Sommer. Memorial. Lectures

Transcription

1 When do the costs of using antibiotics outweigh the benefits? Lecture: May

2 Established risks of antibiotic use Source: CDC

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4 British Journal of Experimental Pathology 1929;79:780.

5 J Clin Invest 1945;24:589.

6 Antibiotics as icons: one of the greatest discoveries of the 20 th century Saved lives Revolutionized medicine St. Mary s Hospital, Paddington

7 The scale of antibiotic use

8 EY Klein et al. PNAS 2018

9 Global antibiotic consumption by country income classification: Overall trends Trends in representative countries EY Klein et al. PNAS 2018

10 Antibiotic consumption rates by income levels of countries HIC, high income countries LMIC-,low & middle income countries UM, upper middle income LM, low & lower middle income EY Klein et al. PNAS 2018

11 [Population: 1,106,757 pregnant women ( )] Proportion (%) receiving a medication Agent %. Any 82.7 Nitrofurantoin 21.6 Metronidazole 19.4 Amoxicillin 18.0 Azithromycin 16.9 Promethazine 13.5

12 Annual antibiotic-prescribing in US children ( ) Millions Condition Annual number Visits for which of visits antibiotics are prescribed Respiratory (ARTIs) Antibiotics are indicated Antibiotics are not indicated Other respiratory conditions Other Skin/cutaneous/mucosal Urinary tract infections Gastrointestinal infections Miscellaneous infections Other Total AL Hersch et al. Pediatrics 2011;128:1053

13 Outpatient antibiotic use in the USA, by age, 2010 Patient Number of Prescriptions age group prescriptions /1000 people (years) (millions) Total LA Hicks et al. N Engl J Med 2013, 368:1461.

14 Cumulative outpatient antibiotic use, by age Average Patient Number of Prescriptions number of courses age group prescriptions /1000 people (years) (millions) During Cumulative period Total L Segal & MJ Blaser. Ann Am Thor Soc 2014 Adapted from L Hicks et al. N Engl J Med 2013, 368:1461.

15 Top 5 antibiotics prescribed in the USA, 2011 Number of Prescriptions Antibiotic prescriptions per 1000 persons (millions) Total Azithromycin Amoxicillin Amoxicillin/Clavulanate Ciprofloxacin Cephalexin Subtotal L Hicks et al. Clin Infect Dis 2015.

16 Incidence of antibiotic use in the first 2 years of life by study site among 2134 children in the MAL-ED birth cohort, ET Rogawski et al. Bull WHO 2017; 95:

17 All 18 detected 58.3% of children were positive

18 Detection of antibiotics in urine by use category Age group Category N A B C Sex A. Human 4 B. Veterinary 3 C. Both 11 A B C H Wang et al. Environ Sci Technol 2015; 49:

19 Variation in antibiotic use

20 Per capita antibiotic use in 31 countries in Europe o

21 Variation in antibiotic prescribing in the first year in life in 839 children in five European countries Median % of Prescription % of infants number of episodes rate per receiving Country illness treated with infant per 1 course episodes antibiotics year of antibiotics Italy Netherlands Austria Switzerland Germany J Stam et al. Acta Pediatr 2012; 101:

22 Source: CDC

23 Proportion of USA outpatient visits involving a physician assistant or a nurse practitioner, 1998 to 2011 GV Sanchez et al. Open Forum Infect Dis 2016;3:ofw168.

24 Rates of antibiotic prescribing for sick children Excluding: preventive visits, CCC (Chronic Complex Conditions) Standardized by: age, sex, age-sex, race, Medicaid status JS Gerber et al. J Pediatric Infect Dis 2015

25 Rates of prescribing broad-spectrum antibiotics Excluding: preventive visits, CCC, antibiotic allergy, prior antibiotics Standardized by: age, sex, age-sex, race, Medicaid status

26 Trends in overall antibiotic prescribing for acute respiratory infections among USA Veterans, BE Jones et al. Ann Intern Med 2015

27 Variation in antibiotic prescribing for acute respiratory infections among USA Veterans, Left. Variation among providers. The histogram shows the distribution of observed proportions of visits with an antibiotic prescription across 2594 providers with at least 100 ARI visits each (n= ). The curve depicts the modeled distribution of antibiotic Rx s across providers, after controls were set for the measured patient, provider, and setting. Right. Sources of variation. The lines depict modeled distributions describing variation in proportion of antibiotic prescriptions attributable specifically to VAMCs, clinics, and providers, respectively, after controls were set for the measured patient, provider, and setting variables. The dashed-and-dotted line corresponds to the curve in the left panel and depicts overall modeled variation in antibiotic prescription across providers, including differences between providers at different clinics and VAMCs.

28 Outpatient antibiotic usage rates by region, 2010 West 638 Midwest 868 Northeast 830 National rate 833/1000 population (258 million courses) South 936 L Hicks et al. N Engl J Med 2013, 368:1461.

