% (145) Clay 32.7% (49) 43.2% (81) 60.2% (254) Collier 14.8% (27) 41.9% (31) 35.3% (85) Columbia 0% (9) 40% (20) 39.2% (51) DeSoto 33.3% (3) 25% (8) 33.3% (12) Dixie 58.3% (12) 64.7% (17) 40% (15) Duval 33.7% (496) 47.3% (763) 57.4% (2006) Escambia 65.6% (64) 67.1% (161) 71% (335) Flagler 42.9% (7) 20% (10) 50% (38) Franklin 20% (5) 63% (27) 60.5% (38) Gadsden 38.5% (26) 44.4% (18) 58.3% (36) Gilchrist 63.6% (11) 45% (20) 73.7% (19) Glades 0% (0) 0% (2) 20% (5) Gulf 50% (10) 57.1% (14) 75% (40) Hamilton 26.5% (34) 52.6% (57) 45.5% (99) Hardee 30.2% (43) 38.6% (44) 54.1% (98) Hendry 0% (6) 7.7% (13) 42.9% (56) Hernando 35% (103) 41.8% (165) 53% (353) Highlands 43.8% (16) 40.9% (22) 46.9% (32) Hillsborough 33.8% (1 095) 42.5% (1328) 53.3% (2634) Holmes 33.3% (3) 0% (1) 0% (0) Indian River 26.4% (87) 43% (93) 43.7% (126) Jackson 20% (15) 50% (6) 40% (25) Jefferson 27.3% (11) 50% (2) 56.3% (16) Lafayette 0% (1) 100% (2) 33.3% (3) Lake 25.2% (230) 41.1% (292) 43.6% (486) Lee 26.7% (247) 32.5% (394) 41.6% (927) Leon 33.3% (60) 40.7% (86) 59.7% (124) Levy 35.3% (17) 54.3% (46) 45.3% (53) Liberty 54.5% (11) 50% (8) 66.7% (9) Madison 33.3% (15) 58.3% (12) 55.6% (18)

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55 (Table 7 continued) Manatee 34.5% (249) 47.2% (320) 51.5% (618) Marion 32.3% (201) 42.1% (261) 50.4% (520) Martin 28.6% (7) 42.6% (108) 46.5% (271) Miami-Dade 0% (4) 29.1% (1821) 39.9% (3342) Monroe 0% (1) 36.2% (69) 47.2% (159) Nassau 35.4% (48) 44.4% (63) 52.1% (163) Okaloosa 51.5% (33) 63.8% (47) 53.3% (107) Okeechobe 20% (10) 57.1% (21) 54.8% (62) Orange 32.7% (740) 43.4% (1028) 50.7% (2039) Osceola 31.1% (161) 43. 1% (255) 49.9% (487) Palm Beach 15.4% (26) 33. 9% (1717) 42.9% (3654) Pasco 33.2% (328) 37.5% (453) 47% (798) Pinellas 38.8% (704) 49.4% (881) 53.7% (1677) Polk 33.8% (385) 46.4% (422) 50.2% (833) Putnam 31.6% (19) 35% (20) 59.3% (54) Santa Rosa 65% (20) 56.5% (69) 58.9% (163) Sarasota 25.5% (216) 35.8% (296) 39.8% (580) Seminole 30.9% (269) 40% (365) 50.6% (720) St. Johns 40.4% (47) 36.1% (61) 45.6% (125) St. Lucie 34.8% (112) 38.6% (166) 47.7% (405) Sumter 45% (40) 27.7% (65) 44.2% (52) Suwannee 66.7% (6) 66.7% (6) 60% (30) Taylor 0% (0) 50% (8) 41.7% (24) Union 0% (3) 66.7% (6) 46.7% (15) Volusia 37.4% (187) 48.1% (310) 52.2% (674) Wakulla 22.2% (27) 63.5% (52) 66.7% (75) Walton 42.9% (7) 43.5% (46) 48.3% (89) Washington 0% (3) 50% (2) 66.7% (3) Missing 45.5% (1142) 52.2% (2017) 56.7% (5587) When crude odds ratios are calculated there are 45 counties that have a significantly higher risk of methicillin resi stance than those in the reference county, Miami-Dade (Table 8). For the crude an alysis excluding those who were missing any variable, the same 45 counties had a 95% conf idence interval that did not include one (Not shown).

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56 Table 8. Crude Odds Ratio and 95% C onfidence Interval For Counties With a Significantly Higher Risk of Methicillin Re sistance When Compared to Miami-Dade County. County OR 95% CI County OR 95% CI Alachua 2.68 2163.32Levy 1.6 1.112.32 Baker 2.59 1.703.95Liberty 2.37 1.125.02 Bay 2.28 1.733.00Manatee 1.56 1.371.77 Bradford 3.06 1.715.48 Marion 1.42 1.241.64 Brevard 1.33 1.191.49Martin 1.46 1.181.80 Broward 1.16 1.071.26 Monroe 1.38 1.051.80 Calhoun 1.86 1.033.34Nassau 1.6 1.262.05 Charlotte 1.39 1.091.76Okaloosa 2.23 1.662.99 Citrus 1.94 1.522.48Okeechobee1.89 1.262.86 Clay 2.01 1.632.48Orange 1.47 1.351.60 Dixie 2.13 1.173.87Osceola 1.43 1.241.65 Duval 1.88 1.722.06Palm Beach1.18 1.091.78 Escambia 4.01 3.324.84 Pasco 1.26 1.121.041 Franklin 2.51 1.564.05Pinellas 1.73 1.581.89 Gadsden 1.69 1.092.63Polk 1.48 1.321.65 Gilchrist 2.66 1.514.70Putnam 1.67 1.102.51 Gulf 3.64 2.156.15S anta Rosa2.53 1.953.27 Hamilton 1.41 1.051.88Seminole 1.38 1.231.57 Hardee 1.45 1.081.94St. Lucie 1.36 1.161.60 Hernando 1.58 1.331.87Suwannee 2.89 1.545.39 Hillsborough 1.53 1.411.65 Volusia 1.69 1.491.92 Leon 1.63 1.272.08Wakulla 2.43 1.763.37 Walton 1.54 1.102.16 When county is included into a logistic regression model with year, gender, and age category, there are 50 counties whose 95% confidence interval for the odds ratio does not include one. These counties have a significantly higher ri sk of methicillin resistance than the reference county, Miami-Dade, when adjusted for age, gender, and year (Table 9). When those who were missing data on count y are put into a sepa rate category and run in a model with gender, year, and age group, the odds ratio for the missing group is 2.08, 95% CI: 1.932.24. Like 50 of the counties, the missing group has a significantly higher risk of methicillin resistance than the reference county.

