Overview of literature around the following emerging and re-emerging infectious diseases relevant to Canadian Emergency Physicians in terms of their epidemiology, recognition, and treatment: - Community-acquired MRSA - Non-vaccine serotype Pneumococcus - Fusobacterium Necrophorum

1. Emerging and Re-emerging
Infectious Diseases
Farooq Khan MDCM
PGY2 FRCP-EM McGill
October 27th 2010

2. Objectives
• Sensitize ED community about 3 new disease
entities
• Special focus on community acquired MRSA
• Challenge some of the dogma in current
infectious disease practice

3. Outline
• Community Acquired MRSA
• Non-vaccine serotype Pneumococcus
• Fusobacterium Necrophorum

4. Community Acquired Methicillin
Resistant Staphylococcus Aureus
Skin and Soft Tissue Infections

5. History
• 1947 – strains of staph aureus noted to be
resistant to penicillin
• 1961 – MRSA isolated
• 1980s – nosocomial MRSA a major problem in
ICUs, now resistant to β-lactams, clindamycin,
erythromycin, gentamicin, quinilones,
trimethoprim
• 2000s – incidence of nosocomial MRSA infection
doubles (22% to 57%) compared to 1990s

6. Emergence of CA-MRSA
• Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired
methicillin resistant Staphylococcus aureus in children with no
identified predisposing risk. JAMA 1998;279:593-598
– Retrospective chart review
– Spike in the number of MRSA cases in children in
Chicago hospitals between 1988-1990 and 1993-95
– 25x increase in those with no links to healthcare
• Daum et al. 2002
– Confirmed unique strain separate from nosocomial
MRSA containing the SCCmecIV cassette

7. Prevalence of CA-MRSA skin and soft
tissue infections
• Moran et al. 2005
– Prospective sample of ED patients at UCLA Medical Center
– Prevalence of MRSA skin infections rose from 29% to 64% from
2001-02 to 2003-04
– Molecular fingerprinting different from the hospital strain
• Frazee et al. 2005
– Prospective sample of ED patients in UCSF Oakland
– 51% prevalence of MRSA in skin infections
– 99% of MRSA isolates possessed the SCCmecIV cassette
• King et al. 2006
– Prospective lab surveillance at Grady Memorial in Atlanta
– 72% of staph infections were MRSA
– 87% of MRSA infections were CA-MRSA

8. Prevalence
• Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-
resistant S. aureus infections among patients in the
emergency department. N Engl J Med. 2006;355:666-674.
– Prospective prevalence study of university affiliated EDs in 11 US
cities.
– 59% prevalence of MRSA in skin infections
– 97% were CA-MRSA
– 74% were single dominant strain
– 57% had been given inappropriate Abx prior to presentation to
ED
• Canadian epidemiology is mirroring that of the US
– Mulvey et al. 2005

9. Challenges in recognition
• Epidemiological risk factors
for CA-MRSA
– Day care children
– High school and professional
athletes
– Soldiers
– Aboriginals
– Sauna/bathhouse/sex club
users
– Jail inmates
– Injection drug users
– Homeless
– MSM
• Clinical risk factors for CA-
MRSA
– More severe purulent skin
infections
– Multiple skin and soft tissue
infections
– Previous failure of beta
lactams
– Known colonization
– Severe invasive infections
• Severe pneumonia
• Empyema
• Nec. fasc.
• Pyomyositis
• Osteomyelitis
• Septic arthritis

10. Challenges in recognition
• Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and
epidemiologic characteristics cannot distinguish community-
associated methicillin-resistant Staphylococcus aureus
infection from methicillin-susceptible S. aureus infection: a
prospective investigation. Clin Infect Dis. 2007;44:471-482.
– Prospectively enrolled 108 MRSA and 78 MSSA
patients at UCLA to compare risk factors
– Could not reliably use clinical and epidemiological
risk factors to distinguish between 2 groups
– BOTTOM LINE: Anyone can get CA-MRSA

