Epidemiology Applications: Disaster and Environmental Epidemiology
Update on resistance and epidemiology of CAP pathogens in...
Transcript of Update on resistance and epidemiology of CAP pathogens in...
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Cao Bin, MDDept Infectious Diseases and Clinical Microbiology
Beijing Chaoyang Hospital, Capital Medical
University
Update on resistance and epidemiology
of CAP pathogens in Asia
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Outlines
• Resistance trends and clinical significance of resistant
pathogens in CAP
– typical pathogens
S. pneumoniae
H. influenzae
– atypical pathogens
Mycoplasma pneumoniae
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CAP pathogens (%)
USA1 Japan2 Argentina3 Spain4 Israel5 Thailand6
Cases No. 2776 200 343 395 346 147
S. pneumo 12.6 21 10.2 16.5 43 22
M. pneumo 12.5 9.5 5.5 3 29 7
C. pneumo 8.9 7.5 3.5 4 18 16
H. influen 6.6 11 5 3 5.5 3
S. aureus 3.4 5.0 2 2 3
Legionella 3.0 1.0 1 4.3 16 5
GNR 4.5 4.5 4 3.3 12
Virus 12.7 3 7 9.9 10 -
TB 1.4 4.9 2 - 2 -
Mixed Infection - 4 6 10 39 6
1Marston et al, Arch Int Med, 1997; 2Miyashita et al, Chest, 2001; 3Luna et al Chest, 2000; 4Ruiz, Am J Respir
Crit Care, 1999; 5 Thorax, 1996 6Wattanathum A, et al. Chest, 2003.
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Epidemiology of CAP in Asia
(ANSORP study)
• A prospective observational study of 955 cases of adult CAP in 14
hospitals in 8 Asian countries.
• S. pneumoniae was the most common pathogens (29.2%), followed by
K. pneumoniae (15.4%) and H. influenzae (15.1%); 17% of CAP had
mixed infection
• Serologic test was positive for M.pneumoniae (11.0%) and
C.pneumoniae (13.4%). Only 1.1% was positive for L.pneumophilia by
urinary antigen test.
• Of pneumococcal isolates, 56% resistant to erythromycin, and 52.6%
were non-susceptible to penicillin.
Song H, et al. IJAA, 2008, 31:107-114
Song H, et al. IJAA, 2008, 31:107-114
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Digivote
Which pathogen is most commonly implicated in
adult ambulatory CAP in China?
1.S. pneumonia
2.S. aureus
3.M. pneumonia
4.P. aeruginosa
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Liu Youning, Chen Minjun, et al. 2009. BMC infect Dis
Etiology of adult CAP in China
0%5%
10%15%20%25%30%35%40%45%50%
M.pn
eumo
niae
S.pne
umon
iae
H.inf
luenz
ae
C.pn
emon
iae
K.pn
eumo
niae
L.pne
umon
iae Viral
Unkn
own
Study period:Dec 2003 - Nov. 2004 610 cases, 12 hospitals in seven cities
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• Prospective cohort study,
– August 1st 2008 to July 31st 2009,
– Fever clinic of Beijing Chaoyang Hospital
• Inclusion criteria: adult ambulatory CAP
• Exclusion criteria:
– patients with HIV infection,
– neutropenia,
– receiving immunosuppressive chemotherapy
– patients from nursing homes or patients who had been admitted to a
hospital within the last 30 days
Community acquired pneumonia in
ambulatory adult patients in Beijing
Cao Bin, LiLi Ren, Fei Zhao, et al. EJCMID 2010, in press
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Etiology of ambulatory adult CAP in Beijing
N %
Bacteria 13 6.6Streptococcus pneumoniae 8
Escherichia coli 2
Klebsiella pneumoniae 2
Pseudomonas aeruginosa 1
Virus 19 9.6IFVA 9
PIV 4
AdV 4
hMPV 2
Mycoplasma pmeumoniae 58 29.4Mycoplasma+virus 5 2.5
RSV 2
HRV 2
COV 1
Bacteria+virus 4 2.1Streptococcus pneumoniae+PIV 1
Klebsiella pneumoniae +IFVA 1
Streptococus spp+AdV 1
Ralstonia pickettii +IFVA 1
Haemophilus influenzae +Mycoplasma+IFVA 1 0.5
Mycobacterium tuberculosis 2 1Unknown 95 48.2Total 197 100
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CLSI 2008 breakpoints of S. pneumoniae
