Emerging and Re-emerging Infectious Diseases

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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

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  • Maryn M.The Many Faces of MRSA: Community-Acquired Infection Knows No Bounds. Annals of emergency medicine. 2008;51(3):285-8.
  • Hospital patients infected with MRSA cost more to treat, have longer lengths of stay, and have a higher risk of death than patients with non-resistant staphDogma: MRSA could not survive outside the hospital environment because its load of resistance factors crippled its evolutionary fitness. When resistant staph was found in the community, it was held to be a leak from hospitals that could not sustain transmission in the outside worldBarber M. Staphylococcal infection due to penicillin-resistant strains. BMJ. 1947;863-865.Jevons M. “Celbenin”-resistant staphylococci. BMJ. 1961:124-125Locksley RM, Cohen ML, Quinn TC, et al. Multiply antibiotic-resistant Staphylococcus aureus: introduction, transmission, and evolution of nosocomial infection. Ann Intern Med. 1982;97:317-324Wisplinghoff 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 InfectDis. 2004;39:309-317
  • Outlined a sharp difference between cases from 1988-1990 and 1993-95, including a 25-fold increase in those with no links to the health care systemDaum 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;186:1344-1347Members of the same group through laboratory studies confirmed new type of MRSA had emerged within the comm with a distinctive molecular fingerprint, a unique suite of toxins, and a shorter chromosomal cassette that retained resistance only to penicillins and cephalosporinsThis shattered the prevailing view, and proved that there was in fact MRSA in the community.Led to further characterization of risk factors for developing CA MRSA infections as well as research into the burden of the disease in the community.
  • Busy slide: the point is several prevalence studies were conducted by Emergency physicians across the US all showing similar high prevalence of MRSA in skin infections and high levels of the CA strain.EPS ON CUTTING EDGE Emergency physicians were far ahead of the curve in recognizing CA-MRSA as a new and distinct phenomenonMoran GJ, Amii RN, Abrahamian FM, et al. Methicillin-resistant Staphylococcus aureus in community-acquired skin infections. Emerg Infect Dis. 2005;11: 928-930revealed a rising proportion of MRSA skin infections. Susceptibility testing confirmed the infecting organism was not the hospital strain, and molecular fingerprinting revealed patterns indistinguishable from the ongoing CA-MRSA jail outbreakFrazee 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: 311-320King 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;144:309-317the SCCmecIV cassette that marks the community strain
  • Moran and his colleagues in the Emergency ID Net Study Group reported During one month incontrovertible evidence that their previous physicians had neither considered the possibility of MRSA nor cultured the infections to checkMulvey 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
  • Which brings up the point, when should we think about CA-MRSA?Classically we all think of MRSA in recently hospitalized, nursing home, HCWs and their families...Right away we see a shift in the last 5 years the paradigm of recognizing these infectionsA lot of us who have graduated in recent years have committed these risk factors to memory 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 PediatrAdolesc 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):149-54Miller LG, Perdreau-Remington F, RiegG, et al. Necrotizing fasciitis caused by community-associated methicillinresistantStaphylococcus 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;117:1673-1679Nicolle 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.
