Update on resistance and epidemiology of CAP pathogens in...

Cao Bin, MDDept Infectious Diseases and Clinical Microbiology

Beijing Chaoyang Hospital, Capital Medical

University

Update on resistance and epidemiology

of CAP pathogens in Asia

Outlines

• Resistance trends and clinical significance of resistant

pathogens in CAP

– typical pathogens

S. pneumoniae

H. influenzae

– atypical pathogens

Mycoplasma pneumoniae

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.

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

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

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

• 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

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

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

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

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

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

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

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

2005-2009: the prevalence of 19A and 19F

19A 19F

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

％

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

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

• 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

Shanghai Study: MIC distribution of

10 antibiotics to M. pneumoniae (n=53)

a Liu Y, et al AAC 2009

Digivote

What is the resistance rate of M. pneumoniae to

macrolides in adult CAP patients in China?

1.

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

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.


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


Hongli Song, Hui Wang, et al. Chinese Journal of Infection and Chemotherapy，2009, issue 3

• 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

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

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



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


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


24 96 256 4 0.25



48 192 128 2 2

• 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

• 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

Update on resistance and epidemiology of CAP pathogens in...

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