11. Challenges in treatment
Nicolle L. Community-acquired MRSA: a practitioner's guide. CMAJ. 2006;175(2):145-

12. Challenges in treatment
• Strategies for Clinical Management of MRSA in
the Community: Summary of an Experts’
Meeting Convened by the Centers for Disease
Control and Prevention. 2006.
– No consensus on first choice, regimen or
combination use
– Lack of evidence on old off-patent drugs
– Studies pending

13. Challenges in treatment
• Who should get treatment?
• Are current guidelines recommending
treatment only patients with clinical and
epidemiological risk factors justified?
• CA-MRSA is also known to express the Panton-
Valentine leukocidin gene, a postulated
virulence factor

14. Challenges in treatment
• Klevens RM, Morrison MA, Nadle J, et al.
Invasive methicillin resistant Staphylococcus
aureus infections in the United States. JAMA.
2007;298:1763-1771.
– Active surveillance of 9 US communities in 2005
– Incidence of invasive MRSA was 31.8 per 100 000
– Of which 13.7% were community-associated
– Overall mortality rate was 6.3 per 100 000 (i.e.
higher than mortality of HIV/AIDS that year)

15. Challenges in treatment
• Pallin D, Egan DJ, Palletier AJ, et al. Increased U.S.
Emergency department visits for skin infections and
changes in antibiotic choices during the community-
associated MRSA epidemic. Ann Emerg Med.
2008;51:291-298
– Population surveillance data from NHAMCS
– Increase in number of ED visits due to CA-MRSA
emergence independent of increasing public awareness
and rising numbers of uninsured patients
– No concomitant increase in admission rate or attributable
mortality compared to MSSA
– However still translates to 200 000 – 300 000 additional
admissions/year due simply to increased incidence

16. Challenge the dogma
• MRSA is increasingly prevalent in the community
• CA-MRSA ≠ Hospital MRSA
• Anyone can get CA-MRSA (risk factors play a limited
role)
• Purulent skin infections are most likely CA-MRSA until
proven otherwise
• More aggressive surveillance is still needed
• Keflex should probably no longer be the go-to drug for
skin/soft tissue infections
• More aggressive empiric therapy of outpatient
skin/soft tissue infections is probably warranted

17. Non-Vaccine Serotype
Multi-drug Resistant
Streptococcus Pneumoniae
Invasive Pneumococcal Disease

18. History
• 2000 - Whitney et al. Report in NEJM increasing prevalence
of invasive pneumococcal disease (IPD) with multidrug
resistance in 1998 in US
• 2002 – Health Canada approves PCV7 (Prevnar) for routine
use in children <5 to reduce the incidence of 7
predominant serotypes
• Prevnar recommended for
– Children < 5 years, especially those <2 years and the elderly
– Children enrolled in daycare
– Children living in aboriginal populations
– Children with underlying medical conditions
– HIV-infected children
– Children with functional or anatomic asplenia

19. Since vaccine introduction
• Several studies show dramatic decrease in
IPD, greater than anticipated due to herd
immunity
• Kyaw et al. 2006
– IPD due to vaccine serotypes drops by 87% from
1999 to 2004
– Overall Pen-resistant and MDR IPD drops by 60%
• Hsu et al. 2009
– Meningitis due to PCV7 serotypes drops by 70%
– Overall incidence decreased by 30%

20. Emergence of Non-Vaccine Serotype
• IPD in
adults >65
Hicks Lauri A, Harrison Lee H, Flannery B, Hadler James L, Schaffner W, Craig Allen S, et al.
Incidence of Pneumococcal Disease Due to Non–Pneumococcal Conjugate Vaccine (PCV7)
Serotypes in the United States during the Era of Widespread PCV7 Vaccination, 1998–
2004. The Journal of Infectious Diseases. 2007;196(9):1346-54

21. Emergence of Non-Vaccine Serotype
• IPD in
children <5
Hicks Lauri A, Harrison Lee H, Flannery B, Hadler James L, Schaffner W, Craig Allen S, et al.
Incidence of Pneumococcal Disease Due to Non–Pneumococcal Conjugate Vaccine (PCV7)
Serotypes in the United States during the Era of Widespread PCV7 Vaccination, 1998–
2004. The Journal of Infectious Diseases. 2007;196(9):1346-54

