Antibiotic Stewardship William R. Sonnenberg, MD Titusville, PA

Antibiotic Stewardship William R. Sonnenberg, MD Titusville, PA 1 Disclosure The speaker has no conflict of interest, financial agreement, or working affiliation with any group or organization. **Remember to Complete Online Session Evaluation https://www.surveymonkey.com/r/nov19_800_sonnenberg 2 It is not too much to state that the introduction of [antibiotics] has represented a force for change in the 20th century of the same general kind as James Watt's modification of the steam engine did in the 18th. The crossing of the historic watershed could be felt at the time. One day we could not save lives, or hardly any lives; on the very next day we could do so across a wide spectrum of diseases. This was an awesome acquisition of power. 1981, Walsh McDermott, MD 3 1

Case Presentation 60 year old male CAD with stents Morbidly obese Admitted to tertiary hospital for cellulitis and sepsis Vancomycin, Zosyn, clindamycin Discharged on Zyvox Changed to SXT/TMP due to availability Developed diarrhea after discharge 4 Physical Examination Afebrile, HR 106, RR 20 Acutely ill in appearance LLQ tenderness 3 cm ulcer left lower leg Positive stool for C. diff. WBC 39,000 Cultures from previous hospitalization all negative 5 Second Case 18 month old, summer Sore throat, runny nose, cough RRS negative Rx Azithromycin In case there is a strain missed by test 6 2

Problem of Antibiotic Resistance and Abuse 7 Alexander Fleming 1945 the microbes are educated to resist penicillin and a host of penicillin fast organisms is bred out. In such a case the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with the penicillin resistant organism. I hope this evil can be averted 8 Challenge of Resistance 2 million illnesses/year 23,000 death/year Family physicians prescribe ¼ of all antibiotic scripts Most of all specialties 30% of child visits result in Abx script 9 Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. 3

Our Use is Crazy Oral antibiotics in 2011 789 scripts per 1,000 in adults 889 scripts per 1,000 children 10 Bacterial Flora Adult flora tend to be stable over time Quadrillion cells 1,000 species Depletion and reduced diversity Firmicutes Bacteriodetes 11 Macrolide Resistance 49% Nationally 12 Keedy K, et al. Poster presented at: 19th Annual MAD-ID Conference; May 5-7, 2016; Orlando, FL. 4

ABX Prescribing Rates, 2010 13 14 Antibiotics and Obesity 142,824 children between 3 18 years 1.6 to 3.3 pounds by age 18 More abx, worse weight gain Macrolides worse 15 Schwartz et al. International Journal of Obesity (21 October 2015) 5

Mechanism of Resistance 16 Sales of Azithromycin and Macrolide Resistance 17 Serisier, David J, The Lancet Respiratory Medicine, Volume 1, Issue 3, 262 274 Pneumococcus and Antibiotic Use 18 Albrich WC, Monnet DL, Harbarth S. Antibiotic selection pressure and resistance in Streptococcus pneumoniae and Streptococcus pyogenes. Emerg Infect Dis 2004 Mar 6

How Resistance Arises Natural resistance of certain bacteria Β lactamase first emerged 1 2 billion years ago Genetic mutation Transfer of resistance from one species to another 19 Mechanism of Macrolide Resistance 20 Plasmid Transfer 21 7

C. Difficle Colitis 22 Its Important Prime nosocomial pathogen, passed MRSA 453,000 cases/year in 2011 29,000 deaths/year ¼ community acquired Quadruples cost of hospitalizations 23 Daniel A. Leffler, M.D., and J. Thomas Lamont, M.D. N Engl J Med 2015; 372:1539 1548 Its Getting Worse 84 cases/100,000 in 2005, twice 1996 Mortality from 0.5 deaths in 1999 to 2.0 deaths/100,000 in 2006 4x increase BI/NAP1/027 strain Higher toxins 20x higher More fluoroquinolone resistance Triple mortality 24 8

Incidence of Nosocomial Clostridium difficile 25 Leffler DA, Lamont JT. N Engl J Med 2015;372:1539 1548. Incidence and Mortality Increasing in USA Principal Diagnosis All Diagnoses Mortality # of CDI Cases per 100,000 Discharges 90 80 70 60 50 40 30 20 10 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 25 20 15 10 5 0 Annual Mortality Rate per Million Population 26 Elixhauser A, et al. Healthcare Cost and Utilization Project: Statistical Brief #50. April 2008. Available at: http://www.hcupus.ahrq.gov/reports/statbriefs/sb50.pdf. Accessed March 10, 2010. Redelings MD, et al. Emerg Infect Dis. 2007;13:1417-1419. C. Difficile Burden by Location 27 Lessa FC et al. N Engl J Med 2015;372:825 834. 9

