ANTIMICROBIAL CHEMOTHERAPY IN THE 20TH CENTURYSome recollections

Professor Alasdair Geddes

Some recollections

Professor Alasdair GeddesSchool of Medicine

University of BirminghamUniversity of BirminghamBirmingham UK

a.m.geddes@bham.ac.uk

1929

Gerhard DomagkGerhard Domagk(1895‐1964)

PRONTOSIL RUBRUM [Sulphonilamide] ‐ 1935

EARLY YEARS OF ANTIMICROBIAL CHEMOTHERAPY 

1930’s/1940’s

Sulphonamides; penicillin; streptomycin

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐[1951 ‐ AG entered Medical School]‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1950’s1950’s

Chloramphenicol tetracyclines erythromycinChloramphenicol; tetracyclines; erythromycin; (vancomycin)

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ ‐‐ [1957 ‐ AG graduated] ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Sir Alexander Fleming ‐ Rector of Edinburgh University ‐ 1951g y

1940

Fleming, Chain & Florey receiving the Nobel Prize in 1945[Team work]

Fleming’s Nobel Prize Oration (1945)Fleming s Nobel Prize Oration (1945)

“The time may come when penicillinThe time may come when penicillin may be bought by anyone in shops.  There is a danger that the ignorantAl d Fl i There is a danger that the ignorant man may under‐dose himself and make the microbes resistant (‘Stewardship’!?) ”

Alexander Fleming(1881‐1955)

the microbes resistant ( Stewardship !?).

“We may not be at the end of the ypenicillin story.  We are in a chemical age and penicillin may be changed by g p y g ychemists  so that its disadvantages may be removed and better derivatives 

Ernst Chain(1906‐1979)

produced.” 

THE ‘GOLDEN‘ DECADES  OF CHEMOTHERAPY *

1960’s (ISC founded in 1961)

[‘Golden years of Pills and Profits’ ‐ David Greenwood]

1960’s (ISC founded in 1961)Semi‐synthetic penicillins:‐ ampicillin, amoxycillin cloxacillin; flucloxacillinamoxycillin, cloxacillin; flucloxacillinEarly cephalosporins:‐ cephaloridinegentamicin; trimethoprimgentamicin; trimethoprim

1970’s (BSAC founded in 1971)1970 s  (BSAC founded in 1971)Newer cephalosporins (++) & cephamycins; carbenicillin; ureidopenicillins (mezlo & azlo);carbenicillin; ureidopenicillins (mezlo & azlo); clindamycin; imipenem

*Investigated in Birmingham

AMPICILLIN‐LIKE PENICILLINS

(a) Ampicillin

(b) Amoxycillin(b) Amoxycillin

19641964

1972

ISOXAZOLYL PENICILLINS

1970

ICC LONDON July 1975ICC LONDON  July 1975

Hosted by the BSAC at i l C llImperial College, 

London, courtesy of E.B. Chain 

July 1975

Discoverer of the original source of the cephalosporin antibiotics from a sewage outfall in the sea off Sardinia:‐

Cephalosporium acremonium(Acremonium chrysogenum)  

Giuseppe BrotzuGiuseppe Brotzu(1895‐1976)

1982

1980’s

Clavulanic acidCLAVULANIC ACID

Clavulanic acid 

N fl i l *New fluoroquinolones*

Ciprofloxacin (typhoid)Ofloxacin; norfloxacin

CIPROFLOXACIN

etc, etc.

* [Nalidixic acid 1964]

1980

INTERNATIONAL CHEMOTHERAPYINTERNATIONAL CHEMOTHERAPY CONGRESS ‐ BIRMINGHAM 1999 

[Hosted by the BSAC]

George Hitchings & Gertrude ElionGeorge Hitchings & Gertrude Elion(Nobel Prize‐winners)

Invented ‘Designer drugs’ based on purine/pyrimidinesynthesis :synthesis :‐

Pyrimethamine (malaria)Pyrimethamine (malaria)

Acyclovir (Herpes virus infections) ‐Martin Wood

Trimethoprim co trimoxazole (TMP + Sulpha)Trimethoprim co‐trimoxazole (TMP + Sulpha) (Typhoid fever)

1990’s ONWARDS

1] Marked slow down in discovery of new1] Marked slow down in discovery of new antimicrobial agents.

2] No major breakthrough in non‐antimicrobial therapy of infections (e.g. immunotherapy).

3] Resurrection of ‘old’ agents (daptomycin(lipopeptide); colistin (polypeptide).(lipopeptide);  colistin (polypeptide). 

4] Growing Interest in ‘natural products’.  Plants, flowers (IJAA).

ANTIBIOTIC POLICIES ‐ Late 20th Century

1] Example & admonition (!) education

2] British National Formulary (Chapter 5.)

3] Prophylaxis dilemmas:‐

Elective orthopaedic surgery (J Charnley)

Endocarditis (BSAC leadership)

INFECTIOUS DISEASES IN BIRMINGHAMINFECTIOUS DISEASES IN BIRMINGHAM(1967 ‐ 1991: 6 wards initially incl. ITU)

• Childhood infections (measles; rotavirus infection; pertussis; meningitis)

• Imported infections (malaria; typhoid; leprosy; leishmaniaisis onchocerciasis)leishmaniaisis, onchocerciasis)

• Exotica: rabies; botulism; tetanus; smallpoxp

• Infection in the immunosuoppressed

• HIV/AIDS ‐ 1982

Collaboration, Research & Training!• Physicians• Physicians

• Microbiologists• Microbiologists

• Epidemiologists• Epidemiologists

• Pharmacists• Pharmacists

• Nurses• Nurses

• Students (all sorts)• Students (all sorts)

DAVID WILLIAMS[1936‐2005]

Dudley Road Hospital,Dudley Road Hospital, Birmingham (until 1975) & The London Hospital

[JAC O b 2005][JAC, October 2005]