22. Increasing prevalence and resistance
of NVS Strep
• Several studies describe increasing incidences of
NVS, including serotypes 19A and 6A in US and Europe
– Moore et al. 2005
– Pichichero et al. 2007
– Muñoz‐Almagro et al. 2008
• More studies found increasing rates of MDR in these
serotypes
– Farrell et al. 2007
• One study found that in Alaskan native children, MDR
NVS IPD rates were increasing to approach pre-vaccine
levels
– Singleton et al. 2007

23. Should we be worried?
• Alanee SRJ, McGee L, Jackson D, Chiou CC, Feldman C, Morris AJ, et
al. Association of Serotypes of Streptococcus pneumoniae with
Disease Severity and Outcome in Adults: An International Study.
Clinical Infectious Diseases. 2007;45(1):46-51
– Prospective sample of 796 patients with IPD from
10 different countries
– Effect of serotype not significant on disease
severity and associated mortality
– Effect of host factors more important
• Age, chronic disease, immune suppression etc.

24. Bottom line
• IPD is still around and may become an increasing
problem despite routine PCV7
• Ongoing surveillance is needed
• Current practice of Ceftriaxone/Cefotaxime and
high dose Vancomycin is still warranted
• If IPD rates increase again, yield of blood cultures
may rise and routine blood cultures in febrile
infants <36 months may be warranted
• Prevnar13 (including 19A and 6A) was approved
for routine use by Health Canada in Jan 2010

25. Fusobacterium Necrophorum
Lemierre’s Syndrome: The forgotten disease
The new sore throat paradigm

26. History
• 1936 - Lemierre describes syndrome of anaerobic
septicemia and death following throat infections
in 20 adolescents
– Characterized by thrombophlebitis of the internal
jugular vein due to Fusobacterium necrophorum
– Followed by bacteremia and metastatic infections
– 90% mortality rate

27. History
• 1940s – 1990s - Lemierre’s syndrome largely
forgotten due to the discovery of penicillin
and a massive drop in incidence
• 2000s - Resurgence in cases of LS at children’s
hospitals in Wisconsin
– Ramirez et al. 2003

28. LS pathophysiology
– Pharyngitis caused by F. Necrophorum or primary
throat infection by another organism leads to
colonization by F. Necrophorum
– Spreads to parapharyngeal space invading blood
vessels and causing IJ thrombus
– Can lead to rapid dissemination of septic
microemboli to lung, joints, intraabdominal organs
and CNS
– Toxin production leads to sepsis and DIC

29. Karkos PD, Asrani S, Karkos CD, Leong SC, Theochari EG, Alexopoulou TD, et al.
Lemierre's syndrome: A systematic review. The Laryngoscope. 2009;119(8):1552-9.

30. Karkos PD, Asrani S, Karkos CD, Leong SC, Theochari EG, Alexopoulou TD, et al.
Lemierre's syndrome: A systematic review. The Laryngoscope. 2009;119(8):1552-9.
LS clinical presentation

31. LS Clinical Evolution
• Begins as tonsillitis in adolescents
• Can improve initially
• Rigors, toxic appearance and bacteremic by
day 3 - 4
• Suppurative IJ thrombophlebitis
• Lung abscesses, pleural effusions
• Disseminated infection

32. LS Outcomes
• Currently mortality estimate 4.6% [95% CI 2.6-
7.3%]
• In most recent case series of 37 patients in
Denmark
– 11 patients required ICU
– 7 were intubated
– 16 required abscess drainage
– 1 patient died
– 3 had permanent sequelae (10.2% [95% CI 2.1-22%] )

33. Epidemiology
• F. Necrophorum causes endemic pharyngitis in
adolescents and young adults (16-30) with an
incidence of 10% (equal to group A strep)
– Amess et al. 2007
– Batty et al. 2005
• Only one prospective study on the incidence of
Lemierre’s syndrome (14.4 per 1000000 adolescents)
– Hagelskjaer Kristensen et al. 2008
• Can estimate that 1 in 400 cases of F. Necrophorum
pharyngitis can lead to Lemierre’s syndrome

34. Is that significant?
Centor RM. Expand the Pharyngitis Paradigm for Adolescents and Young Adults. Annals of
Internal Medicine. 2009;151(11):812-5.