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57 Table 9. Odds Ratio and 95% Confidence In terval For Counties With a Significantly Higher Risk of MRSA When Co mpared to Miami-Dade County. County OR 95% CI County OR 95% CI Alachua 2.76 2.223.44 Levy 1.78 1.222.59 Baker 2.74 1.784.21 Liberty 3.11 1.456.64 Bay 2.65 2.003.50 Madison 2.03 1.113.70 Bradford 2.91 1.615.24 Manatee 1.77 1.562.01 Brevard 1.51 1.351.69 Marion 1.61 1.401.86 Broward 1.14 1.051.24 Martin 1.45 1.171.79 Calhoun 2.32 1.284.21 Monroe 1.37 1.051.79 Charlotte 1.53 1.191.95 Nassau 1.75 1.36-2.24 Citrus 2.13 1.662.73 Okaloosa 2.46 1.823.31 Clay 2.07 1.672.55 Ok eechobe 1.95 1.292.95 Dixie 2.85 1.555.26 Orange 1.64 1.511.79 Duval 2.01 1.842.20 Osceola 1.6 1.381.85 Escambia 4.29 3.555.19 Pa lm Beach 1.16 1.071.26 Franklin 2.81 1.734.58 Pasco 1.44 1.281.62 Gadsden 1.96 1.253.07 Pinellas 1.95 1.782.13 Gilchrist 3.3 1.86-, 5.87 Polk 1.71 1.521.92 Gulf 4.23 2.477.24 Putnam 1.9 1.252.88 Hamilton 1.56 1.162.10 S anta Rosa 2.65 2.043.43 Hardee 1.67 1.242.26 Seminole 1.55 1.371.76 Hernando 1.78 1.502.11 S t. Johns 1.43 1.091.88 Hillsborough 1.74 1.611.89 St. Lucie 1.48 1.261.75 Indian River 1.32 1.041.68 Suwannee 3.01 1.605.66 Lake 1.3 1.131.49 Volusia 1.83 1.612.09 Lee 1.13 1.011.28 Wakulla 2.76 1.993.83 Leon 1.85 1.442.37 Walton 1.56 1.112.18 As a comparison, an analysis using only the first per patient was performed. Using only the first isolate for each patient, there are 61,050 observations. When the full model is run on this set of patients the results are nearly identical to using the first isolate every 365 days for all variables. No odds ratio was more than 0.05 different than the analysis using isolates from patients every 365 days. Other Antibiotics

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58 The percentage of isolates that were resi stant to other antibioti cs varied by year and by whether the isolate was MSSA or MRSA. For MSSA isolates less than 1% of the isolates were resistant to amoxicillin clavuanic and about 85% were resistant to penicillin. These percentages did not vary over the three years. Nearly 100% of the MRSA isolates were resistant to the -lactams amoxicillin clavua nic and penicillin. For trimethoprim-sulfamethoxazole the percent that were resistant decreased slightly from 1.5% to 0.8% among the MSSA isolates. For th e MRSA isolates the percent that were resistant fluctuated from 2% to 4% to 1%. Among the quinolones and floroquinolones group there were differences between the MSSA and MRSA isolates. The MSSA isolates had about 6% of the is olates resistant to ciprofloxa cin and about 5% resistant to levofloxacin. Though the resistance rate fo r ciprofloxacin and le vofloxacin decreased from year to year among the MRSA isolates, the percent that were resistance was higher than the MSSA isolates, 39% and 36% in 2005. For gentamycin the percent of isolates that were resistance among the MSSA isolates was about 1% for the three years. The percent that were resistant among the MRSA isolates was slightly higher, 2.4 % in 2005. MRSA isolates also had a higher resistance rate for tetracycline, erythromyci n, and clindamycin. The percent of isolates that were resistant among the MRSA isolates is about double that of the MSSA isolates for tetracycline. For erythromycin the per cent that were resistant was about 39% among the MSSA isolates and 93% among the MRSA is olates. The percent that were resistant to clindamycin was only 3% in the MSSA group, however among the MRSA isolates there were 22% that were resistant in 2003 and 2004 and 14% in 2005. The percent that

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59 were resistant to rifampin was low in bot h groups, <1% among the MSSA isolates and 1% among the MRSA isolates (Table 10). Table 10. Percent Resistance of MSSA and MRSA Isolates to Other Antibiotics By Class. Antibiotic Percent of MSSA Isolates Resistant For 2003, 2004, 2005 Percent of MRSA Isolates Resistant For 2003, 2004, 2005 Penicillins Amoxicillin Penicillin 0.7%, 0.9%, 0.3% 84.6%, 85.1%, 84.4% 99.9%, 100%, 100% 100%, 100%, 99.9% Folate Pathway Inhibitors Trimethoprim Sulfamethoxazole 1.5%, 1.3%, 0.8% 2.3%, 4.1%, 1.2% Quinolones and Floroquinolones Ciprofloxacin Levofloxacin 6.1%, 7.8%, 6.6% 4.5%, 5.6%, 4.8% 48.5%, 46.6%, 39.2% 46.7%, 43.9%, 36.0% Aminoglycosides Gentamycin 1.0%, 1.3%, 0.8% 3.6%, 5.5%, 2.4% Tetracyclines Tetracycline 4.2%, 6.1%, 5.2% 9.9%, 12.2%, 8.9% Macrolides Erythromycin 38.1%, 38.9%, 39.7% 90.5%, 92.7%, 93.3% Lincosamides Clindamycin 2.5%, 4.4%, 3.2% 22.3%, 22.6%, 14.4% Rifamycins Rifampin 0.07%, 0.7%, 0.5% 1.0%, 1.7%, 1.0% Source In this dataset 79.6% (49,060) of the isol ates were from skin and soft tissue infections. The other sources each make up no more than 5% of the isolates. There were 1,410 isolates from the ear, 1,166 from the eye, 3,296 from nasal swabs, 568 from other sites, 1,910 from respiratory infections, 657 fr om the sinus, 289 from sterile sites, and 3,240 that were unknown (Figure 15).

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60 Number of Isolates By Source From 2003 To 20051,410 1,166 3296 568 1910 657 49060 289 3240 0 10,000 20,000 30,000 40,000 50,000 60,000Ear Eye Na sa l Othe r Re sp Si n us Skin Steri l e Unk n ownSourceNumber of Isolates Figure 15. Number of S. aureus Isolates For Each Source Site In Florida From 2003 To 2005.

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61 Percent of Isolates For Each Culture Site From 2003 To 20052.3 1.9 5.4 0.9 3.1 1.1 79.6 0.5 5.3 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0Ear E ye N asal Other R esp S inus S kin St e ri l e U n kn o wnPercent Figure 16. Percent of S. aureus Isolates For Each Culture Site In Florida From 2003 To 2005. The percentage of S. aureus isolates that were MRSA was highest for skin and soft tissue infections (48.9%), followed by unknow n site of infection (45.5%), sterile site infections (37.1%), other site s of infection (36.2%), eye in fections (29.5%), nasal swabs (28.7%), ear infections (25.8%), sinus infec tions (23.3%), and respiratory infections (21.6%) (Figure 16).

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62 Percentage of Isolates That Were MRSA By Source From 2003 To 20050 20 40 60 80 100Ear Eye Nasal Other Re s p S inu s S k i n S terile Unkn o wnSourcePercentage Figure 17. Percentage of S. aureus Isolates That Were MRSA By Source of Infection From 2003 To 2005. Skin and soft tissue, other, and unknown infections increased from year to year. Eye and sterile site infections show an upwar d trend. Ear, nasal, respiratory, and sinus infections did not show a cl ear trend over the th ree years (Figure 18) Among the skin and soft tissue infections, MRSA accounted fo r 52.7% of the isolates in 2005. This was the highest percent of MRSA of the nine sources. Unknown a nd other isolates also had a high percentage of MRSA, 49.9% and 43.7% in 2005. The percentage of MRSA in 2005 was 39.7% for sterile site infections, 30.5% fo r nasal isolates, 30.4% for eye infections, 25.8% for ear isolates, 23.9% for respiratory in fections, and 23.8% for sinus infections.

