Grand Rounds (week 6): Antibiotic Resistance
Newly Emerging and Resistant Infections--Can Plan Antimicrobials and Probiotics Help?
greatest threat to human health: acquisition of resistance by micro-organisms
now there's a strain of Neisseria gonorrhea which is resistance to all antibiotics
less than 100 years ago we didn't have abx
average RX of Abx in US: 1/person/year
speaker: Nigel Plummer
lean, light brown hair, punky cut with side burns, long in back, spiky in front, clean shaven craggy face
light blue shirt, black and white patterned tie, gray pants, shined shoes
relaxed, humorous
CEO of Pharmax
lives in western Wales in the UK
in mourning for losing the world cup last Saturday
"Americans like to hug"
"Americans don't know how to make tea"
The emergence and progression of multiple drug resistance by pathogenic micro-organisms presents the biggest challenge of medicine in the 21st Century and threatens the basis of our health care platform. Until less than 100 years ago, and for thousands of years previously, botanicals, such as garlic, formed the mainstay of antimicrobial therapy. As antibiotics become less effective and new derivatives are scarce perhaps it is time to review these traditional remedies as well as new forms of biotherapy.
In this lecture, the problem of drug resistance will be reviewed and illustrated with important examples. Similarly, the practical effectiveness of botanicals and probiotics to replace or compliment the use of allopathic antimicrobials will be explored.
BIO - Nigel Plummer PhD has his doctorate in microbial physiology and has worked at Pfizer in antibiotic research and development. His research on the use of normal flora in the prevention and treatment of genito-urinary candidiasis has won him numerous awards. Dr. Plummer continues his solid commitment to research throughout his career in collaboration with research institutes and universities within the UK and Europe, developing an extensive knowledge specializing in probiotics, natural antimicrobials and fish oils. Dr. Plummer lectures extensively in North America and the UK/Europe and has developed an interest in the concept of fetal disease programming, the controlling factors involved and the potential to influence programmed events as a means of prevention of chronic disease development.
HISTORICAL USE OF GARLIC
used by Egyptian slaves, was in Ebers Papyrus 1200BC oldest surviving medical text
Hippocrates used it, Greeks too for athletic performance
Chinese and Indiah med used for infx, worms, GI
Europe: mix with wine to ward off plague, gravediggers use it
WWI: in water as wound poultice, still used in WW2 by the Russians who didn't have penicillin yet
"Russian penicillin"
ANTIBIOTICS WERE GREAT
it was believed we'd eradicate TB, syph, gonorrhea, bact pneumo and meningitis, staph
smallpox is the ONLY dz ever to be eradicated
polio is confined to certain areas and erdication is likely
guinea worm dz also likely to be eradicated (nematode or treponeme in water, burrows through tissues, exits from skin usu at arms)
BUT THEY DIDN'T SAVE US
now 22 million/year die of infx dz
600 million get cholera, 120K die
5 million die of D, 1.5-2 million die of malaria, 3 million die of TB and 1.7 billion have it
"most of this is in the developing nations"
1.2 million die of measles/year, HIV 2.8 million
South Africa: 40% of pop has HIV, no job, and a gun
HOW MICROBES BECOME RESISTANT
selective pressure by use of antibiotics
plasmid transfer
most resistance genes are plasmid borne
MRSA
vancomycin is last major abx that used to work on MRSA
vancomycin resistant staph appeared over 10 years ago
got it from eneterococci via plasmid transfer
BUGS GETTING RESISTANT FASTER
time from introduction of antibiotic to resistance is getting shorter
methiciillin introduced in 1959, resistance in 73
cipro 89, 90
sulfonamide 43, 59
fluconazoel 91, 91
genta 69, 79
acyclovir 84, 89
azt 86, 88
Staph aureus
85% lethal if it gets in the blood
in 1950 100% sensitive to penicillin, 1982 90% resistant, 1992 95% resistant, 1997 95%
methicillin 1982 100% sensitive, 1992 15% (or 40% in hospitals), , 1997 20-40% resistant (40-80% in hospitals)
vancomycin 1992 100% sensitive, 1997 first vancomycin resistant MRSA appears in Japan and USA
Salmonella
1979-89 resistance to more than one first line drug went from 15-->30%
more MRSA resistance in southern Eur 30%, US 15%, northern Eur 2%
