Ehrlich gratuliert Domagk - 75 Jahre antibakterielle Therapie - Hartmut M Lode - Berlin, 18.11.2011 - e|context

Berlin, 18.11.2011

      Ehrlich gratuliert Domagk
- 75 Jahre antibakterielle Therapie -

                Hartmut M Lode
 RCMS - affil. Institute for Clinical Pharmacology
     Charité - Universitätsmedizin Berlin
                     - Berlin -

Paul Ehrlich / Gerhard Domagk
              Gliederung

•   Anfänge der antibakt. Chemotherapie
•   Penicilline/Cephalospor. und mehr
•   Infektionsepidemiologie
•   Bakterien und Menschen
•   Resistenzentwicklung
•   Mangel an Antibiotika
•   Lösungsansätze

Infektionsmedizin…

im 16. Jahrhundert             im 21. Jahrhundert ?

Die Idee der Chemotherapie von
                 Infektionen

• „..die Abtötung der Parasiten ohne
  erhebliche Schädigung des
  Organismus, wir müssen chemisch
  zielen lernen!“ (1906)

• Chemotherapie
  gegen Syphillis
  (Arsenphenarmin)

                                       Paul Ehrlich:
                                       1854-1915

“ Hit hard and hit early ! “

 Paul Ehrlich, Lancet 2 : 445 –
           451, 1913

Paul Ehrlich´s
             Ingredients for Success

 Four German G´s: Geld (money)

                              Geduld (patience)

                              Geschick (cleverness)

                              Glück (luck)

Lancet 1998; 352:1712 - Gesundheit (health)

Das erste synthetische Antiinfektivum

• Entwicklung der
  Sulfonamide

• Nobelpreis 1939
  (1946)

• Entwicklung von
  Isoniazid            Gerhard Domagk 1895-1964

American soldiers were tought to immediately sprinkle
sulfapowder on any open wound to prevent infection. Every
soldier was issued a first aid pouch that was designed to be
             attached to the soldier’s waist belt.

Sulfa's True Significance
 Gerhard Domagk's work in the 1930s on sulfonamides,
though soon eclipsed by the advent of penicillin, was an
   equally crucial chapter in the history of antibiotics

    Dixon B Microbe / Volume 1, Number 11, 2006

Eine mit Penicillium notatum
                                                        kontaminierte Kultur von S. aureus
                                                        (Alexander Fleming, Sept. 1928)

                                                        ● Wiederaufnahme der Isolierungs-
                                                        bemühungen im Jahr 1938
                                                        (nachdem die Sulfonamide
                                                        entdeckt worden waren!)

                                                        ● 1941 erste Behandlung eines Patienten
                                                        mit Staphylokokken-Sepsis

"Wenn mein Geist nicht in einem wahrhaft
 aufnahmebereitem Stadium gewesen wäre,
hätte ich der Schale keine Beachtung geschenkt.
Ich hätte ja in einer schlechten Laune sein können;
mein Verstand hätte von einer jungen Frau angefüllt sein können,
oder ich hätte unter der Nachwirkung einer zu schweren Mahlzeit stehen können,
oder ich hätte zu träge sein können, es zu merken oder etwas zu unternehmen..."
(Flemings Kommentar zu seiner epochalen Beobachtung).

Nobelpreise für Penicillin 1945

Alexander Fleming (1881 – 1955)

• Sept. 1928 Entdeckung des Penicillins als Produkt
  von Penicillium notatum

Ernst Boris Chain (1906 – 1979)
• In Berlin geboren, 1933 nach Tätigkeit am
  Patholog. Institut der Charité emigriert nach England

Howard Walter Florey (1898 – 1968)
• In Adelaide / Australien geboren, seit 1931 in Oxford;
  1938 Gründung des “Oxford-Kreises” zur
  Penicillinforschung

The grim irony of history
•   It had been demonstrated and documented that
    sulphonamides were far less active than ß-lactams.

•A sulfa drug defeated Churchill’s pneumonia and
most probably saved his life in December 1943.

• A ß-lactam saved Hitler’s life. His physician
treated him with penicillin on several occasions;
most notably following the assassination attempt
on July 20, 1944.
•   Alexander Fleming isolated and Howard Walter Florey and
    Ernst Boris Chain, a German-born Jewish refugee from
    Hitler’s Berlin, re-invented penicillin.