  • But do these risk factors mean anything?patients were just as likely to be infected with MRSA whether or not they shared the traditional risk factors: prior health care exposure, injection drug use, incarceration, or pro sports, among othersthe sensitivity, specificity, and predictive values for these factors for discriminating CA-MRSA infection from CA-MSSA infection were relatively poor. Post-hoc modeling revealed that, even in a 10% (i.e., low) MRSA prevalence population, patients lacking the 3 strongest MRSA risk factors would still have a 7% posttest probability of MRSA
  • Which brings us to treatment, i think we can safely say that given the prevalenceYour average outpatient treatment of skin infections with keflex probably doesn’t cut it!So what does? SeptraDoxyClindaRifampinLinezolid, expensive, experience with outpatient therapy is limitedResistance patterns? Clinda has inducible susceptibilityMay be evidence on the way about resistance to septra
  • Strategies for Clinical Management of MRSA in the Community: Summary of an Experts’ Meeting Convened by the Centers for Disease Control and Prevention. 2006.Experts at the CDC can’t decide which drug is the first choice, what the regimen should be and whether it should be used in combination are currently more art than science—andlikely to remain so, given that the drugs are long off-patent and unlikely to be the subject of pharmaceutical company researchNot even clear if I+D enough for CA-MRSA abscessesTo remedy that, the National Institutes of Health last year awarded two 5-year grants to several university teams to research off-patent drugs for CA-MR
  • Here is where there is a bit of controversyCurrent guidelines recommend treating patients with clinical and epidemiological risk factorsNicolle L. Community-acquired MRSA: a practitioner's guide. CMAJ. 2006;175(2):145-Therefore the questions arises, should we treat everyone?Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistantS. aureus infections among patients in the emergency department. N Engl J Med. 2006;355:666-674A growing body of evidence suggests that not only is CA-MRSA more common than MSSA but causes more hospital visits than mssa used to and more severe illness
  • Examples of this in the literature include This study of the incidence and mortality of invasive MRSA infection, which showed some staggering results The media went crazy and called mrsa superbugThe results were probably a bit overblown in that it included nosocomial MRSA which skews the mortality rate given that inpatients have higher co-morbidity and mortality and one cannot necessarily extrapolate that CA-MRSA is responsible for a higher number of deaths than MSSAThe incidence of health care–associated MRSA is related to the use of vascular catheters in chronically ill and hospitalized patients with significant comorbidities who have a relatively limited life expectancy. Also Patients died with MRSA but not necessarily from MRSAIn fact they found the population-based mortality of invasive community-associated MRSA infection in 2005 to be 0.5 per 100,000, of which most deaths occurred in the elderly. This is approximately equal to the risk of dying from forces of nature (eg, lightning, earthquakes,storms, and extremes of temperature).Talan DA.MRSA: Deadly Super Bug or Just Another Staph? Annals of emergency medicine. 2008;51(3):299-302
  • This study on the other hand offered a more sobering view that perhaps CA-MRSA isn’t quite as deadly as we feared but it still is responsible for a very high disease burden in the community on the system and lends more credence to the theory that we should be more aggressive with outpatient treatment.There is still not much evidence to suggest that CA-MRSA causes more severe infections than MSSA. As opposed to nosocomial MRSA.Talan DA.MRSA: Deadly Super Bug or Just Another Staph? Annals of emergency medicine. 2008;51(3):299-302National Hospital Ambulatory Medical Care SurveyNHAMCS is a probability sample of ED visits in all 50 states and the District of Columbia, representing all US EDs, excluding federal, military, and Veterans Administration hospitals
  • Notifiable disease?Culture everything?Should we be prescribing doxy?
  • We all know that strep pneumo can be responsible every URTI under the sun but it also causes more invasive and problematic disease particularly in children in the form ofPneumonia, sepsis, meningitis, OMWhitney CJ et al. Increasing Prevalence of Multidrug-Resistant Streptococcus pneumoniae in the United States. New England Journal of Medicine. 2000;343(26):1917-24.invasive pneumococcal disease in patients identified from 1995 to 1998 in the Active Bacterial Core Surveillance program of the Centers for Disease Control and PreventionThe total population under surveillance for 1998 was 16.5 millionThis changed the way we work up febrile children, the way we treat sepsis and meningitis and also prompted the vaccineNational Advisory Committee on Immunization (NACI). Statement on recommended use of pneumococcal conjugate vaccine. Canada Communicable Disease Report 2002;28(ACS-2):1-32
  • Herd immunity: a subgroup of the population is immune to a disease and by virtue of their numbers, susceptible individuals are less likely to be exposed because there are less people to spread it.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):1455-63peaked in 1999 and decreased by 2004,Pen resistant from 6.3 to 2.7 cases per 100,000 (a decline of 57 % [55-58%]) MDR from 4.1 to 1.7 cases per 100,000 (a decline of 59% [58-60]. Among children >2, pen resistant disease decreased from 70.3 to 13.1 cases per 100,000 (81 % [80-82] >65 disease decreased from 16.4 to 8.4 cases per 100,000 (a decline of 49 %). Rates of resistant disease caused by vaccine serotypes fell 87%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.