to penicillin
MIC (ug/ml)
S I R
Old definition ≤0.06 0.12-1 ≥2
New definition
Menigitis IV Pen ≤0.06 — ≥0.12
Non-menigitis, IV
Pen#
≤2 4 ≥8
Non-menigitis, Oral
Pen
≤0.06 0.12-1 ≥2
MMWR 2008.57(50):1353-1355
# IV Pen: Penicillin:2mu q4h or 4mu q6h
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Resistant trends of S. pneumoniae in
China
AntimicrobialsAll S.p (n=152)
S% MIC90
PSSP(n=110)
S% MIC90
PISP(n=38)
S% MIC90
PRSP(n=4)*
MIC range
Penicillin 72.4 4 100 2 0 4 8
Amo/Cla 72.4 8 93.6 2 18.4 8 4-8
Cefaclor 42.8 >256 59.1 128 0 >256 32 - 128
Cefprozil 46.7 64 64.5 16 0 64 32-64
Ceftriaxone 80.9 4 98.2 1 39.5 4 2-4
Erythromycin 13.2 >256 17.3 256 2.6 >256 >256
Tetracycline 11.4 64 15.0 64 2.6 32 16-32
Levofloxacin 98.7 1 98.2 1 100 1 0.5-1
Moxifloxacin 100 0.25 100 0.125 100 0.250.064-0.125
Hongli Song, Hui Wang, et al.
Chinese Journal of Infection and Chemotherapy,2009, issue 3
*2008 CLSI New breakpointsPSSP=penicillin sensitive S. PneumoniaePISP=penicillin intermediate S. Pneumoniae
PRSP=penicillin resistant S. Pneumoniae
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S. Pneumoniae: impact of modified
non-meningeal penicillin breakpoints in CLSI 2008
• 3729 isolates were identified in a hospital in Taiwan from 2000-2007
• For non-meningeal isolates, penicillin non-susceptibility was reduced
significantly from 75.1% to 16% if the modified breakpoints were used
• However, isolates for which penicillin MICs were 1–2 mg/L increased
significantly from 34.2% in 2000 to 59.8% in 2007. Ceftriaxone non-
susceptibility increased significantly from 2.8% before 2005 to 18.4%
thereafter.
• Using the new breakpoints, clinicians may continue to use penicillin for
the treatment of non-meningeal pneumococcal infections. However, as
isolates with borderline penicillin MICs are increasing, continued
surveillance of pneumococcal susceptibility will be needed.
Su L, et al. Journal of Antimicrobial Chemotherapy (2009) 64, 336–342
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Distribution of pneumococcal serotypes
from mainland China, 2005-2006
0
5
10
15
20
25
30
35
40
45
Non-invasive Invasive
19F
19A
6B
14
23F
15
Non-vaccine
%
Liu Y, Wang H, DMID, 2008
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Antimicrobial susceptibility profiles
among different serotypes
Serotype No. of isolates Penicillin Amoxicillin/clavulanate Cefaclor Ceftriaxone
%R %S %R %S %R %S %R %S
19F 27079.1 7.8 36.6 43.7 90.7 6.9 53.0 23.1
19A 16284.0 11.1 29.6 29.6 88.1 11.9 46 19.9
23F 6932.4 25.0 1.5 95.6 58.8 32.4 38.2 54.4
14 5840.4 26.3 5.3 93.0 66.7 22.8 8.8 78.9
15 5315.1 58.5 1.9 96.2 38.0 60.0 3.8 79.2
3 598.6 89.7 1.7 94.8 11.3 88.7 0.0 93.1
6B 3125.8 41.9
0.096.8 55.2 34.5 0.0 64.5
11 175.9 88.2
0.0 1005.9 88.2
0 94.1
5 1216.7 66.7 8.3 83.3 25.0 58.3 16.7 83.3
NVSa 23111.8 73.2 3.5 95.6 24.7 67.7 6.1 87.7
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2005-2009 PRSP (oral) and PNSSP (parenteral)
rate in Mainland China
Changes in the oral penicillin resistant rates (A) and penicillin parenteral non-susceptible rates (B) of
Streptococcus pneumoniae from 2005 to 2009 among different age groups. Oral penicillin resistance
was defined as MIC ≥2μg/mL and penicillin parenteral non-susceptibility was defined as MIC
≥4μg/mL
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2005-2009: the prevalence of 19A and 19F
19A 19F
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Beta-lactamase prevalence in H. influenzae
from 1996 to 2005 in Mainland China
0
5
10
15
20
25
1996 1999 2000 2001 2002 2005 2006
%
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Discussions
• S.pneumoniae and H. influenzae are an important
pathogens in CAP.