Entwicklung von Antiinfektiva I

    Waksmann
    • 1942 - erstmals begriff „ Antibiotics“
    • 1943 - Neomycin, Streptomycin
    • 1946 - Park Davis : Chloramphenicol
    • 1948 - Brotzu,Sardinien;Abraham /
              Newton/Oxford: Cephalosporin
    • 1952 - Eli Lilly : Erythromycin

1

Entwicklung von Antibiotika I

 Tetracycline und Penicilline
 • 1948 – Lederle : Chlortetracyclin
 • 1949 – Pfizer : Terramycin
 • 1952 – Pfizer/Lederle : Tetracyclin
 • 1959 – Chain, Batchelor, Rolinson (Beecham):
           Para-Aminobenzylpenic.(6-APA)
 • 1959 – Rolinson,Knudsen (Beecham) :
           Methicillin

Historische
Entwicklung
der Penicilline

Die heute noch relevanten
Penicilline sind markiert,
die anderen Derivate
haben keine therapeutische
Bedeutung mehr.

Antibakterielle Chemotherapie
                       - Prinzipien –

  “Seit Paul Ehrlich ist die antibakterielle Chemotherapie
    definiert als eine monokausale, gegen den Erreger
gerichtete Behandlung und zwar mit Substanzen, die eine
selektive und direkte Wirkung auf die Bakterienzelle haben.
     Es resultiert die Verpflichtung, die antibakterielle
  Chemotherapie auch in der praktischen Anwendung an
 ihren naturwissenschaftlichen Grundlagen zu orientieren”

         Naumann P Arzneimittelforschung 1962

Entwicklung verschiedener
    Antibiotikaklassen

Number of new systemic antibacterial agents approved by the US
Food and Drug Administration per 5-year period

  Spellberg, B. Arch Intern Med 2011;171:1080-1081

„Nearly all experts agree
that (by the year 2000) all
 bacterial diseases will
 have been wiped out.“

         TIME Magazine 1966

Das Ende der
          Infektionskrankheiten?

‘The book of infectious
    diseases can now
  ultimately be closed.’

Steinfeld, Surgeon General, 1972

                                   Jesse Leonard Steinfeld

Geschätzte Todesfälle 2002

[Ref.: Fauci et al., Emerg Infect Dis 2006; 4]

Entwicklungstendenz unserer Patienten zu
    vermehrter Infektionsdisposition

  1. Mehr alte und ganz junge Patienten
     (Lebenserwartung i.M.> 85 Jahre/2020)
  2. Zunahme von Patienten mit schweren
     Grunderkrankungen
     (Tumoren, Herz-, Nieren-, Leberinsuffizienz etc.)
  3. Zunahme von Patienten mit definierten
     Immunstörungen
     (Transplantationen, AIDS, Steroidtherapie etc.)
  4. Zunahme aggressiver diagnostischer und
     therapeutischer Maßnahmen

Microbes versus humans

Spellberg B et al. Clin Infect Dis. 2008;46:155-164

Evolution als Prinzip der
 Resistenzentwicklung
         Unterschiedliche Genotypen
         (Mutationsrate 1:105 – 1:107)

         Antibiotika

         Vermehrung der resistenten
           Bakterien

Resistenzentwicklung am Beispiel
               S.aureus
                               DRSA+LRSA (2006)
                             GISA (1997)
       PRSA (1945) MRSA (1965)      VISA (2002)

Penicillin (1929)   Methicillin (1959) Daptomycin 2004
               Vancomycin (1955) Linezolid (2000)

Globale Ausbreitung von Resistenzen: Spain 23F – 1
                                               Finland
                                      France
                                     BM4200
                                      1978 ?
    Cleveland                        Spain
                                                                 South Korea
Tennessee
 Mexico                                                               Taiwan
                                                                    Hong Kong
                                                                      Philippines
                                                               Thailand
      Colombia                                                    Malaysia
                                                              Singapore
                    Brazil

            Chile                                    South
                           Uruguay
                                                     Africa
                    Argentina

An Update on the Development Pipeline from
      the Antimicrobial Availability Task
Force(AATF) of the Infectious Diseases Society
                 of America

  AATF identified particularly Bad Bugs Need        Drugs:
                    problematic pathogens:

   Acinetobacter baumanii, Aspergillus spec.,
ESBL-producing Enterobacter., Vancomycin-resistant
             Enterococcus faecium,
            Pseudomonas aeruginosa,
     Methicillin-resistant Staph. aureus( MRSA)

             Talbot G et al, CID 2006; 42:657-668

Peleg. A & Hooper, D, NEJM 2010;362:1804

Antibiotic Future
The Drug Discovery Pipeline for Antibiotics
                    Is slowing to a trickle . . .
. . . We need to conserve what we have through Appropriate Use

                                                    Drug
                                                    • Gemifloxacin
                                                    • Telithromycin
                                                    • Linezolid

