革蘭氏陽性球菌-Zhengzhou-060310.ppt

1、Po-Ren Hsueh (薛博仁) National Taiwan University Hospital,陽性球菌的耐藥和治療問題,臺灣大學(xué)醫(yī)學(xué)院附設(shè)醫(yī)院,醫(yī)院規(guī)模,Bacteria: A Colorful World,S aureus,S pneumoniae,H influenzae,P aeruginosa,K pneumoniae,C neoformans,Nocardia,M tuberbulosis,Staphylococcus,Aspiration pneumonia,P jirovecii,Aspergillus,8,Resistance Problems in Gram-

2、Positive Infections,No. of isolates,% of isolates,Trends of Penicillin and Erythromycin Resistance Disk Method, S. pneumoniae, NTUH, 1984-2009,Annual Death Rates in the United StatesSelected Infectious Diseases,No. of patients died,Boucher HW and Corey GR. Clin Infect Dis 2008;46:S344-9.,Prevalence

3、of MRSA in China,798 isolates, 2005, 12 Cities, China,%,Wang H et al. Diagn Microbiol Infect Dis 2008;62:226-9.,CHINET 2007 58% (1963/3384) Mohnarin 20062007 56.1%,Community-acquired MRSA in Asia,ANSORP Surveillance in Asia-2005-6,%,Hsueh PR, Song JH et al. ANSORP 2006,Community-acquired S. aureus B

4、acteremia 2001-2006, NTUH, 215 Episodes,Wang JL, Hsueh PR et al. Clin Infect Dis 2008;46:799-806.,CaMRSA: increase 32%/yr CaMSSA: stable,MRSA Causing Nosocomial InfectionsNTUH, 1986-2009,No. of strains,%,2009,%,MRSA Bacteremia at ED 2001-2006, NTUH, 177 Episodes,Liao CH, Hsueh PR et al. Int J Antimi

5、crob Agents 2008;32:326-32.,Overall mortality 59 (33.3%),%,MRSA Bacteremia at ED 2001-2006, NTUH, 177 Episodes,Liao CH, Hsueh PR et al. Int J Antimicrob Agents 2008;32:326-32.,Overall mortality 59 (33.3%),%,MRSA Bacteremia at ED 2001-2006, NTUH, 177 Episodes,Liao CH, Hsueh PR et al. Int J Antimicrob

6、 Agents 2008;32:326-32.,Overall mortality 59 (33.3%),Nosocomial Pneumonia due to MRSA,Sputum and blood: MRSA,Vancomycin-Nonsusceptible S. aureus,Brazil (5) (1998-1999),USA (7)(1997-2000),South Africa (2) (1998),Taiwan (2005),Japan (1) (1996),Korea (1) (1997),France (1) (1995),Greece (1) (2000),Germa

7、ny (1) (1993),U.K (1) (2001),Belgium (3) (1999),VISA,VRSA,(VISA : 24 cases, 1996-2002, VRSA ; 4 cases till 2005),23,Emergence of hetero-VISA in Asia,Song JH et al. Antimicrob Agents Chemother 2004;48;4926.,Europe 1.0% 8% (22%),Low DE et al. Clin Infect Dis 2001;32:S133-S45. SENTRY 2007,United States

8、 17.0%27% (72%),Asia Pacific 1.0% 5% (10%),Latin America 2.0% 9% (36%),Worldwide Prevalence of VRE 1997-1999 VRE (E. faecium) 2005-2007,VRE in China,Yang Q et al. Chin J Infect Chemother 2009 Xiao YH et al. Chin J Nosocom Infect 2008,%,%,Prevalence of VRENTUH, 1996-2009,% of VRE,Clinical isolates,No

9、socomial isolates,No. of patients,Year,% of isolates,VRE Bacteremia NTUH, 2000-2008,No. of enterococcal bacteremia,Vancomycin-resistant E. faecium,Febrile Neutropenia,Etiology of Bloodstream Infections in Adult Hematological Malignancy Patients with Febrile Neutropenia 1242 Patients, NTUH, 2002-6,Ch

10、en CY, Hsueh PR et al. Epidemiol Infect 2009 .,51-63%,34-42%,4-9%,Etiology of Gram-Positive Bacteremia in Hematological Malignancy Patients (N=3974) 524/285 Episodes, 2002-2006, NTUH,(n=147),(n=121),(n=65),(n=40),(n=30),(n=24),(n=86),(n=73),(n=36),(n=31),(n=19),(n=19),% of isolates among all bactere