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63 Percent of Isolates That Were MRSA By Source By Year0 20 40 60 80 100Ear Eye Nas a l O t her R esp Si n us Ski n St e rile U nkn o wnSourcePercentage 2003 2004 2005 Figure 18. Percent of S. aureus Isolates That Were MRSA By Source By Year From 2003 To 2005. USA300/USA400 In 2003 there were 1,241 isolates with a USA300/USA400 type anti-biogram, in 2004 there were 3,239, and in 2005 there were 9,360 (Figure 19). The percent of isolates that had an USA300/USA400 type anti-biogram increased from 15.0% in 2003, to 19.1% in 2004, to 26.0% in 2005 (Figure 20).

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64 Number of Isolates That Had and Did Not Have A USA300/USA400 Type Susceptibility Pattern By Year (All Culture Sites)0 5000 10000 15000 20000 25000 30000 200320042005 YearNumber of Isolates Missing USA300/400 Not USA300/400 Figure 19. Number of Isolat es That Had and Did Not Have A USA300/ USA400 Type Anti-Biogram By Year From 2003 To 2005 For All Culture Sites.

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65 Percent of Isolates That Had A USA300/400 Type Susceptibility Pattern By Year (All Culture Sites)0 10 20 30 40 50 200320042005 YearPercentage Figure 20. Percent of Isolat es That Had a USA300/USA400 Type Anti-Biogram By Year From 2003 To 2005 For All Culture Sites. There are differences in th e percent of isolates that have a USA300/USA400 type anti-biogram by source. The skin and soft tissue category had the highest percent of isolates that were the USA300/USA400 type, 28.7% in 2005. The unknown category had a percent of 25.1% in 2005, among the other cat egories <11% of the isolates meet the criteria for USA300/USA400 in 2005. Except for ear, nasal, and sterile site the percent of isolates that were USA33/USA400 in creased from year to year (Figure 21).

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66 Percent of Isolates That Had A USA300/400 Type Anti-Biogram By Source By Year (All Culture Sites)0 10 20 30 40 50E a r Eye Na s al Ot h er Re s p Si n us Skin S terile Unk n ownSourcePercentage 2003 2004 2005 Figure 21. Percentage of Is olates That Had A USA300/US A400 Type Anti-Biogram By Source By Year From 2003 To 2005. Skin and Soft Tissue Analysis There were 49,060 skin and soft tissue in fections total. There were 48,876 those from patients from a hospital were excluded. Wh en this subset of patients are examined we find that the number and percent of isolates that were methicillin resistant increases from 2003 to 2005 (Figure 22 and Figure 23). In this subset of patie nts the increase in methicillin resistance is faster than in the complete datase t, 52.7% of isolates were methicillin resistant in 2005.

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67 Number of MRSA and MSSA Isolates By Year For Skin and Soft Tissue Infections0 2000 4000 6000 8000 10000 12000 14000 16000 18000 200320042005 YearNumber of Isolates MRSA MSSA Figure 22. Number of S. aureus Isolates That Were MRSA and MSSA By Year Among Skin and Soft Tissue Infections.

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68 Percent of MRSA and MSSA Isolates By Year For Skin and Soft Tissue Infections0 10 20 30 40 50 60 70 200320042005 YearPercentage MRSA MSSA Figure 23. Percent of S. aureus Isolates That Were Methic illin Resistant By Year Among Skin and Soft Tissue Infections. When year is treated as a categorical vari able the crude odds ratios is 1.4, 95% CI: 1.321.49 comparing 2004 to 2003 and 1.87, 95% CI: 1.761.97 comparing 2005 to 2003. The crude odds ratio when year is treate d as a continuous va riable is 1.36, 95% CI: 1.321.39. When year is added to the full model with gender, age category, and county the odds ratio is 1.40, 95% CI: 1.361.44. In this subset of patients the percent of isolates that were methicillin resistant increases for both males and females, but, as in the full dataset, the increases is slightly steeper for females. In 2003, 36.9% of the isolates from females were methicillin resistant and 37.6% were resistant for males (Figure 24). In 2004, 46.0% were resistant for females and 45.1% were resistant for males. In 2005, 53.8% were resistant for

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69 females and 51.6% were resistant for males. Percent of Isolates That Were MRSA By Gender By Year For Skin and Soft Tissue Infections0 10 20 30 40 50 60 200320042005 YearPercentage Male Female Figure 24. Percent of S. aureus Isolates That Were Methicillin Resistant By Gender By Year Among Skin and Soft Tissue Infections. For gender the crude odds ratio and the cr ude odds ratio excluding all those that were missing any variable were the same, OR=1.06, 95% CI:1.021.10. When included in the full model the adjusted odds ratio is 1.07, 95% CI: 1.031.12. As in the full dataset we see a slightly highe r, but significant, risk for females compared to males. There was an increase in the percent of isolates that were methicillin resistant for all age groups. The less th an one age group had very few isolates in 2003 and 2004, 3 and 10 respectively. The number increased to 560 in 2005. The same trend in methicillin resistance by age group that is seen in the full dataset also occurs in this subset of patients. The missing category had the highest percent of isolates that were methicillin resistant (63% in 2005). The 21 to 30 age gr oup had the highest per cent resistant of the

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70 age groups (59% in 2005) followed by the 1 to 10 age group (57.5% in 2005) and the 31 to 40 age group (57% in 2005) (Figure 26). Number of Isolates For Each Age Category By Year For Skin and Soft Tissue Infections0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000< 0 1 to 10 1 1 t o 20 2 1 to 30 3 1 to 40 4 1 t o 50 5 1 to 60 6 1 t o 70 7 1 t o 80 8 1 to 90 > 9 0 MissingAge GroupNumber of Isolates 2003 2004 2005 Figure 25. Number of Isolates For Each Age Category By Year For Skin and Soft Tissue Infections

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71 Percent of Isolates That Were MRSA By Age Group By Year For Skin and Soft Tissue Infection0 10 20 30 40 50 60 70< 0 1 to 10 11 to 20 21 to 3 0 31 to 4 0 41 to 50 51 to 60 61 to 7 0 71 to 8 0 81 to 90 > 90 Mi s si n gAge GroupPercentage 2003 2004 2005 Figure 26. Percent of S. aureus Isolates That Were Methicillin Resistant By Age Group By Year Among Skin and Soft Tissue Infections. The odds ratios that were significant for th e crude analysis were also significant for the crude odds ratios that did not include those who were missing any variable. In the crude analysis those who were 1 to 10, 21 to 30, and 31 to 40 had a significantly higher risk and those who were 41 to 50, 51 to 60, 61 to 70, 71 to 80, and 81 to 90 had a significantly lower risk of methicillin resist ance than the reference category, the 11 to 20 age group (Table 11).

