Emerging Trends in

Resistance in Asia
Bin Cao
China
Emerging Trends in Resistance in Asia

Cao Bin, MD
Dept Infectious Diseases and Clinical Microbiology
Beijing Chaoyang Hospital, Capital Medical
University
9th RTI Forum
Ho Chi Minh City
7-8 March, 2015
 Outlines

• Common Antimicrobial resistance in CAP

– Streptococcus pneumoniae

– Staphylococcus aureus

– Mycoplasma pneumoniae

• ESKAPE pathogens in HAP

• Tuberculosis

• Rational use of antibiotics

 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

1Marstonet 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

 Etiology of adult CAP in China

Study period：Dec 2003 - Nov 2004; 610 cases,

12 hospitals in 7 cities
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
e e e e e e al wn
on
ia
onia en
za oni a on
ia
oni a Vir o
m m u m m m kn
e u eu .inf l ne ne
u
n eu U n
. pn S .pn H C.p K.p L.p
M

Liu Youning, Chen Minjun, et al. 2009. BMC infect Dis

Serotype distribution of Streptococcus pneumoniae
isolates from Asian countries

Kim et al, on behalf of ANSORP Study Group. AAC 2012; 56 (3): 1418-1426.
Which pathogen is most commonly implicated in
adult ambulatory CAP in China?

1. S. pneumoniae
1 0%

2. S. aureus 2 0%

3. M. pneumoniae 3 0%

4. P. aeruginosa 4 0%

1 2 3 4

0:15 Voted: 0
9
Risk factors for respiratory failure in pneumococcal
pneumonia: the importance of pneumococcal
serotypes

Burgos J, et al. Eur Respir J. 2014 Feb;43(2):545-53.

 Community-Acquired Respiratory Tract Infection
Pathogen Surveillance (CARTIPS) study, 2009–2010

• A multicentre resistance surveillance study in Asia

– 17 centers from China (Beijing, Wuhan, Taiwan), Indonesia,
Singapore

• 2963 clinical isolates of Streptococcus pneumoniae,

Haemophilus influenzae, Moraxella catarrhalis, Klebsiella
pneumoniae, methicillin-susceptible Staphylococcus aureus
(MSSA) and Streptococcus spp
• Based on the breakpoints for oral penicillin V recommended
by CLSI

Wang H et al. International Journal of Antimicrobial Agents, 2011, 38(5):376-83

 Results of CARTIPS study
• Penicillin-non-susceptible S. pneumoniae (PNSSP) ranged from 46%
to 100%
• Azithromycin and clarithromycin exhibited variable resistance rates of
0–88% against S. pneumoniae, 0–57% against MSSA and 0–76.5%
against Streptococcus spp
• Extended-spectrum -lactamase-producing K. pneumoniae varied
from 5.1% to 58.5%
• -Lactamase production rates amongst H. influenzae isolates ranged
from 15% to 46.6% and amongst M. catarrhalis isolates from 90% to
100%
• Amongst M. catarrhalis isolates, macrolide resistance and cefaclor
resistance rates of 5.8% and 1.2%

Wang H et al. International Journal of Antimicrobial Agents, 2011, 38(5):376-83

 Results of CARTIPS study

• Moxifloxacin was very active against Streptococcus spp.,

H. influenzae and M. catarrhalis isolates, with MIC90
values of 0.125–0.25, 0.032–0.5 and 0.064–0.125 mg/L
– Levofloxacin resistance rates of 0–3.9% with a MIC90 (minimum
inhibitory concentration causing inhibition of 90% of isolates) of 1–2
mg/L
– Moxifloxacin resistance rates of 0–1.7% with a MIC90 of 0.125–0.5
mg/L were found amongst PNSSP isolates

Wang H et al. International Journal of Antimicrobial Agents, 2011, 38(5):376-83

 Macrolide-resistant S. pneumoniae

Europe
29.4% Asia
74.7%
North America
(USA)
29.2% Middle East
(Saudi Arabia)

