Optimize Durations of Antimicrobial Therapy Evidence & Application Jill Cowper, Pharm.D. Division Infectious Diseases Pharmacist Parallon Supply Chain Solutions Richmond, VA P: 607 221 5101 jill.butterfield@parallon.com
Disclosure I have no relevant finances to disclose.
Objectives Explain the importance of optimizing durations of antibiotic therapy Describe evidence supporting shorter durations of therapy for infectious indications Discuss an initiative to optimize durations of antibiotic therapy Demonstrate improvements in durations of antibiotic therapy
Audience Question Who has implemented a process that requires indications and durations for every antibiotic order?
Optimizing Antimicrobial Therapy Optimal efficacy & safety of antimicrobials depends on the following: Avoiding them when they re not indicated The 4 Ds of optimal therapy 1. Right Drug 2. Right Dose 3. De escalation to pathogen directed therapy 4. Right Duration File TM. J Hosp Med 2012.
Durations of Antimicrobials The Problem False perception that more is better Durations ordered per indication at a 506 bed HCA facility: Average Min Max Recommended or data supporting DOT C. difficile 10 7 28 10 14 CAP 8 3 21 5 HAP 8 5 14 7 COPD exacerbation 7 3 20 5 Intra abdominal 9 3 15 4 Skin and soft tissue 8 3 28 5 6 Upper respiratory infection 7 3 42 5 UTI 7 3 28 3 uncomplicated 7 14 complicated Spellberg B. JAMA Intern Med 2016.
Why is this Important?
Importance of Durations of Antimicrobials Longer courses of antibiotic therapy lead to more resistance development Short course Long course P value Singh et al. 5/37 (15%) 14/37 (35%) 0.017 Chastre et al. 24/57(42.1%) 33/53 (62.3%) 0.04 Singh, et al. Am J Respir Crit Care Med 2000; Chastre, et al. JAMA 2003.
Image available from: https://www.cdc.gov/getsmart/community/about/antibiotic resistance faqs.html.
Importance of Durations of Antimicrobials Longer courses of antibiotic therapy lead to a greater risk of subsequent infection 18 16 NO subsequent infection 16.8 Infection 14 14 12 11.5 10 10 8 Days of therapy for IAI (mean) *P < 0.01 for both comparisons. Days of therapy for IAI (median) Riccio, et al. Surgical Infections 2014.
Importance of Durations of Antimicrobials Longer courses of antibiotic therapy lead to a greater risk of side effects Image available from: https://www.cdc.gov/drugresistance/protecting_yourself_family.html.
Importance of Durations of Antimicrobials C. difficile risk increases with increasing duration of antibiotic therapy Stevens, et al. Clin Infect Dis 2011.
Audience Question Why is it important to optimize durations of antimicrobial therapy? A. Excessive durations of therapy lead to more resistance development B. Longer durations of therapy have been associated with a greater risk of subsequent infection C. Longer durations of therapy increase the risk of antimicrobial related side effects D. There is a dose response relationship between antibiotic days of therapy and risk of C. difficile E. All of the above
Is There Evidence for Shorter Durations?
CAP 5 vs 10 days Multicenter, randomized trial evaluating whether duration of antibiotics based on IDSA guideline criteria was just as effective as conventional therapy Intervention IDSA guideline criteria Minimum of 5 days Antibiotics discontinued if afebrile for 48 hrs and had no more than 1 CAP associated sign of clinical instability (SBP < 90 mm Hg, HR > 100/min, RR > 24/min, arterial O2 saturation < 90%, or PaO2 less than 60 mm Hg in room air) Conventional therapy duration determined by treating physician Uranga, et al. JAMA Intern Med 2016.
CAP 5 vs 10 days Withdrawing antibiotics based on clinical stability criteria after a minimum of 5 days is not inferior to longer treatment durations Control group (n=137) Intervention group (n=146) P value Days on antibiotics, median (IQR) 10 (10 11) 5 (5 6.5) < 0.001 Clinical success at day 10 71 (48.6) 90 (56.3) 0.18 Clinical success at day 30 132 (88.6) 147 (91.9) 0.33 Hospital LOS, mean (SD) 5.5 (2.3) 5.7 (2.8) 0.69 30 d mortality 3 (2.2) 3 (2.1) > 0.99 Readmission by day 30 9 (6.6) 2 (1.4) 0.02 Recurrence by day 30 6 (4.4) 4 (2.8) 0.53 Antibiotic adverse effects by day 30 18 (13.1) 17 (11.7) 0.72 All data presented as No. (%) unless otherwise specified. Uranga, et al. JAMA Intern Med 2016.