29 Antibiotic prescribing per capita in USA, 2011 ALL AGES AGE 2 AGE 3 64 AGE 65 LA Hicks et al. Clin Infect Dis 2015;60:

30 Antibiotic use per 1,000 Medicare Beneficiaries

31 Sex-specific rates of antibiotic prescribing, 2011 Prescriptions/1000 persons Children Adults Sex (Age 19) (Age 20) Female Male LA Hicks et al. Clin Infect Dis 2015;60:

32 Associations between county-level educational and income characteristics and high antibiotic prescribing a Adjusted Odds Ratio Characteristic (95% CI) Four-year college (%) Lowest tertile (<12.3) 1.0 Middle tertile ( ) 0.9 ( ) Highest tertile ( ) 0.6 ( ) Per capita income ( x $1000) Lowest tertile (<20.1) 1.0 Middle tertile ( ) 0.8 ( ) Highest tertile ( ) 0.5 ( ) a Defined as counties in the highest quartile of prescribing. LA Hicks et al. Clin Infect Dis 2015;60:

33 Associations of antibiotic use with long term health consequences Examples: Obesity Allergies Diabetes Kidney stones Neoplasia

34 Comparisons between the geography of obesity and antibiotic use, 2010 Antibiotic prescriptions per 1000 persons, 2010 L Segal & MJ Blaser, Ann Am Thor Soc 2014 Observational data

35 Early life antibiotic exposure and adiposity in 160,000 children in the Geisinger Health System B Schwartz et al. Int J Obesity 2015

36 Prevalence ratios of overweight and obesity according to pre-natal antibiotic exposure among 9,886 Danish school children. Overweight Obesity Adjusted PR Adjusted PR Cases Cases (95% CI) (95% CI) Trimester of exposure Never exposed (referent) (referent) 1 st trimester ( ) ( ) 2 nd trimester ( ) ( ) 3 rd trimester ( ) ( ) No. of prescriptions Never exposed (referent) (referent) ( ) ( ) ( ) ( ) ( ) ( ) D p-value for trend for overweight was and for obesity was A Mor et al. Int J Obesity 2015; 39:1450

37 Child s use of prior antibiotics and risk of allergy to cow s milk Percent Cases Controls (n=15,672) (n=15,672) Type and number of antibiotic purchases Adjusted model a OR (95% CI) Any ( ) Amoxicillin ( ) Macrolides ( ) Cephalosporins ( ) Sulfas/TMP ( ) Pen VK ( ) a Reference group in each case is no use of that antibiotic. Model adjusted for maternal age, smoking, prior deliveries, mode of birth, child s birth weight. J Metsala et al. Epidemiology 2013; 24:303-9.

38 Association between number of antibiotic purchases from birth to diagnosis of cow s milk allergy in Finland OR Unadjusted Adjusted Number of purchases Adjusted model includes maternal age, smoking, prior deliveries, mode of delivery, and child s birth weight. J Metsala et al. Epidemiology 2013; 24:303-9.

39 Maternal use of antibiotics during pregnancy and risk of cow s milk allergy in offspring Percent Cases Controls Type of antibiotic (n=15,672) (n=15,672) Adjusted model a OR (95% CI) Any ( ) Cephalosporin ( ) Extended spectrum penicillin ( ) Macrolides ( ) Tetracyclines ( Pen VK ( ) Sulfas/TMP <1 < ( ) Fluoroquinolones <1 < ( ) pregnancies, and child s use of antibiotics. a Adjusted for maternal age, SES, smoking, parity, multiple J Metsala et al. Epidemiology 2013; 24:303-9.

40 Maternal use of antibiotics before pregnancy and risk of cow s milk allergy in offspring Percent Cases Controls Type of antibiotic (n=15,672) (n=15,672) Adjusted model a OR (95% CI) Any ( ) Cephalosporin ( ) Extended spectrum penicillin ( ) Macrolides ( ) Tetracyclines ( ) Pen VK ( ) Sulfas/TMP ( ) Fluoroquinolones ( ) pregnancies, and child s use of antibiotics. a Adjusted for maternal age, SES, smoking, parity, multiple J Metsala et al. Epidemiology 2013; 24:303-9.

41 Association between number of maternal antibiotic uses and risk of cow s milk allergy in the offspring Before pregnancy During pregnancy OR Number of purchases Number of purchases J Metsala et al. Epidemiology 2013; 24:303-9.