  • Too good to be true?Initial thought was that herd immunity brought down the incidence of all IPD, but effect was short livedWhile PCV7 rates were declining, several of those studies showed an increase in non-vaccine serotypes (NVS)So there actually are a whole bunch of serotypes that were not among the dirty 7 included in vaccine but actually represented a sizeable chunk of IPD especially in the elderly which is who a lot of us see.
  • But the increase in IPD was modest and did not seem to be reaching pre-PCV7 levels, especially among children
  • What are the implications of this?Will serotype replacement erode the effect of PCV7?Will we be seeing the same rates of IPD as before prevnar??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):1016-27Pichichero 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):174-82Farrell 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.c3Singleton 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
  • There was actually a study that came out the same year that challenged that notionWhat is the significance of this?Are host factors more important than strain?
  • Dont get too comfortable!Could this change our practiceTRISKAIVALENTWill this halt the serotype replacement? Are we just going in circles? Will it make a clinically significant impact... This remains to be seen
  • Lemierre, in 1936, who published a series of 20 cases where throat infections were followed by identified anaerobic septicemia, of whom 18 patients diedillnesses started with tonsillitis or peritonsillar abscess. Although they initially had clinical improvement, the adolescents developed clinical signs of bacteremia, including rigors, after approximately 4 days. They then developed suppurativethrombophlebitis of the internal jugular vein, bacteremia, and metastatic infections (most commonly, pulmonary abscesses). Lemierre identified the causative organism as Bacillus funduliformis, later renamed F. necrophorum. He reported a 90% mortality rate among the 20 patients he observedLemierre 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 Fusobacteriumnecrophorum Infections at a Children's Hospital. Pediatrics. 2003;112(5):e380-Spent the next 50 years in obscurityFast forward toThats only the beginning, more cases start to crop up around the worldSending the ENT researcher community into a tizzy trying to figure what is lemierre’s syndrome, why did we forget about it and why is it back?
  • During the primary infection, F. necrophorum colonizes the infection site and the infection spreads to the parapharyngeal space. The bacteria then invade the peritonsillar blood vessels where they can spread to the internal jugular vein.[5] In this vein, the bacteria cause the formation of a thrombus containing these bacteria. Furthermore, the internal jugular vein becomes inflamed. This septic thrombophlebitis can give rise to septic microemboli[11] that disseminate to other parts of the body where they can form abscesses and septic infarctions. The first capillaries that the emboli encounter where they can nestle themselves are the pulmonary capillaries. As a consequence, the most frequently involved site of septic metastases are the lungs, followed by the joints (knee, hip, sternoclavicular joint, shoulder and elbow[12]). In the lungs, the bacteria cause abscesses, nodulary and cavitary lesions. Pleural effusion is often present.[6] Other sites involved in septic metastasis and abscess formation are the muscles and soft tissues, liver, spleen, kidneys and nervous system (intracranial abscesses, meningitis).[5]Production of bacterial toxins such as lipopolysaccharide leads to secretion of cytokines by white blood cells which then both lead to symptoms of sepsis. F. necrophorum produces hemagglutinin which causes platelet aggregation that can lead to diffuse intravascular coagulation and thrombocytopeniaSyed 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): 1605–1610Screaton 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): 369–374Beldman TF, Teunisse HA, Schouten TJ (November 1997). "Septic arthritis of the hip by Fusobacteriumnecrophorum after tonsillectomy: a form of Lemierre syndrome?". European journal of pediatrics (Springer-Verlag) 156 (11): 856–857HagelskjaerKristensen L, Prag J (Aug 2000). "Human necrobacillosis, with emphasis on Lemierre'ssyndrome".Clinical Infectious Diseases 31 (2): 524–532.