HAP/VAP 7 vs 10 15 days Pugh et al. Dimopoulos et al. Antibiotic free days, 4.02 (2.26, 5.78) 3.40 (1.43, 5.37) mean difference (95% CI) Mortality, OR (95% CI) 1.18 (0.77, 1.8) 1.20 (0.84, 1.72) Mortality; NF GNB, 0.95 (0.39, 2.27) 1.33 (0.33, 5.26) OR (95% CI) Recurrence, OR (95% CI) 1.41 (0.94, 2.12) 1.67 (0.99, 2.83) Recurrence; NF GNB, 2.18 (1.14, 4.16) NA OR (95% CI) Superinfection, OR (95% CI) 0.44 (0.21, 0.95) NA ICU LOS, mean difference (95% CI) Hospital LOS, mean difference (95% CI) 0.15 ( 1.00, 1.29) 0.16 ( 0.99, 1.31) 1.0 ( 4.11, 2.11) NA CI, confidence interval; LOS, length of stay; NF GNB, non fermenting gram negative bacilli; OR, odds ratio. Pugh R, et al. Cochrane Database Syst Rev 2015; Dimopoulos G, et al. Chest 2013.
HAP/VAP 7 vs 10 15 days Observational study in patients with VAP due to nonlactose fermenting gram negative rods </= 8 days (n=27) > 8 days (n=127) P value Antibiotic days, 6.4 (0.3) 17.1 (0.7) 0.0001 mean (SD) Deaths, n (%) 6 (22) 18 (14) 0.38 Recurrence, n (%) 6 (22) 43 (34) 0.27 LOS, mean (SD) 65.7 (10.9) 67.9 (4.2) 0.78 Hedrick TL, et al. Surg Infect (Larchmt) 2007.
HAP/VAP 7 vs 10 15 days IDSA guidelines published in 2016: For patients with HAP, we recommend a 7 day course of antimicrobial therapy. Meta analysis conducted by guideline authors: No difference between short (7 8 days) and longcourse regimens (10 15 days) Non lactose fermenting gram negative rods: No difference in pneumonia recurrence (OR, 1.42; 95% CI, 0.66 3.04) No difference in mortality (OR, 0.94; 95% CI, 0.56 1.59) 7 day duration, regardless of pathogen Kalil AC, et al. Clin Infect Dis 2016.
COPD or Chronic Bronchitis Exacerbation 5 vs 7 10 days Meta analysis comparing 5 days to 7 10 day regimens of a macrolide, fluoroquinolone, or beta lactam El Moussaoui R, et al. Thorax 2008.
COPD or Chronic Bronchitis Exacerbation 5 vs 7 10 days Same results when studies grouped by antibiotic class (fluoroquinolones, macrolides, & cephalosporins) El Moussaoui R, et al. Thorax 2008.
COPD or Chronic Bronchitis Exacerbation 5 vs 7 10 days Another meta analysis same results Adverse events significantly lower with short course therapy (RR=0.84, 95% CI 0.72 0.97) Falagas ME, et al. J Antimicrob Chemother 2008.
Sinusitis 5 vs 10 days Meta analysis evaluating 3 7 vs 6 10 days Outcome (N of studies) Clinical Success 3 7 days vs 6 10 days (N=12) Clinical Success 5 days vs 10 days (N=7) Clinical Success Beta lactams (N=6) Adverse Events 3 7 days vs 6 10 days (N=10) Adverse Events 5 days vs 10 days (N=5) Pooled OR (95% CI) 0.95 (0.81, 1.12) 0.98 (0.79, 1.22) 0.95 (0.76, 1.20) 0.88 (0.71, 1.09) 0.79 (0.63, 0.98) Falagas ME, et al. Br J Clin Pharmacol 2009.
Intra Abdominal 4 vs 10 days Multicenter, randomized, open label trial evaluating whether a 4 day duration of antibiotics would lead to similar outcomes as traditional therapy Intervention antibiotics x 4 days after source control Traditional therapy continuing antibiotics until 2 days after resolution of SIRS related physiologic abnormalities (max of 10 days) Afebrile x 1 day WBC < 11 Ability to consume more than half of regular diet without adverse effects Sawyer RG, et al. N Engl J Med 2015.
Intra Abdominal 4 vs 10 days No difference in primary composite outcome (surgical site infection, recurrent intraabdominal infection, or death), P=0.92 Control group 58/260 (22.3%) Intervention group 56/257 (21.8%) No difference in time to event: Sawyer RG, et al. N Engl J Med 2015.
Intra Abdominal 4 vs 10 days No difference in primary outcome when stratified by key subgroups Sawyer RG, et al. N Engl J Med 2015.
Cellulitis 5 vs 10 days Randomized, double blind trial evaluating levofloxacin x 5 days versus 10 days in uncomplicated cellulitis Severity of cellulitis assessed with physician composite score (including erythema, warmth, tenderness, edema, ulceration, drainage, and fluctuance) No difference in clinical response between 5 vs 10 days Hepburn MJ, et al. Arch Intern Med 2004.