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72 Table 11. Crude Odds Ratios and 95% Confidence Interval For Each Age Group Compared to The Reference Group For Skin and Soft Tissue Infections. Age Category OR 95% CI <1 1.04 0.8771.23 1 to 10 1.17 1.091.25 11 to 20 Reference 21 to 30 1.25 1.161.35 31 to 40 1.15 1.071.23 41 to 50 1.04 0.971.11 51 to 60 0.87 0.820.94 61 to 70 0.73 0.670.79 71 to 80 0.8 0.740.87 81 to 90 0.84 0.770.92 >90 0.99 0.831.18 When adjusted for year, gender, and c ounty the 1 to 10, 21 to 30, and 31 to 40 age groups have a significantly higher risk of me thicillin resistance. Only the 61 to 70 age group has a significantly lower ri sk of methicillin resistance than the reference category for the adjusted odds ratios (OR= 0.83, 95% CI: 0.760.90). Table 12. Adjusted Odds Ratios and 95% Confidence Interval For Each Age Group Compared to The Reference Group For Skin and Soft Tissue Infections. Age Category OR 95% CI <1 0.98 0.821.17 1 to 10 1.21 1.121.31 11 to 20 Reference 21 to 30 1.16 1.061.26 31 to 40 1.15 1.061.24 41 to 50 1.06 0.981.14 51 to 60 0.93 0.861.01 61 to 70 0.83 0.760.90 71 to 80 0.94 0.861.02 81 to 90 0.96 0.871.06 >90 1.19 0.991.44

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73 In this subset the crude odds ratio for adult versus pediatric is 0.93, 95% CI: 0.890.97 and the crude odds ratio excluding thos e who were missing any variable is 0.88, 95% CI: 0.850.93. The adjusted odds ra tio is 0.95, 95% CI:0.911.00. Unlike the complete dataset in which adults had a significa ntly greater risk of methicillin resistance, in this subset adults have a lower, but significant risk of methicillin resistance. The percent of isolates that were methici llin resistant increased from year to year in all seven regions. The western panhandle (r egion 1), had the highe st resistance for all three years, 64.1% of isolates were resistan t in 2005. The southwest, region 6, had the lowest resistance for 2004 and 2005, 42.0% of is olates were resistant in 2005. For the missing category 59.0% were re sistant in 2005 (Figure 27).

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74 Percent of Isolates That Were MRSA By Region By Year For Skin and Soft Tissue Infections 0 20 40 60 80 100Wes t ern Panhandle Cen t r a l P anhadle N o r t hea s t West C e ntra l Eastern Cent ra l Sou t hwest Southeast MissingRegionPercentage 2003 2004 2005 Figure 27. Percent of S. aureus Isolates That Were Methic illin Resistant By Region By Year Among Skin and Soft Tissue Infections. The crude odds ratios for all the other regions were signifi cantly higher than region six, the reference category (Table 13). The crude odds ratios for the analysis excluding those with any missing variables we re similar to the crude odds ratios, the same counties were significantly higher than Miami-Dade county. The odds ratios for each region for the full model were also si milar to the crude odds ratios, all were significantly higher than region 6 (Table 14).

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75 Table 13. Crude Odds Ratios and 95% Confid ence Interval For Each Region For Skin and Soft Tissue Infections. Region OR 95% CI Western Panhandle 2.67 2.333.06 Central Panhandle 1.36 1.231.50 Northeast 1.81 1.652.00 West Central 1.58 1.451.71 Eastern Central 1.48 1.361.62 Southwest Reference Southeast 1.28 1.171.40 Table 14. Adjusted Odds Ratios and 95% Confidence Interval For Each Region For Skin and Soft Tissue Infections. Region OR 95% CI Western Panhandle 2.61 2.273.00 Central Panhandle 1.28 1.161.42 Northeast 1.77 1.611.95 West Central 1.62 1.491.77 Eastern Central 1.50 1.371.64 Southwest Reference Southeast 1.19 1.091.31 For the individual counties the number of isolates for each year ranged from 0 to 2,886 and the percent of isolates that were resistant ranged from 0% to 100%.

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76 Table 15. Percent of Isolates That Were MR SA and Total Number of Isolates For Each County By Year For Skin and Soft Tissue Infections. County Percent of Isolates Which Were MRSA (Total Number of Isolates) 2003 2004 2005 Alachua 33.3 % (27) 60.0% (65) 62.7% (212) Baker 0% (5) 62.5% (16) 72.4% (58) Bay 40.4% (57) 63.6% (33) 63.4% (101) Bradford 0% (1) 40.0% (10) 76.0% (25) Brevard 30.0% (243) 45. 5% (332) 52.2% (691) Broward 100% (1) 35.9% (1191) 46.1% (2412) Calhoun 40.0% (10) 50.0% (12) 64.3% (14) Charlotte 43.2% (44) 33.3% (45) 47.7% (130) Citrus 48.3% (29) 56.9% (65) 52.8% (123) Clay 35.3% (34) 40.0% (70) 61.2% (227) Collier 21.4% (14) 46.2% (26) 35.2% (71) Columbia 0% (6) 43.8% (16) 40.0% (45) DeSoto 50.0% (2) 28.6% (7) 33.3% (12) Dixie 75.0% (8) 63.6% (11) 54.5% (11) Duval 37.4% (369) 49.8% (605) 59.4% (1754) Escambia 71.2% (52) 69.6% (135) 73.6% (288) Flagler 60.0% (5) 14.3% (7) 48.6% (35) Franklin 0% (4) 65.2% (23) 61.8% (34) Gadsden 57.1% (14) 46.2% (13) 55.2% (29) Gilchrist 75.0% (8) 56.3% (16) 82.4% (17) Glades 0% (0) 0% (1) 20.0% (5) Gulf 60% (5) 61.5% (13) 77.1% (35) Hamilton 34.8% (23) 56.8% (37) 51.3% (76) Hardee 33.3% (30) 50.0% (32) 56.5% (85) Hendry 0% (4) 9.1% (11) 41.7% (48) Hernando 35.4% (79) 41. 5% (130) 52.8% (320) Highlands 55.5% (9) 41.2% (17) 44.0% (25) Hillsborough 36.8% (785) 46.0% (1016) 56.1% (2158) Holmes 33.3% (3) 0% (0) 0% (0) Indian River 22.7% (66) 46.2% (78) 45.1% (113) Jackson 25.0% (12) 40. 0% (5) 31.6% (19) Jefferson 20.0% (10) 50.0% (2) 53.3% (15) Lafayette 0% (1) 100% (2) 33.3% (3) Lake 26.35 (179) 43.0% (244) 45.2% (423) Lee 24.1% (203) 31.9% (310) 41.0% (788) Leon 34.8% (46) 44.6% (74) 58.9% (107) Levy 42.9% (14) 50.0% (28) 46.2% (39) Liberty 37.5% (8) 42. 9% (7) 71.4% (7) Madison 33.3% (12) 77.8% (9) 61.5% (13)