South America 22.6%

(Brazil) Africa
(South Africa)
9.5%
13.6%
Jones, et al. Diagn Microbiol Infect Dis 2003; 47(4):579-86.
Azithromycin-resistant (MIC > 1 µg/mL) Fouda, et al. J Chemother 2004; 16(6):517-23.
Erythromycin-resistant (MIC > 0.5 µg/mL) Jenkins,
14et al. J Infect 2005; 51(5):355-63.
 STAPHYLOCOCCUS AUREUS

• Over the last decade, community-acquired MRSA (CA-

MRSA) strains has been evolving rapidly
• CA-MRSA have been described worldwide, and their
prevalence varies widely from area to area
– USA300/ST8 has become the dominant clone in USA
– ST80 clone is prevalent in Europe, ST59 in Taiwan and
ST93 in Australia
• A study conducted at Texas Children’s Hospital over a 7-
year period showed an increasing rate of SA pneumonia,
from 4.81 hospitalisations per 10 000 admissions in 2001
to 9.75 per 10 000 admissions in 2009

15
 Community-acquired MRSA: a 6-year
surveillance study of invasive infections in
Chinese children

• The incidence of paediatric invasive MRSA infection,

particularly CA-MRSA infection, increased in Chinese
children between 2006 and 2011
• Invasive CA-MRSA infections rose from 0 to 2.43 per
10 000 admissions from 2006 to 2011
• The median age of the CA patients (n = 29) was
0.33 years, compared with 1.17 years for the HA patients
(n = 30)
• ST59-MRSA-IVa accounted for 40.7% of all isolates and
the Panton–Valentine leukocidin (PVL) gene carriage rate
was significantly higher in patients with necrotizing
pneumonia and osteoarthritis than in those with other
diseases
Yanhong Qiao, et al. Acta Paediatrica 2013; 102: 1081-6.
16
 Macrolide resistance Mycoplasma
pneumoniae (MRMP)

• Since 2000, the prevalence of macrolide-resistant

Mycoplasma pneumoniae (MRMP) has been described
with increasing incidence worldwide. MRMP has become
wide-spread in far East Asia, with up to 90% of
Mycoplasma pneumoniae strains being resistant in China
• Recent reports have also documented the emergence of
MRMP in the West, but still with lower prevalence: 8.2%
in United States, 0.9–2.9% in Denmark, 3% in Germany,
10% in France and 32% in Israel

17
 Rapid incease of M. pneumoniae to
macrolides in Japan
35
30.6
Resistance of M.pneumoniae to

30
25
maclolides %

20
15 12.5 13.5

10
5
5
0
0
2002 2003 2004 2005 2006

2002-2006, 380 stains of M. pneumoniae from 3678 pediatric CAP in Japan

Morozumi M, et al. Antimicrob Agents Chemother, 2008,52(1):348-350.

18
 Resistance of macrolides to M.
pneumoniae in China

• High resistance ratio of macrolides to M. pneumoniae

– 53 clinical isolates from children in Shanghai City: 83%
highly resistant to erythromycin (MICs>128mg/L),
azithromycin, clarithromycin1

– 50 isolates from children in Beijing: 92% resistant to

macrolides2

– 67 isolates from adults with CAP in Beijing: 69% resistance

to macrolides3
1 LiuY, et al. AAC 2000
2 Xin DL et al. AAC 2009

3 Bin Cao, et al. CID 2010

19
 Clinical significance of macrolide-
resistant M. pneumoniae infection
• Duration of fever after initiation of antibiotic therapy were
significantly longer for the erythromycin-resistant group than for
the erythromycin-susceptible group

Erythromycin-susceptible
M. pneumoniae group 3 (1.75-4)

P=0.043
Erythromycin-resistant M. pneumoniae group 4 (2-5)

0 1 2 3 4

Duration of fever after initiation of antibiotics (days)

Bin Cao et al. Clinical Infectious Diseases 2010; 51(2):189–194

20
What is not usually included in ESKAPE
pathogens?

1. Streptococcus pneumoniae 1 0%

2. Pseudomonas aeruginosa 2 0%

3. Klebsiella pneumoniae 3 0%

4. Enterococcus faecium 4 0%

5. Staphylococcus aureus 5 0%

6. Acinetobacter baumannii 6 0%

1 2 3 4 5 6

0:15 Voted: 0
21
The Top Four Pathogens for HAP//VAP in Asia

Chung DR, et al. Am J Respir Crit Care Med. 2011;184 1409–17.