11、mic isolates,VRE 4/19=21%,MRSA 49%/56%,Pen-R 14%/14%,Chen CY, Hsueh PR et al. Epidemiol Infect 2009 .,Factors Responsible for the Shift toward Gram (+) Infections,Oral mucositis (potent chemotherapy) Profound and prolonged neutropenia Increasing use of long-dwelling intravascular catheters Fluoroqui

12、nolone and SXT prophylaxis Use of antacids and H2 blockers,Zinner SH. Clin Infect Dis 1999;29:490-4.,Hughes WT et al. Clin Infect Dis 2002;34:730-51.,Treatment of Resistant Gram-Positive Infections,Gold standard Vancomycin Teicoplanin,Older agents Trimethoprim-sulfamethoxazole Fluoroquinolones Eryth

13、romycin Clindamycin Rifampin Aminoglycosides Tetracyclines Fusidic acid,Drew RH. Pharmacotherapy 2007;27:227-49.,38,38,Evolution of “Mississippi Mud”,Vancomycin for S. aureus InfectionsThe End of An Era ?,Persistent MSSA, MRSA bacteremia in hemodialysis patients MSSA endocarditis with bacteremia Van

14、comycin use, endocarditis: relapse MRSA ventilator-associated pneumonia,Nathwani D et al. Int J Antimicrob Agents 2003;21:521-4.,Higher Infection-related Mortality in IVDU with MSSA IE Vancomycin vs -lactams,P=0.08,P=0.005,P=0.04,Lodise TP Jr et al. Antimicrob Agents Chemother 2007;51:37313,IVDU, in

15、travenous drug users,Vancomycin Susceptibility among S. aureus,VancomycinName MIC, mg/mL susceptibility Susceptible VSSA 2 Heteroresistant hVISA/hGISA 12a Intermediate VISA or GISA 48 Resistant VRSA 16,Sakoulas G and Moellering RC Jr. Clin Infect Dis 2008;46:S360-7. CLSI M100-S20, 2010,a Consist of

16、subpopulations (106) that may grow in media containing 2 mg/mL vancomycin No more disk diffusion methods,Vancomycin Zone Diameter vs. MIC S. aureus,Vancomycin Zone (mm),Vancomycin MIC (g/ml),CLSI AST Subcommittee Agenda Book. 6/08.,SUSC,RES,Former (2008) 15 mm cutoff,Disk (S) but MIC (VISA),MIC test

17、s should be performed to determine the susceptibility of all isolates of staphylococci to vancomycin. The disk test does not differentiate vancomycin-susceptible isolates of S. aureus from vancomycin-intermediate isolates, nor does the test differentiate among vancomycin-susceptible, intermediate, a

18、nd resistant isolates of coagulase-negative staphylococci, all of which will give similar size zones of inhibition.,Clonal Dissemination of VISA (n=43) A Medical Center, Taiwan,20/21 patients (95.2%) belonged to pulsotype A Van (MIC, 4 g/mL) Lin (MIC, 0.5 g/mL,Hsueh PR et al. Data submitted.,Phoenix

19、,Vitek 2,MicroScan,Automated Systems Inadequately Capture Vancomycin MIC Creep,Golan Y, et al. IDSA October 15, 2006; Toronto, Canada. Abstract LB11.,MRSA Blood Isolates From a Tertiary Care Hospital During a 4-Year Period (n=223),VancomycinDosing,Half-life Normal (6 hr), ESRD (200-250 hr) Dosing (a

20、djusted CrCl) Loading dose25-30 mg/kg 50-9015-20 mg/kg q12h (burn, q8h) 10-50 15-20 mg/kg q24-96h 10 15-20 mg/kg q4-7d Hemodialysis, CAPD 15-20 mg/kg q4-7d CAVH, CVVH500 mg q24-48h New membrane: increased clearance (check level),Vancomycin Therapeutic Guidelines Recommended by IDSA, ASHSP, SIDP,A lo

21、ading dose of 2530 mg/kg Trough levels (effectiveness) Obtained just before the fourth doses 10 mg/L to avoid the development of hVISA 15-20 mg/L for complicated infections (bacteremia, endocarditis, HAP osteomyelitis, meningitis) AUC/MIC of 400 MIC 1 mg/L: 1520 mg/kg every 812 h (1.5 g q12h) MIC 2

22、mg/L: not achievable Individual doses 1 g, extended infusion period (1.52 h),Rybak MJ et al. Clin Infect Dis 2009;49:325-7.,Vancomycin-Associated Nephrotoxicity Grave Concern or Death by Character Assassination?,Vancomycin-associated nephrotoxicity 1 g q12h: 0% to 5% Higher doses: increasing rates C

