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50 años de Infecciones Respiratorias: desde destruir bacteria hasta aprender a vivir con ella Doctor Antonio Anzueto. San Antonio, EEUU. SOCIEDAD ESPAÑOLA DE NEUMOLOGÍA Y CIRUGÍA TORÁCICA

Faculty Disclosures Personal financial interests in commercial entities that are relevant to my presentation: NONE Non-commercial, non-governmental interests relevant to my presentation : Member of the ATS/ERS Task force on COPD and COPD Exacerbations, Member of the ATS/IDSA CAP Guidelines committee GOLD Past Member of the Executive and current member Scientific Committee

Visualiza Puedes visualizar la 31ª Conferencia Manuel Tapia en el enlace


Fundación en Madrid, en 1967, de la Sociedad Española de Patología Respiratoria (SEPAR). Arch Bronconeumol 1971;8:11-8 - Vol. 8 Núm.1


Agora - collection of sculptures by Polish artist Magdalena Abakanowicz. All 106 sculptures are 9 feet (2.7 m) tall and were made from a seamless piece of iron.

1987 – Prof. M. García Cosío (Montreal, Canadá) 1988 – Dr. F. Griffith Pearson (Toronto, Canadá) 1989 – Prof. Valentín Lourenço (Chicago, USA) 1990 – Prof. Peter Wagner (California, USA) 1991 – Dr. Jean François Dumon (Marsella, Francia) 1992 – Dr. Victorino Farga (París, Francia) 1993 – Prof. Manuel Paiva (Bruselas, Bélgica) 1994 – Prof. Richard Light (California, USA) 1995 - Dr. Alejandro E. Grassino (Montreal, Canadá) 1996 – Prof. J. Iasha Sznajder (Chicago, USA) 1997 – Dr. Roberto Rodríguez Roisin (Barcelona) 1998 – Dr. Dominique Robert (Lyon, Francia) 1999 – Dr. Josep Maria Antó Boqué (Barcelona) 2000 – Dr. Joaquín Sanchís Aldás (Barcelona) 2001 – Dr. Ferran Morell Brotad (Barcelona) 2002 – Dr. Bartolomé Celli (Boston, USA) 2003 Dr. Daniel Rodenstein (Bélgica)

2004 – Dr. Francisco Rodríguez Panadero (Sevilla) 2005 – Dr. César Picado Vallés (Barcelona) 2006 – Dr. José Antonio Caminero Luna (Las Palmas) 2007 – Dr. Federico Manresa Presas (Barcelona) 2008 – Dr. Moisés Selman (México) 2009 – Dr. Josep Maria Montserrat Canal (Barcelona) 2010 – Dr. Fernando Martínez (Tucson, Arizona. USA) 2011 – Dr. José Luis Álvarez-Sala Walther (Madrid) 2012 – Dr. Antoni Xaubet Mir (Barcelona) 2013 - Dr. Juan Ruiz Manzano (Barcelona) 2014 – Dr. Vicente Plaza Moral (Barcelona) 2015 - Dr. Lorenzo Fernández Fau (Madrid) 2016 – Dr. José Castillo Gómez (Sevilla)

Pulmonary/Critical Care Medicine: Areas of Interest •  Critical Care Medicine –  Acute Lung injury/ARDS –  Mechanical Ventilation –  Sepsis –  Severe Pneumonia

•  Pulmonary –  COPD and COPD Exacerbations –  Pneumonia –  Neuromuscular Disease

Carrer Rationale

• Pharmacotherapy • Epidemiology

• ALI/ARDS • Mechanical Ventilation

Adult with Airway disease

• Exacerbations • CAP

What shape my life ?

my family

my patients

more patients

my teammates

My Long-Distance Friends Central America  


Colombia Venezuela  

Italy Brazil   Australia   Peru  



They give advice and lend a hand

D. Manuel Tapia MartĂ­nez Director del Hospital Nacional de Enfermedades Infecciosas

50 aĂąos de Infecciones Respiratorias: desde destruir bacteria hasta aprender a vivir con ella

St Augis)ne   Plato   Aristoteles   Plo)nus   Eistein   Theory  of  thermodilu)on  

Hauseer H The Phyloso. Review 1937; 46: 503






Next to avoiding a fatal issue, our efforts must be directed to prevent the case going on to chronic bronchitis, especially in those who have had previous attacks R Douglas Powell, London 1878


….the most widespread and fatal of all acute diseases, pneumonia, is now Captain of the Men of Death.. Sir William Osler 4 th ed. The Principles and Practice of Medicine New York: D Appleton; 1901:108

Why were the lower airway believed to be sterile

Johanson et al NEJM 1969; 281:1136-1139

Colonization of the respiratory tract with Gram-negative bacilli among ICU patients

Johanson et al Annals of Internal Medicine 1972; 77:701-706.

