Transcript Slide 1

Emerging Infectious Disease
(EID) involving Respiratory Tract
Sanit Reungrongrat, MD
Pediatrics Department, Faculty of
Medicine, Chiang Mai University
Underlying causes for EID
1. Generalized social changes
•
worldwide urbanization, IV drug abuse,
changing sexual practice
2. Demographic changes
•
human mobility and refugee population
3. 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
4. Economic and commercial trends
•
intensive food production, extended
irrigation, liberalized trading pattern
5. Climatic changes
•
global warming and regional changes
6. 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
Paramyxoviridae
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), LLCMK2, Vero cell lines
– 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
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
F gene
1.
2.
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.
• 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
Seroprevalence of hMPV
Immunofluorescence assays Virus neutralization assays
Age (yrs) n tested n positive (%) n tested n positive (%)
titer
0.5-1
1-2
2-5
20
20
20
5 (25)
11 (55)
14 (70)
12
13
8
3 (25)
4 (31)
3 (38)
16-32
16-32
16-512
5-10
10-20
>20
20
20
20
20 (100)
20 (100)
20 (100)
4
4
4
4 (100)
3 (75)
3 (75)
32-256
32-128
32-128
8-99*
72
72 (100)
11
11 (100)
16-128
*Sero-archeological analysis using sera collection in 1958
1.
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
Nat Med 2001;7:719
Several epidemiologic studies of
hMPV in most parts of the world
36 studies: 2.2-30%
11
Yemen(02-03)
5.8
South Africa(01-03)
N=488,01-7.7%, 02-19%, 03-2.2%, 2.7%;HIV-infected infant
7.1
Austraria(01-04)
N=10,025, 4mo-79yr, mean 8.2yr, median 1.37yr, 92% <5yr
12
India(04-05)
7.3
Korea3(03-05)
4.7
Korea2(00-05)
N=601, age<2yr
N=97, age<5yr
N=381, age<15yr, median age 15 mo
N=515
15.7
Korea1(97-00)
N=166
20.1
Japan(04-05)
N=144
30
China2(02-03)
16.7
China1(02-03)
5.5
Hongkong(01-02)
N=126
N=587, age<18yr
27.4
Taiwan(01-02)
5.4
Thai(01-03)
0
5
N=247
N=116
N=236,mean age 22 mo (9-38 mo)
10
15
20
25
30
35
13
Isarael(01-02)
N=516, age<5yr
17.9
Germany2(02-03)
17.5
Germany1(Jan-May02)
14.5
Austria(03-04)
2.9
Denmark(99-00)
N=63, age<2yr
N=214, mean age 10.1 mo
N=374
8
Finland(00-01)
N=116, age 3mo-16yr
N=132, age 3mo-16yr
21
Norwy(02-03)
N=236, median age 12 mo
25
Italy3(00-02)
Italy2(02-03)
2.8
Italy1(02-03)
3.1
N=1,505, age<15yr
N=1,331, age<15yr
8.5
France(03-04)
2.2
UK(00-01)
0
N=90, age<2yr
N=589, age<5yr
N=711, all age
5
10
15
20
25
30
11
Argentina(98-02)
N=440, age<5yr
16.2
Spain2(03-04)
14
Spain1(00-03)
6
Canada3(01-02)
N=749, age<2yr
N=208, age<3yr
14.8
Canada2(01-02)
7.1
Canada1(93-01)
2.6
USA5(01-04)
N=211, age<1yr
N=445, age 2mo-93yr)
N=38
N=1,294, all age
5
USA4(82-01)
N=2,384; detect AOM 50%
20
USA3(76-01)
6.4
USA2(01-02)
N=296
8.1
USA1(01-02)
0
5
N=248
10
N=668, age<5yr
15
20
25
Epidemiology of hMPV
• In the community ~2.2% - 5%
• In hospitalized children ~5% - 10%
– Age <18 years:
– Age <5 years:
– Age <3 years:
– Age <2 years:
– Age <1 year:
2.8% - 17.9%
5.5% - 13%
4.1% - 6%
11% - 25%
16.2%
Age and Seasonal Distribution of hMPV (All Age)
(Osterhaus A, Fouchier R. Lancet 2003;361:890. (N=115)
30
30
25
20
20
15
10
10
5
5
0
0
0-1
1-2
2-5
5-20 20-65 >65
Age range (years)
O
ct
N
ov
D
ec
Ja
n
Fe
b
M
ar
A
pr
M
ay
Ju
n
15
Ju
l
A
ug
Se
p
Number of patient
25
Month
Netherland
Age distribution of hMPV-positive children (Age <5 yrs)
(Esper F, et al JID 2004;189:1338. N=668)
16
54 cases (8.1%)
12
10
8
6
4
Months
58-60
55-57
52-54
49-51
46-48
43-45
40-42
37-39
34-36
31-33
28-30
25-27
22-24
19-21
16-18
13-15
10-12
7-9
0
4-6
2
0-3
No of patients
14
USA
Age distribution of hMPV-positive children (Age <3 yrs)
(Boivin G, et al Emerg Infect Dis 2003;9:634. N=208)
4
12 cases (6%)
3
2.5
2
1.5
1
Months
33-35
30-32
27-29
24-26
21-23
18-20
15-17
12-14
9-11
6-8
0
3-5
0.5
0-2
No of patients
3.5
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. Queensland Australia, 20012004 (Sloots TP, et al. Emerg Infect Dis 2006;12:1263)