Number of new systemic antibacterial agents approved by the US
Food and Drug Administration per 5-year period

  Spellberg, B. Arch Intern Med 2011;171:1080-1081

Realities are Worrisome

                   Antibacterial resistance

                   . Antibacterial R&D

1998                2009
           YEARS

WHO 2001
Statement zur globalen Resistenzentwicklung:

“Die unaufhaltsame Zunahme des Auftretens, der
Entwicklung und der Ausbreitung von Resistenzen
und der Mangel an neuen Antibiotika, die
gegenüber den resistenten Stämmen aktiv sind,
läßt befürchten, daß wir tatsächlich in die
postantibiotische Ära eintreten werden.”

Massnahmen zur Lösung des
       Resistenzproblems

• Patientennahe Diagnostik
  (point of care)
• Rationale Antibiotikatherapie
  (antibiotic stewartship )
• Infektionsprävention und Hygiene
  (Infektionskontrolle, Vakzination etc.)
• Neue wirksame Antibiotika

Annual Incidence of Invasive Disease Caused by
     Penicillin-Susceptible and Penicillin-Nonsusceptible
      Pneumococci among Children under Two Years of
                      Age, 1996 to 2004

Kyaw MH et al. N Engl J Med 2006; 354:1455-1463

Antibiotic Resistance of IPD in Children in
                         Germany, July 1997 - June 2011
        50                                                                                                   50
                     Clari R (%)
                     Pen I+R (%)
                                                     0-23 Mo                                                                                                  24-59 Mo
                                                                       Start PCV7 Impfung                                     ClariR (%)
        40                                                                                                   40
                                                                                                                              PenI+R (%)
                                                                                                                                                                           Start PCV7 Impfung
→ (%)

        30                                                                                                   30

                                                                                                     → (%)
        20                                                                                                   20

        10                                                                                                   10

         0                                                                                                    0
              97-98 98-99 99-00 00-01 01-02 02-03 03-04 04-05 05-06 06-07 07-08 08-09 09-10 10-11                 97-   98-     99-   00-   01-   02-   03-    04-   05-   06-   07-   08-   09-   10-
                                                                 → Pneumokokken Saison                            98    99      00    01    02    03    04     05    06    07    08    09    10    11

         50                                                                                                  50

                                               60-191 Mo

Effective Antibacterials: at what cost?
 The economics of antibacterial resistance
           and its control (I)

• Antibacterials, along with other anti-
  infective agents are unique in that the
  targets of their action can change and
  become resistant.
• The very use of antibacterials brings
  about their obsolence over time.

  White AR and the BSAC Working Party;JAC 2011;66:1939

Effective Antibacterials: at what cost?
  The economics of antibacterial resistance
            and its control (II)

Rebuild the Model
• Now is the time to rebuild the model:
  Robust data and information on the value of antibacterials
  and the cost of resistance need to be generated,
  communicated and used in order to set prizing and
  reimbursement to commensurate with value.

XX We need a research, development and funding
  model that succeeds and delivers antibacterials
  for future generation throughout their lifetime.
  White AR and the BSAC Working Party; JAC 2011;66:1939

Vielen Dank !

From the past to the future: hypothetical potential scenarios evolving from the relationship
             between antibacterial needs/resistance, antibacterial productivity and policy.

              White A R J. Antimicrob. Chemother. 2011;66:1948-1953

© The Author 2011. Published by Oxford University Press on behalf of the British Society for
 Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
 journals.permissions@oup.com

Mortality of COPD Patients Infected with
               Multi-Resistant Pseudomonas aeruginosa:
                       A Case and Control Study
                     Montero et al. Infection 2009;37:16-19

Results:

During the study period (2000–2005), 50 case patients and 50 controls
were included. Crude mortality at 2 years was 60% for the case
patients and 28% for the control group.

Conclusions:

In COPD patients admitted to the general ward, acute exacerbation with
 MDRP in sputum was associated with higher mortality.

