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Antimicrobials: How to reduce unnecessary Use

Antimicrobials: How to reduce unnecessary Use. Thomas M File, Jr MD MSc MACP FIDSA FCCP Chair, Infectious Disease Division Summa Health System Akron, Ohio; Professor of Internal Medicine, Chair ID Section Northeast Ohio Medical University Rootstown, Ohio.

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Antimicrobials: How to reduce unnecessary Use

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  1. Antimicrobials:How to reduce unnecessary Use Thomas M File, Jr MD MSc MACP FIDSA FCCP Chair, Infectious Disease Division Summa Health System Akron, Ohio; Professor of Internal Medicine, Chair ID Section Northeast Ohio Medical University Rootstown, Ohio

  2. Antimicrobial Resistance: Public Health Crisis • Antibiotic resistance: a threat to global health security May, 2013 Perhaps the single most important action needed to greatly slow down the development and spread of antibiotic-resistant infections is to change the way antibiotics are used..”

  3. IDSA Call-to-Action:Bad Bugs, No Drugs As resistance increases . . . number of new antimicrobials diminishes No. of new antimicrobials IDSA. Infectious Diseases Soc. Of Am. Bad Bugs, No Drugs. Available at: www.idsociety.org/badbugsnodrugs.html.

  4. The Impact of Antimicrobial Resistance • Affects clinical outcomes • Associated with higher mortality • Results in higher healthcare costs • Leads to prolonged hospitalization • Increase challenge for appropriate management • Empiric therapy • Directed therapy File TM, Jr. Chest. 1999;115(suppl):3S-8S.

  5. PART OF SOLUTION “If best infection control practices and antibiotic stewardship were nationally adopted, more than 600,000 infections and 37,000 deaths could be prevented over 5 years.” — MMWR Aug 2015 File TM Jr, et al. Clin Infect dis. 2014; 59 (Supple 3): S93-96. MMWR. August 14, 2015 / Vol. 64 / No. 31 / Pg. 837 - 864; ND 544 – 561.

  6. Promise of vaccines for reducing bacterial infections and enhancing Antimicrobial Stewardship • Prevention of infections will reduce antibiotic use and resistance • In 2000 Conjugate 7 valent pneumococcal vaccine introduced in US for children Kyaw et al, NEJM, 2006,354,1455-63

  7. ACTUAL PRACTICE BEST PRACTICE GAP Variance of Care Guidelines reduce variance; improve care STEWARDSHIP Optimal Practice for Best Patient Outcomes

  8. March, 2015

  9. Diagnostic Tests for Etiologyin Management of CAP • Standard culture methods (blood, sputum) • Low yield, time to results • Gram stain, urinary antigen testing • S pneumoniae, Legionella spp • Newer molecular tests (PCR, MALDI-TOF) • Potential for more rapid diagnosis, greater sensitivity • Allows for pathogen-directed therapy • Biomarkers (Procalcitonin) • Differentiate Bacterial vs virus • Timely response to bacterial load • PCR, polymerase chain reaction; MALDI-TOF, matrix-assisted laser desorption/ionization Time of Flight mass spectrometry

  10. Diagnostic testing: Time to ID • Rapid diagnostic tests • PNA FISH, PCR, MALDI-TOF Goff DA, et al. Pharmacother. 2012;32:677-88.

  11. Who are Using Antimicrobials? From Hicks L et al. Clin Infect Dis. 2015

  12. Who are Using Antimicrobials? From Hicks L et al. Clin Infect Dis. 2015

  13. Appropriate antimicrobial usage:For optimal outcomes and reduce resistance • ‘Antimicrobial Avoidance’ when not indicated • 3 ‘Ds’ • Right DRUG • Guidelines • Local resistance patterns • Patient risk stratification • Right DOSE • Pharmacokinetics/Pharmacodynamics (PK/PD) • Right DE-ESCALATION • Right DURATION

  14. Who of the following patients warrant antibacterial therapy? • 35 year old afebrile, non-smoking male with mild nasal congestion and non-productive cough for three days • 20 year old afebrile college student with non-exudative acute sore throat • 35 year old afebrile female with signs of acute sinusitis of three days duration • 55 year old smoking male with diabetes and acute fever cough and localised rhonchi • All of the above

  15. NQF PERFORMANCE MEASURE: ACUTE BRONCHITIS NQF=National Quality Forum www.qualtiyforum.org/Measures_List.aspx

  16. Antimicrobials for Colds—Why? • “Patient pressures” • Patient satisfaction correlates with quality of patient-doctor intervention, not prescription1 • “Prevent bacterial superinfection” • Several controlled studies showed no benefit for URI/colds2 • 1Hamm RM, et al. J Fam Pract. 1996;43:56-62. • 2Rosenstein N, et al. Pediatrics. 1998;101:181-184.

