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Terry L Dwelle MD MPHTM FAAP CPH
State Health Officer
North Dakota Department of Health
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Antibiotics first employed in the 1940’s
Antibiotics + Vaccination + Sanitation =
Marked decline in deaths from ID’s
Antimicrobial resistance is a major ID threat to
PH
Much attention given to nosocomial infections
– ie VRE
Community acquired resistance is rising – St
Pneu., E Coli, Salmonella, etc.
Is an evolving problem – spans all health care
settings.
2
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Aminoglycosides
Beta lactams – penicillins, cephalosporins, carbapenems, monbactams
Flouroquinolones
Glycopeptides
Ketolides
Lincosamides
Macrolides
Oxazolidinones
Streptogramins
Sulfonamides
Tetracyclines
Levomycetinums
Ionophores
Bambermycins
Polypeptide s
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Treat infections – animals and humans
Prevent infections
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Humans - surgical wounds, dental prophylaxis for
endocarditis, neutropenia
Animals – prevent disease when animals are
susceptible

Promote growth – cattle, poultry and swine
Developed
Countries
19
2%

NE and N
Africa
37
4%

Latin Am and
Carribean
53
6%

925 million hungry
people in 2010, 13.7 % of
the 6.8 billion people
in the world

Asia and
Pacific
578
62%

SS Africa
239
26%
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160 days of illness per year
½ of the 10.9 million deaths per year
Magnifies the effect of diseases like measles
and malaria
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Swine – 3-9% improved weight gain, 3-7%
improved feed efficiency.
Greatest benefit when feed
composition, management practices and health
status of animals is not optimal.
Action
Eliminate bacteria that steal essential nutrients
 Reduce competition with beneficial bacteria that produce
essential nutrients for the animal.
 Control growth of bacteria that cause low-grade
infections or produce toxins – decreasing nutrient
absorption.
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Human and Animal
Tetracyclines
 Sulfonamides
 Penicillins
 Macrolides
 Fluoroquinolones
 Cephalosporins
 Aminoglycosides
 Chloramphenicols
 Streptogramins
 Polypeptides
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Animal only
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Ionophores
Bambermycins
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Strep. Pneumoniae
Moraxella Catarrhalis
Hem Influenza Type B
Strep Pyogenes
E. Coli
Neis. Meningitidis
Campylobacter
Salmonella
Shigella
Staph Aureus
Enterococcus
Mycobacterium Tuberculosis
Pertussis
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Inappropriate antimicrobial prescribing – most
important
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Overuse – 30-60% prescriptions are inappropriate
Inappropriate dosing
Use of broad spectrum AB’s as first line Rx

Animal applications (food)

10
Adults
Colds
URI
Bronchitis

Prescribing Rates
51%
52%
66%

Children
Colds
URI
Bronchitis

44%
46%
75%

Gonzales R et al JAMA 1997:278:901-904. Nyquist AC et al JAMA 1998;279:875-77
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46% of patients with common cold or nonspecific URI’s received antibiotics
Broad spectrum antibiotics used; 54%
general, 51% colds, 53% sinusitis, 62% acute
bronchitis, 65% OM
Lower BS use – blacks, lack of insurance, HMO
membership
Greater use of BS- Northeast and South

JAMA 2003;289:719-725
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12% recently taken antibiotics
27% believed taking antibiotics during a cold
made them better
32% believed taking antibiotics during a cold
prevented more serious illness
48% expected antibiotics when seeking medical
care with a cold
58% not aware of the health risks of antibiotics

Emerg Inf Dis: 9;9, pp 1128-1134 – JD Eng, et al
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Human health hazards
Antibiotic resistance particularly with low dosing
(ie Salmonella)
 Glycopeptide resistant E faecium of animal origin
– find in stools for 14 + days after ingestion of
meat
 Cross resistance
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 ie Virginimycin and Quinupristin-dalfopristin in

enterococci

Sorensen TL, NEJM 2001;3435:1161-6, Welton LA et al AntiAgChem
1998;42:705-8
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Human Health Hazards
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Salmonella enterica (flouroquinolone resistant)
spread from swine to humans in meat

Chiu CH NEJM 2002;346:413-9
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Europe – 1990’s – Avoparin use associated with
vancomycin resistance in humans
US – 1990’s – Campylobacter resistance to
fluoroquinolones
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Use antibiotics only when indicated
Least broad spectrum antibiotics first
Least time exposure possible
Use adequate therapeutic doses
Use non-human antibiotics when possible
With crossover drugs use those where
potential resistance will have the least impact
on humans
Appropriately monitor cultures and
sensitivities
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PRSP rose from 0% (1988) to 20% (1993)
Information campaign – physicians
Regulatory change – patients paid for
prescription drugs
PRSP declined to 15% (1995)

