Motto of the presentation

Transcription

1 Disclosures Research support: Daiichi, Wyeth, Theravance, Merck, CIHR, NIH, Employee: N/A Consultant: BiondVax, Atox-Bio, Astellas, Bayer, Merck, Theravance Major Stockholder: N/A Scientific Advisory Board: Pfizer-Wyeth, Merck- Schering, Bayer, Astellas, Theravance, BiondVax, Atox-Bio, Coronis-Partners Speakers Bureau: Pfizer-Wyeth, Astellas, Cubist.

2 Motto of the presentation Because of the need to initiate appropriate treatment early prior to the causative pathogen(s) being known, empiric antibiotic therapy that will cover all likely pathogens is recommended American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:

3 Facts about nosocomial pneumonia (NP) NP is the 2nd most common nosocomial infection and the leading cause of mortality in the ICU. Flanders SA, Am J Infect Control. 2006;34:84-93 NP occurs at a rate of 5 to 10 cases /1000 hospital admissions, with the incidence increasing by 20-fold in mechanically ventilated patients (=VAP) NP increases hospital stay by 7 to 10 days NP produces an excess cost of more than $40,000 per patient. NP is responsible for more than 50% of all antibiotics prescribed in the ICU ATS and IDSA. Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med ;171:

4 Facts about nosocomial pneumonia (NP) Mortality rates in NP vary depending on the patient population, with HAP mortality as high as 30% to 60%, lower in clinical drug trials 18-25%, higher in epidemiological trials Mortality in VAP varies from 24% to 60%, with the higher mortality rates occurring when VAP is accompanied by acute lung injury (ALI) or adult respiratory distress syndrome (ARDS). The majority of deaths that occur during or after an episode of NP are commonly related to the underlying medical conditions rather than being directly attributable to NP Leroy et al. Treat Respir Med. 2004;3: Edis EC, et-al. Respiration. 2009;78: Connelly SM, et-al. Am J Infect Control. 2009;37:143-9.) Fagon J,et-al. Am J Respir Crit Care Med ;161(3 Pt 1): Fagon JY & Chastre J.. Eur Respir J Suppl Aug;42:77s-83s. Markowicz P, et-al.. ARDS Study Group. Am J Respir Crit Care Med :

5 Facts about staphylococcal NP The proportion of staphylococcal infections that were MRSA in U.S. ICUs was 2% in % in 1995, and 64% in Klevens RM,et-al. Clin Infect Dis ;42: Institutional infection control measures used over a 15-year period (1993 to 2008) have effectively reduced the overall MRSA infection rate in 38 French hospitals from 41.0% to 26.6%. rate in 38 French hospitals MRSA still remains a major pathogen. Jarlier V, et al. Arch Intern Med ;170:552-9 Nosocomial Infection Control Consortium (INICC) reported resistance rates from 2003 to 2008, showing that MRSA was responsible for 84.1% of. hospital associated infections in international ICUs Rosenthal VD, et-al. Am J Infect Control. 2010;38:

6 Facts about MRSA NP Patients with VAP due to MRSA had a longer stay in the ICU than those with (MSSA), regardless of appropriate initial antibiotic therapy (Shorr AF, et-al.crit Care. 2006;10:R97) The risk of death in patients with nosocomial pneumonia due to S.aureus was increased 2.6- fold (95% [CI], 1.7 to 4.0) when the pathogen was MRSA.( Gastemeier P et al. Infection. 2005;33:50-5.)

