What is an antibiotic? A small molecule of defined chemical
structure that targets a bacterial biochemical process, killing
bacteria specifically. For this reason, antibiotics do not affect
viruses, nor do they target human (eukaryotic) cells. Penicillin G
4/35
Slide 5
http://en.wikipedia.org/wiki/List_of_antibiotics Inhibit
bacterial protein biosynthesis ClassExamplesCommon Use Introduce d
Aminoglycosides Kanamycin, Streptomycin Gram-negative bacterial
infections (e.g. E. coli, P. aeruginosa) 1943
LincosamidesClindamycin Staph-, pneumo- and streptococcal
infections in penicillin-allergic patients 1961
MacrolidesErythromycin Streptococcal infections, syphilis,
respiratory infections, Lyme disease 1952
OxazolidinonesLinezolidVRSA1956 Tetracyclines Doxycycline,
Tetracycline Syphilis, chlamydial infections, Lyme disease 1948
Inhibit bacterial cell wall synthesis ClassExamplesCommon
UseIntroduced CarbapenemsMeropenem Broad-spectrum antibacterial
1976 CephalosporinsCefalexin Gram-positive infections 1948
GlycopeptidesVancomycin Gram-positive infections, including MRSA;
oral treatment of C. difficile 1955 Penicillins Amoxicillin,
Methicillin, Penicillin G Broad spectrum; used for streptococcal
infections, sypthilis and Lyme disease 1942 (mass production)
PolypeptidesBacitracin Eye, ear or bladder infections 1945 Disrupt
bacterial membrane potential ClassExamplesCommon UseIntroduced
LipopeptidesDaptomycin Gram-positive infections 1987 Inhibit
bacterial DNA replication ClassExamplesCommon UseIntroduced
QuinolonesCiprofloxacin Urinary tract infections, pneumonia,
gonorrhea 1962 Inhibit bacterial synthesis of folate
ClassExamplesCommon Use Introduce d SulfonamidesSulfa drugs Urinary
tract/eye infections 1932 Bacteria have certain unique biochemical
mechanisms that can be targets for antibiotics while eukaryotic
cells are untouched. 5/35
http://en.wikipedia.org/wiki/List_of_infectious_diseases Viral
DiseaseAgent AIDSHIV ChickenpoxVaricella zoster virus Common
coldusually rhinoviruses and coronaviruses Dengue feverDengue
viruses DEN-1-4 EbolaEbolavirus Hepatitis A-EHepatitis viruses
Herpes simplexHerpes simplex virus 1 and 2
InfluenzaOrthomyxoviridae family MeaslesMeasles virus MERS Middle
East respiratory syndrome coronavirus MumpsMumps virus
PoliomyelitisPoliovirus RabiesRabies virus SARSSARS coronavirus
SmallpoxVariola major/minor West Nile FeverWest Nile virus Yellow
feverYellow fever virus Eukaryotic DiseaseAgent MalariaPlasmodium
genus Hookworm Ancylostoma duodenale / Necator americanus
ScabiesSarcoptes scabiei Prionic DiseaseAgent Bovine spongiform
encephalopathy (mad cow disease) prion Creutzfeldt-Jakobprion
Kuruprion Bacterial DiseaseAgent AnthraxBacillus anthracis
Bacterial pneumoniamultiple Botulism Botulinum toxin from
Clostridium botulinum Bubonic plagueEnterobacteriaceae family
ChlamydiaChlamydia trachomatis CholeraVibrio cholerae*
DiphtheriaCorynebacterium diphtheriae GonorrheaNeisseria
gonorrhoeae LeprosyMycobacterium leprae ListeriosisListeria
monocytogenes Lyme diseaseBorrelia burgdorferi Pertussis (Whooping