Risk Factors Antibiotics Recent hospitalization Environmental contamination Age increases risk and severity 10 times greater over age 65 Acid suppression?? Inflammatory bowel disease 28 Antibiotic Misuse Up to 85% of patients with C. dif. colitis have antibiotic exposure 28 days earlier More than 8 in 10 Americans received antibiotic in 2011 29 Chang HT et al. Infect Control Hosp Epidemiol 2007; 28:926 931 Colonization 7% to 26% colonization in acute care facilities 2% in community ½ are asymptomatic Colonization risk increases daily during hospitalization Symptoms begin within 3 days of colonization Infect Control Hosp Epidemiol. 2010;31(5):431 455 30 10

Bedside Commode vs. BP Cuff?? 11.5% 10.0% 31 Manian FA, et al. Infect Control Hosp Epidemiol. 1966 Mar;17(3):180 2 Antibiotic Class and C. difficle Very Common Clindamycin Ampicillin Amoxicillin Cephalosporins Fluoroquinolones Somewhat Common Other Penicillins Sulfonamides Trimethoprim Macrolides 32 Testing for C. difficile Enzyme assay for toxins Rapid, easy DNA tests Higher sensitivity and specificity Detect BI/NA1/027 strain May detect low levels of uncertain significance Don t test for cure 33 11

Prevention 34 Prevention Methods Antibiotic stewardship Hygiene Isolation Probiotics mixed results 35 Antibiotic Stewardship Right reason Right drug Right dose Right duration 36 12

Prevalence of Inappropriate Use 2 million affected, 23,000 die from ABX resistant infection 262 million annual prescriptions ABX use declined in 90 s, stabilized in 2010 ABX use 506/1,000; 353/1,000 considered appropriate 37 JAMA. 2016;315(17):1864-1873 38 Why Antibiotics are Prescribed if They are not Felt Necessary Prescribe when certain enough they are needed 53% Without certainty, uncomfortable without treating possible bacterial 42% infection Patient is ill and labs take too long 31% Infection does not appear viral or fungal 30% Patient requested an antibiotic 28% Patient does not want nor can afford a test 19% Malpractice concerns 15% Antibiotic won t hurt if not needed and could help 11% Fear of being out of work too long 11% 39 13

Why Patients Ask (or demand) Believe it would cure 85% Want to feel better quickly 65% Need to get back to work quickly 44% Antibiotics can t hurt and it s better to be safe than sorry 27% Antibiotics always work 25% 40 Yox S. Medscape, June 2014 Less New Models 41 42 14

Companies Abandoning ABX Research Pfizer closed antibiotic research in Connecticut 2011 Sanofi, Lilly, Bristol Myers Squibb haven t research antibiotics since 1990 s 43 44 Nursing Home Prescribing Nursing home pts more likely to get ABX on Friday More likely if its covering doctor 45 Schweizer AK, et al. Pharm World Sci. 2005, 27 (3): 159 165. 15

Must Indulge the Rich Each standard deviation increase in offices per capita increases ABX prescribing by 25.9% Poor areas, ABX prescribing increases with adding providers; ABX prescribing per provider remains the same Richer areas, more providers increase ABX scripts per provider 46 J. Antimicrob. Chemother, January 20, 2015 Clinical Situations of Overuse 47 Antibiotics for Bronchitis 90% are viral, 10% 30% multiple viruses Viral shedding is decreasing at presentation 2/3 are treated with antibiotics 55% of patients believe they help for URI s 25% use left over antibiotics 48 ROSS H. ALBERT, MD, PhD, Am Fam Physician. 2010 Dec 1;82(11):1345-1350. 16

Acute Bacterial Bronchitis? Mycoplasma and Chlamydia in young adults No evidence that treatment helps Even when given early Use when considering pertussis 49 ROSS H. ALBERT, MD, PhD, Am Fam Physician. 2010 Dec 1;82(11):1345-1350. Rate of ABX Use for Acute Bronchitis 3000 visits for acute bronchitis, 1996 2010 Extended macrolides increased from 25% to 40% Other broad spectrums prescribed 1/3 of the time Education is not working 50 Michael L. Barnett, MD 1 ; Jeffrey A. Linder, MD, MPH 1 JAMA. 2014;311(19):2020 2022 ABX for Adults With Acute Bronchitis in USA, 1996 2010 51 JAMA. 2014;311(19):2020-2022 17