  • ...(Seizures/coma/death)
  • The Lemierre syndrome remains life-threatening. Four recent case series (8 –11) provide mortality data; the studies had a total of 303 patients and reported 13 deaths, for amortality rate of 4.6% (95% CI, 2.6% to 7.3%). The most recent published case series (11) also included morbidity data. Of 37 patients whose disease started with pharyngitis, 11 required intensive care (with 7 requiring intubation) and 16 required surgical drainage of an abscess. One patient died, and 3 had permanent sequelae. Thus, permanent sequelae occurred in 10.2% (CI, 2.1% to 22%) of patients. Many of those who recovered had a long convalescenceCentor RM.Expand the Pharyngitis Paradigm for Adolescents and Young Adults. Annals of Internal Medicine. 2009;151(11):812-5.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 ClinMicrobiol Infect Dis. 1998;17:561-5. [PMID: 9796654]Riordan T. Human infection with Fusobacteriumnecrophorum (Necrobacillosis), with a focus on Lemierre’s syndrome. ClinMicrobiol Rev. 2007;20:622- 59. [PMID: 17934077]HagelskjaerKristensen L, Prag J. Lemierre’s syndrome and other disseminated Fusobacteriumnecrophorum infections in Denmark: a prospective epidemiological and clinical survey. Eur J ClinMicrobiol Infect Dis. 2008;27:779-89
  • Amess JA, O’Neill W, Giollariabhaigh CN, Dytrych JK. A six-month audit of the isolation of Fusobacteriumnecrophorum from patients with sore throat in a district general Hospital. Br J Biomed Sci. 2007Amess and colleagues (3) in the United Kingdom performed cultures on all throat swabs sent to their laboratory. Among 1157 swabs, they found group A streptococci in 156 (13%), group C streptococci in 47 (4%), group G streptococci in 9 (1%), and F. necrophorum in 57 (5%). In an analysis of the 351 patients aged 16 to 30 years, 33 cultures were positive for F. necrophorum (10%) and 34 cultures were positive for group A streptococci (10%).Batty A, Wren MW. Prevalence of Fusobacteriumnecrophorum and other upper respiratory tract pathogens isolated from throat swabs. Br J Biomed Sci. 2005;62:66-70HagelskjaerKristensen L, Prag J. Lemierre’s syndrome and other disseminated Fusobacteriumnecrophorum infections in Denmark: a prospective epidemiological and clinical survey. Eur J ClinMicrobiol 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 InternMed. 2003;139:113-22.Is it significant?Look at the incidence of ARF 2 to GAS , we get quite riled up about treating GAS pharyngitis to prevent ARF because of its high morbidity and mortalityWell i think i’ve done a pretty good job of convincing you that lemierres syndrome is a nasty disease with higher rates of long term disability and death.This is a table that i took from an editorial
  • Students and residents must learn the natural history of routine pharyngitis: resolution in 3 to 5 days. When disease does not resolve quickly, symptoms worsen, or unilateralneck swelling develops, physicians should consider an expanded differential diagnosis, including suppurative complications (peritonsillar abscess and the Lemierre syndrome);group A, C, or G streptococcal pharyngitis; infectious mononucleosis; and acute HIV infectionIf youre the kind that treats empirically, even if the rapid strep test is negative, until you have enough surveillance in your area to rule out the possibility of fusobacteriumBacteremic symptoms, night sweats, rigors, just the idea of missing a lemierres gives me night sweatsCentor RM.Expand the Pharyngitis Paradigm for Adolescents and Young Adults. Annals of Internal Medicine. 2009;151(11):812-5.
  • Just a bit of extra information about one of the more common invasive MRSA infectionsChallenging to obtain true prevalence without proper denominator, hard to obtain cultures, hard to estimate how many people have pneumonia, due to varying severity and areas of treatment, outpatient vs inpatientReports appear sporadic and not as common as skin and soft tissue infection
  • No good evidence, based on case series and expert opinionsevere, life-threatening, community-acquired pneumonia (eg, severe enough to prompt admission to the ICU). suspicion of concurrent influenza (based on exposure, typical prodromal symptoms, or rapid testing), a rapid progression of symptoms,or necrotizing appearance on chest radiograph or computed tomography Recent skin infection caused by known or suspected MRSA in the patient or a close contactMoranGJ, Talan DA. MRSA Community-Acquired Pneumonia: Should We Be Worried? Annals of emergency medicine. 2009;53(3):366-8.
