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Emerging Infectious Disease (EID) involving Respiratory Tract Sanit Reungrongrat, MD Pediatrics Department, Faculty of Medicine, Chiang Mai University.

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Presentation on theme: "Emerging Infectious Disease (EID) involving Respiratory Tract Sanit Reungrongrat, MD Pediatrics Department, Faculty of Medicine, Chiang Mai University."— Presentation transcript:

1 Emerging Infectious Disease (EID) involving Respiratory Tract Sanit Reungrongrat, MD Pediatrics Department, Faculty of Medicine, Chiang Mai University

2 Underlying causes for EID 1.Generalized social changes worldwide urbanization, IV drug abuse, changing sexual practiceworldwide urbanization, IV drug abuse, changing sexual practice 2.Demographic changes human mobility and refugee population human mobility and refugee population 3.Medical care blood transfusion, organ transplant, re-used syringes for antibiotic injections, contamination vaccines and antibiotic resistanceblood transfusion, organ transplant, re-used syringes for antibiotic injections, contamination vaccines and antibiotic resistance Kuiken T, et al. Curr Opin Biotech 2003;14:641

3 4.Economic and commercial trends intensive food production, extended irrigation, liberalized trading patternintensive food production, extended irrigation, liberalized trading pattern 5.Climatic changes global warming and regional changesglobal warming and regional changes 6.Ecosystem disturbance deforestation, eutrophication of waterways, reduction in predators of disease vector organismsdeforestation, eutrophication of waterways, reduction in predators of disease vector organisms Underlying causes for EID Kuiken T, et al. Curr Opin Biotech 2003;14:641

4 Human Metapneumovirus (hMPV)

5 hMPV Is a pathogen that emerged as a result of increased and tenacious diagnostic efforts rather than through expansion of it range or transmission to a new host speciesIs a pathogen that emerged as a result of increased and tenacious diagnostic efforts rather than through expansion of it range or transmission to a new host species First identified in 2001 by van den Hoogen BC, et al. (Nat Med 2001;7:719)First identified in 2001 by van den Hoogen BC, et al. (Nat Med 2001;7:719) Isolated from 28 young children, stored nasopharyngeal aspiration (NPA) with RTI over 20 years in NetherlandsIsolated from 28 young children, stored nasopharyngeal aspiration (NPA) with RTI over 20 years in Netherlands –New member of Metapneumovirus genus, Paramyxoviridae family

6 Classification of Viral Pathogens of Paramyxoviridae Family McIntosh K, McAdam AJ. N Engl J Med 2004;350:431 Paramyxoviridae Pneumovirinae Metapneumovirus Human Metapneumonvirus

7 Genomic Structure of hMPV Pneumoviruses: 3'-NS1-NS2-N-P-M-SH-G-F-M2-L-5' Metapneumoviruses: 3'-N-P-M-F-M2-SH-G-L-5' Pneumoviruses: 3'-NS1-NS2-N-P-M-SH-G-F-M2-L-5' Metapneumoviruses: 3'-N-P-M-F-M2-SH-G-L-5' 13,350 nucleotides13,350 nucleotides Negative-sense, nonsegmented RNANegative-sense, nonsegmented RNA Pneumovirinae subfamily are distinguished from Paramyxovirinae subfamily byPneumovirinae subfamily are distinguished from Paramyxovirinae subfamily by –Distantly related amino acid sequences –Significant related to F (fusion) and L (polymerase) proteins –Pneumovirinae encode more mRNA (8-10 vs. 6-7), and proteins (NS1, NS2, M2-1,M2-2) which not found in Paramyxovirinae Metapneumovirus lack NS1, NS2 and have different positioning of the genes between M, and LMetapneumovirus lack NS1, NS2 and have different positioning of the genes between M, and L Domachowske JB, et al. Clin Microbiol Newsletter 2003;25:17

8 Electron Micrograph of hMPV PleomorphicPleomorphic Average size nmAverage size nm Nucleocapsids rarely observedNucleocapsids rarely observed Envelope projections of nmEnvelope projections of nm Nat Med 2001;7:719

9 Indirect Immunofluorescence IDF with polyclonal antibodies to hMPVIDF with polyclonal antibodies to hMPV Richards A, et al Nephrol Dial Transplant 2005;20:

10 Virus Isolation, Cell Culture and Growth Characteristics of hMPV Identified byIdentified by RAP-PCR –Is semi-quantitative reverse transcriptase PCR-based technique (RT-PCR) that is used to compare the entire pool of transcripts –Real-time PCR is rapid (<2hr) Culture byCulture by tertiary monkey kidney cells (tMK), LLC- MK2, Vero cell lines very slowly cytopathic effect (CPE) –hMPV grows very slowly (10-14 days) observe by cytopathic effect (CPE) –hMPV replication is trypsin dependent Nat Med 2001;7:719 CPE: morphologic characteristics of monolayer change as virions replicate inside the cells

11 Phylogeny of hMPV Indicator for the relationship between the newly identified virus isolates and members of PneumovirinaeIndicator for the relationship between the newly identified virus isolates and members of Pneumovirinae Phylogenetic trees were constructed based on the N, P, M and F ORFs of these virusesPhylogenetic trees were constructed based on the N, P, M and F ORFs of these viruses

12 Heterogeneity of hMPV Phylogenetic tree analysis of sequence 1Phylogenetic tree analysis of sequence 1 –Divided in two genotypes: A and B –Both genotypes can be divided in two subgroups: A1, A2, B1, B2 –The F protein revealed ~95% amino acid sequence identity between virus genotype A and B –the G protein shared only 30% identity Virus neutralization assays with genotype-specific antibody demonstrated 12- to >100-fold difference between genotype A and BVirus neutralization assays with genotype-specific antibody demonstrated 12- to >100-fold difference between genotype A and B Genotype A has clinical severity than genotype B 2Genotype A has clinical severity than genotype B 2 F gene G gene 1. 1.Van den Hoogen BG, et al. Pediatr Infect Dis J 2004;23:S Vicente D, et al. Clin Infect Dis 2006;42:e111.

13 Seroprevalence of hMPV Immunofluorescence assays Immunofluorescence assays Virus neutralization assays Age (yrs)n testedn positive (%)n testedn positive (%)titer (25)123 (25) (55)134 (31) (70)83 (38) (100)44 (100) (100)43 (75) > (100)43 (75) *7272 (100)1111 (100) Nat Med 2001;7:719 *Sero-archeological analysis using sera collection in Serologic studies showed circulating antibodies to the virus in virtually all children age 5 years or older 2.On the basic antibody prevalence, hMPV has circulate in the human populations at least 45 years and more likely longer

14 Several epidemiologic studies of hMPV in most parts of the world 36 studies: %

15 N=236,mean age 22 mo (9-38 mo) N=116 N=587, age<18yr N=126 N=247 N=144 N=166 N=515 N=381, age<15yr, median age 15 mo N=97, age<5yr N=10,025, 4mo-79yr, mean 8.2yr, median 1.37yr, 92% <5yr N=488,01-7.7%, 02-19%, %, 2.7%;HIV-infected infant N=601, age<2yr

16 N=711, all age N=589, age<5yr N=1,331, age<15yr N=1,505, age<15yr N=90, age<2yr N=236, median age 12 mo N=132, age 3mo-16yr N=374 N=214, mean age 10.1 mo N=63, age<2yr N=116, age 3mo-16yr N=516, age<5yr

17 N=668, age<5yr N=296 N=248 N=2,384; detect AOM 50% N=1,294, all age N=38 N=445, age 2mo-93yr) N=208, age<3yr N=749, age<2yr N=211, age<1yr N=440, age<5yr

18 In the community ~2.2% - 5%In the community ~2.2% - 5% In hospitalized children ~5% - 10%In hospitalized children ~5% - 10% –Age <18 years: 2.8% % –Age <5 years: 5.5% - 13% –Age <3 years: 4.1% - 6% –Age <2 years:11% - 25% –Age <1 year: 16.2% Epidemiology of hMPV

19 Age and Seasonal Distribution of hMPV (All Age) (Osterhaus A, Fouchier R. Lancet 2003;361:890. (N=115) Number of patient Age range (years) Month Netherland

20 Age distribution of hMPV-positive children (Age <5 yrs) (Esper F, et al JID 2004;189:1338. N=668) Months No of patients 54 cases (8.1%) USA