Broad Spectrum Antibiotic Prescribing 52 BMC Medicine201412:96 Do Antibiotics Prevent Pneumonia? 814,000 pts, 1.5 million visits 65% Dx with bronchitis Significant minor adverse side effects in treated group Less hospitalizations for pneumonia in antibiotic group NNT is 12,225 53 Meropol SB et al. Ann Fam Med March/April 2013 vol. 11 no. 2 165 172 Green Mucous Bacterial Infection 54 18

Why is Mucous Green? Not Bacteria nor Sinus Green protein myeloperoxidase from neutrophil and monocyte granules 55 Sinusitis AAO Guidelines 86% placebo v. 91% of ABX get better in 1 2 weeks 90% get antibiotics Watchful waiting for 7 days after 10 days of symptoms Amoxicillin +/ clavulanate 5 10 days 56 Otolarynol Head Neck Surg, April 2015. Vol 152:2 Suppl S1 39 Colds and Sinus CT 31 subjects with 2 4 days of a cold 87% had sinus problems on CT 79% resolved in 2 weeks without antibiotics 94% had normal airway resistant 57 Gwaltney, J. M. et al., Jr., N Engl J Med 1994; 330:25 30 19

Imaging of Presumed ABRS 68% of children with URI s have abnormal sinuses on MRI 42% of Healthy Children had abnormal sinus MRI! 58 Gwaltney JM Jr., et al. NEJM1994;330:25 30. Kristo A, et al. Pediatrics 2003;111:e586 9 Acute Bacterial Sinusitis v. Viral Rhinosinusitis (any of 3 Persistent symptoms 10 days without improvement Severe symptoms or high fever and purulent nasal discharge or facial pain for 3 4 days at onset Worsening symptoms after URI lasting 5 6 days that were initially improving (double sickening) IDSA Dec 2011 59 Natural Course Rhinosinusitis URI 60 20

Do ABX Help Sinusitis? Pts improve without treatment 47% one week 70% two weeks NNT 11 15 Number needed to harm 8 ABX give 5% faster cure 61 Lemiengre MB,et al. Cochrane Database Syst Rev. 2012;(10) Sinus Headache 2,524 subjects self described as having typical sinus headache Physicians used IHS criteria to diagnose headache 62 Schreiber et al. American Headache Society Meeting. June 12-23, Seattle, WA Results Migraine 82% Migrainous 8% Tension Type Headaches 6% Other Type Headaches 4% 0% 20% 40% 60% 80% 100% 63 21

Only 4 patients were excluded for active sinus disease! 64 IDSA Guidelines for Sinusitis Don t use antibiotics unless absolutely necessary Symptoms more than 10 days with worsening Use amoxicillin clavulanate for adults 65 Tice A et al: IDSA. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis. 2004 Jun15;38(12):1651 72 Treatment of Otitis Externa Topical 100 1000 times stronger at infected area 40% use incorrectly, better with help Use systemic Risk of increased morbidity Spread beyond canal Delivery problem with topical 66 Am Fam Physician. 2014 Nov 15;90(10):731-736 22

Asymptomatic Bacteriuria Nursing home 50% of women 40% of men Cause of mental status change? Only if fever, abnormal WBC s Needs cytokines for mental status change 67 Urine Cultures Good Reasons Signs and symptoms of UTI Pregnant 12 16 weeks Prevents preterm labor Prior to TURP Prior to other urologic procedures where mucosal bleeding could occur Nicole LE et al. Clinical Infect Dis 205:60;643 654 Bad Reasons Routine on admission Shotgun workup for fever Routine in: Women with DM Older in community or long term Spinal cord injury Indwelling catheter Preoperative screen 68 Asymptomatic Bacteriuria Population Prevalence Healthy premenopausal women 1 5 Postmenopausal Women 2.8 8.6 Diabetic Women 9 27 Female, Long term 25 50 Male, Long term 15 40 69 Nicole LE et al. Clinical Infect Dis 205:60;643 654 23