23、onfounded by concomitant nephrotoxins, renal insufficiency, or changing hemodynamics Inadequate dosing increases the likelihood of selecting hVISA-MRSA isolates,Hazlewood KA et al. Am J Med 2010;123:182.e1-182.e7.,Vancomycin Therapeutic Guidelines Recommended by IDSA, ASHSP, SIDP,No need to monitor

24、peak levels to decrease the frequency of nephrotoxicity Monitoring trough level Aggressive dose targeting to trough 1520 mg/L At risk of toxicity (concurrent nephrotoxic drugs, AG) Unstable renal function (worse or better) Prolonged courses of therapy (35 days) Once (short-course and low-intensity)

25、Once-weekly (trough 1520 mg/L, 5 days),Rybak MJ et al. Clin Infect Dis 2009;49:325-7.,Time-Kill for MRSAVancomycin, Bactericidal?,GC,Standard dose,Higher dose,GC,Standard dose,Higher dose,Van MIC 0.25 mg/L,Van MIC 2.0 mg/L,Leonard SN, Rybak MJ et al. J Antimicrob Chemother 2009;63:155-60.,Dosing of

26、Teicoplanin,A trough plasma level of 10 g/mL for severe infections and 20 g/mL for endocarditis and bone or prosthetic infections,J Antimicrob Chemother 2003;51: 9715.,4.24,6.47,10.8,6.11,11.22,8.66,Teicoplanin Levels in Critically Ill PatientsLoading Dose Is Needed,6 mg/kg every 12 h for three dose

27、s,Vancomycin and MRSA-An Antibiotic Enters Obsolescence-,MIC “Creep” and poor therapeutic response to vancomycin Limitation of laboratory detection of reduced vancomycin susceptibility Penetration into tissue is poor Increasing dose may not safely overcome its poor activity Inferior to some comparat

28、ors In combination does not improve efficacy,Deresinski S et al. Clin Infect Dis 2007,MRSA, VISA Vancomycin MIC CreepBlood Isolates, 20012005,Steinkraus G et al. J Antimicrob Chemother 2007;60:78894.,%,Vancomycin MIC vs. MRSA Bacteremia,Moise-Broder PA et al. Antimicrob Agents Chemother 2007.,Vancom

29、ycin MIC (g/ml),Days,More Vancomycin Failures at Higher MICs,Vancomycin MIC,Vancomycin Clinical Success %,Sakoulas, et. al., JCM, June 2004; Moise-Broder, PA et al. Clin Infect Dis 2004; 38: 1700-5.; Hidayat L, Arch Intern Med. 2006;166:2138-2144,Need of High-Dose Vancomycin for MRSA Infections,EOT,

30、 end of therapy,Hidayat LK et al. Arch Int Med 2006;166:2138214,Response in patients achieving vancomycin trough 15 g/ml,AUIC 400,Relationship between Initial VancomycinTrough Value and the Rate of Nephrotoxicity,Lodise TP et al. Clin Infect Dis 2009;49:50714.,Initial trough value (mg/L),Rate (%) of

31、 nephrotoxicity,Duration of Persistant MRSA BacteremiaAppropriate vs. Inappropriate Empiric Therapy,Kim SH et al. Clin Microbiol Infect 2006;12:13-21.,19,13,13,Treatment failure,MRSA Bacteremia in NTUHPersistent Bacteremia (7 Days), 30-50/Yr,Average (392/1878),%,Liao CH, Hsueh PR et al. Clin Microbi

32、ol Infect 2010,MRSA Bacteremia in NTUHPersistent Bacteremia (7 Days), 30-50/Yr,Liao CH, Hsueh PR et al. Clin Microbiol Infect 2010,Elevated vancomycin MICs of subsequent MRSA isolates was found in 49 (24.6%) patients, especially those with infective endocarditis (41.9% vs. 21.4%; P = 0.027) The 30-d

33、ay mortality rate was lower in patients who received complete foci eradication (35.6% vs. 51.1%; P = 0.03) Metastatic infection (odds ratio OR, 5.09), congestive heart failure (OR, 4.80), elevated vancomycin MICs of subsequent MRSA isolates (OR, 2.98) were independent predictors of MRSA-related mort

34、ality Isolates with decreased susceptibility to vancomycin emerged during persistent MRSA bacteremia and adversely affected outcome,Vancomycin and S. aureus-An Antibiotic Enters Obsolescence-,Deresinski S et al. Clin Infect Dis 2007.,There is an antibiotic called mud Thats proving to be quite a dud.