21 Age distribution of hMPV-positive children (Age <3 yrs) (Boivin G, et al Emerg Infect Dis 2003;9:634. N=208) Months No of patients 12 cases (6%) Canada

22 Year of study – vary by year or location “periodic epidemics”Year of study – vary by year or location “periodic epidemics” –North America study: more frequent in 2001 than 2000 (7% vs.1.5%) –Italian study: more frequent in 2002 and 2000 than 2001 (43%, 37% vs.7%) –African study: more frequent in 2002 than 2001 and 2003 (19% vs. 7.7%, 2.2%) SeasonalitySeasonality –Temperate region: late winter to spring –Subtropics region: late spring to summer (HK) Epidemiology of hMPV

23 Seasonal incidence of hMPV. Queensland Australia, (Sloots TP, et al. Emerg Infect Dis 2006;12:1263) Su, summer (Dec-Feb); Au, autumn (Mar-May); W, winter (Jun-Aug); Sp, spring (Sep-Nov) N=10,025, All ages

24 Asymptomatic infection is rare Incubation period 4-6 days, duration of symptoms before seeking medical usually <7 days, viral shedding ~ 1-2 weeks Peak age 6-12 months, male predomonant 30-85% of hospitalized children have underlying disease –prematurity, chronic lung disease congenital heart disease, cancer, HIV-infected, asthma, renal failure, GERD Epidemiology of hMPV

25 Coinfection (5-17%) with virus or bacteria, most common is RSV –Others are influenza, parainfluenza, adenovirus, CMV, rhinovirus, SARS, S pneumoniae, M pneumoniae, C pneumoniae, H influenzae, K pneumoniae, E coli Cocirculation of different hMPV genotypes in one year Epidemiology of hMPV

26 Rates, by year, of each genetypes of hMPV Data are from 1982 to 2001 in the Vanderbilt Vaccine Clinic Williams JV, et al. JID 2006;193:387

27 Distribution of hMPV subtype in Queenland, Australia, Year Total samples tested hMPV subtypes A1A2B1B Sloots TP. Et al. Emerg Infect Dis 2006;12:1263 Clinical records: 74.4% admitted, LOS median, 3 days; mean 6.5 day, predominant S&S, cough, rhinorrhea, crackles, fever (N=273 cases)Clinical records: 74.4% admitted, LOS median, 3 days; mean 6.5 day, predominant S&S, cough, rhinorrhea, crackles, fever (N=273 cases) Classification severity: mild 46.8%, moderate 42.5%, severe 10.7%Classification severity: mild 46.8%, moderate 42.5%, severe 10.7%

28 Comparison of hMPV and RSV (1) Overall, hMPV is less commonly isolated from respiratory specimens than RSVOverall, hMPV is less commonly isolated from respiratory specimens than RSV RSV appears more common than hMPV in infants <6 monthsRSV appears more common than hMPV in infants <6 months Similar to RSV, majority of hMPV cases occur in young ( 65 yrs)Similar to RSV, majority of hMPV cases occur in young ( 65 yrs) hMPV peaks later (April), where as RSV peaks earlier (December-February)hMPV peaks later (April), where as RSV peaks earlier (December-February) hMPV and RSV have similar clinical presentation in children and elderlyhMPV and RSV have similar clinical presentation in children and elderly In 1 study (Greensill J, et al. Emerg Infect Dis 2003;9:372), hMPV/RSV coinfection was detected in 70%In 1 study (Greensill J, et al. Emerg Infect Dis 2003;9:372), hMPV/RSV coinfection was detected in 70%

29 Comparison of hMPV and RSV (2) While both hMPV and RSV can provokes severe infections, disease severity and hospitalization appears more common with RSVWhile both hMPV and RSV can provokes severe infections, disease severity and hospitalization appears more common with RSV –Compared the clinical symptoms hMPV with age- matched RSV infected children; RSV-infected found more dyspnea, hypoxemia and feeding difficulties –Two studies in hospitalized patients show that hMPV did not need PICU, contrast to some of RSV and Influenza-infected patients 1,2 –Pneumonia was more often associated with RSV 1. Viazou S, et al. J Clin Microbiol 2003;41: Boivin G, et al. Emerg Infect Dis 2003;9:634.