Mortality of COPD Patients Infected with
Multi-Resistant Pseudomonas aeruginosa
                                         - Mortality -

         1 month:                   12% MDRP - 8% controls

         1        year:             32% MDRP - 18% controls

         2 years:                   60% MDRP - 28% controls

Montero et al. Infection 2009;37:16-19

Angriffspunkte der antibakteriell wirksamen Antibiotika
                                                       Struktur und Funktion                    Struktur und Funktion
  Zellwandsynthese
                                                       der Zellmembran                          der DNA
  ß-Laktam-Antibiotika
                                                       Colistin, Polymyxin B                    Chinolone
  Glykopeptide
                                                       Daptomycin                               Nitrofurane
  Fosfomycin
                                                                                                Nitroimidazole

Folsäure-
Metabolismu                                                                                                    DNA-abhängige
                                                                        DNA
s                            THFS                                                                              RNA-Polymerase
                                                                                                               Rifampicin
                                 (Reduktase)
 Trimethoprim
                             DHFS                                                                           Proteinsynthese
                                                                Ribosomen
                                  (Einbau       50 S                                          mRNA          • Blockade
 Sulfonamide                      in DHFS)                                                                  der 50S-Untereinheit;
                                                                                                            Hemmung der
                              PABS                                                                          Transpeptidierung
                                             30 S
                                                                                                            Chloramphenicol
                                                                                                            Streptogramine

                                                                                                     Proteinsynthese
                                                                                                     • Blockade
                                                                       Proteinsynthese               der 50S-Untereinheit;
Proteinsynthese                          Proteinsynthese               • Blockade                    Hemmung der Translokation
• Hemmung der Bildung                    • Fehlsteuerung der           der 30S-Untereinheit          Makrolide, Azalide, Ketolide
des Initiationskomplexes                 Synthese                      (Akzeptorposition)            (Ketolide hemmen zusätzlich
Oxazolidinone                            Aminoglykoside                Tetracycline                  die Bildung der 30S- und 50S-
                                                                                                     Untereinheiten)

PABS = p-Aminobenzoesäure, DHFS = Dihydrofolsäure; THFS = Tetrahydrofolsäure

Die treibenden Kräfte der
       Resistenzentwicklung

• Mutation
     Mutationsrate, Übertragungsmöglichkeit durch
     Konjugation, Transformation oder Transduction

• Selektion
      einseitiger massiver Antibiotikagebrauch

• klonale Ausbreitung
      sexuelle Übertragung, durch Fäkalien u.ä.

The Urgent Need for New
         Antibacterial Agents

• “I find it continually amazing that society
  as a whole does not recognize the
  consequences of rising antimicrobial
  resistance as a threat it most certainly is.”
• In 2009 the WHO called antibiotic
  resistance one of the greatest threats to
  human health and in 2011 the focus of
  World Health Day was “Combating
  Antibiotic Resistance”.
  Wise R and the BSAC Working Party, JAC 2011;66: 1939

The development of new classes of
     antimicrobial agents has slowed

Livermore DM et al. Ann Med 2003;35:226-231

Antibiotikaentwicklung weltweit
• Rückgang der Anmeldungen
  neuer Substanzen bei der
  FDA um mehr als 50% seit
  1983

• Keine Antibiotikaanmeldung
  2002-4

 Spellberg B. CID 2004; 38: 1279-86

Systemic (i.e., nontopical) antibacterial new molecular entities
approved by the US Food and Drug Administration, per 5-year period

     Spellberg B et al. Clin Infect Dis. 2008;46:155-164

Antibacterial and anti-HIV new molecular entities (NMEs) approved by
the US Food and Drug Administration, per 5-year period

     Spellberg B et al. Clin Infect Dis. 2008;46:155-164

Antibacterials: value to society from cradle to grave.

           White A R J. Antimicrob. Chemother. 2011;66:1948-1953

© The Author 2011. Published by Oxford University Press on behalf of the British Society for
 Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
 journals.permissions@oup.com

Die Zukunft der Infektionen
              - Der Mensch -

• Extremes Alter          • Rauchen
• Armut                   • Alkohol
• Mangelernährung
                          • Reisegewohnheiten
• Sexualverhalten
• Bevölkerungskontrolle   • Immunstatus

Die Zukunft der Infektionen
                - Erreger -

• Veränderung des genetischen Materials

• Veränderung der Resistenz

• Kommensale Erreger werden pathogen

• Toxinproduktion nimmt zu

• „Neue“ Erreger werden entdeckt

• Erreger-Wirt Interaktionen nehmen zu

From sulphonamides to fluoroquinolones Time Magazine,
                     January 10, 1944
                           Medicine: Admirable M&B

•   "On the 11th of December I felt so tired out that I had to ask General
    Eisenhower for a few days' rest before proceeding. This was accorded
    me in the most generous manner.

•   The next day came the fever, and the day after, when the photographs
    showed that there was a shadow on one of my lungs, I found that
    everything had been foreseen. . . . Excellent nurses and the highest
    medical authorities in the Mediterranean arrived from all quarters as if
    by magic. This admirable M & B [sulfapyridinewas originally called
    May & Baker 693, after the firm which made it], from which I did not
    suffer any inconvenience, was used at the earliest moment and after
    a week's fever the intruders were repulsed. I hope all our battles will
    be equally well conducted.”