7 MRSA prolongs ICU stay in VAP, despite initially appropriate Abx Rx Shorr AF, et al. Crit Care Med. 2006;34:700.

8 Facts about Gram (-) NP Ps.aeruginosa is the most common organism 24%, associated with a mortality of ~50% Other emerging organisms resistant to Rx include: Acinetobacter spp. KPC, NDM-1, VIM s, AMP-C Enterobacter, Klebsiella, E.coli etc, Stenotrophomonas sp. Therapy options for these organisms: carbapenems (include. doripenem), colistinpolymyxin, amikacin, intra-tracheal amikacin, colistin,levofloxacin and aztreonam

9 Emergency department radiograph

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11 MRSA susceptibility Oxacillin Fluoroquinolone Erythromycin Vancomycin Linezolid Clindamycin Cephalosporins Trimethoprim sulphamethoxazole Resistant Intermediate Resistant Sensitive Sensitive Sensitive Resistant Sensitive

12 STAPHYLOCOCCAL PNEUMONIA (SP) Post flu classically described post-world war 1, healthy young; high mortality pre-antibiotics & complications but also recently Staphylococcal pneumonia- not post flu; young adults, predisposing risk factors, infections in hospital, high mortality Right sided endocarditis or SSTIs in IVDU leading to SP; less severe Post inhalation/aspiration; less severe HAP/VAP

13 Confluent staphylococcal bronchopneumonia with invasion of vessels in the lungs, producing a florid vasculitis (arrow). Secondary thrombosis is occluding the pulmonary vascular system. (Haematoxylin eosin stain; original magnification 100)

14 Virulence Factors PSM (=phenol soluble protein) PVL δ toxin Agr II- less vancomycin susceptible Agr III- in CA MRSA strains more commonly (Agr operon upregulates secretion of virulence factors and downregulates expression of virulence factors on the bacterial surface)

15 S.aureus aetiology of CAP: culture + and hospitalised? Author S.aureus (%) MRSA Kollef et al % - Large US outcomes database Stralin & Soderquist % - Single institution Marrie % - Review of seven studies Torres et al 2009 Woodhead % 4.9 % - - Country specific across Europe Review of 41 prospective studies

16 Hayward et al. Emerg Inf Dis. 2008;14:720

17 Brazil

18 MRSA Load in the UK Male age standaradized rate of death due to MRSA /mio 25/mio than decreasing in % Female 6.7/Mio 14.5/Mio than decreasing in % MRSA change in death certificates +39%

19 HAP /VAP

20 Incidence of Nosocomial pneumonia caused by S. aureus 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 2% 50% Pujol et al. Eur J Clin Microbiol Inf Dis 1998;17:622 Germaud et al. Rev Pneumol. Clin 1999;55:83

21 France 13.1% of 169 French ICU s (1993-5) 55.7% MRSA (Trouillet JL et al.am J Respir Crit Care Med 1998; 157: 531-9; Chastre et al. idem 2002;165: ) VAP caused by MRSA 11 additional ICU days stay compared to MSSA (Schorr et al. Crit Care Med 2006; 34: 700-6) Universal screening and preventive isolationcost benefit of $ / patient in 6 ICU s (Lucet et al. Arch Intern Med 2003; 163: 181)

22 USA S.aureus in 20% of cases of HAP or 1% of all hospitalizations, MRSA 10% of HAP (NNIS data) MRSA VAP- adds 4.4 additional days of MV and 5 additional ICU days (compared to MSSA) excess cost $7731 (Schorr et al. Crit Care 2006; 10: R97)

23 The Vancomycin Creep

24 Vancomycin MIC creep MIC 0.5mg/L MIC=0.75mg/L MIC=1.0mg/L MIC>1.0mg/L Percentage Year Steinkraus, White and Friedrich. J Antimicrob Chemother 2007;60:

25 Vancomycin MIC significantly predicts mortality in MRSA Treatment group Risk of mortality (OR [95% CI]) P-value Vancomycin MIC=1 1 Vancomycin MIC= (0.87, 9.35) 0.08 Vancomycin MIC= (1.68, 24.3) <0.001 Inadequate therapy* 3.62 (1.20, 10.9) < *Inadequate therapy defined as empirical therapy to which the MRSA strain was resistant Soriano A et al. Clin Infect Dis 2008;46:

26 Reduced vancomycin efficacy with higher MIC Data taken from 30* MRSA bloodstream isolates from US hospitals P=0.01 Success, % n=9 n= Vancomycin MIC, µg/ml *23 isolates were vancomycin treatment failures, 7 were treatment successes Sakoulas G et al. J Clin Microbiol. 2004;42:

27 Therapy

28 Risk Factors for Multidrug-Resistant Pathogens Causing HAP or VAP ABx Rx in the preceding 90 days Current hospital stay > 5 days ABX resistance that is highly prevalent in hospital/unit Immunosuppressive disease or therapy Hospitalization of > 2 days in the last 90 days Residence in a nursing home or extended care facility Infusion home therapy Receipt of long-term dialysis in the last 30 days Wound care Family member with MDR pathogen Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388.