  17. Interventions to Improve Appropriate Antibiotic Usefor Acute Respiratory Tract Infections • “Watchful Waiting Strategy” • Electronic Decision Support • clinic-based education interventions • multifaceted intervention that combined a clinical • algorithm, clinical tutor training, and provider education Agency for Healthcare Research and Quality; 2015

  18. From American/s Knowledge of and Attitudes towards Antimicrobial Resistance. From Pew Health Group

  19. A cough and sneeze; NO antibiotics please!! • Antibiotics cure bacterial infections, NOT viral infections such as: colds and flu, most coughs and runny noses • Antibiotics are the only drug where use in one patient can impact the effectiveness in another • If everyone does not use antibiotics well, we will all suffer the consequences • Antibiotics are a shared resource (and becoming a scarce resource) Get Smart: Know When Antibiotics Work. Available at: www.cdc.gov/getsmart. Accessed 5 July 2012. CDC: Division of Healthcare Quality Promotion

  20. Antibiotic Prescriptions: US Title: Setting a national goal to reduce antibiotic overuse in the United States 2016 Authors: Katherine Fleming-Dutra, Adam Hersh‎, Daniel Shapiro, Monina Bartoces, Eva Enns, ‎Thomas File, Jonathan Finkelstein, Jeffrey Gerber, Jeff Linder, Ruth Lynfield, David Margolis, Larissa May, Linda McCaig, Dan Merenstein, Josh Metlay, ‎Jason Newland, Jay Piccirillo, Rebecca Roberts, Guillermo Sanchez, Katie Suda, Ann Thomas, Teri Woo, Lauri Hicks GOAL: Reduce further by 31%

  21. Interventions to Improve Appropriate Antibiotic Usefor Acute Respiratory Tract Infections • “Watchful Waiting Strategy” • Electronic Decision Support • clinic-based education interventions • multifaceted intervention that combined a clinical • algorithm, clinical tutor training, and provider education Agency for Healthcare Research and Quality; 2015

  22. PROCALCITONIN (PCT): Viral vs. Bacterial infection • Peptide precursor of calcitonin • ‘Hormokine’ • Expressed by neuroendocrine cells (e.g. thyroid) • Healthy individuals, non detected • Released like a cytokine by variety of parynchymal cells (e.g. liver, monoctes) in response to microbial toxins and proinflammatory mediators (IL-1, TNF-α, IL-6) • Increased in bacterial infection • Inhibited by TNF-ϒ in response to variety viral infections • Distinguishes Bacterial from viral infection • Levels change rapidly in response to bacterial infection • Rapid response to treatment of bacterial infection Brunkhorst FM, et al. Intensive Care Med. 1998 Aug;24(8):888-889. Gilbert D. Clin Infect Dis. 2011 May;52 Suppl 4:S346-350.

  23. Use of Procalcitonin for Antimicrobial Stewardship for RTIs File TM Jr. Clin Cherst Med. 2011; modified from Schuetz P. et al. Eur Respir J 2011;37(2): 384–92.

  24. Hospital Stewardship-CDC • Incorrect prescribing and variability in current usage patterns suggest that improvements are needed and will benefit patients. • CDC recommends all hospitals implement antibiotic stewardship • Urgent action needed to ensure these lifesaving drugs work in the future.

  25. Hospital Antimicrobial Stewardship: • Definition • “An ongoing effort…to optimize antimicrobial use in order to improve patient outcomes, ensure cost-effective therapy, and reduce adverse sequelae of antimicrobial use (including antimicrobial resistance)” • Secondary goal: Reduce costs Dellit T, et al. Clin Infect Dis. 2007;44:159-177.

  26. Common Principles of Antimicrobial Stewardship • Avoid Antimicrobials if not warranted • ? Value of delayed prescription for RTIs • Appropriate agent (based on susceptibility) • Avoid discordant therapy • De-escalation • Dose Optimization • Based on renal function, weight, MIC • Stop ABX if not warranted • Reduce duration • Switch to oral

  27. What is appropriate therapy for a 55 year old asymptomatic diabetic female with >105E. coli in urine culture? a. Trimethoprim/Sulfamethoxazole (e.g. Septra, Bactrim) three DS tablets as a single dose b. Ciprofloxacin (Cipro) 250 mg po b.i.d. for 6 doses c. Nitrofurantoin (e.g. Macrobid) 100 mg po b.i.d. for three days d. None of the above; no therapy is required

