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Resistant pathogens that cause pneumonia: a global perspective Francesco Blasi Department Pathophysiology and Transplantation, University of Milan, Italy

Disclosures I have accepted grants, speaking and conference invitations from Almirall, Angelini, AstraZeneca, Bayer, Chiesi, GSK, Guidotti-Malesci, Menarini, Novartis, Pfizer, and Zambon I have had recent or ongoing consultancy with Almirall, Angelini, AstraZeneca, GSK, Menarini, Mundipharma and Novartis

Infectious Disease Society of America. Available at

MDR Gram-negatives causing pneumonia  Pseudomonas aeruginosa  Acinetobacter  Enterobacteriaceae  Stenotrophomonas maltophilia

Multiresistant Gram negative Bacteremia Episodes of MDR-GNB Bacteremia (45% ESBL) during a 4-year period compared with Bacteremia with susceptible gram negative pathogens 747 Bacteremias, 372 (49.7%) with GNB –51 (13.7%) with MDR Mortality for MDRGNB 41% versus 21% for susceptible Pathogens (p=0.003) Inadequate Therapy for MDR 69% (versus 9%; p<0.001) Pretreatment with antibiotics (OR 3.57) and Urin-Catheter (OR 2.41) were independent risk factors for MDR Gudiol C et al. JAC 2011 Mar;66(3):

Multiresistant Gram negative Bacteremia Episodes of MDR-GNB Bacteremia (45% ESBL) during a 4-year period compared with Bacteremia with susceptible gram negative pathogens 747 Bacteremias, 372 (49.7%) with GNB –51 (13.7%) with MDR Mortality for MDRGNB 41% versus 21% for suseptible Pathogens (p=0.003) Inadaequate Therapy for MDR 69% (versus 9%; p<0.001) Pretreatment with antibiotics (OR 3.57) and Urin-Catheter (OR 2.41) were independent risk factors for MDR Gudiol C et al. JAC 2011 Mar;66(3): Carbapenemes, Carbapenemes, Carbapenemes, …., what more?

AntibioticMIC mg/L(S/I/R) Amp/Sulb >32 R Pip/Tazo>128 R Ceftriaxone>64 R Ceftazidime>64 R Cefepime>64 R Ertapenem>32 R Imipenem>32 R Meropenem>32 R Aztreonam>64 R Amikacin>64 R Gentamicin2 S Tobramycin>16 R Ciprofloxacin>4 R Fosfomycin32 S Tigecycline1 S Colistin0.4 S AntibioticMIC mg/L(S/I/R) Amp/Sulb >32 R Pip/Tazo>128 R Ceftriaxone>64 R Ceftazidime>64 R Cefepime>64 R Ertapenem>32 R Imipenem>32 R Meropenem>32 R Aztreonam>64 R Amikacin>64 R Gentamicin4 I Tobramycin>16 R Ciprofloxacin>4 R Fosfomycin>32 R Tigecycline4 R Colistin16 R AntibioticMIC mg/L(S/I/R) Amp/Sulb>256 R Pip/Tazo>256 R Ceftriaxone>32 R Ceftazidime64 R Cefepime16 R Ertapenem32 R Imipenem2 S Meropenem1 S Aztreonam64 R Amikacin4 I Gentamicin1 S Tobramycin4 R Ciprofloxacin>32 R Fosfomycin32 S Tigecycline1 S Colistin0.4 S Emergence of carbapenem-R K. pneumoniae XDR/TDR phenotypes

First isolates, late 1990s Yigit et al - AAC 2001 KPC = Klebsiella pneumoniae carbapenemase Antibiotic K. pneumoniae 1534 MIC (mg/L) Imipenem16 Meropenem16 Ampicillin>64 Amoxi/clav>32/16 Pip/tazo>128/4 Ceftazidime32 Cefoxitin32 Cefpodoxime>16 Cefotaxime64 Ceftriaxone>64 Aztreonam>64 Gentamicin>16 Tobramycin>16 TMP/SMX>8 Chloramphenicol32

Carbapenem-R Klebsiella pneumoniae, USA Epidemic diffusion of KPC-producing strains New York area Bradford et al – CID 2004 Landman et al – JAC 2007 Nadkami et al – AJIC 2009

CDC 2012  KPC reported in most states Carbapenem-R Klebsiella pneumoniae, USA

Nordmann et al - Emerg Infect Dis 2011 Cuzon et al - Emerg Infect Dis 2010 Baraniak et al – AAC 2011 Andrade et al – AAC 2011 KPC-producing K. pneumoniae pandemic diffusion

