5/2/2017. Lisa Dykes, PharmD PGY-1 Pharmacy Practice Resident Iowa City VA Medical Center May 2, 2017

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1 Lisa Dykes, PharmD PGY-1 Pharmacy Practice Resident Iowa City VA Medical Center May 2, 2017 Lindenauer et al. Ann Int Med 2006;144: Merinopoulou et al. Internat J COPD 2016;11: Sethi et al. NEJM 2008;359: After participating in this presentation, PHARMACISTS will be able to: Describe the overarching goals of chronic obstructive pulmonary disease (COPD) management Determine when antibiotic therapy is indicated based on cardinal symptoms and clinical presentation Identify three risk factors for infections with resistant, atypical organisms, or Pseudomonas Apply two principles of stewardship to recommend appropriate antibiotic regimens Recommend a strategy for prevention of exacerbations 1

2 After participating in this presentation, TECHNICIANS will be able to: Recognize the financial and clinical impact of COPD Describe the utility antibiotics may have when used appropriately in exacerbations Recall the three cardinal symptoms used to determine if antibiotic therapy is warranted Identify two antibiotics used in the treatment of exacerbations Explain how pharmacists & technicians are important in the management of exacerbations Estimated 15.7 million carry the diagnosis Comparing adults with and without COPD: Inability to work (24% vs. 5%) Activity limitations (50% vs. 17%) Difficulty walking/climbing stairs (38% vs. 11%) Special equipment needed (22% vs. 7%) Costs: ~$32 billion (direct), ~ $20 billion (indirect) Exacerbations are largest portion 3 rd leading cause of adult deaths in the U.S. Guarascio et al. CEOR 2013;5: Wheaton et al. MMWR 2015;64(11): REDUCE SYMPTOMS + REDUCE RISK Chronic obstructive lung disease (COPD) CDC 2016 Wheaton et al. MMWR 2015;64(11): Tobacco cessation Lifestyle modifications Physical activity/exercise Nutrition Limit occupational & environmental exposures Pharmacologic therapy Bronchodilators Oxygen Steroids Roflumilast Mucolytics/Antioxidants Non-pharmacologic therapy Pulmonary rehabilitation Breathing, energy conservation Self-management education Procedural intervention (bronchoscopy, surgery, transplant) 2

3 Progressive, respiratory condition with airflow obstruction due to airway/alveolar abnormalities Not always emphysema or chronic bronchitis Symptoms (not limited to): SOB, chronic cough, sputum production Diagnosis established with spirometry FEV 1 /FVC < 0.7 Significant contributor to morbidity, disability, and mortality Healthy Chronic obstructive lung disease (COPD) CDC 2016 Wheaton et al. MMWR 2015;64(11): Smoke Tobacco Exposures TGF-β, altered tissue repair, aging of cells Inhaled oxidants FIBROBLASTS Oxidative/ carbonyl stress Cellular reactive oxygen species (ROS) MACROPHAGES Host factors protease, cytokines metalloproteinases, phagocytosis oxidation, fragmenting, chemokines, newly formed antigens EXTRACELLULAR MATRIX (ECM) leakage, permeability, senescence angiogenesis ENDOTHELIUM Antioxidant depletion NEUTROPHILS T-CELLS protease, elastase, resolution of inflammation cytotoxins, perforin, granzyme mucus secretion, inflammatory substances, senescence EPITHELIAL CELLS COPD B-CELLS autoantibodies Adapted from Rahman et al. Curr Opin Pharmacol 2012;12: Level of Evidence (LOE) A B C D Sources RCTs Significant high-quality evidence without major limitations or bias RCTs with important limitations Limited evidence Non-randomized trials Observational studies Valuable but insufficient evidence Expert consensus 3

4 GOLD severity of airflow limitation mmrc 0: SOB with strenuous exercise mmrc 1: SOB when in a hurry or walking up a slight incline mmrc 2: tend to walk slower than those of same age or stop to catch breath walking at own pace on flat ground mmrc 3: SOB after walking 100 m or after a few minutes on flat ground mmrc 4: SOB at rest or when dressing/ undressing Exacerbations per year mmrc 0-1 CAT < 10 mmrc 2 CAT 10 GOLD severity of airflow limitation LAMA or LAMA + LABA Short- or long-acting bronchodilator LAMA + LABA or LAMA + LABA + ICS LABA or LAMA or LAMA + LABA 2 1* 0 Exacerbations per year mmrc 0-1 CAT < 10 mmrc 2 CAT 10 Acute worsening of symptoms necessitating additional therapy Mild: short-acting bronchodilators Moderate: + antibiotics and/or oral corticosteroids Severe: + ED visit or hospital admission with/without acute respiratory failure Most common pathogens Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Risk factors: previous exacerbations, respiratory infections, severe COPD/airflow limitation, environmental exposures, higher eosinophil counts? Chronic obstructive lung disease (COPD) CDC 2016 COPD among adults in Iowa CDC