E coli 8% resistant in North America, 40% in China and SE Asia, and 31% in south america
resistant to tetra, ampi, trimeth, chloramphen, gentamycin
TB
Isoniazid and Rifampin used to tx, longterm tx needed to catch bug actually growing
any increase in resistance will result in 50% of the MDRTB cases being virtually untreatable
TB goes into vegetative state and hides in body, ABX only work on growing cells
THERE IS STILL AN ADVANTAGE FOR NON-RESISTANT STRAINS
resistant strains have "baggage"
due to metabolic drain of carrying "armour"
they are not as competitive as "wild type" strains
DON'T GO TO THE HOSPITAL
USA: 6% of pts admitted to hospital acquire new infx
-->2 million nosocomial infx/yaer, death by infx in US = 80K/year
FACTORS ACCELERATING RESISTANCE
overprescription, prescribing for viral infx
poor pt compliance
use in animal feed for prophylaxis and growth promotion (globally 2/3 of use is in animal husbandry)
((36 days for chicken to grow to grocery size from hatch!! 2-5% increase in growth rate due to abx, growth promotion abx use is banned in Europe now dt travel of resistance, avoparcin antibiotic caused resistance to vancomycin))
available OTC in many countries
increased overseas travel
COMPLICATORS ON WORLD SCENE
new abx class development declining
new abx expensive and inaccessible to many, have SEs
climate change causing shift in dz distribution
HIS WORK
tried to find safe effective plant derived anti-fungal to tx muco-cutaneous candida albicans infx
wanted it to be compatible with normal flora and probiotics
drugs: nystatin not absorbed through GI, amphotericina has SEs, fluorocytosine - candida is resistant, azoles now most widely used
screened over 100 natural substances that lit said had antifungal activity
over half showed no antifungal activity: aloe, cran, ginger, sage, artemesia, juniper, tannic, etc
target bugs: candida, fusarium spp, and lactobacillus acidophilus as positive control
the ones that did have antifungal activity: cassia alata, GSE has minimal activity, juglans, lauric acid (coconut)
MIC = minimmum inhibitory concentration (MIC) is 10-100mg/ml, MIC is min that stops org from growing
Potency level 1 (10-100ug/l): allicin (garlic is strongest of all), undecanoic acid, berberine, sanguinarine, cinnamon bark oil, oregano oil, nystatin, tea tree oil
Potency level 2 (100-10,000ug/ml): caprylates, Mg, Ca, gallic acid, propolis, saponin
published about 20 papers on antimicrobial activities of garlic
ALLICIN is most potent anti-yeast substance found
a certain concentration is needed to be effective, between 25-50mcg/ml, same MIC range as nystatin
doesn't bother lactobacillus acidophilus at all!!
diallyl thiosulphonate is made of two cysteine mols linked with S-S in middle
c=c-c-s-s-c-c=c, unique sulfur compound, one of the sulfurs has a double bond to an oxygen
enzyme released by crushing, allyinase and allyin get combined-->formation of allicin is instantaeous
compared allicin with abx for E.coli, worked better than chloramphenicol, furazolidone, oxytretracycline, sulphonamide
allicin causes blebbing and obliteration of E.coli cells
works for Clostridium, Staph, Salmonella, E. Coli, Rotavirus
Doesn't touch: Pseudomonas aeruginosa, Lactobacillus, Enterococci most immune, Pediococci, Bifidobacteria, (Lactic acid bacteria as a group)
allicin shows no toxicity to mammalian tissue
ALLICIN FOR PROTOZOANS
highly effective for enteric infections
studied Cryptosporidium parvum in mice
dz of dairy cows
works at 10mg/day/mouse of allicin concentrate
Seroyal protocol for protozoa = 3mg/day per mouse
works well on Giardia, whole garlic extract
highly effective for Trichomonas vaginalis at fairly low concentrations
GARLIC FUNCTIONALITIES SUMMARIZED
Bact: E coli, staph, salmontell
virus: rota, flu, HSV, HIV
protozoa: crypto, entamoaba histolytica, giardia, trich, blastocystis
fungi: candida, saccharomyces, aspergillus
NONTOXIC
once absorbed it is quickly converted into diallyl suphides in liver
LD50 of allicin is between 1-2 g/kg/day = 14kg/day
MOA OF ALLICIN
inhibs cell memb biosyn, DNA polymerases and prob RNA syn, destrx of HS groups, inhib thiol enzymes
"it targets sulfhydryl groups" "there is no resistance to garlic" "because it targets so many metabolic pathways"
our cells are protected via GSH interaction with allicin
don't know why lactic acid bact are not susceptible
ALLICIN for HIV?
