When do the costs of using antibiotics outweigh the benefits? Lecture: May 11 2018
Established risks of antibiotic use Source: CDC
British Journal of Experimental Pathology 1929;79:780.
J Clin Invest 1945;24:589.
Antibiotics as icons: one of the greatest discoveries of the 20 th century Saved lives Revolutionized medicine St. Mary s Hospital, Paddington
The scale of antibiotic use
EY Klein et al. PNAS 2018
Global antibiotic consumption by country income classification: 2000-2015 Overall trends Trends in representative countries EY Klein et al. PNAS 2018
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
[Population: 1,106,757 pregnant women (2000-2007)] Proportion (%) receiving a medication Agent %. Any 82.7 Nitrofurantoin 21.6 Metronidazole 19.4 Amoxicillin 18.0 Azithromycin 16.9 Promethazine 13.5
Annual antibiotic-prescribing in US children (2006-2008) Millions Condition Annual number Visits for which of visits antibiotics are prescribed Respiratory (ARTIs) 65.6 31.7 Antibiotics are indicated 29.9 21.5 Antibiotics are not indicated 19.5 5.8 Other respiratory conditions 16.2 4.5 Other 158.6 12.2 Skin/cutaneous/mucosal 28.2 5.2 Urinary tract infections 1.4 0.9 Gastrointestinal infections 2.3 0.1 Miscellaneous infections 8.7 0.8 Other 117.9 5.1 Total 224.2 43.9 AL Hersch et al. Pediatrics 2011;128:1053
Outpatient antibiotic use in the USA, by age, 2010 Patient Number of Prescriptions age group prescriptions /1000 people (years) (millions) 0-1 16.6 1365 2-9 29.0 1021 10-19 28.9 677 20-39 55.4 669 40-64 81.6 797 65 41.1 1020 Total 258.0 833 LA Hicks et al. N Engl J Med 2013, 368:1461.
Cumulative outpatient antibiotic use, by age Average Patient Number of Prescriptions number of courses age group prescriptions /1000 people (years) (millions) During Cumulative period 0-1 16.6 1365 2.73 2.73 2-9 29.0 1021 8.17 10.90 10-19 28.9 677 6.78 17.68 20-39 55.4 669 13.38 31.06 40-64 81.6 797 19.93 50.98 65 41.1 1020 - - Total 258.0 833 L Segal & MJ Blaser. Ann Am Thor Soc 2014 Adapted from L Hicks et al. N Engl J Med 2013, 368:1461.
Top 5 antibiotics prescribed in the USA, 2011 Number of Prescriptions Antibiotic prescriptions per 1000 persons (millions) Total 262.5 842 Azithromycin 54.1 174 Amoxicillin 52.9 170 Amoxicillin/Clavulanate 21.2 68 Ciprofloxacin 20.9 67 Cephalexin 20.0 64 Subtotal 169.1 543 L Hicks et al. Clin Infect Dis 2015.
Incidence of antibiotic use in the first 2 years of life by study site among 2134 children in the MAL-ED birth cohort, 2009-14 ET Rogawski et al. Bull WHO 2017; 95: 49-61.
All 18 detected 58.3% of children were positive
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: 5070-9
Variation in antibiotic use
Per capita antibiotic use in 31 countries in Europe o
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 3 18.4 1.3 55 Netherlands 3 9.8 0.6 37 Austria 4 6.7 0.5 33 Switzerland 4 3.9 0.2 18 Germany 4 5.1 0.5 33 J Stam et al. Acta Pediatr 2012; 101:929-34.
Source: CDC
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.
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
Rates of prescribing broad-spectrum antibiotics Excluding: preventive visits, CCC, antibiotic allergy, prior antibiotics Standardized by: age, sex, age-sex, race, Medicaid status
Trends in overall antibiotic prescribing for acute respiratory infections among USA Veterans, 2005-2012 BE Jones et al. Ann Intern Med 2015
Variation in antibiotic prescribing for acute respiratory infections among USA Veterans, 2005-2012 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= 480 875). 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.
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.