35. Challenge the dogma
• Current guidelines for pharyngitis: look for strep and avoid
antibiotics otherwise (Guidelines differ on empirical
treatment vs. culture guided treatment)
• Rapid strep test alone is probably not sufficient and
additional anaerobic culture may be required
• Red flags
– Symptoms do not resolve in 3-5 days
– Symptoms rapidly worsen
– Unilateral neck swelling
• Consider empiric treatment despite rapid strep test
negative with penicillin/cephalosporin (no macrolides)
• Consider empiric treatment if bacteremic symptoms with
penicillin/flagyl or clindamycin

36. References
• Maryn M. The Many Faces of MRSA: Community-Acquired Infection Knows No
Bounds. Annals of emergency medicine. 2008;51(3):285-8.
• Barber M. Staphylococcal infection due to penicillin-resistant strains. BMJ.
1947;863-865.
• Jevons M. “Celbenin”-resistant staphylococci. BMJ. 1961:124-125
• Locksley RM, Cohen ML, Quinn TC, et al. Multiply antibiotic-resistant
Staphylococcus aureus: introduction, transmission, and evolution of nosocomial
infection. Ann Intern Med. 1982;97:317-324
• Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in
US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance
study. Clin Infect Dis. 2004;39:309-317
• Daum RS, Ito T, Hiramatsu K, et al. A novel methicillin-resistance cassette in
community-acquired methicillin-resistant Staphylococcus aureus isolates of diverse
genetic backgrounds. J Infect Dis. 2002;186:1344-1347
• Moran GJ, Amii RN, Abrahamian FM, et al. Methicillin-resistant Staphylococcus
aureus in community-acquired skin infections. Emerg Infect Dis. 2005;11: 928-930
• Frazee BW, Lynn J, Charlebois ED, et al. High prevalence of methicillin-resistant
Staphylococcus aureus in emergency department skin and soft tissue infections.
Ann Emerg Med. 2005;45: 311-320
• King MD, Humphrey BJ, Wang YF, et al. Emergence of community-acquired
methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant
cause of skin and soft tissue infections. Ann Intern Med. 2006;144:309-317

37. References
• Mulvey MR, MacDougall L, Cholin B, et al; Saskatchewan CA-MRSA Study Group. Community
associated methicillin-resistant Staphylococcus aureus, Canada. Emerg Infect Dis 2005;11:844-50
• Shahin R, Johnson IL, Jamieson F, et al. Methicillin-resistant Staphylococcus aureus carriage in a
child care center following a case of disease. Toronto Child Care Center Study Group. Arch Pediatr
Adolesc Med. 1999;153:864- 868.
• Lindenmayer JM, Schoenfeld S, O’Grady R, et al. Methicillin-resistant Staphylococcus aureus in a
high school wrestling team and the surrounding community. Arch Intern Med. 1998;158: 895-899.
• Baggett HC, Hennessy TW, Rudolph K, et al. Community-onset methicillin resistant Staphylococcus
aureus associated with antibiotic use and the cytotoxin Panton-Valentine leukocidin during a
furunculosis outbreak in rural Alaska. J Infect Dis. 2004;189:1565- 1573.
• Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus
among professional football players. N Engl J Med. 2005;352:468-475.
• Pan ES, Diep BA, Carleton HA, et al. Increasing prevalence of methicillin resistant Staphylococcus
aureus infection in California jails. Clin Infect Dis. 2003;37:1384-1388.
• Lee NE, Taylor MM, Bancroft E, et al. Risk factors for community-associated methicillin-resistant
Staphylococcus aureus skin infections among HIV positive men who have sex with men. Clin Infect
Dis. 2005;40:1529-1534.
• Main CL, Jayaratne P, Haley A, et al. Outbreaks of infection caused by community-acquired
methicillin- resistant Staphylococcus aureus in a Canadian correctional facility. Can J Infect Dis Med
Microbiol 2005;16(6):343-8.
• Gilbert M, MacDonald J, Gregson D, et al. Outbreak in Alberta of community-acquired (USA300)
methicillin-resistant Staphylococcus aureus in people with a history of drug use, homelessness or
incarceration. CMAJ 2006;175(2):149-54