20
N=10,025, All ages
15
10
5
0
Su Au W Sp
Su Au W Sp
Su Au W Sp
Su Au W Sp
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
Total
Year samples
tested
2001
59
A1
A2
B1
B2
58
24
8
10
2002
2003
2004
20
10
1
51
36
23
12
30
59
17
24
17
122
189
270
hMPV subtypes
• 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 agematched 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
40
35%
35
30
29%
hMPV 64 cases (14%)
RSV 376 cases (76%)
26%
hMPV
RSV
25%
25
20
17%
18%
17%
14%
15
12%
10
7%
5
0
<3 Months
3-6 Months
6-9 Months
9-12 Months
>12 Months
Monthly Distribution of hMPV and RSV (Age <1yr)
(Ordas J, et al. J Clin Microbiol 2006:2739. N=211)
100
RSA
hMPV
hMPV 18 cases (16.2%)
RSV 96 cases (45.5%)
90
80
70
60
50
40
30
20
10
Fe
pr
il
A
ar
ch
M
br
ua
r
y
y
nu
ar
em
ec
D
Ja
be
r
r
be
m
ov
e
N
O
ct
ob
er
0
Clinical Manifestation of hMPV (1)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Fever
Cough
Rhinorrhea
Sore throat
Hoarseness
Lacrimation
Conjunctivitis
Influenza-like illness
Common cold
Otitis media
Diarrhea
Vomiting
Febrile seizure
Truncal rash
Feeding difficulties
57 - 100%
63 - 100%
46 - 92%
50 - 59.5%
1 - 6%
25%
5 - 7%
50 - 53%
7 - 52%
12 - 51%
6 - 37.5%
10 - 48.5%
16%
10 - 19%
36 - 65%
Clinical Manifestation of hMPV (2)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Hypoxia
Wheeze
Dyspnea
Retractions
Hyperventilation
Cyanosis
Rhinitis
Rhinopharyngitis
Pharyngitis
Laryngitis
Tachycardia
Pneumonia
Bronchiolitis
Asthma exacerbation
Bronchitis
24 - 47%
0 - 83%
28 - 83%
60 - 92%
42%
4 - 8%
27 - 80%
5%
13 - 39%
5%
23 - 57%
8 - 73%
10 - 67%
14 - 22%
0 - 60%
Clinical Manifestation of hMPV (3)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Croup
Asthma
Irritability
Apnea
Noisy breathing
Tachypnea
67%
Rhonchi
Crackles (rales)
Sneezing
Dry mouth
Enlarged liver
Headache
Anorexia
Drowsiness
Lethargy
18%
14%
43%
2 - 6%
14%
20%
8 - 100%
45.5%
23%
6%
30%
45%
85%
26%
Lab Investigation
•
•
•
•
•
•
Lymphopenia (<1,500 cumm)
Neutropenia (<1,00 cumm)
Elevated transaminase
WBC (cumm)
LDH (IU/L)
CRP (mg/dL)
29%
6.5%
3.3%
5,930 - 16,500
269 - 649
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
– Exam by light and
electron microscopy
– BAL
Red cytoplasmic inclusion
• BAL showed
– Epithelial degenerative
changes and eosinophilic
cytoplasmic inclusions
within epithelial cells,
multinucleated giant cell,
histocytosis
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
Bronchodilator
Corticosteroids
Antibiotics
Mechanical ventilation
PICU
24.3 - 34.3%
30 - 32.4%
8.1 - 17%
22.2 - 94%
2%
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:
– 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
1. The Panton-Valentine leukocidin (PVL)
genes
2. SCC mec IV
•
Molecular methods
1. Pulsed-field gel electrophoresis (PFGE)
2. 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
Activation of T cells
EF, NP, TSS-like illness
Superantigen
-Enterotoxin
-Staph enterotoxin
A,B,C,G,H
-Staph exotoxin T
Pore-forming toxins
-PVL (LukSPV+LukFPV)
-LukE+LukD
LukE+LukDv
-hemolysin
Possible against immunity
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
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
PCR
PFGE
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 CAMSSA (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
CA-MRSA: Pneumonia
Necrotizing tracheobronchitis:
1. sloughing of bronchial mucosa
2. extensive necrosis of
subepithelial connective tissue
3. necrotic debris
Gonzalez BE, et al. Clin Infect Dis 2005;41:583
Necrotizing pneumonia:
1. patchy areas of hemorrhage
2. extensive intraalveolar
hemorrhage admixed with
neutrophil infiltrates
3. karyorrhectic debris
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 MLSBresistance phenotype
(macrolide-lincosamidestreptogramin B)
24 hrs, Temp 35 oC
Positive
– Inducible clindamycin
resistance (erm-mediated)
– No induction (msrAmediated erythromycin
resistance)
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?