Pathogenesis of Airway Infection Bacteria Airway cells

Cytokines, mediators

Gern JE, Busse WW. Clin Microbiol Rev. 1999;12:9–18.

How should we treat them?






“fall & rise� of bacteria in COPD Bacterial load (CFU/ml)

New strain / Individual factors / External modifying factors

Clinical threshold

Time (days) AE



Time to relapse Modified from Miravitlles. Eur Respir J 2002: 20: 9s-19s

Bacterial load and airway inflammation

rho = 0.459 p = 0.02

Patel et al Thorax 2002






n o i t ira

How should I treat a patient with Lung infections ? Is this treatment improving patient outcomes?

Introduction of new antibiotic classes

Pneumonia Mortality/ 100.000 patients

Gilbert K, Fine MJ; Sem Respir INF. 1994; 9:140-52

Pneumonia Guidelines 1943 1.  A glass of water every hour. 2.  Open air- on porch or with bedroom windows open. (If the patient is old and weak delete or modify this order. 3.  To take a patient with active pneumonia to the x-ray room is not only a confession of complete incompetence, it may almost be said to be malpractice. 4.  Apply flannel pneumonia jacket and chest compress if grateful to patient. 5.  The bowels should be opened. 6.  Alcoholics with pneumonia may become noisy and if they do, should be given alcoholic drinks. Clendening L and Hashinger EH. Methods of treatment. 8th ed. 1943. 564-569

Pneumonia Guidelines 1943

Pneumonia Guidelines 1943

Guidelines adherence is associated with improved outcome

Dambrava et al ERJ 2008; 32:892 Menendez et al ERJ 2007; 29:751

CAP - Kaplan-Meier plots cumulative 10-year survival Expected survival PSI < 90 Pneumococcal Pneumonia

PSI ≥ 90 to <120, PSI ≥ 120

Sandvall et al CID 2013;56:1145

Mortality of hospital admitted patients with invasive pneumococcal disease 1952-62



13% Mortality1 N = 1130

12% Mortality2 N = 4432

12% Mortality3 N = 5837

Although the management of critically ill patients has improved by far and there are no resistance problems with regard to S. pneumoniae, mortality of IPD remains tremendous. 1. 2. 3.

Austrian R, Gold J. Ann Intern Med 1964;60:759-76. Fine MJ, et al. JAMA 1996;275(2):134-41. Feikin DR, et al. Am J Public Health 2000;90(2):223-9.

Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD

Corrales-Medina VF, et al. JAMA 2015


S. Pneumo cardiac micro-lesions and latter scaring

Brown et al AJRCCM 2015

Introduction of new antibiotic classes

Development of bacterial resistance

Carl Woese

Norman Pace

16S Ribosomal Subunit

Carl Woese Phylogenetic structure of the prokaryotic domain: the primary kingdoms Woese and Fox, 1977 PNAS 74(11) pp 5088-5090 Norman Pace Rapid determination of 16S ribosomal RNA sequences for phylogenetic analyses Lane et al, 1985 PNAS 82(20) pp 6955-6959

There are more bacteria out there than we first imagined.....

Zoetendal EG. et al. 2008. Gut. Nov;57(11):1605-15

Airway Phylogenetic Tree

Hilty M, et al. PLoS ONE 2010; 5: e8578.

Decline in microbiome diversity

Bacterial Communities in Healthy Subjects

Bassis et al; Mbio 2015 Mar 3,6(2) e00037

Does the indigenous bacterial microbiota is different in the lungs?

Erb-Downward et al. PLoS One. 2011;6(2):e16384.

