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

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

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

Human Metapneumovirus (hMPV)

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 species 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 Netherlands New member of Metapneumovirus genus, Paramyxoviridae family

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

Genomic Structure of hMPV 13,350 nucleotides Negative-sense, nonsegmented RNA Pneumovirinae 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 L Pneumoviruses: 3'-NS1-NS2-N-P-M-SH-G-F-M2-L-5' Metapneumoviruses: 3'-N-P-M-F-M2-SH-G-L-5' Domachowske JB, et al. Clin Microbiol Newsletter 2003;25:17

Electron Micrograph of hMPV Pleomorphic Average size 100-600 nm Nucleocapsids rarely observed Envelope projections of 13-17 nm Nat Med 2001;7:719

Indirect Immunofluorescence IDF with polyclonal antibodies to hMPV Richards A, et al Nephrol Dial Transplant 2005;20:2848-50

Virus Isolation, Cell Culture and Growth Characteristics of hMPV Identified 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 by tertiary monkey kidney cells (tMK), LLC-MK2, Vero cell lines hMPV grows very slowly (10-14 days) observe by cytopathic effect (CPE) hMPV replication is trypsin dependent CPE: morphologic characteristics of monolayer change as virions replicate inside the cells Nat Med 2001;7:719

Phylogeny of hMPV Indicator 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 viruses

Heterogeneity of hMPV Phylogenetic tree analysis of sequence1 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 B Genotype A has clinical severity than genotype B2 F gene G gene Van den Hoogen BG, et al. Pediatr Infect Dis J 2004;23:S25. Vicente D, et al. Clin Infect Dis 2006;42:e111.

Seroprevalence of hMPV Immunofluorescence assays Virus neutralization assays Age (yrs) n tested n positive (%) titer 0.5-1 20 5 (25) 12 3 (25) 16-32 1-2 11 (55) 13 4 (31) 2-5 14 (70) 8 3 (38) 16-512 5-10 20 (100) 4 4 (100) 32-256 10-20 3 (75) 32-128 >20 8-99* 72 72 (100) 11 11 (100) 16-128 *Sero-archeological analysis using sera collection in 1958 Serologic studies showed circulating antibodies to the virus in virtually all children age 5 years or older On the basic antibody prevalence, hMPV has circulate in the human populations at least 45 years and more likely longer Nat Med 2001;7:719

Several epidemiologic studies of hMPV in most parts of the world

N=601, age<2yr N=488,01-7.7%, 02-19%, 03-2.2%, 2.7%;HIV-infected infant N=10,025, 4mo-79yr, mean 8.2yr, median 1.37yr, 92% <5yr N=97, age<5yr N=381, age<15yr, median age 15 mo N=515 N=166 N=144 N=247 N=126 N=587, age<18yr N=116 N=236,mean age 22 mo (9-38 mo)

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

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

Epidemiology of hMPV In the community ~2.2% - 5% In hospitalized children ~5% - 10% Age <18 years: 2.8% - 17.9% Age <5 years: 5.5% - 13% Age <3 years: 4.1% - 6% Age <2 years: 11% - 25% Age <1 year: 16.2%

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

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

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

Epidemiology of hMPV 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%) Seasonality Temperate region: late winter to spring Subtropics region: late spring to summer (HK)

Seasonal incidence of hMPV Seasonal incidence of hMPV. Queensland Australia, 2001-2004 (Sloots TP, et al. Emerg Infect Dis 2006;12:1263) N=10,025, All ages Su, summer (Dec-Feb); Au, autumn (Mar-May); W, winter (Jun-Aug); Sp, spring (Sep-Nov)

Epidemiology of hMPV 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 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

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

Distribution of hMPV subtype in Queenland, Australia, 2001-2004 Year Total samples tested hMPV subtypes A1 A2 B1 B2 2001 59 58 24 8 10 2002 122 20 51 12 17 2003 189 36 30 2004 270 1 23 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% Sloots TP. Et al. Emerg Infect Dis 2006;12:1263

Comparison of hMPV and RSV (1) Overall, hMPV is less commonly isolated from respiratory specimens than RSV RSV appears more common than hMPV in infants <6 months Similar to RSV, majority of hMPV cases occur in young (<5 yrs) and elderly (>65 yrs) hMPV peaks later (April), where as RSV peaks earlier (December-February) hMPV 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%

Comparison of hMPV and RSV (2) While 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 patients1,2 Pneumonia was more often associated with RSV 1. Viazou S, et al. J Clin Microbiol 2003;41:3043. 2. Boivin G, et al. Emerg Infect Dis 2003;9:634.