Stephenson J, JAMA 1996;275-175, Gunnlaugsson A, AntiAgChem
Conf, 1999, Abstract 1026
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Macrolide use tripled in the 1980’s
Erythromycin resistance for Gp A strep rose
sharply (17%) in the early 1990’s
National campaign for physicians
Resistance declined to 9% from 1992 to 1996

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1980’s
Appropriate use of advanced spectrum
antibiotics – 65%
All advanced spectrum antibiotic orders
received a form to be completed within 24
hours (justification of usage)
No adequate response – consult or could result
in loss of privileges
Appropriate use increased to > 95%

20
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Europe – Vancomycin resistance
Denmark – reduction in resistance in E
Faecium in broiler chickens (from 60-80% to 535%) WHO Internation Panel Ruling, Nov,
2002)
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Public Information Campaigns
Intensive Information Campaigns for
Physicians
Proactive Hospital Antibiotic Usage Programs
Collaborative task force –
Veterinarians, Physicians, and Public Health

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ND Health Officer Discusses Antimicrobial Resistance and Stewardship

  • 1. Terry L Dwelle MD MPHTM FAAP CPH State Health Officer North Dakota Department of Health
  • 2.       Antibiotics first employed in the 1940’s Antibiotics + Vaccination + Sanitation = Marked decline in deaths from ID’s Antimicrobial resistance is a major ID threat to PH Much attention given to nosocomial infections – ie VRE Community acquired resistance is rising – St Pneu., E Coli, Salmonella, etc. Is an evolving problem – spans all health care settings. 2
  • 3.                Aminoglycosides Beta lactams – penicillins, cephalosporins, carbapenems, monbactams Flouroquinolones Glycopeptides Ketolides Lincosamides Macrolides Oxazolidinones Streptogramins Sulfonamides Tetracyclines Levomycetinums Ionophores Bambermycins Polypeptide s
  • 4.   Treat infections – animals and humans Prevent infections    Humans - surgical wounds, dental prophylaxis for endocarditis, neutropenia Animals – prevent disease when animals are susceptible Promote growth – cattle, poultry and swine
  • 5. Developed Countries 19 2% NE and N Africa 37 4% Latin Am and Carribean 53 6% 925 million hungry people in 2010, 13.7 % of the 6.8 billion people in the world Asia and Pacific 578 62% SS Africa 239 26%
  • 6.    160 days of illness per year ½ of the 10.9 million deaths per year Magnifies the effect of diseases like measles and malaria
  • 7.    Swine – 3-9% improved weight gain, 3-7% improved feed efficiency. Greatest benefit when feed composition, management practices and health status of animals is not optimal. Action Eliminate bacteria that steal essential nutrients  Reduce competition with beneficial bacteria that produce essential nutrients for the animal.  Control growth of bacteria that cause low-grade infections or produce toxins – decreasing nutrient absorption. 
  • 8.  Human and Animal Tetracyclines  Sulfonamides  Penicillins  Macrolides  Fluoroquinolones  Cephalosporins  Aminoglycosides  Chloramphenicols  Streptogramins  Polypeptides   Animal only   Ionophores Bambermycins
  • 9.              Strep. Pneumoniae Moraxella Catarrhalis Hem Influenza Type B Strep Pyogenes E. Coli Neis. Meningitidis Campylobacter Salmonella Shigella Staph Aureus Enterococcus Mycobacterium Tuberculosis Pertussis
  • 10.  Inappropriate antimicrobial prescribing – most important     Overuse – 30-60% prescriptions are inappropriate Inappropriate dosing Use of broad spectrum AB’s as first line Rx Animal applications (food) 10
  • 11. Adults Colds URI Bronchitis Prescribing Rates 51% 52% 66% Children Colds URI Bronchitis 44% 46% 75% Gonzales R et al JAMA 1997:278:901-904. Nyquist AC et al JAMA 1998;279:875-77 11
  • 12. • • • • 46% of patients with common cold or nonspecific URI’s received antibiotics Broad spectrum antibiotics used; 54% general, 51% colds, 53% sinusitis, 62% acute bronchitis, 65% OM Lower BS use – blacks, lack of insurance, HMO membership Greater use of BS- Northeast and South JAMA 2003;289:719-725 12
  • 13.      12% recently taken antibiotics 27% believed taking antibiotics during a cold made them better 32% believed taking antibiotics during a cold prevented more serious illness 48% expected antibiotics when seeking medical care with a cold 58% not aware of the health risks of antibiotics Emerg Inf Dis: 9;9, pp 1128-1134 – JD Eng, et al 13
  • 14.  Human health hazards Antibiotic resistance particularly with low dosing (ie Salmonella)  Glycopeptide resistant E faecium of animal origin – find in stools for 14 + days after ingestion of meat  Cross resistance   ie Virginimycin and Quinupristin-dalfopristin in enterococci Sorensen TL, NEJM 2001;3435:1161-6, Welton LA et al AntiAgChem 1998;42:705-8 14
  • 15.  Human Health Hazards  Salmonella enterica (flouroquinolone resistant) spread from swine to humans in meat Chiu CH NEJM 2002;346:413-9 15
  • 16.   Europe – 1990’s – Avoparin use associated with vancomycin resistance in humans US – 1990’s – Campylobacter resistance to fluoroquinolones
  • 17.        Use antibiotics only when indicated Least broad spectrum antibiotics first Least time exposure possible Use adequate therapeutic doses Use non-human antibiotics when possible With crossover drugs use those where potential resistance will have the least impact on humans Appropriately monitor cultures and sensitivities
  • 18.     PRSP rose from 0% (1988) to 20% (1993) Information campaign – physicians Regulatory change – patients paid for prescription drugs PRSP declined to 15% (1995) Stephenson J, JAMA 1996;275-175, Gunnlaugsson A, AntiAgChem Conf, 1999, Abstract 1026 18
  • 19.     Macrolide use tripled in the 1980’s Erythromycin resistance for Gp A strep rose sharply (17%) in the early 1990’s National campaign for physicians Resistance declined to 9% from 1992 to 1996 19
  • 20.      1980’s Appropriate use of advanced spectrum antibiotics – 65% All advanced spectrum antibiotic orders received a form to be completed within 24 hours (justification of usage) No adequate response – consult or could result in loss of privileges Appropriate use increased to > 95% 20
  • 21.   Europe – Vancomycin resistance Denmark – reduction in resistance in E Faecium in broiler chickens (from 60-80% to 535%) WHO Internation Panel Ruling, Nov, 2002)
  • 22.     Public Information Campaigns Intensive Information Campaigns for Physicians Proactive Hospital Antibiotic Usage Programs Collaborative task force – Veterinarians, Physicians, and Public Health 22