one study showed activity vs HIV, another didn't
no followup yet
he's willing to return to report on this when he has mor einfo
OTHER OILS
cinnamaldehyde is strongest EO vs bacteria, this has been shown repeatedly in research, also vs candida, doesn't bother lactic acid
works vs helicobacter (prevalence: 1% of pop per year of age in North america, 60% of 60 year olds have H.pylori, they get atrophic gastritis and chronic B12 def,)
cinnamaldyhyde not good for protozoa
for helicobacter: oregano is best, clove, wormwood, ginger also help
oregano esp vs helicobacter, E..coli
nutmeg vs E.coli
berberine is cytotoxic so use with care
tea tree oil quite cytotoxic, do not take internally
PROBIOTICS and ANTIBIOTICS
microflora is best anti-infective barrier
bugs must attach to become infective, can't attach if coating of happy enterics
Salmonella infective dose decreases 10K if give abx at same time
Abx tx incr susceptibility to clostridium x50
Abx, gi infx, gi surgery and starvation all disturb normal flora
PROBIOTICS
helps for decr D dt abx
stops C.Diff diarrhea in hospitalized pts, soon to be required in UK hospitals
synergistic effect btw allicin and abx (oxacillin)
for MRSA
add garlic and more of the remaining bact are susceptible to the antibiotic at lower concentrations
resistance = resists over 4mcg/ml
garlic "disables" resistance to antibiotic
they're going to try to patent this use
could be used as adjunct to all abx use
greatest threat to human health: acquisition of resistance by micro-organisms
now there's a strain of Neisseria gonorrhea which is resistance to all antibiotics
less than 100 years ago we didn't have abx
average RX of Abx in US: 1/person/year
speaker: Nigel Plummer
lean, light brown hair, punky cut with side burns, long in back, spiky in front, clean shaven craggy face
light blue shirt, black and white patterned tie, gray pants, shined shoes
relaxed, humorous
CEO of Pharmax
lives in western Wales in the UK
in mourning for losing the world cup last Saturday
"Americans like to hug"
"Americans don't know how to make tea"
The emergence and progression of multiple drug resistance by pathogenic micro-organisms presents the biggest challenge of medicine in the 21st Century and threatens the basis of our health care platform. Until less than 100 years ago, and for thousands of years previously, botanicals, such as garlic, formed the mainstay of antimicrobial therapy. As antibiotics become less effective and new derivatives are scarce perhaps it is time to review these traditional remedies as well as new forms of biotherapy.
In this lecture, the problem of drug resistance will be reviewed and illustrated with important examples. Similarly, the practical effectiveness of botanicals and probiotics to replace or compliment the use of allopathic antimicrobials will be explored.
BIO - Nigel Plummer PhD has his doctorate in microbial physiology and has worked at Pfizer in antibiotic research and development. His research on the use of normal flora in the prevention and treatment of genito-urinary candidiasis has won him numerous awards. Dr. Plummer continues his solid commitment to research throughout his career in collaboration with research institutes and universities within the UK and Europe, developing an extensive knowledge specializing in probiotics, natural antimicrobials and fish oils. Dr. Plummer lectures extensively in North America and the UK/Europe and has developed an interest in the concept of fetal disease programming, the controlling factors involved and the potential to influence programmed events as a means of prevention of chronic disease development.