35、 Its provenance is jungle Its use is a bungle It just wont get rid of your crud.,Vancomycin was derived from a streptomycete recovered from a sample of soil obtained in the Borneo rain forest (“Mississippi mud”),Novel Agents for Gram-Positives,MIcek ST et al. Clin Infect Dis 2007;45:S184-90.,Linezol

36、id,Gram (+), anaerobes (some), mycobacteria, nocardia Inhibiting protein synthesis (bacteriostatic) No cross resistance Time-dependent PK/PD, PAE (AUIC) T1/2, 4-6 hours Good tissue penetration (CSF, lung) Nosocomial pneumonia, meningitis Marrow suppression (anemia, thrombocytopenia),CLSI-2010Staphyl

37、ococci,Linezolid 4 mg/ml, susceptible; 8 mg/ml, resistant Vancomycin MIC tests should be performed The disk test does not differentiate vancomycin-susceptible isolates of S. aureus from vancomycin-intermediate isolates, nor does the test differentiate among vancomycin-susceptible, intermediate, and

38、resistant isolates of coagulase-negative staphylococci, all of which will give similar size zones of inhibition,CLSI M100-S20, 2010,Susceptibility of MRSA in China,798 Isolates, 2005, 12 Cities, China,%,(g/mL) MIC range MIC90 Vancomycin 0.125-2 2 Linezolid 0.25-2 2 Tigecycline 0.064-0.5 0.5 Cefobipr

39、ole 0.125-2 2,Wang H et al. Diagn Microbiol Infect Dis 2008;62:226-9.,Linezolid MIC Distributions for S. aureus ZAAPS Program, 20022007,ZAAPS: The Zyvox Annual Appraisal of Potency and Spectrum,Jones RN et al. Diagn Microbiol Infect Dis 2009;64:191-201.,Dosage GuidelinesLinezolid,Infection Dosage (r

40、oute) Duration (days) VRE (faecium) infection, Including bacteremia600 mg (IV, PO) q12h 14-28 Nosocomial pneumonia600 mg (IV, PO) q12h 10-14 Complicated SSSI600 mg (IV, PO) q12h 10-14 CAP and bacteremia600 mg (IV, PO) q12h 10-14 Uncomplicated SSSI400 mg (PO)q12h 10-14,US FDA,Sputum, pleural effusion

41、 and blood: MRSA,Case 1,Linezolid Penetrationin the Epithelial Lining Fluid (ELF),Stein GE, Wells EM. Curr Med Res Opin 2010; 26:571-88.,Vancomycin Penetrationin the Epithelial Lining Fluid (ELF),Stein GE, Wells EM. Curr Med Res Opin 2010; 26:571-88.,Vancomycin distribution into ELF may be below MIC

42、s for susceptible staphylococci, which may diminish its efficacy in treatment of MRSA pneumonia Linezolid shown to achieve high ELF concentrations A possible explanation for reported clinical outcomes with linezolid may be due to excellent tissue distribution and sustained activity against MRSA,Noso

43、comial pneumonia due to MRSA Vancomycin and Linezolid,Stein GE, Wells EM. Curr Med Res Opin 2010; 26:571-88.,Risk Factors for Treatment Failure in MRSA VAP,Surg Infect 2010;11:21-28.,Algorithm for the Management of VAP When MRSA Risk Factors Are Present,Niederman MS. J Infect 2009; 59:S25-31.,MRSA+

44、Clinical response,Continue ?,Yes,Previous vancomycin exposure,Changes in Etiology of CAP,Community-associated MRSA,Rubinstein E et al. Clin Infect Dis 2009;46;S378.,Necrotizing pneumonia,Survival of S. aureus PneumoniaCorrelation with Panton-Valentine Leukocidin (PVL) Gene,Rubinstein E et al. Clin I

45、nfect Dis 2008;46:S375-85.,Efficacy of Linezolid against Panton-Valentine leukocidin (PVL)-positive MRSA A Mouse model of Hematogenous Pneumonia,Yanagihara K, et al. Int J Antimicrob Agents 2009;Aug 6.,PVLpositive with severe necrotising pneumonia Three days after antibiotics (P0.05) Viable bacteria

46、: control, VAN and LZD groups was 6.77+/-0.14, 5.29+/-0.27, and 4.25+/-0.33 log CFUs/lung, respectively Survival rate at Day 7 post-inoculation: LZD group (100%), VAN group (50%) or the control group (0%) LZD significantly reduced bacterial numbers and inflammation in a mouse model of PVL-positive S