From sulphonamides to fluoroquinolones
 Bayer’s prontosil and May & Baker’s sulfapyridine

From sulphonamides to fluoroquinolones
    History of sulphonamides:
•   Sulfanilamide had been synthesized by the Australian PhD-student
    Paul Gelmoin 1908. Bayer produced it as an intermediate for the
    production of p-azo-dyes on a scale of hundreds of kilograms per day.
•   Domagk’s technician MargareteGerresheim performed the first in vivo
    experiment with 4’-sulfonamido-2,4-diaminoazo-benzene mid-December
    1932 while Domagk attended a conference. Domagk was sceptical
    of her results and repeated the experiments personally a few days
    prior to Christmas.
•   Trefouelet al. discovered that the reductive cleavage product of
    prontosil, i.e. sulfanilamide, was the active principle.
•   Domagk was awarded with the Nobel Price in 1939 and finally
    accepted the price in 1947.

From sulphonamides to fluoroquinolones
   Contents:
   1. Sulphonamides
      •   History
      •   Chemistry, or: it is just due to their structural resemblance
      •   Mode of action
      •   PK/PD and protein binding
   2. Fluoroquinolones
      •   History
      •   Chemistry
      •   PK/PD

Antimikrobielle Therapie
Direkte Bekämpfung          Stärkung der
                   oder
    der Erreger         körpereigenen Abwehr
      „Chemotherapie“                  „Serotherapie“

               Medikamen     Patient
                   t

                        Erreger

From azodyes to sulphonamides
•   In 1931 it was noted that azodyes, “compounds A and B”,
    were highly active in vitro against E coli but not in vivo in
    Domagk’s ß-hemolytic streptococcal sepsis model. But,
    another azodye, “compound C”, cured rats infected with
    M. leprae.
•   Question:is the para- or meta-positioning of one of the
    phenyl rings decisive for antibacterial activity?
•   In October 1932 Domagk described that azodyes with a
    sulfonamide moiety para to the azogroup was active in vivo.
•   Shortly thereafter it became clear that an alkyl side chain -
    indispensible for antiparasitic action of e.g. Plasmo - or
    Resoquine was not required for antistreptococcal activity of
    4’-sulfonamido-2,4- diaminobenzobenzene (KI 730, or
    Streptozon, or Prüfpräparat D 5214 = Prontosil).

Sulphonamides: The grim irony of history

                    The Nazis discovered it.
                    The Allies won the war with it.
                    It conquered diseases,changed
                    laws, and single-handedly
                    launched the era of antibiotics.
                    This incredible discovery was
                    sulfa, the first antibiotic. In The
                    Demon Under the Microscope,
                    Thomas Hager chronicles the
                    dramatic history of the drug
                    that shaped modern medicine.

„Zufällige“ Entdeckung des
                 Penicillins

Alexander Fleming: 1881-1955

Main causes of death among children
            Ages 0 to 4 yrs, estimates 1998, worldwide

                         Perinatal
                           20%

           Nutritional
               3%

         Non-                            Infectious
     communicable                         diseases
       conditions
                                            63%
          8%

               Injuries
                  6%

WHO 1999

Evolution als Prinzip der
 Resistenzentwicklung
         Unterschiedliche Genotypen
         (Mutationsrate 1:105 – 1:107)

         Antibiotika

         Vermehrung der resistenten
           Bakterien

Wettlauf: Antibiotika vs. Resistenzen

Historical evolution quinolones

WHO 1999
Statement zur globalen Resistenzentwicklung:

“Die unaufhaltsame Zunahme des Auftretens, der
Entwicklung und der Ausbreitung von Resistenzen
und der Mangel an neuen Antibiotika, die
gegenüber den resistenten Stämmen aktiv sind,
läßt befürchten, daß wir tatsächlich in die
postantibiotische Ära eintreten werden.”

Resistenzentwicklung

 existenter genetischer Komplex

Mutation oder Aufnahme von Genen

        Selektionsdruck

    Überleben im Ökosystem

  Ausbreitung in der Umgebung

The Situation Today

     • Bad Bugs, No Drugs: As Antibiotic
       Discovery Stagnates… A Public Crisis Brews1

     • Lack of Development of New Antimicrobial
       Drugs: A Potential Serious Threat to Public
       Health2

           2005, ESCMID

1. IDSA White Paper, July 2004
2. Norrby SR, et al. Lancet Infect Dis 2005;5:115-119

Structures of the first-generation cephalosporins

Third-generation quinolones