 Bacterial spectrum for pneumonia after
abdominal surgery in elderly Chinese patients

• 5431 patients aged 65 years and over who had undergone abdominal
surgery at the 2nd affiliated hospital of Kunming medical college
between June 2003 and June 2011

• Postoperative pneumonia developed in 86 patients (1.58%).

• Gram-negative bacilli were the principal microorganisms (82.86%)

isolated from patients.
– The most common organisms isolated were Klebsiella spp. (28.57%),
Acinetobacter spp. (17.14%) and Pseudomonas aeruginosa (17.14%).

Chen P, et al. Arch Gerontol Geriatr 2014;59(1):186-9

Susceptibility of Klebsiella spp. to antimicrobial
agents in 2013 CHINET (%, n=12121)

ESBL:31.8%

Chin J infect Chemother, 2014;14(5):369-378

Susceptibility of P. aeruginosa to antimicrobial
agents in 2013 CHINET (%, 8257)

Chin J infect Chemother, 2014;14(5):369-378

Susceptibility of Acinetobacter spp. to antimicrobial
agents in 2013 CHINET (%, n=10120)

Chin J infect Chemother, 2014;14(5):369-378

Resistance rate of CRABA to antimicrobial agents
in 2014 Chao-Yang Hospital (n=252)

Ciprofloxacin
CRABA: carbapenem-resistant Imipenem
Acinetobacter baumannii Cefepime
Ceftriaxone
SICU,
Ceftazidime
RICU, 15% Piperacillin-tazobactam
15%
Ampicillin-sulbactam
ER, 13%
Piperacillin
EICU, RMW1, Meropenem
17% 4%
NICU, 4% Gentamicin
CICU, 4% Cefoperazone-sulbactam
Other, RMW5,
Amikacin
18% 3% Levofloxacin
Tobramycin
NICU, 3%
Minocycline
RMW4,
2% RMW2,
Trimethoprim-…
2% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90%100%

RMW: Respiratory Medicine Ward R(%) I(%) S(%)

Resistance rate of CRPAE to antimicrobial agents
in 2014 Chao-Yang Hospital (n=126)

CRPAE:carbapenem-resistant Imipenem

Pseudomonas aeruginosa Meropenem

Aztreonam

Piperacillin
SICU, 9% Hyperbaric Piperacillin-tazobactam
EICU, 9% oxygen, 8%
ER, 11%
Cefoperazone-sulbactam

Ceftazidime
SICU, 5%
RICU, 19% Respir
Ciprofloxacin
Ward
2, 5%
Cefepime
Respir
Ward1, Levofloxacin
Others, 26% 4%
NICU, 4% Gentamicin

Tobramycin

Amikacin
0%10%20%30%40%50%60%70%80%90%
100%

R(%) I(%) S(%)

Pulmonary Tuberculosis
Epidemiology
 National Survey of Drug-Resistant
Tuberculosis in China
• Among 3037 patients with new cases of tuberculosis and 892
with previously treated cases, 5.7% (95% confidence interval
[CI], 4.5 to 7.0) and 25.6% (95% CI, 21.5 to 29.8),
respectively, had multidrug-resistant (MDR) tuberculosis
(defined as disease that was resistant to at least isoniazid and
rifampin).
• Approximately 8% of the patients with MDR tuberculosis had
extensively drug-resistant (XDR) tuberculosis (defined as
disease that was resistant to at least isoniazid, rifampin,
ofloxacin, and kanamycin).

Yanlin Zhao, et al. N Engl J Med 2012;366:2161-70.