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77 (Table 15 Continued) Marion 33.9% (171) 43.3% (224) 50.7% (473) Martin 40.0% (5) 48.8% (82) 51.2% (205) Miami-Dade 0% (3) 36.8% (1151) 47.0% (2313) Monroe 0% (0) 37.9% (58) 49.6% (139) Nassau 38.2% (34) 50.0% (52) 52.7% (146) Okaloosa 52.2% (23) 64.3% (42) 56.6% (99) Okeechobe 25.0% (8) 60.0% (15) 56.4% (55) Orange 38.4% (524) 48.7% (748) 53.7% (1690) Osceola 32.5% (120) 48. 0% (204) 50.7% (402) Palm Beach 19.0% (21) 40. 5% (1194) 47.0% (2866) Pasco 36.6% (243) 42.8% (320) 49.9% (655) Pinellas 39.6% (556) 51.9% (696) 54.8% (1421) Polk 35.5% (318) 47.9% (365) 51.9% (729) Putnam 37.5% (16) 38.9% (18) 59.6% (47) Santa Rosa 85.7% (14) 60.3% (58) 60.3% (146) Sarasota 25.5% (157) 38.8% (209) 41.8% (469) Seminole 34.4% (186) 45.2% (263) 53.1% (610) St. Johns 36.1% (36) 41.7% (48) 44.0% (109) St. Lucie 34.2% (73) 38.4% (125) 50.9% (344) Sumter 45.2% (31) 31.1% (45) 46.7% (45) Suwannee 50.0% (4) 66.7% (6) 63.0% (27) Taylor 0% (0) 50.0% (6) 50.0% (16) Union 0% (2) 66.7% (6) 50.0% (14) Volusia 39.5% (153) 49.8% (261) 53.1% (603) Wakulla 18.2% (22) 66.7% (45) 68.6% (70) Walton 33.3% (6) 43.6% (39) 48.8% (80) Washington 0% (3) 50.0% (2) 66.7% (3) Missing 47.7% (859) 54.6% (1560) 59.0% (4711) For the county variable there is a diffe rence between the crude odds ratios and the adjusted odds ratios. The crude odds ratios a nd the crude odds ratios that did not include any patient with a missing variable were si milar, the same counties were significantly higher or lower than the refe rence county. For the crude odds ratios there were 24 counties that had a significantl y higher risk of me thicillin resistance than the reference county and there were 2 counties that had a si gnificantly lower risk than the reference county (Table 16). When adjusted for age gr oup, gender, and year there are 32 counties

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78 that had a significantly higher risk of methic illin resistance compar ed to the reference county and 2 counties that had a significantly lower risk of me thicillin resistance (Table 17). There were differences in significance fo r 10 of the counties between the crude and adjusted odds ratios. Sarasota county has a significantly lower risk for the crude odds ratio, but not in the adjusted. Hendry has a si gnificantly lower risk in the adjusted odds ratio, but not the crude. Brevard, Hardee, Hernando, Leon, Marion, Nassau, Osceola, and Pasco counties have a significantly higher risk of methicillin resistance when adjusted for year, gender, and age group, but not for the crude odds ratios. Table 16. Crude Odds Ratios For Each Count y For Skin and Soft Tissue Infections (Counties which had an OR that included one not shown). County Odds Ratio 95% CI County Odds Ratio95% CI Alachua 1.91 1.502.42 Lee 0.74 0.650.84 Baker 2.50 1.564.00 Manatee 1.25 1.081.44 Bay 1.69 1.262.26 Martin 1.31 1.041.67 Bradford 2.29 1.164.54 Ok aloosa 1.78 1.302.45 Citrus 1.49 1.131.96 Orange 1.28 1.161.41 Clay 1.53 1.221.91 Pinellas 1.34 1.211.49 Dixie 2.24 1.064.72 Polk 1.16 1.021.31 Duval 1.54 1.391.70 Santa Rosa 2.11 1.592.79 Escambia 3.37 2.734.16 Sarasota 0.79 0.680.93 Franklin 1.87 1.123.12 Seminole 1.19 1.041.37 Gilchrist 3.13 1.596.16 Suwannee 2.13 1.094.15 Gulf 3.28 1.805.99 Volusia 1.31 1.141.50 Hillsborough 1.28 1.171.40 Wakulla 1.93 1.362.74

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79 Table 17. Adjusted Odds Ratios For Each County For Skin and Soft Tissue Infections (Counties which had an OR that included one not shown). County Odds Ratio 95% CI County Odds Ratio 95% CI Alachua 1.89 1.482.40 Lee 0.79 0.690.90 Baker 2.53 1.574.08 Leon 1.38 1.051.82 Bay 1.95 1.452.62 Manatee 1.37 1.181.58 Bradford 2.11 1.064.21 Marion 1.25 1.071.46 Brevard 1.25 1.101.42 Martin 1.32 1.041.68 Citrus 1.63 1.242.16 Nassau 1.38 1.051.81 Clay 1.55 1.231.95 Okaloosa 1.997 1.452.76 Dixie 2.83 1.336.00 Orange 1.38 1.251.52 Duval 1.59 1.441.76 Osceola 1.27 1.081.50 Escambia 3.40 2.744. 21 Pasco 1.23 1.071.40 Franklin 2.01 1.193.40 Pinellas 1.51 1.371.68 Gilchrist 3.64 1.847.21 Polk 1.29 1.141.47 Gulf 3.46 1.866.42 Sant a Rosa 2.09 1.582.78 Hardee 1.41 1.011.97 Seminole 1.28 1.111.48 Hendry 0.58 0.340.997 Suwannee 2.18 1.114.29 Hernando 1.31 1.081.57 Volusia 1.42 1.231.63 Hillsborough 1.39 1.271.53 Wakulla 2.12 1.493.01

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80 Discussion Methicillin resistance in S. aureus has become a problem in the state of Florida. In 2005, 49.7% of all S. aureus isolates in this dataset were methicillin resistant. With nearly half of the 2005 S. aureus isolates having methicillin resistance, the -lactam antibiotics may no longer be the ideal choice for treating S. aureus infections in Florida. In this population, the percentage of MR SA isolates that were resistant to trimethoprim-sulfamethoxazole, tetracycline, ge ntamycin, and rifampin was low. These results are similar to previously reported susceptibilities (Nakamur a, Rohling, Shashaty, Lu, Tang, & Edwards, 2002; Sattler, Mason, & Kaplan 2002). These antibiotics may be viable alternatives to treat S. aureus infections in Florida. In 2005, 98% of the MRSA isolates and 99% of the MSSA isolates remained susceptible to trimethoprim-sulfamethoxazole. This antibiotic has oral and intravenous formulations, excellent oral bioavailability, has been used for decades, and is inexpensive (Ellis & Lewis, 2002). For tetracycline, 91% of the MRSA isolates and 95% of the MSSA isolates remained susceptible. Minocycline and doxycyclin e are two long acting tetracycline derivatives that al so have excellent bioavilability, are well absorbed by the gastrointestinal tract and are inexpensive. These two antibiotics may be possible alternatives for treating patients with less se rious infections (Ellis & Lewis, 2002; Ruhe, Monson, Bradsher, & Menon, 2005). Rifampin re sistance was less than 1% in both the