• Resistance in S. pneumoniae is increasing worldwide
– In Asia, macrolides resistance is higher than in
other areas
– Penicillin and macrolides resistance are clinically
significant
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Rapid increase of M.pneumoniae to
macrolides in Japan
0
5
12. 5 13. 5
30. 6
0
5
10
15
20
25
30
35
2002 2003 2004 2005 2006
Re
si
st
an
ce
o
f
M.
pn
eu
mo
ni
ae
t
o
ma
cl
ol
id
es
%
12.Morozumi M, et al. Antimicrob Agents Chemother, 2008,52(1):348-350.
2002-2006,380 stains of M. Pneumoniae from 3678 pediatric CAP in Japan
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• High resistance ratio of macrolides to
M.pneumoniae
– a 53 clinical isolates from children in Shanghai City:
83% highly resistant to erythromycin
(MICs>128mg/L) ,azithromycin, clarithromycin
– b 50 isolates from children in Beijing: 92% resistant
to macrolides
Resistance of macrolides to M.pneumoniae in China
a Liu Y, et al AAC 2009; b Xin DL et al AAC 2009
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Shanghai Study: MIC distribution of
10 antibiotics to M. pneumoniae (n=53)
a Liu Y, et al AAC 2009
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Digivote
What is the resistance rate of M. pneumoniae to
macrolides in adult CAP patients in China?
1.
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Agents ≤0.008 0.
01
6
0.
03
2
0.
06
4
0.
12
5
0.
25
0.5 1 2 4 8 16 32 64 12
8
25
6
Erythromycin 16 1 1 6 30
Clarithromycin 16 1 1 10 26
Azithromycin 16 1 3 14 16 3 1
Moxifloxacin 1 6 47
Gatifloxacin 1 15 29 9
Levofloxacin 4 2 39 6 2 1
Ciprofloxacin 1 1 12 38 2
Tetracycline 1 8 14 19 8 4
Minocycline 2 10 20 15 4 3
Macrolide resistance of M. pneumoniae from Adult
ambulatory CAP in Beijing: 68.7%
Bin Cao, Chunjiang Zhao, Yudong Yin, Hui Wang, Chen Wang, et al. CID 2010 in press
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Mutation of domain V of the 23S rRNA gene was
associated with macrolide resistance
A2063G,
A2064G,
A2063T.
The mutations of 23S rRNA have been deposited in the GenBank sequence database
and were assigned the accession numbers HM043729, HM043730, HM043731, respectively.
Bin Cao, Chunjiang Zhao, Yudong Yin, Hui Wang, Chen Wang, et al. CID 2010 in press
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Phenotypic and genotypic characteristics of
67 M. Pneumoniae isolates
PFGE
type
Mutation in Isolates
(n)
MIC (μg/ml) Range a
23S
rRNA
gene
ribosomal
proteins genes
L4 L22 AZM LVX MXF GAT TET
I A2063G None T508C 41 2-32 0.125-2 ≤.008-
0.032
0.016-
0.064
0.032-0.5
I A2064G None T508C 4 4-8 0.5-0.25 0.032 0.016-
0.064
0.125-
0.25
I A2063T None T508C 1 0.064 0.25 0.032 0.064 0.25
I None None T508C 10 0.008 0.008-0.5 0.016-
0.032
0.016-
0.064
0.032-0.5
I None A209T T508C 3 0.008 0.25-0.25 0.032-
0.032
0.032-
0.032
0.064-
0.125
IIb None C162A+
A430G
T279C
+T508C
8 0.008 0.008-
0.25
0.016-
0.032
0.008-
0.032
0.016-
0.125
Bin Cao, Chunjiang Zhao, Yudong Yin, Hui Wang, Chen Wang, et al. CID 2010 in press
Hongli Song, Hui Wang, et al. Chinese Journal of Infection and Chemotherapy,2009, issue 3
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• Among pediatric patients: total febrile days and the number of febrile
days during macrolide administration were longer for pediatric
patients who were infected by macrolide-resistant M. pneumoniae
• Case report from Japan 2009
– 28 year-old woman with M. pneumoniae pneumonia (MIC of 64μg
/ml for clarithromycin) failed to respond to 4-day treatment with
sulbactam/ampicillin and clarithromycin
– Pazufloxacin was given in place of the previous 2 antibiotics and
rapid clinical improvement occurred
Clinical significance of macrolide-resistant
M. pneumoniae infection
Suzuki, et al. Antimicrob Agents Chemother 2006; 50:709-12
Isozumi R, et al. Respirology 2009; 14:1206-8
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Our study: Comparison between ambulatory
adult CAP caused by M. pneumoniae with
different in vitro susceptibilityErythromycin resistant M.