Antibiotic prescribing per capita in USA, 2011 ALL AGES AGE 2 AGE 3 64 AGE 65 LA Hicks et al. Clin Infect Dis 2015;60:1308-16
Antibiotic use per 1,000 Medicare Beneficiaries
Sex-specific rates of antibiotic prescribing, 2011 Prescriptions/1000 persons Children Adults Sex (Age 19) (Age 20) Female 941 990 Male 841 596 LA Hicks et al. Clin Infect Dis 2015;60:1308-16
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 (12.4-17.4) 0.9 (0.8-1.0) Highest tertile (17.5-63.7) 0.6 (0.5-0.8) Per capita income ( x $1000) Lowest tertile (<20.1) 1.0 Middle tertile (20.1-23.8) 0.8 (0.7-0.9) Highest tertile (23.8-64.4) 0.5 (0.4-0.6) a Defined as counties in the highest quartile of prescribing. LA Hicks et al. Clin Infect Dis 2015;60:1308-16
Associations of antibiotic use with long term health consequences Examples: Obesity Allergies Diabetes Kidney stones Neoplasia
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
Early life antibiotic exposure and adiposity in 160,000 children in the Geisinger Health System B Schwartz et al. Int J Obesity 2015
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 467 1.00 (referent) 183 1.00 (referent) 1 st trimester 139 1.09 (0.91-1.31) 66 1.29 (0.98-1.70) 2 nd trimester 129 1.39 (1.11-1.73) 50 1.27 (0.87-1.85) 3 rd trimester 131 1.43 (1.17-1.76) 55 1.23 (0.86-1.76) No. of prescriptions Never exposed 467 1.00 (referent) 183 1.00 (referent) 1 170 1.19 (1.00-1.40) 72 1.26 (0.96-1.65) 2 65 1.26 (0.98-1.62) 24 1.13 (0.74-1.73) 3 39 1.49 (1.10-2.02) 20 1.78 (1.14-2.79) D p-value for trend for overweight was 0.001 and for obesity was 0.016 A Mor et al. Int J Obesity 2015; 39:1450
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 21 15 1.71 (1.59-1.84) Amoxicillin 14 11 1.39 (1.29-1.51) Macrolides 8 6 1.65 (1.49-1.82) Cephalosporins 6 3 2.43 (2.14-2.77) Sulfas/TMP 1 1 1.60 (1.27-2.02) Pen VK 1 1 1.97 (1.50-2.58) 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.
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.
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 28 24 1.21 (1.14-1.28) Cephalosporin 13 10 1.27 (1.17-1.38) Extended spectrum penicillin 14 13 1.14 (1.06-1.23) Macrolides 4 3 1.32 (1.15-1.51) Tetracyclines 1 1 0.97 (0.72-1.29 Pen VK 2 2 1.04 (0.86-1.27) Sulfas/TMP <1 <1 0.87 (0.51-1.47) Fluoroquinolones <1 <1 1.66 (0.92-3.01) 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.
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 41 35 1.26 (1.20-1.33) Cephalosporin 16 13 1.29 (1.20-1.39) Extended spectrum penicillin 12 10 1.16 (1.06-1.26) Macrolides 11 8 1.26 (1.15-1.38) Tetracyclines 10 8 1.25 (1.14-1.37) Pen VK 4 3 1.14 (0.99-1.31) Sulfas/TMP 3 2 1.00 (0.84-1.18) Fluoroquinolones 2 2 1.09 (0.91-1.32) 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.
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.