cough) Bordetella pertussis SalmonellosisSalmonella genus Scarlet
fever Erythrogenic toxin from Streptococcus pyogenes Shigellosis
(Bacillary dysentery) Shigella genus SyphilisTreponema pallidum
TetanusClostridium tetani Tuberculosis usually Mycobacterium
tuberculosis Typhoid Fever Salmonella enterica enterica serovar
Typhi 7/35
Slide 8
Adapted from CDC: Achievements in Public Health, 1900-1999;
July, 1999 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm
8/35
Slide 9
CDC: Achievements in Public Health, 1900-1999; July, 1999
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm 9/35
Slide 10
WHO, Antimicrobial Resistance Report, 2014 Our arsenal of
antibiotics is not getting larger 10/35
Slide 11
Boucher et al., IDSA Public Policy, 2013 Our arsenal of
antibiotics is not getting larger 11/35
Slide 12
Ling et al., Nature, 2015 though this might be changing 12/35
Teixobactin kills Staphylococcus aureus after 24 hr and doesnt
develop resistance over 25 days
Slide 13
The first rule of antibiotics is try not to use them, and the
second rule is try not to use too many of them. -Paul Marino, The
ICU Book, 2007 13/35
Elixhauser and Steiner, AHRQ Statistical Brief 35, 2007
16/35
Slide 17
Office for National Statistics (UK), Aug. 2013; CDC, Active
Bacterial Core Surveillance Report, 2012 though were improving in
this regard as well 17/35 In the US, the CDC reports 30,800 fewer
severe MRSA infections and 9000 fewer MRSA-related deaths in 2011
vs. 2005
Slide 18
The time may come when penicillin can be bought by anyone in
the shops. Then there is the danger that the ignorant man may
easily underdose himself and by exposing his microbes to non-lethal
quantities of the drug make them resistant. -Alexander Fleming,
Penicillin: Nobel Lecture, Dec. 11, 1945 18/35
Slide 19
McNulty et al., Journal of Antimicrobial Chemotherapy, 2007 n =
7120 There is still a lot of misinformation in the general public
19/35
Slide 20
n = 7120 McNulty et al., Journal of Antimicrobial Chemotherapy,
2007 even among educated people. 20/35
Slide 21
21/35
Slide 22
Mellon et al., Union of Concerned Scientists, 2001 22/35
Slide 23
Gilbert, Nature, 2012; Cawood, North Queenland Register, Dec 31
2014 23/35 2011: EU voted to ban prophylactic use of antibiotics in
agriculture 2012: FDA in US bans prophylactic use of 2
cephalosporin antibiotics in livestock; currently considering
expanding ban Nevertheless, worldwide, 70-80% of all antibiotics
produced are still used in livestock Steps are being taken to limit
prophylactic use
Slide 24
Larry Frolich, 2006; Gregorious Pilosus 2009 Horizontal Gene
Transfer: harmless bacteria can share resistance genes with harmful
bacteria 24/35
Slide 25
The Fundamental Problem with Antibiotics: We use human
ingenuity to engineer new or discover ancient, pre-existing
antibiotic compounds. There compounds are static tools. Bacteria
use the principles of environmental pressure and natural selection
to develop resistance. This a dynamic process. Weve been winning
the race for the last 70 years but how long can we keep up?
