Nosocomial Infections: What Are the Unmet Needs Jean Chastre, MD Service de Réanimation Médicale Hôpital Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie, Paris 6, France www.reamedpitie.com
Nosocomial Infections: What Are the Unmet Needs 1. Emergence of antibiotic resistance in many bacterial species is a worldwide issue 2. Despite improvements in prevention, most nosocomial infections remain highly prevalent and associated with considerable morbidity and mortality 3. New therapies and preventive measures are desesperately needed
Pseudomonas aeruginosa: proportion of invasive isolates resistant to carbapenems in 2009 European Antimicrobial Resistance Surveillance Network (EARS-Net)
Klebsiella pneumoniae: proportion of invasive isolates resistant to thirdgeneration cephalosporins in 2009 European Antimicrobial Resistance Surveillance Network (EARS-Net)
Mortality in ESBL vs non-esbl Enterobacteriaceae bacteraemia Schwaber, Carmeli. J Antimicrob Chemother 2007;60:913-20
Klebsiella pneumoniae: proportion of invasive isolates resistant to carbapenems in 2009 European Antimicrobial Resistance Surveillance Network (EARS-Net)
Emerging KPC and VIM carbapenemases in Klebsiella Greece Clone with KPC replacing epidemic of bla VIM plasmids VIM KPC Widespread >1 outbreak 1 outbreak Sporadic http://www.ecdc.europa.eu; Grundmann et al. Euro Surveill 2010;15:19711; ARMRL, data on file; http://www.hpa.org.uk/web/hpawebfile/hpaweb_c/1294740725984
Worldwide Resistance to Selected Antimicrobials: United States 1997-1999 2003-2004 6 MRSA 1 34.2% 50.3%* P aeruginosa/cefepime 2 6.8% 4.9% P aeruginosa/pip-tazo 2 10.3% 12.2% VRE 3 17.0% 22.8%* ESBL (K pneumoniae) 4 7.6% 12.2%* S pneumoniae/penicillin 5 14.0% 17.2%* *Significant increase. MRSA indicates methicillin-resistant Staphylococcus aureus; PIP-TAZO, piperacillin-tazobactam; VRE, vancomycin-resistant enterococci; ESBL, extended-spectrum - lactamases. 1. Diekema DJ et al. Clin Infect Dis. 2001;32:S114-S132. 4. Winokur PL et al. Clin Infect Dis. 2001;32:S94-S103. 2. Jones RN et al. Diagn Microbiol Infect Dis. 2002;43:239-243. 5. Hoban DJ et al. Clin Infect Dis. 2001;32:S81-S93. 3. Low DE et al. Clin Infect Dis. 2001;32:S133-S145. 6. Data on file, Ortho-McNeil-Janssen Pharmaceuticals, Inc. 8
Worldwide Resistance to Selected Antimicrobials: Latin America 1997-1999 2003-2004 6 MRSA 1 34.9% 38.1% P aeruginosa/cefepime 2 13.9% 17.1%* P aeruginosa/pip-tazo 2 23.5% 22.2% VRE 3 2.0% 4.6%* ESBL (K pneumoniae) 4 45.4% 44.8% S pneumoniae/penicillin 5 11.7% 11.6% * Significant increase. MRSA indicates methicillin-resistant Staphylococcus aureus; PIP-TAZO, piperacillin-tazobactam; VRE, vancomycin-resistant enterococci; ESBL, extended-spectrum - lactamases. 1. Diekema DJ et al. Clin Infect Dis. 2001;32:S114-S132. 4. Winokur PL et al. Clin Infect Dis. 2001;32:S94-S103. 2. Jones RN et al. Diagn Microbiol Infect Dis. 2002;43:239-243. 5. Hoban DJ et al. Clin Infect Dis. 2001;32:S81-S93. 3. Low DE et al. Clin Infect Dis. 2001;32:S133-S145. 6. Data on file, Ortho-McNeil-Janssen Pharmaceuticals, Inc. 9
Worldwide Resistance to Selected Antimicrobials: Asia Pacific 1997-1999 2003-2004 6 MRSA 1 46.0% 46.2% P aeruginosa/cefepime 2 6.5% 11.1%* P aeruginosa/pip-tazo 2 10.9% 14.1* P aeruginosa/imipenem 2 8.6% ((TK from client)) VRE 3 1.0% 7.7%* ESBL (K pneumoniae) 4 24.6% 18.2% S pneumoniae/penicillin 5 17.8% 39.9%* * Significant increase. MRSA indicates methicillin-resistant Staphylococcus aureus; PIP-TAZO, piperacillin-tazobactam; VRE, vancomycin-resistant enterococci; ESBL, extended-spectrum - lactamases. 1. Diekema DJ et al. Clin Infect Dis. 2001;32:S114-S132. 4. Winokur PL et al. Clin Infect Dis. 2001;32:S94-S103. 2. Jones RN et al. Diagn Microbiol Infect Dis. 2002;43:239-243. 5. Hoban DJ et al. Clin Infect Dis. 2001;32:S81-S93. 3. Low DE et al. Clin Infect Dis. 2001;32:S133-S145. 6. Data on file, Ortho-McNeil-Janssen Pharmaceuticals, Inc. 10
Current healthcare challenges in nosocomial infections 1. Antibiotic resistance is a worldwide issue 2. Despite improvements in prevention, most nosocomial infections remain highly prevalent and associated with considerable morbidity and mortality 3. New therapies are desesperately needed
International Study of the Prevalence and Outcomes of Infection in Intensive Care Units Vincent JL, et al. JAMA. 2009;302(21):2323-9 A 1-day, prospective, prevalence study with follow-up conducted on May 8, 2007 Demographic, bacteriological, therapeutic, and outcome data were collected for 14 414 patients in 1265 participating ICUs from 75 countries on the study day On the day of the study, 7087 patients (51%) were considered infected
