Update on resistance and epidemiology of CAP pathogens in Asia. Cao Bin, MD

Transcription

1 Update on resistance and epidemiology of CAP pathogens in Asia Cao Bin, MD Dept Infectious Diseases and Clinical Microbiology Beijing Chaoyang Hospital, Capital Medical University

2 Outlines Resistance trends and clinical significance of resistant pathogens in CAP typical pathogens S. pneumoniae H. influenzae atypical pathogens Mycoplasma pneumoniae

3 CAP pathogens (%) USA 1 Japan 2 Argentina 3 Spain 4 Israel 5 Thailand 6 Cases No S. pneumo M. pneumo C. pneumo H. influen S. aureus Legionella GNR Virus TB Mixed Infection Marston et al, Arch Int Med, 1997; 2 Miyashita et al, Chest, 2001; 3 Luna et al Chest, 2000; 4 Ruiz, Am J Respir Crit Care, 1999; 5 Thorax, Wattanathum A, et al. Chest, 2003.

4 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: Song H, et al. IJAA, 2008, 31:

5 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

6 Etiology of adult CAP in China Study period:dec Nov cases, 12 hospitals in seven cities 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% M.pneumoniae S.pneumoniae H.influenzae C.pnemoniae K.pneumoniae L.pneumoniae Viral Unknown Liu Youning, Chen Minjun, et al BMC infect Dis

7 Community acquired pneumonia in ambulatory adult patients in Beijing 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 Cao Bin, LiLi Ren, Fei Zhao, et al. EJCMID 2010, in press

8 Etiology of ambulatory adult CAP in Beijing N % Bacteria Streptococcus pneumoniae 8 Escherichia coli 2 Klebsiella pneumoniae 2 Pseudomonas aeruginosa 1 Virus IFVA 9 PIV 4 AdV 4 hmpv 2 Mycoplasma pmeumoniae Mycoplasma+virus RSV 2 HRV 2 COV 1 Bacteria+virus Streptococcus pneumoniae+piv 1 Klebsiella pneumoniae +IFVA 1 Streptococus spp+adv 1 Ralstonia pickettii +IFVA 1 Haemophilus influenzae +Mycoplasma+IFVA Mycobacterium tuberculosis 2 1 Unknown Total

9 MMWR (50): CLSI 2008 breakpoints of S. pneumoniae to penicillin MIC (ug/ml) S I R Old definition New definition Menigitis IV Pen Non-menigitis, IV Pen# Non-menigitis, Oral Pen # IV Pen: Penicillin:2mu q4h or 4mu q6h

10 Resistant trends of S. pneumoniae in China Antimicrobials All S.p (n=152) PSSP(n=110) PISP(n=38) PRSP(n=4)* S% MIC 90 S% MIC 90 S% MIC 90 MIC range Penicillin Amo/Cla Cefaclor 42.8 > > Cefprozil Ceftriaxone Erythromycin 13.2 > >256 >256 Tetracycline Levofloxacin Moxifloxacin PSSP=penicillin sensitive S. Pneumoniae PISP=penicillin intermediate S. Pneumoniae PRSP=penicillin resistant S. Pneumoniae *2008 CLSI New breakpoints Hongli Song, Hui Wang, et al. Chinese Journal of Infection and Chemotherapy,2009, issue 3

11 S. Pneumoniae: impact of modified non-meningeal penicillin breakpoints in CLSI isolates were identified in a hospital in Taiwan from 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 Ceftriaxone nonsusceptibility 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,

12 Distribution of pneumococcal serotypes from mainland China, % F 19A 6B 14 23F 15 Non-vaccine 0 Non-invasive Invasive Liu Y, Wang H, DMID, 2008

13 Antimicrobial susceptibility profiles among different serotypes Serotype No. of isolates Penicillin Amoxicillin/clavulanate Cefaclor Ceftriaxone %R %S %R %S %R %S %R %S 19F A F B NVS a