Proportion % Year EARS-NET database Carbapenem-R Klebsiella pneumoniae Greece Italy KPC epidemic VIM epidemic KPC epidemic Vatopoulos et al – Eurosurveillance 2008 Giakkoupi et al – JAC 2011

Giani et al – JCM 2009 Santoriello et al – unpublished Fontana et al – BMC Res Notes 2010 Marchese et al – J Chemother 2010 Ambretti et al – New Microb 2010 Gaibani et al – Eurosurv 2011 Mezzatesta et al – CMI 2011 Agodi et al – JCM 2011 Richter et al – JCM 2011 Di Carlo et al – BMC Gastroenterol 2011 Rossolini GM – unpublished late 2008 The first reported cases of KPC-Kp KPC-producing K. pneumoniae – the Italian epidemic early 2011 AMCLI – CoSA CRE network Frasson et al – JCM 2012 ARISS – CoSA survey 2012 late 2012

Proportion of Carbapenems Resistant (R) Klebsiella pneumoniae Isolates in Participating Countries in 2012

Estimated annual burden of non-CF P. aeruginosa infections, USA Arlington Medical Resources (Jul - Dec 2009) Indication CategoryTotal Patients in US, NP. aeruginosa, n (%) Lower Respiratory Infections 5,653,408626,947 (11) Genitourinary Infections 3,686,910237,384 (6) Skin/Skin Structure Infections 3,494,846192,776 (6) Systemic Infections 1,831,038171,640 (9) Abdominal Infections 888,09830,967 (3) Bone/Joint Infections 294,77614,513 (5) TOTAL 15,849,0761,274,227 (8)

Proportion of Carbapenems Resistant (R) Pseudomonas aeruginosa Isolates in Participating Countries in 2012

Proportion of Fluoroquinolones Resistant (R) Pseudomonas aeruginosa Isolates in Participating Countries in 2012

MRSA vs. MSSA infections: -increased mortality -increased LOS in hospital -increased healthcare-associated costs Boucher & Corey – CID 2008 Köck et al - Eurosurveillance 2010 Global impact MRSA (methicillin-resistant S. aureus): the paradigm of MDR difficult-to-treat pathogen

Proportion of Methicillin Resistant Staphylococcus aureus (MRSA) Isolates in Participating Countries in 2012

Proportion of Macrolides Resistant (R) Streptococcus pneumoniae Isolates in Participating Countries in 2012

Geographical distribution of antimicrobial consumption of Antibacterials For Systemic Use (ATC group J01) in the community (primary care sector) in Europe, reporting 2011 DDD/1000/DAY to < to < to < to < to

HEALTH CARE – ASSOCIATED STATUS The evolution of MDR pathogens as a dynamic process

HCAP: original defintion ATS / IDSA guidelines for HA, VAP and HCAP, Am J Respir Crit Care Med 2005

When HCAP = resistant pathogens, predictive values of HCAP are poor Shorr AF et al., Arch Intern Med 2008 (Zilberberg, Micek, Kollef)

22,456 pts Sub‐analysis by region found that HCAP performed poorly in European studies and in prospective/high quality studies.

New approach: Stratify risk factors New findings: Different risk factors have different importance for MDR prediction Chronic renal failure is an independent risk factor for MDR (A window of patient’s functional status) Patient’s targeted approach for empiric antibiotic therapy is possible

Curr Opin Crit Care 2012  Several platforms developed (multiplex RT-PCR, microarrays)  Role as an add-on or replacement of conventional diagnostics (e. g. viral infections)  Advantages: rapidity, sensitivity (positivity also in case of antibiotic exposure)  Disadvatages: cost, limited number of targets

Is there anything better than Antibiotics? Infection Control Improved Infection control –Effectiveness may be limited –What is really necessary? –Hand Hygiene only? –Isolation policy? –Screening measures? –Alert systems?

MRSA proportion (%) Year EARS-NET NL IT UK Lessons from MRSA experiences

Is there anything better than Antibiotics? Preventive Measures Vaccination –Available vaccines Influenza Pneumococci –Improve implementation –In development Staphylococci –A story of disappointments Pseudomonas –Ongoing Phase III trials

Is there anything better than Antibiotics? Immunomodulation Immunoglobulins/Monoclonal antibodies Encouraging results in animal models Waiting for clinical data  Some Phase II/III trials ongoing

Development of new antimicrobial agents –Incentives for the pharmaceutical industry –Adaption of regulatory Guidelines Reduction of antibiotic consumption –Standardisation of diagnostic and treatment procedures –Implementation of SOPs in clinical practice National and international cohorts Structured Education and Training Future Perspectives 000

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