30 Age distribution of hMPV and RSV (Age <2yrs) (Garcia-Garcia ML, et al. Arch Dis Child 2006;91:290. N=749 hMPV 64 cases (14%) RSV 376 cases (76%)

31 Monthly Distribution of hMPV and RSV (Age <1yr) (Ordas J, et al. J Clin Microbiol 2006:2739. N=211) hMPV 18 cases (16.2%) RSV 96 cases (45.5%)

32 Clinical Manifestation of hMPV (1) Fever %Fever % Cough %Cough % Rhinorrhea %Rhinorrhea % Sore throat %Sore throat % Hoarseness1 - 6%Hoarseness1 - 6% Lacrimation25%Lacrimation25% Conjunctivitis5 - 7%Conjunctivitis5 - 7% Influenza-like illness %Influenza-like illness % Common cold7 - 52%Common cold7 - 52% Otitis media %Otitis media % Diarrhea %Diarrhea % Vomiting %Vomiting % Febrile seizure16%Febrile seizure16% Truncal rash %Truncal rash % Feeding difficulties %Feeding difficulties %

33 Clinical Manifestation of hMPV (2) Hypoxia %Hypoxia % Wheeze0 - 83%Wheeze0 - 83% Dyspnea %Dyspnea % Retractions %Retractions % Hyperventilation42%Hyperventilation42% Cyanosis4 - 8%Cyanosis4 - 8% Rhinitis %Rhinitis % Rhinopharyngitis5%Rhinopharyngitis5% Pharyngitis %Pharyngitis % Laryngitis5%Laryngitis5% Tachycardia %Tachycardia % Pneumonia8 - 73%Pneumonia8 - 73% Bronchiolitis %Bronchiolitis % Asthma exacerbation %Asthma exacerbation % Bronchitis %Bronchitis %

34 Clinical Manifestation of hMPV (3) Croup18%Croup18% Asthma14%Asthma14% Irritability43%Irritability43% Apnea2 - 6%Apnea2 - 6% Noisy breathing14%Noisy breathing14% Tachypnea67%Tachypnea67% Rhonchi20%Rhonchi20% Crackles (rales) %Crackles (rales) % Sneezing45.5%Sneezing45.5% Dry mouth23%Dry mouth23% Enlarged liver6%Enlarged liver6% Headache30%Headache30% Anorexia45%Anorexia45% Drowsiness85%Drowsiness85% Lethargy26%Lethargy26%

35 Lab Investigation Lymphopenia (<1,500 cumm)29%Lymphopenia (<1,500 cumm)29% Neutropenia (<1,00 cumm)6.5%Neutropenia (<1,00 cumm)6.5% Elevated transaminase3.3%Elevated transaminase3.3% WBC (cumm)5, ,500WBC (cumm)5, ,500 LDH (IU/L) LDH (IU/L) CRP (mg/dL) CRP (mg/dL)

36 CXR Abnormal CXR % Infiltrates66% Air trapping19% Atelectasis40% Other: peribronchial cuffing, pulmonary edema, cardiomegaly, lobar pneumonia (coinfection with bacteria), pleural thickening

37 CXR Obtained in a 6-Month-Old Infant with hMPV Bronchiolitis Hyperinflation and diffuse perihilar infiltrates Willaims JV, et al N Engl J Med 2004;350:

38 Pathology of hMPV Pathology specimens of hMPV-positivePathology specimens of hMPV-positive –Exam by light and electron microscopy –BAL BAL showedBAL showed –Epithelial degenerative changes and eosinophilic cytoplasmic inclusions within epithelial cells, multinucleated giant cell, histocytosis Vargas SO, et al. Pediatr Dev Pathol 2004;7:478 Red cytoplasmic inclusion Degenerative epithelial cells Multi nucleated giant cell

39 Pathology of hMPV Lung biopsy showedLung biopsy showed –Lipoid pneumonia –Chronic airway inflammation –Intraalveolar foamy –Cholesteral clefts –Hemosiderin-laden macrophages Vargas SO, et al. Pediatr Dev Pathol 2004;7:478

40 Management Supportive care and managing airway obstructionSupportive care and managing airway obstruction Antiviral therapyAntiviral therapy PreventionPrevention