HISTORICAL USE OF GARLIC
used by Egyptian slaves, was in Ebers Papyrus 1200BC oldest surviving medical text
Hippocrates used it, Greeks too for athletic performance
Chinese and Indiah med used for infx, worms, GI
Europe: mix with wine to ward off plague, gravediggers use it
WWI: in water as wound poultice, still used in WW2 by the Russians who didn't have penicillin yet
"Russian penicillin"
ANTIBIOTICS WERE GREAT
it was believed we'd eradicate TB, syph, gonorrhea, bact pneumo and meningitis, staph
smallpox is the ONLY dz ever to be eradicated
polio is confined to certain areas and erdication is likely
guinea worm dz also likely to be eradicated (nematode or treponeme in water, burrows through tissues, exits from skin usu at arms)
BUT THEY DIDN'T SAVE US
now 22 million/year die of infx dz
600 million get cholera, 120K die
5 million die of D, 1.5-2 million die of malaria, 3 million die of TB and 1.7 billion have it
"most of this is in the developing nations"
1.2 million die of measles/year, HIV 2.8 million
South Africa: 40% of pop has HIV, no job, and a gun
HOW MICROBES BECOME RESISTANT
selective pressure by use of antibiotics
plasmid transfer
most resistance genes are plasmid borne
MRSA
vancomycin is last major abx that used to work on MRSA
vancomycin resistant staph appeared over 10 years ago
got it from eneterococci via plasmid transfer
BUGS GETTING RESISTANT FASTER
time from introduction of antibiotic to resistance is getting shorter
methiciillin introduced in 1959, resistance in 73
cipro 89, 90
sulfonamide 43, 59
fluconazoel 91, 91
genta 69, 79
acyclovir 84, 89
azt 86, 88
Staph aureus
85% lethal if it gets in the blood
in 1950 100% sensitive to penicillin, 1982 90% resistant, 1992 95% resistant, 1997 95%
methicillin 1982 100% sensitive, 1992 15% (or 40% in hospitals), , 1997 20-40% resistant (40-80% in hospitals)
vancomycin 1992 100% sensitive, 1997 first vancomycin resistant MRSA appears in Japan and USA
Salmonella
1979-89 resistance to more than one first line drug went from 15-->30%
more MRSA resistance in southern Eur 30%, US 15%, northern Eur 2%
E coli 8% resistant in North America, 40% in China and SE Asia, and 31% in south america
resistant to tetra, ampi, trimeth, chloramphen, gentamycin
TB
Isoniazid and Rifampin used to tx, longterm tx needed to catch bug actually growing
any increase in resistance will result in 50% of the MDRTB cases being virtually untreatable
TB goes into vegetative state and hides in body, ABX only work on growing cells
THERE IS STILL AN ADVANTAGE FOR NON-RESISTANT STRAINS
resistant strains have "baggage"
due to metabolic drain of carrying "armour"
they are not as competitive as "wild type" strains
DON'T GO TO THE HOSPITAL
USA: 6% of pts admitted to hospital acquire new infx
-->2 million nosocomial infx/yaer, death by infx in US = 80K/year
FACTORS ACCELERATING RESISTANCE
overprescription, prescribing for viral infx
poor pt compliance
use in animal feed for prophylaxis and growth promotion (globally 2/3 of use is in animal husbandry)
((36 days for chicken to grow to grocery size from hatch!! 2-5% increase in growth rate due to abx, growth promotion abx use is banned in Europe now dt travel of resistance, avoparcin antibiotic caused resistance to vancomycin))
available OTC in many countries
increased overseas travel
COMPLICATORS ON WORLD SCENE
new abx class development declining
new abx expensive and inaccessible to many, have SEs
climate change causing shift in dz distribution
HIS WORK
tried to find safe effective plant derived anti-fungal to tx muco-cutaneous candida albicans infx
wanted it to be compatible with normal flora and probiotics
drugs: nystatin not absorbed through GI, amphotericina has SEs, fluorocytosine - candida is resistant, azoles now most widely used
screened over 100 natural substances that lit said had antifungal activity
over half showed no antifungal activity: aloe, cran, ginger, sage, artemesia, juniper, tannic, etc
target bugs: candida, fusarium spp, and lactobacillus acidophilus as positive control
the ones that did have antifungal activity: cassia alata, GSE has minimal activity, juglans, lauric acid (coconut)
MIC = minimmum inhibitory concentration (MIC) is 10-100mg/ml, MIC is min that stops org from growing
Potency level 1 (10-100ug/l): allicin (garlic is strongest of all), undecanoic acid, berberine, sanguinarine, cinnamon bark oil, oregano oil, nystatin, tea tree oil
Potency level 2 (100-10,000ug/ml): caprylates, Mg, Ca, gallic acid, propolis, saponin
published about 20 papers on antimicrobial activities of garlic
ALLICIN is most potent anti-yeast substance found
a certain concentration is needed to be effective, between 25-50mcg/ml, same MIC range as nystatin
doesn't bother lactobacillus acidophilus at all!!