38. References
• Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by
community-associated methicillinresistant Staphylococcus aureus in Los Angeles. N
Engl J Med. 2005;352: 1445-1453.
• Gonzalez BE, Teruya J, Mahoney DH, Jr., et al. Venous thrombosis associated with
staphylococcal osteomyelitis in children. Pediatrics. 2006;117:1673-1679
• Nicolle L. Community-acquired MRSA: a practitioner's guide. CMAJ.
2006;175(2):145-
• Ellis MW, Hospenthal DR, Dooley DP, et al. Natural history of community-acquired
methicillin-resistant Staphylococcus aureus colonization and infection in soldiers.
Clin Infect Dis. 2004;39: 971-979.
• Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus
infections among patients in the emergency department. N Engl J Med.
2006;355:666-674
• Talan DA. MRSA: Deadly Super Bug or Just Another Staph? Annals of emergency
medicine. 2008;51(3):299-302
• Whitney CJ et al. Increasing Prevalence of Multidrug-Resistant Streptococcus
pneumoniae in the United States. New England Journal of Medicine.
2000;343(26):1917-24.
• National Advisory Committee on Immunization (NACI). Statement on
recommended use of pneumococcal conjugate vaccine. Canada Communicable
Disease Report 2002;28(ACS-2):1-32

39. References
• Kyaw MH, Lynfield R, Schaffner W, Craig AS, Hadler J, Reingold A, et al. Effect of Introduction of the
Pneumococcal Conjugate Vaccine on Drug-Resistant Streptococcus pneumoniae. New England
Journal of Medicine. 2006;354(14):1455-63
• Hsu HE, Shutt KA, Moore MR, Beall BW, Bennett NM, Craig AS, et al. Effect of Pneumococcal
Conjugate Vaccine on Pneumococcal Meningitis. New England Journal of Medicine.
2009;360(3):244-56.
• Moore Matthew R, Gertz J, Robert E., Woodbury Robyn L, Barkocy‐Gallagher
Genevieve A, Schaffner W, Lexau C, et al. Population Snapshot of Emergent Streptococcus
pneumoniae Serotype 19A in the United States, 2005. The Journal of Infectious Diseases.
2008;197(7):1016-27
• Pichichero ME, Casey JR. Emergence of a Multiresistant Serotype 19A Pneumococcal Strain Not
Included in the 7-Valent Conjugate Vaccine as an Otopathogen in Children. JAMA.
2007;298(15):1772-8.
• Muñoz‐Almagro C, Jordan I, Gene A, Latorre C, Garcia‐Garcia Juan J, Pallares R. Emergence of
Invasive Pneumococcal Disease Caused by Nonvaccine Serotypes in the Era of 7‐Valent Conjugate
Vaccine. Clinical Infectious Diseases. 2008;46(2):174-82
• Farrell DJ, Klugman KP, Pichichero M. Increased Antimicrobial Resistance Among Nonvaccine
Serotypes of Streptococcus pneumoniae in the Pediatric Population After the Introduction of 7-
Valent Pneumococcal Vaccine in the United States. The Pediatric Infectious Disease Journal.
2007;26(2):123-8 10.1097/01.inf.0000253059.84602.c3
• Singleton RJ, Hennessy TW, Bulkow LR, Hammitt LL, Zulz T, Hurlburt DA, et al. Invasive
Pneumococcal Disease Caused by Nonvaccine Serotypes Among Alaska Native Children With High
Levels of 7-Valent Pneumococcal Conjugate Vaccine Coverage. JAMA. 2007;297(16):1784-92