Antibiotic impact on long-term physiology through microbiota changes PLoS Pathogens 2015
KH Mikkelson et al. J Clin Endocrinol Metab 2015
Adjusted ORs for type 2 diabetes according to antibiotic exposure before initiation of diabetes treatment Adjusted Odds Ratio (95% CI) a Type of Antibiotics 2-4 5 Any antibiotic 1.21 (1.19-1.23) 1.53 (1.50-1.55) Narrow-spectrum 1.22 (1.20-1.23) 1.55 (1.53-1.57) Broad-spectrum 1.18 (1.16-1.20) 1.31 (1.29-1.34) Bactericidal 1.18 (1.17-1.20) 1.48 (1.46-1.50) Bacteriostatic 1.20 (1.19-1.22) 1.39 (1.36-1.41) 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
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 2012. KH Mikkelson et al. J Clin Endocrinol Metab 2015
GE Tasian et al. JASN 2018
Odds of kidney stone disease according to oral antibiotic class GE Tasian et al. JASN 2018
Odds of kidney stone disease according to recentness of oral antibiotic exposure GE Tasian et al. JASN 2018
Oxalobiome
Antibiotic use and colorectal adenoma risk, in 16,642 nurses >60 years old Antibiotic use at age 20 39 [OR (95% CI)] None 1 14 days 15 days-2 month 2 + months p-trend No. of cases with adenoma 141 653 296 105 (n=1195) Age-adjusted 1 (referent) 1.13 (0.93 1.37) 1.40 (1.13 1.74) 1.36 (1.04 1.79) 0.001 Multivariable Y Cao et al. Gut 2017 1 (referent) 1.12 (0.92 1.36) 1.41 (1.13 1.75) 1.36 (1.03 1.79) 0.002
Antibiotic use and colorectal adenoma risk, in 16,642 nurses >60 years old Antibiotic use at age 40 59 [OR (95% CI)] None 1 14 days 15 days-2 month 2 + months p-trend No. of cases with adenoma 66 637 357 135 (n=1195) Age-adjusted 1 (referent) 1.35 (1.04 1.75) 1.53 (1.17 2.01) 1.74 (1.28 2.37) <0.001 Multivariable Y Cao et al. Gut 2017 1 (referent) 1.32 (1.01 1.72) 1.51 (1.14 1.99) 1.69 (1.24 2.31) 0.001
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 40 59 [OR (95% CI)] None 1 14 days 15 days-2 month 2 + months p-trend 29 382 228 70 Age-adjusted 1 (referent) 1.84 (1.25 2.71) 2.24 (1.51 3.34) 2.07 (1.32 3.22) 0.01 Multivariable Y Cao et al. Gut 2017 1 (referent) 1.89 (1.28 2.79) 2.29 (1.53 3.42) 2.13 (1.35 3.35) 0.01
Solutions
Concentrated Animal Feeding Operations (CAFOs)
Consolidation of Hog farms in the USA, 1965-2009
Antimicrobial use in USA farm animals, 2013
Corn, green onion, cabbage Chlortetracycline 2-17 ng/g USA Source food Antibiotic residues in food Antimicrobial agents in surveys Concentration Country Shrimp Fluoroquinolones 0.1-1.0 ng/g USA Salmon, trout, shrimp tissues Fluoroquinolones 0.28-16 ng/g Canada Swine, chicken, shrimp tissues Fluoroquinolones 1-100 ng/g China Bob veal, heavy calves, sows, heifers, market hogs, nonformula-fed veal, roaster pig Sulfonamides 0.1-1 ppm USA Moxidectin Bull meat 89.13 ppb USA (milbemycin) Goat meat Oxytetracycline 4.66 ppm USA Market hog, roaster pig meat Carbadox 47-110 ppb USA Catfish, basa Fluoroquinolones 1.9-6.5 ppb China Honey Erythromycin 50-1776 ng/g Turkey
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
Reduction of antibiotic use from 2009-2015: 58% 61
Cumulative antibiotic use in the USA, by age Number of courses taken USA Age (years) During Cumulative period 2 2.73 2.73 3 - - 10 8.17 10.90 20 6.78 17.68 40 13.38 31.06 65 19.93 50.98 Adapted from L. Hicks NEJM 2013; 368:1461 (USA)
Cumulative antibiotic use in the USA and Sweden Number of courses taken USA Sweden Age (years) During During Cumulative Cumulative period period 2 2.73 2.73 - - 3 - - 1.39 1.39 10 8.17 10.90 2.90 4.28 20 6.78 17.68 2.52 6.80 40 13.38 31.06 5.92 12.72 65 19.93 50.98 8.48 21.20 Adapted from L. Hicks NEJM 2013; 368: 1461 (USA) A. Ternhag NEJM 2013; 369: 1175 (Sweden)
Inpatient Antibiotic Days of Therapy per 1000 Bed Days of Care ICHE 2017, 38:513-520
Conclusions
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.