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81 MRSA and the MSSA groups. If used, rifampin should be used in combination with another antibiotic to treat S. aureus infections (Ellis & Lewis, 2002). The percent of isolates that were resist ant to clindamycin was 3% for the MSSA group and 14% for the MRSA in 2005. Howeve r, in isolates that are clindamycin susceptible and erythromycin resistant, cli ndamycin resistance can be induced (Kowalski et al., 2005). In 2005, 40% of the MSSA isol ates and 93% of the MRSA isolates were erythromycin resistant. For isolates that are susc eptible to clindamycin and erythromycin, clindamycin may be considered for treatment, but in isolates that are erythromycin resistant clindamycin should not be used unless a D-zone disk diffusion is performed to test for inducible clindamyci n resistance (Gemmell et al., 2006: Moran et al., 2006). A D-test is not ge nerally performed and in this population 40% of MSSA and 93% of MRSA isolates were erythromycin resistant. Due to a high prevalence of erythromycin resistance, clinda mycin may not an ideal choice for initial treatment in this population. There were 25 isolates with a reported resistance to vancomycin, however the Vitek system that was used to asses antib iotic resistance may give false positives for vancomycin (Raney, Williams, McGowan, and Tenove r, 2002). It is believed this is what happened with these isolates and that all isolates were susceptible to vancomycin; however, the non-availability of an oral formulation of any glycopeptide may limit their use in outpatient populations (Gemmell et al., 2006). There was an increase in the number of isol ates over the three years in the dataset. For each increase in year the number of isol ates doubled, from 8,286 isolates in 2003 to 16,980 isolates in 2004 to 35,946 isolates in 2005 This may be due to a number of

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82 factors. There may be an act ual increase in the number of S. aureus infections. The increase in the number of isolates may also be due to other factors such as an increase in cultures being obtained from patients or the lab company’ s market share may have increased during this time period. This may al so be due to a combination of an increase in infections and physician aw areness. There was also an increase in the percent of isolates that were methicillin resistant ove r the three years. This measure may be less susceptible to other extraneous variables causi ng a change than the number of isolates. It is expected that if more cultures were obtai ned or the lab was receiving more isolates to test, that the number of MSSA and MRSA isolates would both increase and the percentage of methicillin resist ance would not be affected. The increase in methicillin resistant isolates over the three years was significant. When treated as a categorical variable, the odds ratio for 2004 compared to 2003 was 1.31, 95% CI: 1.241.38 and the odds ratio for 2005 compared to 2003 was 1.82, 95% CI: 1.731.91. In this population the odds that an isolate was methicillin resistant in 2004 was 1.3 times the odds of an isolate being methicillin resistant in 2003 and the odds that an isolate was methicillin resistant in 2005 was 1.8 times the odds of an isolate being methicillin resistant in 2003. When treated as a continuous variable, the odds of an isolate being methicillin resistant increases by 36% for each year(OR= 1.36, 95% CI: 1.331.39). When adjusted for age group, ge nder, and county the odds of an isolate being methicillin resistant increases by 45% for each year (OR= 1.45, 95% CI: 1.411.48). For the analysis of only skin and soft tissu e infections the percent of isolates that were methicillin resistant was slightly higher th an for the entire dataset, 52.7% of isolates

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83 were resistant in 2005. The odds that an is olate was methicillin resistant in 2004 was 1.40 times the odds of an isolate being resi stant in 2003 and the odds of resistance in 2005 was 1.87 times the odds of being resistan t in 2005. When treated as a continuous variable and adjusted for gender, age, and c ounty the odds of an isolate being methicillin resistant increases by 40% per year. This is a slower increase than for the full dataset, but the skin and soft tissue subset had a highe r percent of methicillin resistance in 2003. For age category, the percent of isolates which were methicillin resistant increases with increasing age group to the 21 to 30 year olds, then decreases with increasing age group to the 61 to 70 year old age group, th en increases with increasing age. The difference between the age group with the highe st resistance, 21 to 30 year olds, and the age group with the lowest resistance, those le ss than 1, was 11%. While some of the age groups had a significantly higher ri sk of methicillin resistance compared to the reference category, there was not a large difference in the percent of isolates that were methicillin resistant between the age groups. Only 1.5% of the total isolates were missing data on age and missing values is not likely to have had a significant impact on the results. For the skin and soft tissue analysis, the pe rcent of isolates that were resistant in 2005 were different than for the full dataset. In both datasets the missing category had the highest percent of isolates that were me thicillin resistant and the 21 to 30 age group had the highest of the age groups. In the fu ll dataset the greater th en 90 category had the second highest percent resistant (50% in 2005) followed by the 31 to 40 age group (49% in 2005). In the skin and soft tissue subset the 1 to 10 age group had the second highest percent resistant (58% in 2005) followed by the 31 to 40 age group (57% in 2005). The

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84 same trend of increasing with age to the 21 to 30 age group then decreasing to the 61 to 70 age group then increasing again is seen in both datasets. For the skin and soft tissue isolates the di fference in the percent of isolates that were resistant between the age group with th e highest percent resist ant and the group with the lowest percent resistant was 15%. In skin and soft tissue infections physicians may need to consider the age of the patient as those who were 61 to 90 had a lower percent of isolates that were resistant than the other age groups. The odds ratios for age group for the crude and adjusted analysis were different between the two datasets. For the adjusted odds ratios in th e full dataset the less than 1 age group had a significantly lo wer risk of methicillin resi stance and the older age groups (21 to 50 and 71 and older) were at significantly higher risk of methicillin resistance than the reference group. In the skin and soft ti ssue subset the younger age groups (1 to 10 and 21 to 40) had a significantly higher risk of methicillin resistance and the 61 to 70 age group had a significantly lower risk of methicillin resistance. This difference may be due to a difference in risk factors between all S. aureus infections and skin and soft tissue infections. For the full dataset adults had a significantly higher risk of methicillin resistance compared to those under 18. There was only a sm all difference in the percent of isolates that were methicillin resistant between adults and children. The difference in the percent of isolates that were methicillin resistant was 5.8 in 2003, 8.6 in 2004, and 2.4 in 2005. For the skin and soft tissue infections adu lts had a lower but not significant risk of methicillin resistance, OR= 0.95, 95% CI: 0.910.995.

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85 Females had a slightly higher risk of me thicillin resistance than males in this population, adjusted OR=1.05, 95% CI: 1.011.08. However, the 95% confidence interval was just slig htly above one and with such a large dataset even the smallest difference can be significant. With 49.0% of isolates resistant for males and 50.2% for females in 2005 there is not a large difference in methicillin resistan ce between the sexes. Only 1% difference is not clinically signifi cant. For gender only 1.3% of the isolates were missing data on gender and is not likely to have an impact on the results. The results for the skin and soft tissue analysis were similar to that of the entire dataset. Females had a slight, but significantly higher ri sk of methicillin resistance, however the difference in the percent between ma les and females in 2005 was only 2.2% While there were some differences in meth icillin resistance w ith regards to both age and gender, the differences were not substa ntial for the entire dataset. Only in the skin and soft tissue analysis was methicillin resistance different depending on age. Age may need to be considered in making initial treatment decisions for skin and soft tissue infections. The number of isolates varied greatly by region, but the population of the regions varies as well. It is expe cted that regions with a smaller population will have fewer isolates. There were a large number of is olates that were missing data on region and county, 14.2% of the total number of isolates This number of missing isolates could have an impact on the results if those who are missing county are not equally distributed among the explanatory variables or methicillin resistance. The percent of isolates that were methicillin resistant varied by region of the state. The region with the highest percent resist ance, the western pa nhandle (region 1), was