Cellulitis 5 vs 10 days Phase 3 randomized, double blind, multinational trial in patients with skin & skin structure infections Randomization: Tedizolid x 6 days Linezolid x 10 days No difference in clinical response rates Moran GJ, et al. Lancet Infect Dis 2014.
UTIs & Pyelonephritis 5 7 vs 10 14 days Meta analysis comparing 7 days versus > 7 days for pyelonephritis and UTIs with sepsis Studies included the following regimens: Short course Ciprofloxacin x 7 days Levofloxacin x 5 days Levofloxacin x 5 days Ciprofloxacin x 7 days Ceftriaxone/cefixime x 7 days Fleroxacin x 7 days Pivampicillin x 7 days Ampicillin x 7 days Long course Ciprofloxacin x 14 days Ciprofloxacin x 10 days Ciprofloxacin x 10 days TMP/SMX x 14 days Ceftriaxone/cefixime x 14 days Fleroxacin x 14 days Pivampicillin x 21 days Ampicillin x 1 month Eliakim Raz N, et al. J Antimicrob Chemother 2013.
UTIs & Pyelonephritis 5 7 vs 10 14 days No difference in clinical failure during follow up Eliakim Raz N, et al. J Antimicrob Chemother 2013.
UTIs & Pyelonephritis 5 7 vs 10 14 days Concurrent bacteremia? Still no difference in clinical failure Eliakim Raz N, et al. J Antimicrob Chemother 2013.
Audience Question For each indication, what is the evidence based duration of therapy? a) CAP b) HAP/VAP c) COPD exacerbation d) Sinusitis e) Intra abdominal infection f) Skin and soft tissue infection g) Pyelonephritis
What is the Solution?
New Interventions to Address the Antibiotic Resistance Crisis Studies to define shortest effective courses of antibiotics for infections Spellberg B, et al. N Engl J Med 2013.
Duration for every Antibiotic Order
Recommended Durations by Source FDA approved Guidelines Literature CAP 5 5 5 HAP/VAP 7 7 7 COPD exacerbation 7 5 7 5 Sinusitis 5 5 7 5 C. difficile 10 10 14 10 14 Intra abdominal infection Skin and soft tissue infection UTI, complicated 7 5 (levofloxacin) Pyelonephritis 7 5 (levofloxacin) 4 14 4 7 4 5 14 5 5 7 5 (levofloxacin) 10 14 5 (levofloxacin) 7 (ciprofloxacin) 5 7 5 7
How do I Implement This?
Indication & Duration for every Antibiotic
Default Durations Default durations will auto populate based on drug ordered and indication selected Default Duration CAP 5 HAP/VAP 7 COPD exacerbation 5 C. difficile infection 14 Skin and soft tissue 14 UTI Levofloxacin 5 All other antibiotics 7 Genitourinary/Pyelonephritis Levofloxacin 5 Ciprofloxacin 7 All other antibiotics 14
Provider Report Orders to Stop Provider report with list of patients the provider has a relation with if one or more medication orders due to stop on the current day or within the next 3 days Meds due to stop 1st displayed 1st Meds due to stop on current or next day will be in red font Rx for antibiotics are prefixed with a + symbol
Antibiotic Indication & Duration Report Report displaying patient, location, start & stop dates, antibiotics, dose, route, sig, indication, & duration Identify unusual combinations, prolonged duration of broad spectrum therapy, durations that don t match up with start/stop dates
Show Your Impact Data, Data, Data! Fluoroquinolone DDD/1K Adjusted Patient Days
Show Your Impact Data, Data, Data! * * * * *P < 0.05
Show Your Impact Data, Data, Data! Impact of providing default durations of therapy to provider (CAP 5d, UTI 7d (levo 5d), C.diff (14d) Pre Default Post Default Average Duration Ordered (Days) 14 12 10 8 6 4 CAP levofloxacin *P=0.0002 UTI levofloxacin P=0.068 CAP ceftriaxone UTI ceftriaxone *P=0.006 C. difficile oral vanco Facility G data
Show Your Impact Data, Data, Data! A B G I J L
Keep Adding Enhancements Antifungal Indications & Durations HAP/VAP duration of 7 days Fluoroquinolone FDA Advisory for uncomplicated infections
Antifungal Indications & Durations Indication Antifungals Message Displayed All indications Fluconazole 150mg Clostridium difficile Surgical Prophylaxis COPD Exacerbation Pneumonia all types Genitourinary or UTIs All antifungals All antifungals All antifungals Fluconazole Echinocandins Echinocandins Liposomal amphotericin B Itraconazole Voriconazole Posaconazole Fluconazole 150mg is only indicated as a one dose treatment for vulvovaginal candidiasis. If this is not vulvovaginal candidiasis, please select a different dose. Antifungals are not indicated for C.difficile infection. Choose alternative therapy or select correct indication. Antifungals are not indicated for surgical prophylaxis use. Choose alternative therapy or select correct indication. Antifungals are not indicated for COPD exacerbations. Choose alternative therapy or select correct indication. Growth of Candida from respiratory secretions usually indicates colonization and rarely requires treatment with antifungal therapy. This antifungal is not recommended for UTIs due to poor urine concentrations.