Relationship Between Rate of Infection and Disease Severity and Organ Failure Vincent JL, et al. JAMA. 2009;302(21):2323-9
Relationship Between Rate of Infection and the Duration of Stay in the ICU before the Study Day Vincent JL, et al. JAMA. 2009;302(21):2323-9
Hospital-acquired infections are a major challenge to patient safety Peleg AY, Hooper DC. N Engl J Med 2010;362:1804-13 o It is estimated that in 2002, a total of 1.7 million HAIs occurred (4.5 per 100 admissions) o Almost 99,000 deaths resulted from or were associated with HAIs, making HAIs the sixth leading cause of death in the US o Similar data have been reported from Europe o The estimated costs to the U.S. health care budget are $5 billion to $10 billion annually
Catheter-related bloodstream infection: Prevention using a bundle approach Pronovost P et al. NEJM 2006;355:2725-32 1. Hand washing (Pittet et al. Lancet 2000) 2. Cleaning the skin with chlorhexidine (Maki et al. Lancet 1991) 3. Using full-barrier precautions during the insertion of central venous catheters (Mermel et al. Am J Med 1991) 4. Avoiding the femoral site if possible (Merrer et al. JAMA 2001) 5. Removing unnecessary catheters
An Intervention to Decrease Catheter-Related BSI in the ICU Pronovost P et al. NEJM 2006;355:2725-32
Cumulative risk of VAP before and after a preventive intervention. Bouadma L et al. Clin Infect Dis. 2010;51:1115-22
Preventing nosocomial infections: The zero- infection rate In the US, the Centers for Medicare & Medicaid Services has proposed stopping hospital reimbursements for preventable complications, including nosocomial infections. This was immediately associated with several studies reporting an astonishing quasi-zero rate of nosocomial infections in ICU after implementation of various care bundles
Preventing nosocomial infections: The zero- infection rate If prevention of VAP and central line-associated bacteremia was effective, use of antibiotics in the ICU should have decreased dramatically The disturbing issue is that very low rates of infection have not been associated with corresponding reports of decreased antibiotic use, duration of MV or mortality One explanation for the discrepancy is that the reporting system is being gamed by avoiding the diagnosis of infection while continuing to treat patients using antibiotics
Current healthcare challenges in nosocomial infections 1. Antibiotic resistance is a worldwide issue 2. Despite improvements in prevention, most nosocomial infections remain highly prevalent and associated with considerable morbidity and mortality 3. New therapies are desperately needed
Selection of initial antibiotic therapy is frequently suboptimal Appropriateness of antimicrobial therapy and survival in 5715 patients with pneumonia and septic shock 75% Kumar et al. Chest 2009;136:1237-48
Efficacy of Selected Combination Therapies Against 84 Episodes of VAP Occurring after > 7 Days of MV and prior Antibiotic Use Trouillet et al. AJRCCM 1998 Imipenem + AMK + vancomycin Ceftazidime + AMK + vancomycin Piperacillin-tazo. + AMK + vancomycin Aztreonam + AMK + vancomycin 68 78 82 88 0 20 40 60 80 100 % susceptibility
Susceptibility Results for 419 A. baumannii Isolates from 15 Brooklyn, NY, Hospitals, July through Sept 1999 Landman et al. Arch Intern Med 2002 Amikacine Ampi./sulbactam Cefepime Ceftazidime Ciprofloxacine Imipenem Meropenem Pip./taz. All antibiotics 12 31 33 33 53 65 69 73 66 0 20 40 60 80 Resistant, %
Fixing the Broken Antibiotic Pipeline? James M. Hughes JAMA Published on line Feb. 22, 2011 From 1983 to 1987, 16 new antibiotics were approved by the US FDA; From 2003 to 2007, just 5 were approved. Since 2008, only 2 have been approved
Is Targeting Pathogen Viability with Antibiotics the Best Therapeutic Option? Clatworthy AE, et al. Nat Chem Biol. 2007;9:541-8
Peleg AY, Hooper DC. NEJM 2010;362:1804-13
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Selection for antimicrobial-resistant Strains Resistant Strains Rare Antimicrobial Exposure Resistant Strains Dominant
Alternative Approaches Designed to Target Virulence Factors Clatworthy AE, et al. Nat Chem Biol. 2007;9:541-8
Alternative Approaches Targeting Virulence Factors Clatworthy AE, et al. Nat Chem Biol. 2007;9:541-8 These approaches have several potential advantages: They expand the repertoire of bacterial targets. They preserve the host endogenous microbiome. They exert less selective pressure for the development of antibiotic resistance relative to current antibiotics.