29 *Mortality refers to crude or infection-related mortality Alvarez-Lerma F et al. Intensive Care Med 1996;22: Ibrahim EH et al. Chest 2000;118L Kollef MH et al. Chest 1999; 115: Kollef MH et al. Chest 1998;113: Luna CM et al. Chest 1997;111: Rello J et al. Am J Resp Crit Care Med 1997;156: Mortality Associated With Initial Inadequate Therapy In Critically Ill Patients With Serious Infections in the ICU Alvarez-Lerma,1996 Rello, 1997 Kollef, 1999 Kollef, 1998 Initial appropriate therapy Initial inadequate therapy Ibrahim, 2000 Luna, 1997 Mortality* 0% 20% 40% 60% 80% 100%

30 Mortality Rates Associated With Inadequate, Inappropriate, Delayed, or Lack of Antibiotic Treatment for NP Random effects model. Heterogeneity: Cochran s Q (15 df)=79.04, p < Data abstracted from: Sorbello, Komo, Valappil (2010) DIAJ, 44,

31 Random Effects Model for Imputed Placebo Eliminating Three Studies to Reduce Heterogeneity Heterogeneity: Cochran s Q (12 df)=8.38, p=0.75 Note: Imputed placebo may be an underestimate since most patients received some treatment.

32 Mortality Risk with Increasing Delays in Initiation of Effective Antimicrobial Therapy Kumar et al, CCM 2006:34: Odds Ratio of Death (95% Confidence Interval) > Time (hrs)

33 Linezolid vs Comparator(s) in HAP/VAP Study Pneumonia Linezolid Comparator Cepeda et al 86 15/18 (83%) 24/29 (72%) Wilcox et al 88 42/45 (93%) 42/46 (91%) Kaplan et al 89 9/10 (90%) 10/10 (100%) Wunderink et al /168 (68%) 111/171 (65%) San Pedro et al 92 63/71 (89%) 62/70 (89%) Stevens et al 93 9/12 (75%) 12/16 (75%) Rubinstein et al 94 71/107 (66%) 62/91 (68%) Total 323/431 (74 9%) 323/433 (74 6%)

34 Linezolid vs vancomycin for Gram-positive nosocomial pneumonia: clinical cure rates Linezolid Vancomycin 80 P=0.182 P=0.009 Clinical cure, % S. aureus (n=272) MRSA* (n=123) Wunderink R et al. Chest 2003;124: Type of pneumonia Data from patients with indeterminate or missing clinical outcomes were excluded *A subset of patients with S. aureus pneumonia

35 Wunderink RG, et al. Chest. 2008;134:1200

36 Wunderink RG, et al. Chest. 2008;134:1200

37 Vanco(popotamus) Large molecule Penetrates slowly Slowly cidal Difficult to measure

38 Not such smart therapy Vanco in the lung:: Concentrations in Plasma:ELF=6:1 36% of patients ELF vanco conc. < 4 mg/l

39 Vancomycin therapy for MRSA VAP Patients with MRSA VAP treated with vancomycin have 50% mortality, patients with MSSA VAP treated with vancomycin have a 47% mortality (Gonzalez et al. Clin Inf Dis 1999;29:1171-7) Patients with MSSA VAP treated with betalactam have a mortality of ~5% (Rello et al. A J R C C M 1994;150:1545).