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86 22% higher than the region with the lowest re sistance, the southwest (region 6). In the western panhandle there is a much greater chance that an S. aureus isolate is methicillin resistant then in the central panhandle (regi on 2) and the southwest. The odds ratio for region the western panhandle compared to the southwest is 2.50, 95% CI: 2.202.83. The odds of an isolate being methicillin resi stant in region the western panhandle was 2.5 times greater than that of region the southwest. The skin and soft tissue subset was comparab le to the entire dataset. The percent of isolates that were methicillin resistant was similar for the seven regions. For the skin and soft tissue analysis, all the regions had a significantly higher risk of methicillin resistance compared to southwest. In the entire dataset however, the central panhandle and the southeast were not signifi cantly different than southwest. Geographic area was further divided into c ounty. The number of isolates for each county ranged from 4 isolates in Holmes to 5,486 in Palm Beach. There are differences in the populations of the 67 counties and the la rger counties are expected to have more isolates (Appendix 1). In 2005, the percentage of isolates that were methicillin re sistant varied from 20% to 75% among the counties. However, so me of the counties had a small number of isolates. Glades County had the lowest resi stance in 2005 (20%), but there were only 5 isolates from this county. Gulf County ha d the highest percent of resistant isolates (75%), but there were only 40 isolates. In counties with small numbers of isolates, it is likely that there will be more random variation then in the counties with larger numbers of isolates. The smaller counties may have few providers that use the lab company which provided the data, which could have influenced sampling in these counties. The very

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87 high or low percentage of me thicillin resistance could be due to random variation or sampling variations in some counties, particular ly those with small numbers of isolates. There were some counties with a high per centage of MRSA that did have larger numbers of isolates. In Alachua county, 62.6% of the 246 isolates were methicillin resistant. In Escambia county, 71.0% of the 335 isolates were methicillin resistant. In counties such as Alachua, Baker, Bay, Bradfor d, Clay, and Franklin, where the percent of isolates that were methicillin resistant was gr eater than 60%, there is a 60% chance that if a -lactam antibiotic is used as first line thera py it will be ineffective. In Escambia and Gulf counties there is a 70% chance that the infection will be resistant to a -lactam antibiotic. For most of the counties the percen t of isolates that were resistant was in the 40% to 50% range. In 35 of the 67 counties (52%), the percent of isolates that were methicillin resistant was 50% or greater. Meth icillin resistance is a problem in all the counties and clinicians in Florida need to be aware of methicillin resistance and consider it when deciding on treatment options. For the skin and soft tissue dataset ther e were fewer counties (16) that were significantly different than the reference c ounty. Unlike the entire dataset in which all the counties that were significantly different ha d a higher risk of meth icillin resistance, in the skin and soft tissue analysis there were two counties that had a significantly lower risk of methicillin resistance when adjusted for age, gender, and year (Hendry and Lee Counties). In the full dataset Lee was signi ficantly higher than th e reference county and Hendry was not significantly different. In th is subset the number of isolates for each county ranged from 0 to 2,886 and the percent th at were methicillin ranged from 0% to 100%. The counties with 0% and 100% had very few isolates (1 to 5). Some counties

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88 with a high percentage of MR SA had larger number of isolates. In Alachua, Bay, Clay, and Santa Rosa greater than 60% of the 100 or more isolates were methicillin resistant. Like region, there were 14.2% of isolates that were missing data on county. This could cause a bias and have an impact on the results if not evenly distributed between the counties and methicillin resistance. As part of secondary analysis, data on source of infection and whether isolates had a USA300/USA400 type suscep tibility profile were also examined. Most of the isolates in the full dataset were from skin and soft tissue infecti ons, nearly 80%. Among the different sources, the percent that were re sistant to methicillin varied. The difference in the percent resistant between the highest re sistance, skin and soft tissue infections, and the lowest resistance, respiratory infections, was 28%. This indicates that there could be a difference in the percent of methicillin resistance depending on the source of the infection and this should also be taken into account when deciding on antibiotic therapy. The USA300/USA400 type of isolate is associated with community acquired MRSA. In this dataset there were few isolates that had this type of antibiogram. Of the nine sources, skin and soft tissue isolat es had the highest pe rcent of USA300/USA400 type isolates, 38.7% in 2005. For all sources there was an increas e in the percent of isolates that had a USA300/USA400 type antibiogram, pot entially indicating an increase in CA-MRSA. In this analysis PFGE was not performed, therefore it is uncertain whether these isolat es actually were USA300/USA400 strains. Li et al. (2005b) used statewide, populati on-based antimicrobial susceptibility test data collected from both outpatients and i npatients in Hawaii from 2000 to 2002. They included 31,482 isolates of S. aureus in the analysis, of which 23,550 were from

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89 outpatients. In their dataset, the proportion of MR SA was much lower than in the current study, 22% for outpatients and 39% for inpatient s. As in the current study they also found a significant increase in the proportion of MRSA during their 3-year study period. Most of the outpatient MRSA isolates were from skin and soft tissue infections. Among pediatric outpatients 95% MRSA isolates were from wounds and among the adult outpatients 80% were from wounds. In the current study 79.6% of all isolates were classified as skin and soft tissue infections. Moran et al (2006) performed a prospec tive prevalence study of adult patients who presented to hospitals in the EMERGE ncy ID Net in August of 2004. Of the 320 S. aureus skin and soft tissue infections, 78% were methicillin resistant. All patients were seen in an emergency department. Am ong this population 49% of patients were nonHispanic black, 25% were non-Hispanic white 22% were Hispanic, and 4% were other races. This population of ER patients may not be indicative of the entire population of the United States. This is the first study to use a large ou tpatient dataset to asses methicillin resistance in Florida. Many previous studi es have been conducted on patients in the hospital. These two populations may not be the same. Patients in the hospital may be different than patients attending outpatient clinics. Those in the hospital may have more severe S. aureus infections, co-morbid conditions, diffe rent risk factors for methicillin resistance, and differe nt demographics. The prevalence of MRSA also varies w ith geographic region (Nakamura et al., 2002). There have been no previous studies of S. aureus conducted in Florida and one cannot generalize rates from one area to anothe r. For physicians tr eating outpatients in

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90 Florida, data from this study may be more appropriate for basing treatment decisions on because previous studies used different popul ations in different geographical areas and this is the most recent data. There are several limitations to this study. First, data on other factors such as race, economic status, and known risk factors fo r methicillin resistance was not collected by the laboratory that conducte d the resistance testing. Th erefore these variables were not in the dataset and could not be included in the analysis. There is the possibility that potential confounding factors and other risk factors not includ ed in the dataset could be causing the associations between year, age, gender, region, and county. Second, there were some patients in the dataset that were missing information on the exposure or outcome variables. In the complete regres sion model, there were 9,643 observations that were excluded because they were missing one or more variables. This still leaves 51,953 isolates for analysis, but if those who were missing data differed from those who were not then the results may not accurately reflect the true associations in this population. There is also the possibility of da ta entry error on the part of the lab company. There were some sources recorded which made no sense and must have been typed wrong. There is the possibility that this also occurred with ot her variables. However, it is unlikely that this would have occurred differentially among the patients and led to a bias. This was also a laboratory only analysis. This population may not represen t everyone in the state. Further studies are needed to assess other explanatory variables such as known risk factors (prolonged hospitalization, care in an intensive care unit, prolonged antimicrobial therapy, surgical procedures, di alysis, presence of an indwelling catheter, use of injectable drugs, residence in a nursing home or long term care facility, and close

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91 proximity to a patient in the hospital who is infected or colonized with MRSA), race, and economic status (Salgado, Farr, & Calfee, 2003; Li et al., 2005b). The changing resistance rates from 2003 to 2005 indicate that studies need to be done periodically to keep up with changes in resistance rates over time.