5 Acute worsening of symptoms NO YES OUTPATIENT Severe symptoms, acute respiratory failure, new onset physical signs, failure of initial therapy, serious comorbidities, inadequate home support ED/INPATIENT Bronchodilators, corticosteroids +/- antibiotics Severe dyspnea not improving, AMS, persistent/worsening hypoxemia +/- respiratory acidosis, need for invasive mechanical ventilation, hemodynamic instability COPD action plan YES NO Duration of treatment: 5-7 days ICU Parenteral steroids +/- antibiotics, vasopressors, invasive mechanical ventilation Stable for transfer to ward WARD CXR, O2, blood gases, pulse ox, bronchodilators, oral steroids +/- antibiotics, non-invasive ventilation, fluid status, VTE ppx, treat other conditions/symptoms DISCHARGE AND FOLLOW-UP Review therapy, reassess inhaler technique, need for O2, arrange early (1-4 wks) and late (12-16 wks) follow-up Majority of exacerbations can be managed outpatient Possible factors to consider for hospitalization assessment Severe symptoms Dyspnea at rest Elevated respirations Decreased oxygen saturation Confusion Drowsiness Acute respiratory failure Failure to respond to initial medical management Onset of new physical signs Cyanosis Peripheral edema Serious comorbidities Heart failure New onset arrhythmias Inadequate home support system Hurst JR, Vestbo J, Anzueto A, et al. NEJM 2010;363(12): LD is a 59 YO male with PMH of COPD, HTN, HLD, and CAD/STEMI s/p 4-vessel CABG (12/2016) who presents to the ED with worsening shortness of breath and productive cough. He was admitted to the hospital for an exacerbation earlier this year and treated as an outpatient for another exacerbation 2 months ago with azithromycin + prednisone. Reports getting short of breath only when walking up stairs or if he is in a hurry. He has been compliant with all of his medications. Most recent pulmonary assessment: FEV 1 /FVC < 0.7 FEV 1 45% of predicted CAT 9 1. In what stage of COPD would LD fall? A, B, C, or D 5

6 Management of Exacerbations in COPD When used appropriately, may reduce (LOE B): Recovery time Hospital days Treatment failure Relapse Albert RK et al. NEJM 2011;365(8):689-98; Mandell LA et al. Clin Infect Dis 2007;44:S27-72; Ray WA et al. NEJM 2012;366(20):1881-9; Siddiqi et al. Internatl J COPD 2008;3(1):31-44; Stoller JK. UpToDate 2016; Wenzel RP et al. NEJM 2012;367(4):

7 START HERE Patient has a diagnosis of COPD + 3 cardinal symptoms (for 5 days)* dyspnea sputum production sputum purulence and/or mechanical ventilation *or 2 symptoms if one is sputum purulence NO Antibiotics NOT indicated (usually viral) Observe and provide symptomatic treatment, optimize respiratory medications Patient to report changes in symptoms YES Risk factors for resistance? (1 or more) Age 65 y.o. FEV1 <50% of predicted 3 exacerbations/year Recent antibiotics (past 3 months) 7

8 YES Risk for resistance? NO ANTIBIOTIC SELECTION Azithromycin* 1500mg, OR [500mg Q24h x3 days or 500mg x mg Q24h x4 days] Doxycycline 100mg Q12h, OR SMX-TMP 800mg/160mg Q12h Oral therapy is preferred *avoid in significant cardiac disease Tennessee Medicaid enrollees aged 30-74, no life-threatening non-cv illness, drug abuse, nursing home stay within 12 months, or hospitalization within 30 days Retrospective cohort Intervention Received azithromycin for 5-10 days Matched controls: no antibiotics, amoxicillin, ciprofloxacin, levofloxacin Primary endpoints Cardiovascular death and all-cause mortality Ray WA et al. NEJM 2012;366(20): Cumulative mortality (no./1m Rxs) Days of Therapy Days 1-5 Days 6-10 Entire course AZM No ABX AMOX CIPRO LEVO AZM vs. No ABX HR 2.88 [ ] p<0.001 HR 0.88 [ ] p=0.72 HR 1.86 [ ] p=0.002 AZM vs. AMOX HR 2.49 [ ] p=0.002 HR 0.95 [ ] p=0.89 HR 1.87 [ ] p=0.01 AZM vs. CIPRO HR 3.49 [ ] p= Ray WA et al. NEJM 2012;366(20):