47、. aureus hematogenous infection and improved the survival rate of infected mice compared with VAN,Falagas ME et al. Lancet Infect Dis. 2008;8:53-66.,Linezolid vs. Glycopeptides or -lactam for Treatment of Gram-positive Bacterial Infections Bacteremia,P=0.02,Treatment for Skin and Soft Tissue Infecti

48、onAlgorithm,Gram (+) bacteria,Streptococci, Enterococci, CoNS,MRSA,MSSA,Vancomycin Teicoplanin,Linezolid,Beta-lactams,TSST-1, PVL (SA) SPEs (GAS),Falagas ME et al. Lancet Infect Dis. 2008;8:53-66.,Linezolid vs. Glycopeptides or -lactam for Treatment of Gram-positive Bacterial Infections Skin and Sof

49、t-Tissue Infection,P0.0001,Rate (%),Linezolid for VRE Infections490 Patients, Compassionate Use,53/61,22/28,19/26,Birmingham MC, et alClin Infect Dis 2003;36:159-68.,VRE BacteremiaLinezolid vs. Daptomycin,98 adult patients Linezolid (n=68) , daptomycin (n=30) No differences between baseline conditio

50、ns Daptomycin vs. linezolid (P 0.2). Higher mortality rate (26.7% vs. 20.6%) Longer median duration of bacteremia (3 days vs. 2 days) Higher relapse rate (6.7% vs. 2.9%) Microbiological cure rates (90% vs. 88.2%) (P = 0.92). Conclusions: A trend towards worse outcomes of daptomycin .,Mave V et al. J

51、 Antimicrob Chemother 2009 (May 7),Falagas ME et al. Lancet Infect Dis. 2008;8:53-66.,Linezolid vs. Glycopeptides or -lactam for Treatment of Gram-positive Bacterial Infections Overall Efficacy,Jaksic B et al. Clin Infect Dis 2006;42:597-607.,Algorithm for Initial Management of Febrile Neutropenic P

52、atients,Oral,IV,Ciprofloxacin + Amoxicillin-clavulanate (adults only),Reassess after 3-5 days,Monotherapy,Cefepime, Ceftazidime, or Carbapenem,Two Drugs,Aminoglycoside+ Antipseudomonal penicillin, Cefepime, Ceftazidime, or carbapenem,Vancomycin +,Vancomycin+ Cefepime, ceftazidime or Carbapenem amino

53、glycoside,High risk,Fever (temperature 38.3C) + Neutropenia (500 neutrophils/mm3),Low risk,Vancomycin Not needed,Vancomycin needed,Hughes WT et al. Clin Infect Dis 2002;34:730-51.,IDSA,Jaksic B et al. Clin Infect Dis 2006;42:597-607.,Flow diagram for analysis population,Antibiotic Therapy in Febrile

54、 NeutropeniaLinezolid vs. Vancomycin Mean Time to Defervescence,Days,Jaksic B et al. Clin Infect Dis 2006;42:597-607.,P=0.04,P=0.01,Fewer drug-related effects (24% vs. 17.2%): Renal failure (2.3% vs. 0.3%),Linezolid for Neutropenic Patients Are Bacteriostatic Agents Appropriate?,Bactericidal antibio

55、tics are required in neutropenic patients ? Two prospective comparative studies Linezolid was administered to 438 neutropenic patients A compassionate-use: other antibiotics failed to or were associated with significant adverse events Clinical cure rate (57- 87.3%) in the intention-to-treat 56 out o

56、f 438 (12.7%) patients died Only one randomized controlled trial (linezolid vs. vancomycin) Mortality was 5.6 versus 7.6%, respectively (p = 0.4). Conclusion: linezolid may be successful in a significant proportion of neutropenic patients with infection,Rafailidis PI et al., Expert Review of Anti-in

57、fective Therapy 2009;7: 415-22.,Time to Detection (Positive),Time-to-positive (11.01 h),Growth curve,Suggestive of CRBSI (No other source of infection) Both sets recover the same organism (same ID/AST profile) Both positive for the same organism and the set from catheter become positive 120 min earlier Both positive for the same organism and the set from catheter has at least 5X greater CFU/ml One peripheral set positive for S. aureus or Candida spp. Inconclusive of CRBSI Only peripheral or catheter set is positive CRBSI is unlikely: both negative,Blood Cultures-CRBINontunneled and