42 Antibiotic impact on long-term physiology through microbiota changes PLoS Pathogens 2015

43 KH Mikkelson et al. J Clin Endocrinol Metab 2015

44 Adjusted ORs for type 2 diabetes according to antibiotic exposure before initiation of diabetes treatment Adjusted Odds Ratio (95% CI) a Type of Antibiotics Any antibiotic 1.21 ( ) 1.53 ( ) Narrow-spectrum 1.22 ( ) 1.55 ( ) Broad-spectrum 1.18 ( ) 1.31 ( ) Bactericidal 1.18 ( ) 1.48 ( ) Bacteriostatic 1.20 ( ) 1.39 ( ) a OR for type 2 diabetes with redemption of 2-4 or 5 antibiotic prescriptions, compared with 0-1 redemptions. KH Mikkelson et al. J Clin Endocrinol Metab 2015

45 Ratio of antibiotic use in cases versus controls in the 15 years before initiation of treatment for T2D Results are only for cases with an index between 2010 and KH Mikkelson et al. J Clin Endocrinol Metab 2015

46 GE Tasian et al. JASN 2018

47 Odds of kidney stone disease according to oral antibiotic class GE Tasian et al. JASN 2018

48 Odds of kidney stone disease according to recentness of oral antibiotic exposure GE Tasian et al. JASN 2018

49 Oxalobiome

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51 Antibiotic use and colorectal adenoma risk, in 16,642 nurses >60 years old Antibiotic use at age [OR (95% CI)] None 1 14 days 15 days-2 month 2 + months p-trend No. of cases with adenoma (n=1195) Age-adjusted 1 (referent) 1.13 ( ) 1.40 ( ) 1.36 ( ) Multivariable Y Cao et al. Gut (referent) 1.12 ( ) 1.41 ( ) 1.36 ( ) 0.002

52 Antibiotic use and colorectal adenoma risk, in 16,642 nurses >60 years old Antibiotic use at age [OR (95% CI)] None 1 14 days 15 days-2 month 2 + months p-trend No. of cases with adenoma (n=1195) Age-adjusted 1 (referent) 1.35 ( ) 1.53 ( ) 1.74 ( ) <0.001 Multivariable Y Cao et al. Gut (referent) 1.32 ( ) 1.51 ( ) 1.69 ( ) 0.001

53 No. of cases with proximal adenoma (n=709) Antibiotic use and proximal colorectal adenoma risk, in 16,642 nurses >60 years old Antibiotic use at age [OR (95% CI)] None 1 14 days 15 days-2 month 2 + months p-trend Age-adjusted 1 (referent) 1.84 ( ) 2.24 ( ) 2.07 ( ) 0.01 Multivariable Y Cao et al. Gut (referent) 1.89 ( ) 2.29 ( ) 2.13 ( ) 0.01

54 Solutions

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56 Concentrated Animal Feeding Operations (CAFOs)

57 Consolidation of Hog farms in the USA,

58 Antimicrobial use in USA farm animals, 2013

59 Corn, green onion, cabbage Chlortetracycline 2-17 ng/g USA Source food Antibiotic residues in food Antimicrobial agents in surveys Concentration Country Shrimp Fluoroquinolones ng/g USA Salmon, trout, shrimp tissues Fluoroquinolones ng/g Canada Swine, chicken, shrimp tissues Fluoroquinolones ng/g China Bob veal, heavy calves, sows, heifers, market hogs, nonformula-fed veal, roaster pig Sulfonamides ppm USA Moxidectin Bull meat ppb USA (milbemycin) Goat meat Oxytetracycline 4.66 ppm USA Market hog, roaster pig meat Carbadox ppb USA Catfish, basa Fluoroquinolones ppb China Honey Erythromycin ng/g Turkey

60 Reduction of antimicrobial use and resistance in livestock The Dutch Policy Dr. Christianne Bruschke Chief Veterinary Officer Livestock production in The Netherlands 4 million cattle 12 million swine 0.3 million horses 1.5 million sheep and goats 100 million poultry Share 34,000 sq km land with 17 million people 60

61 Reduction of antibiotic use from : 58% 61

62 Cumulative antibiotic use in the USA, by age Number of courses taken USA Age (years) During Cumulative period Adapted from L. Hicks NEJM 2013; 368:1461 (USA)

63 Cumulative antibiotic use in the USA and Sweden Number of courses taken USA Sweden Age (years) During During Cumulative Cumulative period period Adapted from L. Hicks NEJM 2013; 368: 1461 (USA) A. Ternhag NEJM 2013; 369: 1175 (Sweden)

64 Inpatient Antibiotic Days of Therapy per 1000 Bed Days of Care ICHE 2017, 38:

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66 Conclusions

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68 Conclusions 1. Massive use and overuse of antibiotics is causing shifts in human, animal, and environmental ecology, with selection for alternative microbiomes. 2. Antibiotic resistance is one manifestation of this global crisis, but microbiome-mediated increases in incidence of human diseases is another important consequence. 3. As people begin to understand that antibiotic use paradoxically worsens their health, that of their children, and future generations, antibiotic use will diminish. 4. To improve human and animal health, we must restore the pre-antibiotic era ecology.