Hinweis der Redaktion

  1. This talk is about antimicrobial resistanceWhat can we do in human and veterinary medicine to control this issue.
  2. This slide just lists the major antibiotic categories we utilize now – 71 years after Florey and Chain. Aminoglycosides – gentamicin, neomycin, kanamycin Beta lactams – penicillins (peni, amox, amp, augmentin), cephalosporins (1sr, 2nd, 3rd generation), carbapenems (imipenem, meropenem, doripenem), monbactams (aztreonam, tigemonam,nocardicin A, tabtoxin)Flouroquinolones (cipro, levoflox, moxifloxicin, naldixic acid)Glycopeptides (vancomycin, avoparcin)Ketolides (telithromycin,cethromycin, selithromycin)Lincosamides (lincomycin, clindamycin) Macrolides (erythromycin, azithromycin, vilprafen, tylosin)Oxazolidinones (linizolid, posizolid,torezolid, radezolid, cycloserine)Streptogramins (quinupristin/dalfopristin, pristinamycin, virginiamycin) Sulfonamides (sulfamethoxazole, sulfadiazine, sulfacetamide, sulfadoxime)Tetracyclines (demeclocycline, doxycycline, minocycline)Levomycetinums – (chloramphenicol)Ionophores– (A23187, Beauvericin, Calcimycine, Enniatin, Gramicidin A, Ionomycin, Lasalocid, Monensin, Nigericin, Nonactic, Nystatin, Salinomycin, Valinomycin) – inhibit various membrane ions from transfering. Bambermycins – (flavophosphlipols, moenomycins A and C) from streptomycesbambergiensis – used in animal feeds – swine, poultry, cattle.Polypeptides – (bacitracin)The field of antibiotics is vast - not only for human use but animal use.
  3. Why do we use antibiotics?Treat infections – animals and humansPrevent infections Humans - surgical wounds, dental prophylaxis for endocarditis, neutropeniaAnimals – prevent disease when animals are susceptiblePromote growth – cattle, poultry and swineHelp meet the food needs for a growing world – significant concern
  4. This is estimated data from 2010There were 925 million hungry people worldwide in 2010 (13.7% of the 6.8 billion people in the world);88% SS Africa, Asia and Pacific
  5. Children are the greatest at risk group for undernutrition / malnutritionMalnourished - 160 days of illness per yearMalnutrition associated - ½ of the 10.9 million deaths per year Malnutrition - magnifies the effect of diseases like measles and malariaDiseases like diarrhea, measles, malaria and pneumonia may exacerbate or cause malnutrition. Adequate food production for the expanding population particularly children who are growing is key. Animal proteins are more bioavailable that plant proteins – amino acid profiles of animal proteins – more similar to human profiles therefore more easily absorbed. Increasing animal and plant protein in important for the future of the world – deal with human hunger issues.
  6. Antibiotics and animal growthStudies from the 1950’s – animals given low does of antibiotics for a long time – gained more weight for a given amount of feed versus untreated animals.Swine – 3-9% improved weight gain with a 3-7% improvement in feed efficiency versus those not given low does of antibiotics.Greatest benefit when feed composition, management practices and health status of animals is not optimal.Studies suggest - no benefit is seen when these factors are optimal. Potential action – antibiotics and animal growthEliminate bacteria that steal essential nutrientsReduce competition with beneficial bacteria that produce essential nutrients for the animal.Control growth of bacteria that cause low-grade infections or produce toxins – decreasing nutrient absorption.