  28. 82 y/o female transferred from LTCF with chest pain; has acute MI. Has foley catheter. Afebrile; + pyuria; Culture: 105 Klebsiella pneumoniae Course of action? • Start antimicrobial • Await susceptibility test and chose most cost effective agent for therapy • No antimicrobial therapy warranted • Methenamine

  29. You are evaluating a 58 y/o female with who weighs 45 kg and has a creatinine of 1.5. She has cystitis due to Klebsiella sp. susceptible to ciprofloxacin and nitrofurantoin Which of the following is most appropriate? • Ciprofloxacin 750 mg BID • Ciprofloxacin 250 mg BID • Nitrofurantoin 100 mg BID Calc Cr Cl = 30

  30. De-escalation Susceptibility results used to more specifically target microbiological results; narrowing the antibiotic spectrum by changing from a broad spectrum agent to a narrow spectrum agent or by eliminating a drug from combination therapy. Should ideally occur as soon as possible, but within 48 hours of the availability of culture results. Benefits include reduced bacterial resistance, decreased incidence of bacterial, viral, and fungal superinfections, limited exposure to unnecessary drug therapy and the associated risks decreased costs.

  31. 82 y/o female transferred from LTCF with fever, decrease mental status; WBC-15,000. Exam unremarkable. Has long-term foley catheter: + pyuria; Treated initially with ciprofloxacin. Day #3 lab reports culture with > 100,000 E. coli resistant to ciprofloxacin but susceptible to all other agents tested. What is the appropriate choice now? Stop ciprofloxacin and start: • Cefepime • Ampicillin • Piperacillin/tazobactam • Imipenem

  32. Fosfomycin (Monuril™) • Phosphonic acid derivative, approved in US for single dose Rx of UTI • Inhibits cell wall synthesis (cidal) by inactivating pyruvyltransferase (critical cell wall synthesis) • Active against many GNB (not Pseudomonas) • Available as sachet containing 3 g fosfomycin to be dissolved in H2O • Bioavailability: 30% (fed) - 37% (fasting) • Pregnancy Category B • Dose (cost $37/dose) • Uncomplicated cystitis: 3 gm as single dose • Complicated UTI: 3 gm every 2-3 days for 3 doses • Prostatitis: 3 gm every 2-3 days for 21 days

  33. Etiology and sensitivity of uropathogens in uncomplicated UTI in women • Multicenter study, 803 woman • E. coli 80%; S saprophyticus 4.4%; P mirabilis 4.3%; enterococcus 3.2%; K pneumoniae 2.3% • Susceptibility E coli: • Fosfomycin 97%; nitrofurantoin 94%; cipro 88%; cotrimoxazole 66%; amox/clav 75%; ampicillin 45%; Pigrau et al. Med Clin Oct 2010

  34. Azithromycin and Cardiovascular events (QT effect) • NEJM 2012 (Ray et al. Tennessee, USA) • Older population; Azithro associated with higher mortality • NEJM 2013 (Svanstrom et al. Denmark) • General population; no association with mortality • JAMA 2014 (Mortensen et al. VA database, USA) • Azithro associated with slight increase of MI but overall reduced mortality in hospitalized patients • J AM Coll Cardiology 2015 ( Cheng et al) • Metaanalysis: higher risk sudden cardiac death • MY TAKE: Risk small; Azithro safe for general population and associated with better outcomes for hospitalized patients. Need to consider risk-benefit for patients with CV disease (QT prolongation). Avoid 2 drugs that prolong QT

  35. Augmentin XR™ • Pharmacokinetic design • Bilayer tablets with immediate release layer of amoxicillin and clavulanate, and extended release layer of amoxicillin • Each tablet contains 1 gm amox and 62.5 gm clavulanate • Increases daily dose of amoxicillin—2000 mg BID = 4000 mg/day • Maintains daily dose of clavulanate—125 mg BID = 250 mg/day • Extends coverage to include S. pneumoniae with elevated amoxicillin MICs • Indications (When PRSP is a concern): CAP; Acute Bacterial Sinusitis • Tolerability • Similar to Augmentin 875 (clavulanate dose is the same) • Diarrhea approx 10% (most are mild)

  36. Goal= 4.8 hours Pharmacokinetic Profile Comparison: Augmentin XR™ vs. Amox/Clav 875/125 Amox/Clav 875/125 20 Augmentin XR 1000/62.5 mg, 2 tabs Augmentin XR 15 Maintains extended plasma concentrations Mean amoxicillin concentration (µg/mL) 875mg 10 S. pneumoniae with amox MIC = 2 µg/mL 5 4.8 hours 40% 7.2 hours 60% 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hours) 40% of 12-hour dosing interval = 4.8 hours

  37. Duration of Therapy: How low to go (Clinically resolving)

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