41 Supportive Care Administer humidified oxygenAdminister humidified oxygen Nasal suctioning to clear upper airwayNasal suctioning to clear upper airway Monitor for apnea, hypoxia and impending respiratory failureMonitor for apnea, hypoxia and impending respiratory failure Normalize body temperatureNormalize body temperature Rehydrate with oral or intravenous fluidsRehydrate with oral or intravenous fluids Monitor hydration statusMonitor hydration status

42 Managing Airway Obstruction and Antiviral Therapy BronchodilatorsBronchodilators CorticosteroidsCorticosteroids RibavirinRibavirin Intravenous immunoglobulinIntravenous immunoglobulin

43 Effect of Ribavirin and Glucocoticoid Treatment in Mouse Model of hMPV infection A. Mean viral titers in lungs A. Mean viral titers in lungs of hMPV-infected mice (BALB/c). On day 5 postinfection B. Lung inflammation B. Lung inflammation in hMPV-infected mice evaluation with mean histopathological scores Hamelin ME, et al Antimicrob Agents Chemother 2006;50:774

44 Data of Management Oxygen administration %Oxygen administration % Bronchodilator %Bronchodilator % Corticosteroids %Corticosteroids % Antibiotics %Antibiotics % Mechanical ventilation2%Mechanical ventilation2% PICU2%PICU2% Duration of fever: 4 (2-7) daysDuration of fever: 4 (2-7) days Duration of hospitalization: 4 (3-7) daysDuration of hospitalization: 4 (3-7) days School absence, median (range): 10 (3-15) daysSchool absence, median (range): 10 (3-15) days 1. Wang SM, et al Clin Microbiol Infect 2006;12:1221, 2. Foulongne V, et al. Pediatr Infect Dis J 2006;25:354, 3. Takao S, et al. Jpn J Infect Dis 2003;56:127, 4. Wolf DG, et al. Pediatr Infect Dis J 2006;25:320

45 Clinical and Socioeconomic Impact Among Household Contacts Disease similar to infected child (%)16 (12.5)Disease similar to infected child (%)16 (12.5) Additional medical visits (%)16 (12.5)Additional medical visits (%)16 (12.5) Antipyretic prescriptions (%)14 (10.9)Antipyretic prescriptions (%)14 (10.9) Antibiotic prescriptions (%) 6 (4.7)Antibiotic prescriptions (%) 6 (4.7) Lost working days, median (range) 4 (2-10)Lost working days, median (range) 4 (2-10) Lost of school days, median (range) 4 (3-15)Lost of school days, median (range) 4 (3-15) Bosis S, et al. J med Virol 2005;75:101.

46 Prevention Effort to reduce spread include:Effort to reduce spread include: –Limiting contact with infected patients –Removal from day care and group setting –Proper hygiene: frequent hand washing –Disinfecting surface exposed to infectious secretions –Cohorting hospitalized patients VaccinationVaccination ImmunoprophylaxisImmunoprophylaxis

47 Community-Acquired MRSA (CA-MRSA)

48 CA-MRSA: Definition CDC: diagnosis made in the community setting or by culture positive for MRSA within 48 hrs after admission to hospitalCDC: diagnosis made in the community setting or by culture positive for MRSA within 48 hrs after admission to hospital –It is known that patients may be colonized with HA-MRSA for year before developing infection –Nosocomial outbreak of CA-MRSA have been reports (MMWR Mar 31, 2006;55:329)

49 Molecular marker (Lyon) for definitionMolecular marker (Lyon) for definition 1.The Panton-Valentine leukocidin (PVL) genes 2.SCC mec IV Molecular methodsMolecular methods 1.Pulsed-field gel electrophoresis (PFGE) 2.Multilocus sequence typing (MLST) –PCR-based method CA-MRSA clones; ST1 (USA 400), ST8 (USA 300) CA-MRSA: Definition Vandenesch F et al. Emerg Infect Dis 2003;9:978

50 CA-MRSA: History S aureus is gram-positive coccid bacterium, originally susceptible to penicillinS aureus is gram-positive coccid bacterium, originally susceptible to penicillin 1940s: Penicillinase-producing strains appear1940s: Penicillinase-producing strains appear 1959: Methicillin introduced1959: Methicillin introduced 1961: MRSA emerged as nosocomial pathogen, first at UK1961: MRSA emerged as nosocomial pathogen, first at UK Early 1990s: CA-MRSA infections reportedEarly 1990s: CA-MRSA infections reported