Gut-Lung Axis of Immunoregulation Antigen


Gut Immune System

Pulmonary Immune System


Immune Regulation Outcome of Pulmonary Challenge

Lung Microbiome Community Signatures in Chronic Lung Disease

Dickson et al., Annu Rev Physiol. 2016 78 481-504

Fecal Microbiota in critically ill patients

Lankema et al ICM 2016; 43:59

Species breakdown of all cultured isolates before and after treatment

Brill SE, et al. Thorax 2015

Characteristics of the microbiota in patients prior to and after azithromycin treatment

Slater et al Thorax 2014;69:673â&#x20AC;&#x201C;674

Antibiotics and Steroids have Differential Effects on the Microbiome in AECOP

Positive Changes in Relative Abundance (log2) indicate an increase in the latter time point compared. Huang et al., JCM J Clin Microbiol. 2014; 52(8):2813-23

Distribution of bacterial phyla at each time point after rhinovirus (RV) inoculation CONTROL

Molyneaux et a l AJRCCM 2013:188, 1224â&#x20AC;&#x201C;1231


ICS -Kapplan-Meier Estimate to first Pneumonia



Crim et al ERJ 2009; 34:641


What happens to a drug after deposition in the lungs?

Ruge CA, et al. Lancet Respir Med 2013



Rapid Microbiological Diagnostic Platforms •  LightCycler SeptiFast Test (Roche) •  Matrix-assisted laser desorption-ionized time-offlight (MALDITOF) •  Mass Spectrometry (MS, VITEK MS) •  Polymerase Chain Reaction (PCR) •  DNA-based microarray platforms (Mobidiag) •  Verigene gram-positive blood culture assay (Nanosphere)



Brendish et al Lancet Respiratory 2017 on line May 2016


MinION (Oxford Nanopore Technologies, Oxford UK) palmsized DNA sequencer

Pendleton et al AJRCCM 2017 on line May 2017

Lateral Thinking


theGRID by Charis Tsevis



Targets of antimicrobials in the bacteria replisome

van Eijk et al Ant Micro and Chem Therapy 217;72:1275

7 January 2016 â&#x20AC;˘ 5:44pm SCIENCE

First new antibiotic in 30 years discovered in major breakthrough Teixobactin has been found to treat many common bacterial infections such as tuberculosis, septicaemia and C. diff, and could be available within five years. Northeastern University in Boston, Massachusetts, have discovered a way of using an electronic chip to grow the microbes in the soil and then isolate their antibiotic chemical compounds.

Lacto-bacillus supplement: time to microbiologically confirmed VAP Lacto-­‐bacillus

No-­‐ Lacto-­‐bacillus  

Morrow et al AJRCCM 2010;182:1058–1064

Fecal Microbiota Transplantation

Bafeta et al Ann Inter Med 2017; on line May 30 2017

Epithelium immune response

Evans et al BJP 2011; 163: 195


Restitutio ad integrum

Muller-Redetzky et al Eur Respir Rev 2015; 24:516

Mortality: G-CSF in Pneumonia

What is a Stem Cell?

Mesenchymal Stem Cells

Whatâ&#x20AC;&#x2122;s next ?

Human Microbial Metagenomics: Understanding Our Microbial Selves

â&#x20AC;&#x153; ..Is the journey and not the arrival that matters..



Muchas Gracias!!!


Microbiota: Mycobiota


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The National Institutes of Health Human Microbiome Project

Naturally Ocurring Exacerbations: Changes in the Microbiome

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Huang et al, JCM, J Clin Microbiol. 2014; 52(8): 2813-23

Bacterial Families Hang out Together

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Huang et al, JCM, J Clin Microbiol. 2014; 52(8): 2813-23

Variation Across Age

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Yatsunenko et al, Nature, 2012

What is a Stem Cell?

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Bacterial Communities in Health Subjects

Bassis et al; Mbio 2015 Mar 3,6(2) e00037

The gut microbiota can also be altered by antibiotics, medications and diet

Dietary Phenols
















Fiber, sugar, starch

GI Mucosal Cells



31º conferencia magistral Manuel Tapia Madrid 2017. Dr. Antonio Anzueto  

50 años de infecciones respiratorias: Desde destruir bacteria hasta aprender a convivir con ella. Conferencia Magistral Manuel Tapia. 50º Co...

31º conferencia magistral Manuel Tapia Madrid 2017. Dr. Antonio Anzueto  

50 años de infecciones respiratorias: Desde destruir bacteria hasta aprender a convivir con ella. Conferencia Magistral Manuel Tapia. 50º Co...