25/35
Slide 26
So, naturalists observe, a flea Has smaller fleas that on him
prey; And these have smaller still to bite em, And so proceed ad
infinitum. -Jonathan Swift, On Poetry: A Rhapsody, 1733 26/35
Slide 27
http://www.mansfield.ohio-state.edu/~sabedon/beg_phage_images.htm
Bacteriophages (phages): Viruses that specifically target and
attack bacteria 27/35
10 6 bacteria / ml seawater 10 8 phages / ml seawater 70% of
all marine bacteria may be infected by phages Nicholas Mann, PLOS
Biology, 2005 29/35
Slide 30
Anonymous Germany (Augsburg) 1476 Naaman, a leper who dipped
himself 7 times in the River Jordan and became clean 2 Kings 5
Illustrations from Spiegel Menschlicher Behltnis. Woodcut Sch. IV,
1-178 Harvard Art Museums/Fogg Museum, Gift of Philip Hofer, M3719
30/35
Slide 31
Abedon et al., Bacteriophage, 2011; Fruciano and Bourne, Can J
Infect Dis Med Microbiol, 2006 Flix d'Herelle 1873-1949 1911:
dHerelle successfully stops locust infestation in Argentina using a
strain of Cocobacillus George Eliava 1892-1937 1934: Joseph Stalin
invites dHerelle to establish Eliava Institute for phage research
with George Eliava in Tbilisi, Georgia 1917: dHerelle discovers
phage activity against dysentery bacteria; develops phage therapies
1934: Phage therapy discredited in a series of articles in JAMA
(the Eaton-Bayne-Jones reports) 1991: Georgian Civil War leaves
Institute in ruins 1997: Exposure by the BBC spurs international
support for Institute 31/35
Slide 32
Abedon et al., Bacteriophage, 2011 StudyYearAimEtiologic
Agent(s)Patients Success (% w/ cleared bacteria) Sakandelidze and
Meipariani 1974 Peritonitis, osteomyelitis, lung abscesses,
postsurgical wound infections Staphylococcus, Streptococcus and
Proteus 23692% Meladze et al.1982Lung/pleural
infectionsStaphylococcus 223 phages; 117 ABs 82% w/ phages; 64% w/
ABs Slopek et al.1987 Gastrointestinal tract, skin, head and neck
infections Staphylococcus, Pseudomonas, E. coli, Klebsiella and
Salmonella 55092% Kochetkova et al.1989 Postoperative wound
infections Staphylococcus and Pseudomonas 65 phages; 66 ABs 82% w/
phages, 61% w/ ABs Sakandelidze1991Infectious allergoses
Staphylococcus, Streptococcus, E. coli, Proteus, enterococci and P.
aeruginosa 360 phages; 404 ABs; 576 phage+ABs 86%, 48%, 83%,
respectively Perepanova et al.1995 Acute and chronic aurogenital
inflammation E. coli, Proteus and Staphylococcus 4692%
Markoishvili2002Ulcers and wounds E. coli, Proteus, Pseudomonas,
Staphylococcus 9670% 32/35
Slide 33
AntibioticsPhage Therapy Kill broad spectrum of bacteria
(including beneficial gut flora) Specifically targets infectious
bacterial strain Broad spectrum activity allows for trivial
widespread use Most successful phage treatments must be bred
specifically for each patient Potential for allergic response Only
minor side effects seen; no immune response reported Dose-dependent
Self-multiplying and self- limiting Static; if bacteria develop
resistance, new antibiotic must be developed Dynamic; can evolve in
parallel with bacteria to thwart resistance 33/35
Slide 34
listex.eu 34/35
Slide 35
Harald Brussow, Virology, 2012 What is needed for phage therapy
to become a reality in Western medicine? Several small clinical
trials have taken place in Switzerland and Bangladesh; a phase I
clinical trial (Intralytix) in the US was successful in 2009.
Others are currently underway. Minimum investment for a
broad-spectrum cocktail similar to a new antibiotic: $10-50 million
USD (8.542 million EUR). Commercial phage cocktails need to be
sequenced, screened and tested. Phage therapies will likely need to
be customized for an individual patients needs. 35/35
Slide 36
Further Reading Boucher, H. et al. 10 x 20 Progress Development
of New Drugs Active Against Gram-Negative Bacilli: An Update from
the Infectious Diseases Society of America. CID 56, 2013, 1685-1694
Brssow, H. What is needed for phage therapy to become a reality in
Western medicine? Virology 434, 2012, 138-142 Abedon, S. et al.
Phage treatment of human infections. Bacteriophage 1:2, 2011, 66-85
Chanishvili, N. et al. Phages and their application against
drug-resistant bacteria. J Chem Technol Biotechnol 76, 2001,
689-699 Fruciano, DE and Bourne, S. Phage as an antimicrobial
agent: dHerelles heretical theories and their role in the decline
of phage prophylaxis in the West. Can J Infect Dis Med Microbiol
18(1), 2007, 19-26