14 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

15 : the prevalence of 19A and 19F 19A 19F

16 Beta-lactamase prevalence in H. influenzae from 1996 to 2005 in Mainland China %

17 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

18 Resi st ance of M. pneumoni ae t o macl ol i des % Rapid increase of M.pneumoniae to macrolides in Japan ,380 stains of M. Pneumoniae from 3678 pediatric CAP in Japan 12.Morozumi M, et al. Antimicrob Agents Chemother, 2008,52(1):

19 Resistance of macrolides to M.pneumoniae in China 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 a Liu Y, et al AAC 2009; b Xin DL et al AAC 2009

20 Shanghai Study: MIC distribution of 10 antibiotics to M. pneumoniae (n=53) a Liu Y, et al AAC 2009

21 Digivote What is the resistance rate of M. pneumoniae to macrolides in adult CAP patients in China? 1. <10% % % %

22 Macrolide resistance of M. pneumoniae from Adult ambulatory CAP in Beijing: 68.7% Agents Erythromycin Clarithromycin Azithromycin Moxifloxacin Gatifloxacin Levofloxacin Ciprofloxacin Tetracycline Minocycline Bin Cao, Chunjiang Zhao, Yudong Yin, Hui Wang, Chen Wang, et al. CID 2010 in press

23 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

24 Phenotypic and genotypic characteristics of 67 M. Pneumoniae isolates PFGE type 23S rrna gene Mutation in ribosomal proteins genes Isolates (n) MIC (μg/ml) Range a L4 L22 AZM LVX MXF GAT TET I A2063G None T508C I A2064G None T508C I A2063T None T508C I None None T508C I None A209T T508C IIb None C162A+ A430G T279C +T508C 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

25 Clinical significance of macrolide-resistant M. pneumoniae infection 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 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 Suzuki, et al. Antimicrob Agents Chemother 2006; 50: Isozumi R, et al. Respirology 2009; 14:1206-8

26 Our study: Comparison between ambulatory adult CAP caused by M. pneumoniae with different in vitro susceptibility Erythromycin resistant M. pneumoniae group (N=42) Erythromycin susceptible M. pneumoniae group (N=17) Age (ys) ys 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 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) Duration of fever after initiation of antibiotics (days) 6 (5-8) 5 (3-7) (2-5) 3 (1.75-4) b Duration of respiratory symptoms (days) 10 (8-14) 8 (6-12) Duration of antibiotic therapy (days) 9 (7-12) 7 (6-11) b Antibiotics changed 20 (47.6) 6 (35.3) Changed to Macrolides 1 0 Changed to fluoquinolones 17 6 Changed to -lactams+macrolides 2 0 P

27 Our study: adult CAP patients with macrolides as initial antibiotics Age (y) sex PSI Initial Antibiotics Deferescence after initial antibiotics Antibiotic change T1 a (hr) T2 b (hr) MIC (μg/ml) ERY AZM LVX 17 M 17 Azithromycin 500mg qd iv x 48hr 23 M 23 Azithromycin 500mg qd po x 48hr 26 F 16 Azithromycin 500mg qd iv x 72hr 29 F 19 Rovamycin 200mg tid po x 168hr 21 M 21 Azithromycin 500mg qd po x 96hr 16 F 6 Azithromycin 500mg qd iv x 72hr 34 F 24 Azithromycin 500mg qd iv x72hr 16 M 16 Azithromycin 250mg qd iv x 120hr 19 F 9 Azithromycin 250mg qd po x 72hr 25 M 25 Azithromycin 500mg qd po x 144hr No No No Cefuroxime 1.5 Bid iv+azithromyci n500mg iv Levofloxacin 500mg iv Cefuroxime 1.5 Bid iv +azithromycin 500mg iv > No Levofloxacin 500mg po No Levofloxacin 500mg iv Yes No No No No Levofloxacin 500mg iv Azithromycin 500mg iv Levofloxacin 500mg iv Levofloxacin 500mg iv > >

28 Discussions 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.

29 Acknowledgements 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