A systematic review of antibiotic utilization
in China

Xiaoxv Yin, et al. J Antimicrob Chemother 2013; 68: 2445–2452

Use and Prescription of Antibiotics in
Primary Health Care Settings in China

Jin Wang, et al. JAMA Intern Med. 2014;174(12):1914-1920

Use and Prescription of Antibiotics in
Primary Health Care Settings in China

Jin Wang, et al. JAMA Intern Med 2014;174(12):1914-1920

 Antibiotic misuse: a global crisis
 Antibiotic resistance has developed and spread predictably since
the advent of the first antibiotics and with each new drug brought to
market.
 Lack of microbiological diagnosis to support precise use of
antibiotics in hospitals
 Ideally, antibiotics on basis of accurately and timely
microbiological identification
 Clinical Microbiological capacity is essential and urgent for
 Unrestricted availability in communities
 Payment policies that promote physician prescribing of antibiotics

Bell M. JAMA Intern Med. 2014;174(12):1920-1

Clinical Microbiological capacity is essential
for Rational use of antibiotics

Microbiologic Lab
Serving for a
large hospital
with 1500 beds
One room for all
Bacteria, fungi
and TB

35

Photograph in 2006
Room for Identification Room for Blood culture

Photograph in 2009
Room for Fungi Room for serology

36
摄于2009.6.21
 ×

× ×
×
37
 VRE nosocomial infection rate
decreased

8
I
6.8
s 7
o
l 6 5.6
a
5
t
(

i
% 4
o 3.1
2.6
)

n 3
1.8
r 2
a 0.7
t
1
e 0
2003 2004 2005 2006 2007 2008
Year

2015/3/20
38
Changes in Chinese Policies to Promote the
Rational Use of Antibiotics

Yong H Xiao, et al. PLoS Med 2013; 10(11): e1001556

Changes in Antimicrobial Use Prevalence in China:
Results from Five Point Prevalence Studies

Figure 1. Changes in antimicrobial use prevalence (AUP; 95% confidence intervals) from 2001–
2010. A. The overall AUP of Chinese hospitals decreased over time. B. The AUP of the
Neurosurgery departments decreased over time. C. The AUP of the general intensive care units
remained stable. D. The AUP of the Infectious Diseases departments increased over time.

Chun H, Li, et al. PLoS ONE 2013; 8(12): e82785

Changes in Antimicrobial Use Prevalence in China:
Results from Five Point Prevalence Studies

Figure 2. A. Changes in the proportion of single or combination antimicrobial therapy (with 95%
confidence intervals) and B. the bacterial culture rate (BCR, with 95% confidence intervals).
• Administration of a single antimicrobial increased while that of two or more antimicrobials
declined over time.
• The overall BCR of Chinese hospitals increased over time.
Chun H, Li, et al. PLoS ONE 2013; 8(12): e82785
 Conclusions

 Resistance in S. pneumoniae and M. pneumoniae is

increasing in Asia
 Resistant Klebsiella spp., Acinetobacter spp. and
Pseudomonas aeruginosa are the main problems for HAP
 MRSA levels are stable but continue to be high
 Misuse of antibiotics is the main causes for bacterial
resistance
 Increased awareness of resistance through educational and
campaign activities is the basic and essential strategy to
control antimicrobial resistance
 Acknowledgements
• Beijing Chao-Yang Hospital, Beijing Institute of respiratory Medicine
– Microbiologic Staff: Yingmei Liu, Bin LiLi, JiuXin Qu, Chunlei Wang, Chunxia Yang

– Doctors: Li Gu, Yu-Dong Yin, Shu-Fan Song, Ran Li, Yiqun Guo, Yimin Wang

– Medical Students: Bo Liu, Hui Li, Fei Zhou, Men Liu, Shujing Shi

• Peking University Ren Min Hospital

– Hui Wang, MD

– Hongbin Chen, PhD

– Chun Jiang Zhao, PhD

– Qi Wang, PhD

43