  • Vancomycin penetrates poorly into alveolar lining fluid of the lung. Post hoc subgroup analysis of clinical trials of patients with health care–associated pneumonia found that linezolid treatment of MRSA-infected patients was associated with improved survival compared with vancomycin. Prospective trials are ongoing to determine whether a difference truly exists. There are theoretical reasons to believe that agents such as linezolid or clindamycin may have an additional benefit because they act at the ribosome to inhibit protein synthesis of bacterial toxins,7 but the clinical significance of this phenomenon is unprovenBecause clindamycin resistance among community-associated strains of MRSA appears to be increasing, it is not recommended as the sole agent for empiric treatment of severe pneumonia that may be due to community-associated strains of MRSA.Daptomycin is inactivated by pulmonary surfactant, so it would not be appropriate for therapy of pneumonia. Trimethoprim-sulfamethoxazole is frequently used for outpatient management of community-associated strains of MRSA skin and soft tissue infections but is poorly studied for pneumonia. Some studies suggest that vancomycin may be superior to trimethoprim-sulfamethoxazole for severe staphylococcal infections,8 but there are no comparative trials for MRSApneumonia. Ceftobipirole and ceftaroline are new cephalosporins that have activity against MRSA and will provide another treatment option when they become available in the United States. For the time being, either vancomycin or linezolid would be acceptable
  • If we were able to identify a subset of outpatients withhigher risk for MRSA, or if we find someday that MRSA hasbecome a common cause of community-acquired pneumonia,then doxycycline might be a more appropriate choice foroutpatient treatment instead of a macrolide or fluoroquinoloneCurrent guideline “If CA-MRSA is a consideration, add vancomycin orlinezolid”“perfect storm” of an influenza pandemic combined withwidespread community-associated strains of MRSAsuperinfection, leading to even higher mortalityPrevalence studies pending!
  • Hospital-acquired-MRSA became endemic in hospitals through simple failures in infection control; several studies in the past decade have demonstrated that EDs’ record of hand-washing is poor.34-36 The risks of poor hygiene in an ED are likely to be exacerbated not only by ED stress and crowding, but also by MRSA’s known ability to remain viable on hospital surfaces—in one study, for more than 12 days.37And if EDs become amplifiers of CAMRSA, it may not only be patients who are at risk. Last year, a Garland, TX firefighter and emergency medical technician died of invasive MRSA,38 and a Troy, NY firefighter/EMT was temporarily disabled by extensive soft tissue infection.39Suffoletto BP, Eliot HC, Kaveh I, Donald MY. Prevalence of Staphylococcus aureus Nasal Colonization in Emergency Department Personnel. Annals of emergency medicine. 2008;52(5):529-33.Bisaga AB, Katherine P, Linda S, Elise OL. A Prevalence Study of Methicillin-Resistant Staphylococcus aureus Colonization in Emergency Department Health Care Workers. Annals of emergency medicine. 2008;52(5):525-8.
  • Emerging and Re-emerging Infectious Diseases

    1. 1. Emerging and Re-emerging Infectious Diseases Farooq Khan MDCM PGY2 FRCP-EM McGill October 27th 2010
    2. 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. 3. Outline • Community Acquired MRSA • Non-vaccine serotype Pneumococcus • Fusobacterium Necrophorum
    4. 4. Community Acquired Methicillin Resistant Staphylococcus Aureus Skin and Soft Tissue Infections
    5. 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. 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. 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. 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. 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. 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. 11. Challenges in treatment Nicolle L. Community-acquired MRSA: a practitioner's guide. CMAJ. 2006;175(2):145-
    12. 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. 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. 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. 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. 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. 17. Non-Vaccine Serotype Multi-drug Resistant Streptococcus Pneumoniae Invasive Pneumococcal Disease
    18. 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. 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. 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. 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. 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. 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. 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. 25. Fusobacterium Necrophorum Lemierre’s Syndrome: The forgotten disease The new sore throat paradigm
    26. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 44. Challenges in treatment • In vitro studies show activity against CA-MRSA for – Vancomycin – Trimethoprim-sulfamethoxazole – Daptomycin – Tigecycline – Linezolid
    45. 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. 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

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