  7. This lists some common antibiotics used in both human medicine and also used to stimulate animal growth.Tetracyclines (chlortetracycline)SulfonamidesPenicillins (penicillin)Macrolides (tylosin)FluoroquinolonesCephalosporinsAminoglycosidesChloramphenicolsStreptogramins (virginiamycin)Polypeptides (bacitracin)The second column lists the antibiotics used almost exclusively for animal growthIonophores (lasalocid,monesin) BambermycinsDepending - choice of antibiotics for supporting animal growth - significant overlap in many categories except for the ionophores – Nystatin used in candidiasis- and bambermycins. Choice is important.
  8. This slide just lists some of the orgranisms that have caused concern due to development of resistance over the past few decades.Strep. Pneumoniae– peni,ceph, ery, quinolonesMoraxella Catarrhalis and Hem Influenza Type B – beta lactamase producers – attacks beta lactam antibiotics (peni, ceph, monobactams, carbapenams)Strep Pyogenes – Ery, fortunately peni sensitivity remains E. Coli – amp, t/s, quinolonesNeis. Gonorrhea – Peni, quinolones (cipro), cephNeis. Meningitidis– Peni (Spain – 71% in 1997)Campylobacter – C. Jejuni - Cipro (Spain 75-81% in 1998, Thailand – 84% in 1995)Salmonella – Amp, chloro, tetra, sulfonamides – DT104 decreased sens quinolones in Europe – rising ceph – 27% S typhimurium resist 5+ antibiotics. NEJM study 2001 – Ground meat – 20% samples + for Sal – 53% resist at least 3 antibiotics – 16% resist ceftriaxoneShigella – Minn, 1999 – 85% not suscept amp, 25% resist T/SStaph Aureus – MRSA 19-80% colonization – group studied (Samoan’s, N Amer, develop disabled residents – 45% resist to mupirocin.Enterococcus - VREMycobacterium Tuberculosis – MDR and XDRPertussis – Ery (Minn, 2000)
  9. Another study – adults and children – 2003 -confirms46% of patients with common cold or non-specific URI’s received antibioticsBroad spectrum antibiotics – narrower spectrum could have been used.
  10. Europe – 1990’s – Avoparin – glycopeptide - use to boost growth characteristics of chickens and pigs Avoparin resistant bacteria emerged in these animals Vancomycin resistance in humans noted at the same time.European Union banned use of avoparin to improve animal growth in 1997.Avoparin resistant bacteria in poultry and swine decreased to near zero.Resistance to vancomycin in humans saw an identical drop Resistance can be reversed.US – 1990’s – Campylobacter resistance to fluoroquinolones - increasedCamplylobacter is a commensal in the intestine of chickens.People can get infected by eating undercooked chicken - diarrhea1989 – none of the Campylobacter strains from ill people were fluoroquinolone resistant.1995 the FDA approve the use of quinolones in poultry.Soon afterward Campy strains from ill humans were noted resistant to quinolones. Doubt coincidence
  11. Use antibiotics only when indicatedUtilize the least broad spectrum antibiotic possibleUse antibiotics for the least amount of time possible – This decreases the time organisms have to develop resistance mechanisms.Use adequate therapeutic doses (e.g. adequate doses of amox can actually treat intermediate resistant peni resistant St. Pneumo)The last two are particularly related to animal usage.Use non-human categories in animals when possible (ionophores, bambermycins)When using crossover drugs (used in both animals and humans) use antibiotics in animals that will have the least impact on humans – If resistance occurs it will influence the least number of people possible.Appropriately monitor cultures and sensitivities. Many human clinicians use non-culture techniques to diagnose and commonly fail to survey for sensitivities via culture.
  12. Maintaining resistance takes energy.When antibiotic exposure is reduced below some threshold, antibiotic resistance decreases.Europe – FollowingAvoparin being banned, vancomycin resistance in humans decreased.Denmark – reduction in resistance in E Faecium in broiler chickens (from 60-80% to 5-35%) WHO Internation Panel Ruling, Nov, 2002)