9 Cumulative mortality (no./1m Rxs) Days of Therapy Days 1-5 Days 6-10 Entire course AZM No ABX AMOX CIPRO LEVO AZM vs. No ABX HR 1.85 [ ] p=0.002 HR 0.68 [ ] p=0.20 HR 1.27 [ ] p=0.15 AZM vs. AMOX HR 2.02 [ ] p=0.005 HR 0.60 [ ] p=0.10 HR 1.20 [ ] p=0.33 AZM vs. CIPRO HR 1.75 [ ] p= Ray WA et al. NEJM 2012;366(20): YES Risk for resistance? YES ANTIBIOTIC SELECTION Oral (preferred) IV Amox/clav* 875mg/125mg Q12h, OR Ceftriaxone^ 1-2g Q24h, OR Doxycycline*^ (local data) 100mg Q12h, OR Moxifloxacin^ 400mg Q24h Cefuroxime mg Q12h, OR Cefdinir^ 300mg Q12h or 600mg Q24h, OR Cefpodoxime^ 200mg Q12h, OR Moxifloxacin^ 400mg Q24h, OR *first line ^mild PCN allergy: 3 rd gen CSP; severe PCN/CSP allergy: doxy or moxi COPD +/- smoking are risk factors for Legionella, may consider adding azith or doxy or choosing a FQ if bacterial superinfection (e.g. CAP) suspected + urinary antigen test 1056 patients 60 y.o. w/copd exacerbation, FEV 1 <60% of predicted, 2+ exacerbations in the past year Randomized, double-blind, double-dummy, non-inferiority Intervention Moxifloxacin 400mg daily x5d or amoxicillin/clavulanate 875/125mg twice daily x7d + matching placebo Primary endpoint Clinical failure at 8 weeks (per protocol population) Wilson et al. Eur Respir J 2012;40:

10 % patients Clinical failure at 8 weeks Clinical failure at 8 weeks (primary outcome) 30 (subgroup: pathogens identified) p=n/a p=0.571 p= p=0.016 NNT= % patients 10 0 PP Moxi Amox/clav ITT 0 PP Moxi Amox/clav ITT Wilson et al. Eur Respir J 2012;40: July 2016 Drug Safety Communication associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient. Recommendations Reserve fluoroquinolones for situations when no alternative is available Use lowest effective dose and shortest course of therapy if necessary Educate patients regarding adverse effects and when/how to report Provide FDA Medication Guide with every prescription FDA Drug Safety Communication 2016 Risk for resistance? Antibiotic selection Concern for Pseudomonas? Bronchiectasis Previous Pseudomonas infection, colonization Frequent antibiotics ( 4 courses in the past year, esp. FQ, BL/BLI, 3 rd gen CSP, CBPM) Recent admission ( 2 days in past 3 months) Severe COPD (FEV 1 <50%) Agents: Pip/tazo g IV Q8h (over 4 hours), cefepime 2g IV Q8h, ceftazidime 1-2g IV Q8h, or levofloxacin 750mg IV Q24h Obtain sputum culture + pulmonary consult 10

11 36 studies from multiple databases surrounding drug-resistant Pseudomonas colonization/infection Systematic review Focus Extensively-drug resistant P. aeruginosa (XDR-PA) Endpoints Independent risk factors, prevalence, surveillance systems Buhl et al. Expert Rev Anti Infect Ther 2015;13(9): Risk for acquisition (8 studies) Fluoroquinolones (5 studies) Carbapenems (1 study) Trimethoprimsulfamethoxazole (1 study) Amikacin (1 study) Risk for colonization (2 studies) Fluoroquinolones (2 studies) Carbapenems (1 study) FQ > CBPM > TMP-SMX > Amikacin Buhl et al. Expert Rev Anti Infect Ther 2015;13(9): ,651 veterans 65 y.o. hospitalized with healthcare associated pneumonia (HCAP) Retrospective cohort Focus Pseudomonas or MRSA HCAP, or neither, by ICD-9 codes Primary endpoint Patient characteristics associated with each type of HCAP Metersky et al. Respirol 2016;21:

12 Drug Class (use within 90 days) Beta-lactams, cephalosporins, carbapenems Antibiotics with Grampositive activity* Positive association with Pseudomonas pneumonia compared to other or unknown HCAP etiologies Patient factor associated Independently with discharge diagnosis associated factor Other antibiotics^ + + Fluoroquinolones + ns Macrolides/ketolides + ns Aminoglycosides ns ns ns = not statistically significant Metersky et al. Respirol 2016;21: *clindamycin, dalfopristin, linezolid, vancomycin ^doxycycline, tetracycline, metronidazole, TMP-SMX Pneumonia Consult applicable guidelines Infectious Diseases Society of America (IDSA) Consider atypical coverage (e.g. Legionella) Influenza Oseltamivir, if indicated Laboratory/microbiological testing, imaging, physical exam, signs/symptoms, supportive care Harper et al. Clin Infect Dis 2009;48: Kalil et al. Clin Infect Dis 2016;63(5):e Mandell LA et al. Clin Infect Dis 2007;44:S studies across multiple databases comparing antimicrobial regimens in acute exacerbations of chronic bronchitis (AECB) Meta-analysis of randomized controlled trials Focus Regimens of the same antibiotic for different durations (short: 5 days, long: 7-10 days) Primary endpoints Treatment success and drug-related adverse events Falagas et al. J Antimicrob Chemo 2008;62:

13 Shorter duration (5 days) appears just as efficacious as longer durations (7-10 days) of therapy Population Relative Risk [95% CI] Intention-to-treat 0.99 [ ] Clinically evaluable 0.99 [ ] Microbiologically evaluable 0.98 [ ] Fewer adverse events and no difference in mortality with short duration of therapy Additional studies needed to ascertain long-term outcomes of the different durations Falagas et al. J Antimicrob Chemo 2008;62: Early follow-up (< 4 weeks) has been associated with less readmissions due to exacerbations Opportunity to review and change discharge therapy if necessary Subsequent visit at 12 weeks Assess need for antimicrobial prophylaxis or refillable antibiotics and corticosteroids Albert RK et al. NEJM 2011;365(8):689-98; Mandell LA et al. Clin Infect Dis 2007;44:S27-72; Ray WA et al. NEJM 2012;366(20):1881-9; Siddiqi et al. Internatl J COPD 2008;3(1):31-44; Stoller JK. UpToDate 2016; Wenzel RP et al. NEJM 2012;367(4):

14 Antimicrobial prophylaxis may be indicated with 2 exacerbations/year despite compliance with COPD therapy No significant cardiac or liver disease Erythromycin (LOE A) Azithromycin (LOE A) Doxycycline? Self-management (LOE A) Action plan with refillable antibiotics and corticosteroids Vaccines Influenza (LOE A) Pneumococcal (LOE B) 109 outpatients, moderate to severe COPD (FEV %), limited reversibility to SABAs, current/former tobacco use Randomized, double-blind, placebo-controlled Intervention Erythromycin 250mg or placebo PO BID for 1 year Primary endpoints Exacerbation frequency and airway inflammation Results/Conclusions Significantly reduced frequency of exacerbations w/erythromycin (81 vs. 125, Rate Ratio [ ], p=0.003) No significant difference in inflammatory markers Seemungal et al. Am J Respir Crit Care Med 2008;178: mg PO daily NEJM (2011) Randomized, parallel-group, placebo-controlled Azith 250mg or placebo PO daily for 1 year Primary endpoint: time to first acute exacerbation of COPD Azith time to and frequency of exacerbations and improved quality of life Median 266 vs. 174 days, p< mg PO Mon-Wed-Fri COLUMBUS trial (2014) Randomized, double-blind, placebo-controlled Azith 500mg or placebo PO 3x/week for 1 year Primary endpoint: rate of COPD exacerbations during treatment period Azith showed significant reduction in exacerbation rate Rate Ratio 0.58 [ ], p=0.001 Albert et al. NEJM 2011;365(8): Uzun et al. Lancet Respir Med 2014;2:

15 Has demonstrated in-vitro modulation of inflammatory process In-vivo activity in stable COPD unclear Dalvi et al. (2011) Randomized, observer-blinded, parallel-group Doxycycline 100mg or placebo PO daily x4 weeks Significantly improved pulmonary function, reduced CRP Prins et al. (2016) Randomized, double-blind, parallel-group Doxycycline 100mg or placebo PO daily x3 weeks No difference in pulmonary function or inflammation Why the difference? Population characteristics, duration of treatment, area of body (lungs) Dalvi et al. Ann Thorac Med 2011;6(4): Di Caprio et al. Mediat Inflamm doi: /2015/ Prins et al. Respir Med 2016;110: Meet criteria for antibiotics? Identification of risk factors for resistance/poor outcomes Antibiotic selection & stewardship Allergies/ADRs, interactions, dosing, IV to PO, duration Concomitant infection(s) Contacting outside hospital/clinic/pharmacy, if applicable Appropriate COPD therapy (steroids, respiratory agents) Medication reconciliation Order preparation, dispensing, counseling COPD is the 3 rd leading cause of death in the U.S. High financial and clinical impact but very manageable Goals: reduce symptoms + reduce risk 3 cardinal symptoms for antibiotics in exacerbations Increased dyspnea, sputum production, and sputum purulence Practicing antimicrobial stewardship leads to optimal therapy Strategies for prevention of future exacerbations are essential Pharmacists and technicians play an important role in the management of COPD and exacerbations 15

16 Lisa Dykes, PharmD PGY-1 Pharmacy Practice Resident Iowa City VA Medical Center May 2,