diallyl thiosulphonate is made of two cysteine mols linked with S-S in middle
c=c-c-s-s-c-c=c, unique sulfur compound, one of the sulfurs has a double bond to an oxygen
enzyme released by crushing, allyinase and allyin get combined-->formation of allicin is instantaeous
compared allicin with abx for E.coli, worked better than chloramphenicol, furazolidone, oxytretracycline, sulphonamide
allicin causes blebbing and obliteration of E.coli cells
works for Clostridium, Staph, Salmonella, E. Coli, Rotavirus
Doesn't touch: Pseudomonas aeruginosa, Lactobacillus, Enterococci most immune, Pediococci, Bifidobacteria, (Lactic acid bacteria as a group)
allicin shows no toxicity to mammalian tissue
ALLICIN FOR PROTOZOANS
highly effective for enteric infections
studied Cryptosporidium parvum in mice
dz of dairy cows
works at 10mg/day/mouse of allicin concentrate
Seroyal protocol for protozoa = 3mg/day per mouse
works well on Giardia, whole garlic extract
highly effective for Trichomonas vaginalis at fairly low concentrations
GARLIC FUNCTIONALITIES SUMMARIZED
Bact: E coli, staph, salmontell
virus: rota, flu, HSV, HIV
protozoa: crypto, entamoaba histolytica, giardia, trich, blastocystis
fungi: candida, saccharomyces, aspergillus
NONTOXIC
once absorbed it is quickly converted into diallyl suphides in liver
LD50 of allicin is between 1-2 g/kg/day = 14kg/day
MOA OF ALLICIN
inhibs cell memb biosyn, DNA polymerases and prob RNA syn, destrx of HS groups, inhib thiol enzymes
"it targets sulfhydryl groups" "there is no resistance to garlic" "because it targets so many metabolic pathways"
our cells are protected via GSH interaction with allicin
don't know why lactic acid bact are not susceptible
ALLICIN for HIV?
one study showed activity vs HIV, another didn't
no followup yet
he's willing to return to report on this when he has mor einfo
OTHER OILS
cinnamaldehyde is strongest EO vs bacteria, this has been shown repeatedly in research, also vs candida, doesn't bother lactic acid
works vs helicobacter (prevalence: 1% of pop per year of age in North america, 60% of 60 year olds have H.pylori, they get atrophic gastritis and chronic B12 def,)
cinnamaldyhyde not good for protozoa
for helicobacter: oregano is best, clove, wormwood, ginger also help
oregano esp vs helicobacter, E..coli
nutmeg vs E.coli
berberine is cytotoxic so use with care
tea tree oil quite cytotoxic, do not take internally
PROBIOTICS and ANTIBIOTICS
microflora is best anti-infective barrier
bugs must attach to become infective, can't attach if coating of happy enterics
Salmonella infective dose decreases 10K if give abx at same time
Abx tx incr susceptibility to clostridium x50
Abx, gi infx, gi surgery and starvation all disturb normal flora
PROBIOTICS
helps for decr D dt abx
stops C.Diff diarrhea in hospitalized pts, soon to be required in UK hospitals
synergistic effect btw allicin and abx (oxacillin)
for MRSA
add garlic and more of the remaining bact are susceptible to the antibiotic at lower concentrations
resistance = resists over 4mcg/ml
garlic "disables" resistance to antibiotic
they're going to try to patent this use
could be used as adjunct to all abx use