51 Methicillin Resistance Altered penicillin-binding proteins (PBP2a) that had markly reduced affinity for all beta-lactam antibioticsAltered penicillin-binding proteins (PBP2a) that had markly reduced affinity for all beta-lactam antibiotics PBP2a is encoded by the mecA gene which carried on the mobile DNA element (the staphylococcal cassette chromosome mec (SCCmec)PBP2a is encoded by the mecA gene which carried on the mobile DNA element (the staphylococcal cassette chromosome mec (SCCmec) The other important component of SCCmecThe other important component of SCCmec –The chromosome cassette recombinase (ccr) genes encodes for proteins that enable precise intregation into and excision from specific site of S. aureus chromosome (attBscc) Foster TJ. J Clin Invest 2004;114:1693

52 SCCmec have 5 subtypes, varying in size from ~20 kilobase pairs (kb) to 68 kbSCCmec have 5 subtypes, varying in size from ~20 kilobase pairs (kb) to 68 kb –Type I: hospital origin –Type II: hospital origin, additional antibiotic resistance genes –Type III: hospital origin, additional antibiotic resistance genes –Type IV: community origin associated with frequent PVL gene –Type V: community origin SCCmec type IVSCCmec type IV –does not carry multiple antibiotic resistance genes –usually resistant only to methicillin, other beta-lactam antibiotic (cephalosporins, carbapenems) and erythromycin –susceptible to TMP-SMX, clindamycin, tetracycline, ciprofloxacin, gentamicin, rifampin Methicillin Resistance

53 Virulence Factors SCCmecResistant to methicillin Collagen-adhesin proteinAdherence to host cellEF,NP,arthritis,osteomyelitis Bacteriocin of SA (bsa)interspeciesEF Superantigen -Enterotoxin -Staph enterotoxin A,B,C,G,H Activation of T cellsEF, NP, TSS-like illness -Staph exotoxin TPossible against immunity Pore-forming toxins -PVL (LukSPV+LukFPV) -LukE+LukD LukE+LukDv  -hemolysin Necrosis, edema Destruction of intestinal microvilli Necrosis Necrosis, vascular leak, shock EF,NP Postantibiotic diarrhea EF EF, NP, Bullous impetigo Exfloliative toxin A,B EF=epidermic furunculosis, NP=necrotizing pneumonia, TSS=toxic shock syndrome

54 PVL An extracellular bicomponent toxin that targets and induces leukocyte death with release of cytokines and intracellular proteases by creating pores in the cell membraneAn extracellular bicomponent toxin that targets and induces leukocyte death with release of cytokines and intracellular proteases by creating pores in the cell membrane PVL genes are present in the majority of CA-MRSA isolatedPVL genes are present in the majority of CA-MRSA isolated Associated skin and soft tissue infection (furunculosis, abscesses) or more rarely necrotizing pneumoniaAssociated skin and soft tissue infection (furunculosis, abscesses) or more rarely necrotizing pneumonia Agarose gel electrophoresis demonstrative PVL Lane 1: molecular weight markerLane 1: molecular weight marker Lane 2: positive PVL control strain of S aureusLane 2: positive PVL control strain of S aureus Lane 3: negative PVL control strain of S aureusLane 3: negative PVL control strain of S aureus Lane 4: negative clinical isolate of S aureusLane 4: negative clinical isolate of S aureus Lane 5: patient isolate of S aureus demonstrating a positive PCR product representing PVLLane 5: patient isolate of S aureus demonstrating a positive PCR product representing PVL

55 Burden of MRSA hospitalization (3 times)Increased hospitalization (3 times) –MRSA infections increase the median length of hospital stay for nosocomial infections (median: 12 days for MRSA vs. 4 days for MSSA) Increased cost (3 times)Increased cost (3 times) –MRSA infections increase per-patient hospital compared with MSSA (US$48,824 vs. US$14,141) Increased mortality (3 times)Increased mortality (3 times) –Nosocomial MRSA infections are associated with higher mortality compared with MSSA (21% vs. 8%) Abramson MA, Sexton DJ. Infect Control Hosp Epidemiol 1999;20:408, Engemann JJ et al. Clin Infect Dis 2003;36:592, Rubin RJ et al. Emerg Infect Dis 1999;5:9