40. References
• Lemierre A. On certain septicæmias due to anaerobic organisms. The Lancet.
1936;227(5874):701-3.
• Ramirez S, Hild TG, Rudolph CN, Sty JR, Kehl SC, Havens P, et al. Increased
Diagnosis of Lemierre Syndrome and Other Fusobacterium necrophorum
Infections at a Children's Hospital. Pediatrics. 2003;112(5):e380-
• Syed MI, Baring D, Addidle M, Murray C, Adams C (September 2007). "Lemierre
syndrome: two cases and a review". The Laryngoscope (The American
Laryngological, Rhinological & Otological Society; Lippincott Williams &
Wilkins) 117 (9): 1605–1610
• Screaton NJ, Ravenel JG, Lehner PJ, Heitzman ER, Flower CD (November
1999). "Lemierre Syndrome: Forgotten but Not Extinct-Report of Four
Cases". Radiology (Radiological Society of North America) 213 (2): 369–374
• Beldman TF, Teunisse HA, Schouten TJ (November 1997). "Septic arthritis of the
hip by Fusobacterium necrophorum after tonsillectomy: a form of Lemierre
syndrome?". European journal of pediatrics (Springer-Verlag) 156 (11): 856–857
• Hagelskjaer Kristensen L, Prag J (Aug 2000). "Human necrobacillosis, with
emphasis on Lemierre's syndrome".Clinical Infectious Diseases 31 (2): 524–532.
• Centor RM. Expand the Pharyngitis Paradigm for Adolescents and Young Adults.
Annals of Internal Medicine. 2009;151(11):812-5.

41. References
• Eykyn SJ. Necrobacillosis. Scand J Infect Dis Suppl. 1989;62:41-6. [PMID:2685991]
• Hagelskjaer LH, Prag J, Malczynski J, Kristensen JH. Incidence and clinical
epidemiology of necrobacillosis, including Lemierre’s syndrome, in Denmark 1990-
1995. Eur J Clin Microbiol Infect Dis. 1998;17:561-5. [PMID: 9796654]
• Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis),
with a focus on Lemierre’s syndrome. Clin Microbiol Rev. 2007;20:622- 59.
• Amess JA, O’Neill W, Giollariabhaigh CN, Dytrych JK. A six-month audit of the
isolation of Fusobacterium necrophorum from patients with sore throat in a
district general Hospital. Br J Biomed Sci. 2007
• Batty A, Wren MW. Prevalence of Fusobacterium necrophorum and other upper
respiratory tract pathogens isolated from throat swabs. Br J Biomed Sci.
2005;62:66-70
• Hagelskjaer Kristensen L, Prag J. Lemierre’s syndrome and other disseminated
Fusobacterium necrophorum infections in Denmark: a prospective epidemiological
and clinical survey. Eur J Clin Microbiol Infect Dis. 2008;27:779-89
• Neuner JM, Hamel MB, Phillips RS, Bona K, Aronson MD. Diagnosis and
management of adults with pharyngitis. A cost-effectiveness analysis. Ann Intern
Med. 2003;139:113-22.

42. CA-MRSA Pneumonia Prevalence
• Is it as high as for skin/soft tissue infections?
• Kallen AJ, Brunkard J, Moore Z, et al. Staphylococcus aureus
community-acquired pneumonia during the 2006 to 2007
influenza season. Ann Emerg Med. 2009;53:358-365.
– Large case series (n=51) of staph pneumonia over 19 states
– 47% of cases were MRSA of which only 43% received
appropriate Abx
– 47% occurred after viral infection (33% flu)
– 44% had no significant PMH
– 51% died
– Limitations
• no real denominator (no true prevalence)
• reporting bias of younger and more severe presentations

43. Challenges in recognition
• Severe, life-threatening CAP (enough for ICU).
• Rapid progression
• Suspicion of concurrent influenza
• Necrotizing appearance CXR or CT
• Recent MRSA skin infection

44. Challenges in treatment
• In vitro studies show activity against CA-MRSA
for
– Vancomycin
– Trimethoprim-sulfamethoxazole
– Daptomycin
– Tigecycline
– Linezolid

45. Future considerations
• Current guidelines : if MRSA is consideration
add vancomycin or linezolid
• Further prevalence studies need to be done to
see if MRSA becomes a common cause of CAP
• If so, appropriate outpatient treatment may
consist doxycycline instead of macrolides or
quinilones

46. HCWs: risks of infection and
transmission
• ED HCW MRSA colonization prevalence ranges
from 4.3 to 15%
– Suffoletto et al. 2008
– Bisaga et al. 2008
• EDs may become amplifiers of CA-MRSA