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%)

Monthly Distribution of hMPV and RSV (Age <1yr) (Ordas J, et al 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%)

Clinical Manifestation of hMPV (1) Fever 57 - 100% Cough 63 - 100% Rhinorrhea 46 - 92% Sore throat 50 - 59.5% Hoarseness 1 - 6% Lacrimation 25% Conjunctivitis 5 - 7% Influenza-like illness 50 - 53% Common cold 7 - 52% Otitis media 12 - 51% Diarrhea 6 - 37.5% Vomiting 10 - 48.5% Febrile seizure 16% Truncal rash 10 - 19% Feeding difficulties 36 - 65%

Clinical Manifestation of hMPV (2) Hypoxia 24 - 47% Wheeze 0 - 83% Dyspnea 28 - 83% Retractions 60 - 92% Hyperventilation 42% Cyanosis 4 - 8% Rhinitis 27 - 80% Rhinopharyngitis 5% Pharyngitis 13 - 39% Laryngitis 5% Tachycardia 23 - 57% Pneumonia 8 - 73% Bronchiolitis 10 - 67% Asthma exacerbation 14 - 22% Bronchitis 0 - 60%

Clinical Manifestation of hMPV (3) Croup 18% Asthma 14% Irritability 43% Apnea 2 - 6% Noisy breathing 14% Tachypnea 67% Rhonchi 20% Crackles (rales) 8 - 100% Sneezing 45.5% Dry mouth 23% Enlarged liver 6% Headache 30% Anorexia 45% Drowsiness 85% Lethargy 26%

Lab Investigation Lymphopenia (<1,500 cumm) 29% Neutropenia (<1,00 cumm) 6.5% Elevated transaminase 3.3% WBC (cumm) 5,930 - 16,500 LDH (IU/L) 269 - 649 CRP (mg/dL) 0.76 - 2.54

CXR Abnormal CXR 28 - 87% Infiltrates 66% Air trapping 19% Atelectasis 40% Other: peribronchial cuffing, pulmonary edema, cardiomegaly, lobar pneumonia (coinfection with bacteria), pleural thickening

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;350:443-450

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

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

Management Supportive care and managing airway obstruction Antiviral therapy Prevention

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

Managing Airway Obstruction and Antiviral Therapy Bronchodilators Corticosteroids Ribavirin Intravenous immunoglobulin

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

Data of Management Oxygen administration 24.3 - 34.3% Bronchodilator 30 - 32.4% Corticosteroids 8.1 - 17% Antibiotics 22.2 - 94% Mechanical ventilation 2% PICU 2% Duration of fever: 4 (2-7) days Duration of hospitalization: 4 (3-7) days School 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

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

Prevention Effort to reduce spread include: Vaccination 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 Vaccination Immunoprophylaxis

Community-Acquired MRSA (CA-MRSA)

CA-MRSA: Definition CDC: 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) http://www.cdc.gov/ncidod/hip/ARESIST/mrsa_comm_faq.htm

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

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

Methicillin Resistance Altered 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) The 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

Methicillin Resistance SCCmec 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 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

Virulence Factors SCCmec Resistant to methicillin Collagen-adhesin protein Adherence to host cell EF,NP,arthritis,osteomyelitis Bacteriocin of SA (bsa) interspecies EF Superantigen -Enterotoxin -Staph enterotoxin A,B,C,G,H Activation of T cells EF, NP, TSS-like illness -Staph exotoxin T Possible 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, NP, Bullous impetigo Exfloliative toxin A,B EF=epidermic furunculosis, NP=necrotizing pneumonia, TSS=toxic shock syndrome

Agarose gel electrophoresis PVL An 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 isolated Associated skin and soft tissue infection (furunculosis, abscesses) or more rarely necrotizing pneumonia Agarose gel electrophoresis demonstrative PVL Lane 1: molecular weight marker Lane 2: positive PVL control strain of S aureus Lane 3: negative PVL control strain of S aureus Lane 4: negative clinical isolate of S aureus Lane 5: patient isolate of S aureus demonstrating a positive PCR product representing PVL

Burden of MRSA 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) MRSA infections increase per-patient hospital compared with MSSA (US$48,824 vs. US$14,141) 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

CA-MRSA: Epidemiology The first report in children (Herold BC, et al.)* Prevalence of CA-MRSA without risk factors increased from 10/10,000 in 1988-90 to 259/10,000 in 1993-5 (8 cases and 35 cases) Cellulitis (55%), abscess (27%), pneumonia (13.5%) CA-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

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

CA-MRSA: Epidemiology Four pediatric deaths from CA-MRSA – Minnesota and North Dakota, 1997-99 (MMWR, Aug 20 1999:48;707) Case 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 3rd 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

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 7th hospital day from cerebral edema and MOFS 12-month-old boy with bronchiolitis, vomiting, and dehydration. He had high fever and petechial rash. On 2nd 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

CA-MRSA: Epidemiology Number of S aureus isolate/year (14-year study, OPD & IPD in Driscoll Children’s Hospital) was relative stable in 1991-2000 (range, 214-330) before precipitously increasing from 402 in 2001 to 820 in 2003 Mainly is MRSA (19% in 2001 to 62.4% in 2003) Purcell K, et al. Arch Pediatr Adolesc Med 2005;159:980

CA-MRSA: Epidemiology 1,002 MRSA cases were CA-MRSA 982 cases (92.6%) Mean 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 infection Purcell K, et al. Arch Pediatr Adolesc Med 2005;159:980

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

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

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

Necrotizing tracheobronchitis: Necrotizing pneumonia: 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

CA-MRSA: Treatment Hospitalized, 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 infections IV Vancomycin* or IV Clindamycin# IV Clindamycin + Gentamicin *alternative regimen: Vancomycin + Cloxacillin, Vancomycin + 3rd Cephalosporin #suggestion to use Vancomycin in life-treatening until known negative D-test

CA-MRSA: Clindamycin In patients with bacteremia, complicated pneumonia and musculoskeletal infections Dose: 40 mg/kg/day IV Duration: median, 20 days (range, 10-56 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

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

Conclusions Available 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-MRSA What is the CA-MRSA situation in Thailand?