40 RECENT STUDIES IN HAP/VAP Tigecycline Effective in HAP but not VAP Ceftobiprole Effective in HAP but not VAP (Rejected by the FDA) Doripenem Effective in HAP & VAP Telavancin Effective in HAP & VAP (Rejected by the FDA) Linezolid inhap/vap-effective

41 Therapy of S.aureus CAP

42 Following his admission to the intensive care unit, the patient was administered cefuroxime and prednisone intravenously

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44 Patient 1 Ceftriaxone 15 h after admission Addition of vancomycin clindamycin Patient 2 Ceftriaxone, amikacin, and levofloxacin 14 h after admission Clindamycin and linezolid plus Tegeline J Clin Microbiol. 2010;48:

45 Characteristics of pneumonia caused by PVL+ S.aureus Rare Mortality 40% and rapid (within 1-4 d) Rapid progression Young patients Hempthysis 40% Leukopenia 40% 10% survival when WBC<1000

46 Diep et al. Proc Natl Acad Sci USA (2010) vol. 107 (12) pp PVL contributes to virulence of USA300 in rabbit model of necrotizing pneumonia

47 Clinical features of PVL-associated pneumonia ( ) Sicot N et al

48 Similar kinetic of death for MRSA and MSSA cases Cumulative probability of survival CA-MRSA pneumonia CA-MSSA pneumonia 0.2 Days Sicot N et al (in press)

49 350% PVL level reported to control by MSSA 300% 250% 200% 150% 100% 50% 0% 200% 150% 100% 50% No antibiotic * * * * * * No antibiotic ⅛ MIC ¼ MIC ½ MIC Oxacillin Clindamycin Linezolid Fusidic acid Rifampicin * * * * * * * * * 0% No antibiotic Pristinamycin Tetracycline Ofloxacin Co-trimoxazole Vancomycin

50 β-lactams which bind PBP1 enhance PVL production Level of PVL production PVL mrna fold change No atb OXA IMI CTX CCL FOX Selective ligand : PBP1-4 PBP1 PBP2 PBP3 PBP4 Dumitrescu et al Antimicrob Agents Chemother 2007;51: Dumitrescu et al Clin Microbiol Infect 2008; 14:

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53 Which antibiotics on MRSA? Vancomycin (in vitro) Linezolid (in vivo) Ceftobiprole (in vivo) ATCC Log 10 CFU / Thigh T>MIC Time (hours) Linezolid better than vancomycin But only ceftobiprole kills rapidly MRSA Palmer SM et al. Antimicrob Agents Chemother 1996;40: Houlihan HH et al Antimicrob Agents Chemother. 1997;41: Craig WA et al. Antimicrob Agents Chemother. 2008;52:

54 Guidelines for treatment Guidelines for CA-MRSA pneumonia only in UK : combination of clindamycin 1.2 g iv qds, linezolid 600 mg iv bd and rifampicin 600 mg bd until the patient has improved and is clinically stable, 1-2g/kg of IVIG, be repeated after 48 h if there is still evidence of sepsis, or failure to respond US Guidelines for MRSA pneumonia : American Thoracic Society/Infectious Disease Society of America: vancomycin trough concentrations of mg/ml and linezolid as alternative choice.

55 New therapeutic options for Resistant Gram (-) NP Colistin (IT + systemic) ~50-66% efficacy Tigecycline and alike IT amikacin, aztreonam, ciprofloxacin, levofloxacin-phase II clinical trials. New fluoroquinolones with activity in acidic ph and with anaerobic activity. New vaccines Biologic modifiiers

56 Remaining issues to be discussed Place of IT Abx therapy Is vanco creep an issue? Is renal failure in MRSA patients an indication for linezolid? Is step down therapy important? When? How long to treat? Single vs. combi?

57 The real world utilization of the bundle approach in the ICU, is it applicable toall patients? The role of antecedent partially preventable LRTI (H1N1, H5N1, pneumococcal pneumonia, COPD, etc )

58 Rubinstein et al. A A C 2003;47:

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60 Liang Beibei, et al. International Journal of Antimicrobial Agents 2010; 35:

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