Treatment of Asymptomatic UTI in Diabetic Women RCT of TMP/SMX v. placebo Time to UTI same Placebo no more likely to get pyelonephritis, admission, or nephropathy Less ABX exposure in placebo group More adverse effects in treated group 70 Harding GK et al. NEJM 2002;357:1576 1587 Pharyngitis and Antibiotics 60% receive antibiotic, 10% should 15% get azithromycin Penicillin is drug of choice, prescribed 9% of time No PCN resistance, but more common in new, broad spectrum antibiotics 71 Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997 2010. (Research letter) JAMA Intern Med 2013 Pharyngitis Children 37% Strep positive 56.2% get antibiotic Adults (20 64 yrs) 18% had strep 72.4% get antibiotic 72 JAMA. 2016;315(17):1864-1873 24

Pearls Involvement of more than one mucous membrane makes strep less likely Strep not common under age 3 Pus is not diagnostic, viruses can do that too, 42% of time its EBV If it really looks like a cold, don t culture 73 Alternating Antipyretics? ½ of pediatricians recommended alternating ibuprofen with acetaminophen No safety evidence No efficacy evidence for greater effect nor faster effect Confusing; q4 hours and q 6 hours 74 Mayoral CE, et al. Alternating antipyretics: is this an alternative? Pediatrics May 2000;105:1009 12 Why Treat Strep?? Abx shorten duration 16 hours Acute rheumatic fever Relative risk reduction 0.28 NNT 3,000 to 4,000 Treat within 9 days Reduces suppurative peritonsillar and retropharyngeal abscesses; RRT 0.15 75 25

Cellulitis Nearly always unilateral Mostly lower extremities Misdiagnosis as high as 33% Stasis dermatitis common mimic 76 Is It a Real Infection? Infections have > 10 6 organisms/cm 2 No low growth infections Expect moderate to heavy growth 77 Mimics of Cellulitis 78 26

Simvastatin for Venous Ulcers RCT 66 patients, Simvastatin 40 mg. v. control 5 cm; 100% healing simvastatin v. 50% control group > 5 cm; 67% healing simvastatin v. 0% control 79 Br J Dermatol. 2014 May;170(5):1151 7 Advancing Stewardship 80 Effect of Stewardship 450 bed hospital in Scotland Antibiotic use monitored Ceftriaxone 95% Ciprofloxacin 72.5% C. diff 77% MRSA 25% 81 Dancer SJ, et al. Int J Antimicrob Agents 2013;41:137 142 27

No antibiotics for apparent viral URIs (AAP) Don t treat bacteriuria in elderly without symptoms (Am Ger Soc.) Don t obtain a C. difficile toxin test to confirm cure if symptoms have resolved (Long Term Care) Don t routinely use antibiotics to treat bilateral swelling and redness of the lower leg unless there is clear evidence of infection (Dermatology) Avoid prescribing antibiotics in the emergency department for uncomplicated sinusitis (ER) Don t use oral antibiotics for treatment of atopic dermatitis unless there is clinical evidence of infection (Dermatology) 82 83 Don t prescribe antibiotics for otitis media in children aged 2 12 years with non severe symptoms where the observation option is reasonable. (FP) Don t obtain a urine culture unless there are clear signs and symptoms that localize to the urinary tract (Long term Care) Don t order antibiotics for adenoviral conjunctivitis (pink eye). (Ophthalmology) Don t routinely prescribe antibiotics for acute mild to moderate sinusitis unless symptoms last for seven or more days, or symptoms worsen after initial clinical improvement (FP) 84 Don t prescribe oral antibiotics for uncomplicated acute external otitis (ENT) 28

Don t use antimicrobials to treat bacteriuria in older adults unless specific urinary tract symptoms are present Geriatrics) Don t continue surgical prophylactic antibiotics after the patient has left the operating room (Epidemiology) Don t continue antibiotics beyond 72 hours in hospitalized patients unless patient has clear evidence of infection (Epidemiology) Don t use antibiotic therapy for stasis dermatitis of lower extremities (Infectious Disease) Avoid antibiotics and wound cultures in emergency department patients with uncomplicated skin and soft tissue abscesses after successful incision and drainage and with adequate medical follow up (ER) 85 Voltaire The art of medicine consists in amusing the patient while nature cures the disease 86 Managing Antibiotic Expectations Call it a chest cold Set realistic expectations, about 3 weeks Explain antibiotics don t help; create resistance and side effects Doesn t prevent pneumonia Consider pocket script 87 29

Every antibiotic expected by a patient, every unnecessary prescription written by a doctor, every uncompleted course of antibiotics is potentially signing a death warrant for a future patient Dryden, et al. 2009 **Remember to Complete Online Session Evaluation 88 https://www.surveymonkey.com/r/nov19_800_sonnenberg 30