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92 References Abramson, M. A. & Sexton, D. J. (1999). Nosocomial Methicillin Resistant and Methicillin Susceptible Staphylococcus aureus Primary Bacteremia: At What Costs? Infection Control and Hosp ital Epidemiology, 20, 408411. Anstead, G. M. & Owens, A. D. (2004). Recen t Advances in the Trea tment of Infections Due to Staphylococcus aureus. Current Opinion in Infectious Disease s, 17(6), 549555. Applebaum, P. C. (2006a). The Emer gence of Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus. Clinical Microbiolical Infections, 12, S16S23. Applebaum, P.C. (2006b) MRSAthe Tip of the Iceberg. Clinical Microbiolical Infections, 12, S3S10. Baggett, H. C., Hennessy, T. W., Leman, R., Hamlin, C., Bruden, D., Reasonover, A., et al. (2003). An Outbreak of Commu nity-Onset Methicillin-Resistant Staphylococcus aureus Skin Infections in Southwestern Alaska. Infection Control and Hospital Epidemiology 24 (6), 397402. Barrett, T. W., & Moran, G. J. (2004). News From the Centers for Disease Control and Prevention. Annals of Emergency Medicine 43 (1), 43-45. BEBR 4/1/2005 Population for Counties and Municipalities for Revenue Sharing. Retrieved July 16, 2006 from the World wide Web: http://edr.state.f l.us/population.htm

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93 Begier, E. M., Frenette, K., Barrett, N. L., Mshar, P. Petit, S., Boxrud, et al.. (2004). A High-Morbidity Outbreak of Methicillin-Resistant Staphylococcus aureus Among Players on College Football Team, Facilita ted by Cosmetic Body Shaving and Turf Burns. Clinical Infectious Diseases, 39, 14461453. Blot, S I., Vandewoude, K. H., Hoste, E. A ., & Colardyn, F. A. (2002). Outcome and Attributable Mortality in Cr itically Ill Patients with Bact eremia Involving MethicillinSusceptible and Methicillin-Resistant Staphylococcus aureus. Archives of Internal Medicine 162. 22292235. Buescher, E. S. (2005). Commun ity-Acquired Methicillin-Resistant Staphylococcus aureus in Pediatrics. Current Opinion in Pediatrics 17 (1), 6770. Chambers, H. F. (2001). The Changing Epidemiology of Staphylococcus aureus ? Emerging Infectious Diseases, 7 (2), 178-182. Charlebois, E. D., Perdreau-Remington, F., Kr eiswirth, B., Bangsberg, D. R., Ciccarone, D., Diep, et al. (2004). Origins of Community Strains of Methicillin-Resistant Staphylococcus aureus Clinical Infectious Diseases, 39, 47-54. Conterno, L. O., Wey, S. B., & Castelo, A. (1998) Risk Factors for Mortality in Staphylococcus aureus Bacteremia. In Cotterill, S., Evans, R., & Fraise, A. P. ( 1996). An Unusual Source for an Outbreak of Methicillin-Resistant Staphylococcus aureus on an Intensive Therapy Unit. Journal of Hospital Infection 32, 207216.

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94 Creech, C. B., Kernodle, D. S., Douglas, S., Al sentzer, A., Wilson, C., & Edwards, K. M. (2005). Increasing Rates of Nasal Carriage of Methic illin-Resistant Staphylococcus aureus in Healthy Children. The Pediatric Infectious Disease Journal, 24 (7), 617621. Daum, R. S. & Seal, J. B.. Evol ving Antimicrobial Chemotherapy for Staphylococcus aureus Infections : Our Backs to the Wall. Critical Care Medicine 29 (4), N9296. Diekema, D. J., BootsMiller, B. J., Vaughn, T. E., Woolson, R. F., Yankey, J. W., Ernst, E. J., et al. (2004). Antimicrobial Resist ance Trends and Outbreak Frequency in the United States Hospitals. Clinical Infectious Diseases, 38 7885. Diekema, D. J., Pfaller, M. A., Schmitz, F. J., Smayevsky, J., Bell, J., Jones, R. N., et al. (2001). Survey of Infections Due to Staphylococcus aureus : Frequency of Occurrence and Antimicrobial Susceptibility of Isolates Collected in the United States, Canada, Latin America, Europe, and the West ern Pacific Region for the SENTRY Antimicrobial Surveillance Program, 19971999. Clinical Infectious Diseases, 32 S114S132. Ellis, M. W., & Lewis, J. S. (2002). Tr eatment Approaches for Community-Acquired Methicillin-Resistant Staphylococcus aureus Infections. Current Opinion In Infectious Disease, 18 (6), 496501. Ellis, M. W., Hospenthal, D. R., Dooley, D. P., Gray, P. J., & Murray, C. K.. (2004). Natural History of Community-Acquired Methicillin-Resistant Staphylococcus aureus Colonization and Infection in Soldiers. Clinical Infectious Diseases 39 971-979.

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103 Appendix 1

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104 Appendix 1 A-1. Estimated April 1, 2005 Population For the Counties In Florida Based on the 2000 Census (BEBR 4/1/2005 Population for Counties, n.d.). County Estimated PopulationCounty Estimated Population ALACHUA 240,764 LEE 549,442 BAKER 23,953 LEON 271,111 BAY 161,721 LEVY 37,985 BRADFORD 28,118 LIBERTY 7,581 BREVARD 531,970 MADISON 19,696 BROWARD 1,740,987 MANATEE 304,364 CALHOUN 13,945 MARION 304,926 CHARLOTTE 154,030 MARTIN 141,059 CITRUS 132,635 MIAM I-DADE 2,422,075 CLAY 169,623 MONROE 82,413 COLLIER 317,788 NASSAU 65,759 COLUMBIA 61,466 OKALOOSA 188,939 DE SOTO 32,606 OKEECHOBEE 37,765 DIXIE 15,377 ORANGE 1,043,437 DUVAL 861,150 OSCEOLA 235,156 ESCAMBIA 303,623 PALM BEACH 1,265,900 FLAGLER 78,617 PASCO 406,898 FRANKLIN 10,845 PINELLAS 947,744 GADSDEN 47,713 POLK 541,840 GILCHRIST 16,221 PUTNAM 73,764 GLADES 10,729 ST. JOHNS 157,278 GULF 16,479 ST. LUCIE 240,039 HAMILTON 14,315 SANTA ROSA 136,443 HARDEE 27,333 SARASOTA 367,867 HENDRY 38,376 SEMINOLE 411,744 HERNANDO 150,784 SUMTER 74,052 HIGHLANDS 93,456 SUWANNEE 38,174 HILLSBOROUGH 1,131,546 TAYLOR 21,310 HOLMES 19,157 UNION 15,046 INDIAN RIVER 130,043 VOLUSIA 494,649 JACKSON 49,691 WAKULLA 26,867 JEFFERSON 14,233 WALTON 53,525 LAFAYETTE 7,971 WASHINGTON 23,097 LAKE 263,017 FLORIDA 17,918,227

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105 A-2. Estimated April 1, 2005 Population For th e Seven Regions of Florida Based on the 2000 Census. (BEBR 4/1/2005 Population for Counties, n.d.). Region Estimated Population 1 966,620 2 556,659 3 2,073,204 4 3,717,196 5 3,491,114 6 1,602,059 7 5,511,375