pneumoniae group (N=42)
Erythromycin susceptible M.
pneumoniae group (N=17)
P
Age — (ys) 29.1 11.7 30.7 10.1 0.615
16-17ys 5 (11.9) 1 (5.9)
18-50ys 32 (76.2) 15 (88.2)
51ys 5 (11.9) 1 (5.9)
Male 18 (42.9) 8 (41.2) 1.0
Initial antibiotios 0.395
-lactams 20 (47.6) 11 (64.7)
Macrolides 9 (21.4) 1 (5.9)
fluoquinolones 10 (23.8) 4 (23.5)
-lactams+macrolides 3 (7.1) 1 (5.9)
Duration of fever from onset of illness
(days)
6 (5-8) 5 (3-7) 0.138
Duration of fever after initiation of
antibiotics (days)
4 (2-5) 3 (1.75-4) 0.043 b
Duration of respiratory symptoms (days) 10 (8-14) 8 (6-12) 0.109
Duration of antibiotic therapy (days) 9 (7-12) 7 (6-11) 0.032 b
Antibiotics changed 20 (47.6) 6 (35.3) 0.523
Changed to Macrolides 1 0
Changed to fluoquinolones 17 6
Changed to -lactams+macrolides 2 0
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Our study: adult CAP patients with
macrolides as initial antibiotics
Age (y)
sex PSI Initial Antibiotics Deferescence after initial antibiotics
Antibiotic change
T1a(hr)
T2b(hr)
MIC (μg/ml)
ERY AZM LVX
17 M 17 Azithromycin 500mg qd iv x 48hr
No Cefuroxime 1.5 Bid iv+azithromycin500mg iv
48 96 >256 8 0.25
23 M 23 Azithromycin 500mg qd po x 48hr
No Levofloxacin 500mg iv
24 72 256 4 0.25
26 F 16 Azithromycin 500mg qd iv x 72hr
No Cefuroxime 1.5 Bid iv +azithromycin500mg iv
48 120 128 4 0.25
29 F 19 Rovamycin 200mg tid po x 168hr
No Levofloxacin 500mg po
48 216 128 2 0.25
21 M 21 Azithromycin 500mg qd po x 96hr
No Levofloxacin 500mg iv
24 120 256 4 0.25
16 F 6 Azithromycin 500mg qd iv x 72hr
Yes 72 ≤0.008 ≤0.008 0.25
34 F 24 Azithromycin 500mg qd iv x72hr
No Levofloxacin 500mg iv
12 84 >256 8 0.50
16 M 16 Azithromycin 250mg qd iv x 120hr
No Azithromycin 500mg iv
24 144 >256 8 0.25
19 F 9 Azithromycin 250mg qd po x 72hr
No Levofloxacin 500mg iv
24 96 256 4 0.25
25 M 25 Azithromycin 500mg qd po x 144hr
No Levofloxacin 500mg iv
48 192 128 2 2
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• Duration of therapy and time to resolution of fever were significantly
longer in those patients who received macrolide and were infected
with macrolide-resistant strains.
• Among 10 adult CAP patients with M. pneumoniae infection who
received macrolides monotherapy, resolution of fever 72 hours after
initiation of azithromycin was achieved in only one patient (MIC of
azithromycin ≤0.008μg/ml).
• No fever response at 72 hour after initiation of azithromycin with MIC
of azithromyicn ≥ 2 μg/ml.
Discussions
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• Beijing Chao-Yang Hospital, Beijing Institute of respiratory Medicine
– Yu-Dong Yin, Shu-Fan Song, Lu Bai, Li Gu, MD
– Yingmei Liu, Ping Guo, Fang Li, Bin Bin Li. PhD
• Peking Union Medical College Hospital
– Hui Wang, PhD
– Chun Jiang Zhao, PhD
• Chinese Center for Disease Control and Prevention
– Fei zhao, PhD
– Jian Zhong Zhang, PhD
• Institute of Pathogen Biology, Chinese Academy of Medical Science
– Li Li ren PhD
– Jian wei Wang, PhD
Acknowledgements