56 CA-MRSA: Epidemiology The first report in children (Herold BC, et al.)*The first report in children (Herold BC, et al.)* –Prevalence of CA-MRSA without risk factors increased from 10/10,000 in to 259/10,000 in (8 cases and 35 cases) –Cellulitis (55%), abscess (27%), pneumonia (13.5%) CA-MRSA outbreaks have been reported throughout the worldCA-MRSA outbreaks have been reported throughout the world –USA, Canada, Brazil, Uruguay, Belgium, Denmark, France, Germany, Greece, Holland, Latvia, Norway Sweden, Switzerland, UK, Taiwan, Korea, HK, Australia, Newzeland Harold BC, et al. JAMA 1998;279(8):593

57 Result of PCR to detect mecA gene and PFGE of whole cell DNA PCR PFGE Harold BC, et al. JAMA 1998;279(8):593 M=standard lane, C=control lane containing a MSSA isolate

58 CA-MRSA: Epidemiology Four pediatric deaths from CA-MRSA – Minnesota and North Dakota, (MMWR, Aug :48;707)Four pediatric deaths from CA-MRSA – Minnesota and North Dakota, (MMWR, Aug :48;707) Case reportsCase reports –7-year-old black girl with high fever and Rt groin pain, she underwent surgical drainage for Rt hip infection and treated with cefazolin. On 3 rd day antimicrobial was changed to vancomycin when cultures of blood and joint fluid grew MRSA. Her course was complicated by ARDS, pneumonia and empyema. She died from pulmonary hemorrhage after 5-weeks of hospitalization

59 Case reports (cont.)Case reports (cont.) –16-month-old girl with shock, high fever, seizure, diffuse petechial rash. She was treated with ceftriaxone but developed respiratory failure and cardiac arrest and died within 2 hours –13-year-old girl with fever, hemoptysis and respiratory distress. CXR revealed LLL infiltrate and pleural effusion. She was treated with cefriaxone and nafcillin. Within 5 hours of arriving at hospital, she become hypotensive and was intubated and treated with vancomycin and cefotaxime. She died on the 7 th hospital day from cerebral edema and MOFS –12-month-old boy with bronchiolitis, vomiting, and dehydration. He had high fever and petechial rash. On 2 nd hospital day he has large Rt pleural effusion and treated with vancomycin, cefuroxime and ICD. He developed respiratory failure and hypotension the following day and died

60 CA-MRSA: Epidemiology Number of S aureus isolate/year (14-year study, OPD & IPD in Driscoll Children’s Hospital) was relative stable in (range, ) before precipitously increasing from 402 in 2001 to 820 in 2003Number of S aureus isolate/year (14-year study, OPD & IPD in Driscoll Children’s Hospital) was relative stable in (range, ) before precipitously increasing from 402 in 2001 to 820 in 2003 Mainly is MRSA (19% in 2001 to 62.4% in 2003)Mainly is MRSA (19% in 2001 to 62.4% in 2003) Purcell K, et al. Arch Pediatr Adolesc Med 2005;159:980

61 CA-MRSA: Epidemiology 1,002 MRSA cases were CA-MRSA 982 cases (92.6%)1,002 MRSA cases were CA-MRSA 982 cases (92.6%) Mean age was 7.9 years and 51.3% were maleMean age was 7.9 years and 51.3% were male Number of MRSA case/year was 43 cases in 2000 to 467 cases in 2003, this increase was solely by rise in number of CA-MRSA infectionNumber of MRSA case/year was 43 cases in 2000 to 467 cases in 2003, this increase was solely by rise in number of CA-MRSA infection Purcell K, et al. Arch Pediatr Adolesc Med 2005;159:980

62 CA-MRSA: Risk Factors ChildrenChildren Overcrowed facilities: prisoners, militrary recruitsOvercrowed facilities: prisoners, militrary recruits Closed contact sports: football, wrestling, fencingClosed contact sports: football, wrestling, fencing Low socioecomomic status, lack of sanitationLow socioecomomic status, lack of sanitation Intravenous drugs abusers (IVDA)Intravenous drugs abusers (IVDA) Native Americans, Aboriginal groups etc.Native Americans, Aboriginal groups etc. Man who have sex with manMan who have sex with man

63 CA-MRSA: Clinical Manifestations Skin and Soft tissue infections (~70-90%)Skin and Soft tissue infections (~70-90%) –Cellulitis, Folliculitis, Furunculosis, Abscesses, Impetigo, Wound Infection Invasive Infections (~10-30%)Invasive Infections (~10-30%) –Bacteremia, Toxic Shock Syndrome –Musculoskeletal Infections Osteomyelitis, Septic arthritis, Bursitis, Pyomyositis, FasciitisOsteomyelitis, Septic arthritis, Bursitis, Pyomyositis, Fasciitis –Pneumonia, Empyema (~30-50%) Others: Lymphadenitis, Endocarditis, etc.Others: Lymphadenitis, Endocarditis, etc. Kaplan S. Semin Pediatr Infect Dis 2006;17:113

64 CA-MRSA: Pneumonia Clinical findings are no different with other organisms such as S pneumoniae Duration of hospitalization was longer than CA- MSSA (mean, 19 vs.14 days) Children with primary pneumonia are younger than secondary pneumonia from infections at other sites (mean, 3.5 vs. 9.9 years) CA-MRSA have been associated with necrotizing pneumonia, esp. coinfected with virus (influenza or parainfluenza) Kaplan S. Semin Pediatr Infect Dis 2006;17:113 Gonzalez BE, et al. Clin Infect Dis 2005;41:583

65 CA-MRSA: Pneumonia Necrotizing tracheobronchitis: 1. sloughing of bronchial mucosa 2. extensive necrosis of subepithelial connective tissue 3. necrotic debris Necrotizing pneumonia: 1. patchy areas of hemorrhage 2. extensive intraalveolar hemorrhage admixed with neutrophil infiltrates 3. karyorrhectic debris Gonzalez BE, et al. Clin Infect Dis 2005;41:583

66 CA-MRSA: Treatment Hospitalized, non-life-treatening invasive or noninvasive infections and without toxic appearanceHospitalized, non-life-treatening invasive or noninvasive infections and without toxic appearance –IV Clindamycin + (I&D, if abscess is present) Criticallly ill with life-treatening invasive infectionsCriticallly ill with life-treatening invasive infections –IV Vancomycin* or IV Clindamycin # –IV Clindamycin + Gentamicin *alternative regimen: Vancomycin + Cloxacillin, Vancomycin + 3 rd Cephalosporin #suggestion to use Vancomycin in life-treatening until known negative D-test

67 CA-MRSA: Clindamycin In patients with bacteremia, complicated pneumonia and musculoskeletal infectionsIn patients with bacteremia, complicated pneumonia and musculoskeletal infections –Dose: 40 mg/kg/day IV –Duration: median, 20 days (range, days) –Complication: relatively rare Clostridium difficile enteritis, loose stools or diarrhea is most common, rash –Inducible resistance to clindamycin detected by double-disk diffusion test (D-test) Martinez-Aguilar G, et al. Pediatr Infect Dis J 2003;22:593

68 D-Test If the results show a blunted shape or “D”; clindamycin resistance is presence and presumed to be due to inducible MLS B - resistance phenotype (macrolide-lincosamide- streptogramin B)If the results show a blunted shape or “D”; clindamycin resistance is presence and presumed to be due to inducible MLS B - resistance phenotype (macrolide-lincosamide- streptogramin B) –Inducible clindamycin resistance (erm-mediated) –No induction (msrA- mediated erythromycin resistance) Positive Negative 24 hrs, Temp 35 o C

69 Conclusions Available evidence suggests that CA-MRSA is an emerging problem in pediatricsAvailable evidence suggests that CA-MRSA is an emerging problem in pediatrics Clinicians should be aware that therapy with beta-lactam antimicrobials can no longer be relied on as the sole empiric therapy for severe illness patients whose infections may be CA-MRSAClinicians should be aware that therapy with beta-lactam antimicrobials can no longer be relied on as the sole empiric therapy for severe illness patients whose infections may be CA-MRSA What is the CA-MRSA situation in Thailand?What is the CA-MRSA situation in Thailand?


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