Antifungal Indications & Durations Indication Antifungals Default Duration All indications Fluconazole 150mg 1 Genitourinary/Pyelonephritis Azoles 14 Echinocandins 14 Amphotericin B 7 Liposomal amphotericin B 7 Flucytosine 14 UTIs Azoles 14 Echinocandins 14 Amphotericin B 7 Liposomal amphotericin B 7 Oral/ENT Infection Flucytosine 7 Azoles Echinocandins Amphotericin B Liposomal amphotericin B 14
Antifungal Indications & Durations Indications & durations entered for antifungals Antifungal Indications Antifungal Average Durations 1% 4% Candidemia 11.6 5 14 Febrile neutropenia Intra abdominal 31% 25% 14 9.5 Genitourinary Oral/ENT 4% 4% 7% 2% 2% 19% 1% 14 14 7 7 14 5 Aspiration pneumonia CAP Prophylaxis Sepsis Skin and soft tissue UTI Facility J data
Keep Adding Enhancements Antifungal Indications & Durations HAP/VAP duration of 7 days Fluoroquinolone FDA Advisory for uncomplicated infections
HAP/VAP Duration of 7 days Impact of default duration of 7 days for HAP Average Duration Ordered (Days) 16 14 12 10 8 6 4 Pre Default Post Default *P=0.0001 *P=0.0001 *P=0.0001 Total Antibiotics Pip/Tazo Meropenem Cefepime Levofloxacin Facility J data
Keep Adding Enhancements Antifungal Indications & Durations HAP/VAP duration of 7 days Fluoroquinolone FDA Advisory for uncomplicated infections
Fluoroquinolone FDA Advisory In 2015, fluoroquinolones accounted for the most reports of persistent adverse effects that became long term health issues (e.g. painful joint, muscle, & tendon disorders) FDA has stated that these adverse effects outweigh their benefits for uncomplicated infections and alternatives should be used When an uncomplicated infection is chosen for a fluoroquinolone, a warning message is presented with alternative first line options Genitourinary Infections Upper Respiratory Infections Urinary Tract Infections
Fluoroquinolone FDA Advisory Number of fluoroquinolone orders for each indication before & after fluoroquinolone FDA advisory message: Genitourinary Infection Upper respiratory infection Facility H Before (n=238) After (n=200) P value Facility I Before (n=166) After (n=223) P value 11 (19.6%) 4 (7.5%) 0.095 16 (23.5%) 8 (12.9%) 0.174 10 (34.5%) 4 (11.1%) 0.034 9 (40.9%) 2 (7.1%) 0.006 UTI 54 (35.3%) 18 (16.2%) 0.0007 26 (34.2%) 25 (18.8%) 0.019 Total 75 (31.5%) 26 (13.0%) 0.0001 51 (30.7%) 35 (15.7%) 0.0005
Conclusion Optimal antimicrobial use includes avoiding them when they re not indicated and giving the right drug, right dose, de escalating to pathogen directed therapy, and treating for the right duration. Excessive durations of therapy leads to more resistance development, greater risk of other infections, and a greater risk of side effects, including C. difficile. Shorter durations of therapy have been shown to be just as effective as longer durations for several infectious indications, including CAP, HAP/VAP, COPD exacerbations, sinusitis, intra abdominal infections, skin and soft tissue infections, & pyelonephritis.
Post Test Question 1 Excessive durations of antibiotic therapy have been found to: A. Improve clinical cure rates B. Increase the risk of a subsequent infection C. Result in similar efficacy and safety D. Decrease rates of C. difficile
Post Test Question 2 How many days of antibiotics do patients with hospital acquired or ventilator associated pneumonia need based on recent evidence? A. 5 B. 7 C. 7 8 for most organisms; 15 for non lactose fermenting gram negative rods D. 10 for most organisms; 15 for non lactose fermenting gram negative rods
Questions?
Optimize Durations of Antimicrobial Therapy Evidence & Application Jill Cowper, Pharm.D. Division Infectious Diseases Pharmacist Parallon Supply Chain Solutions Richmond, VA P: 607 221 5101 jill.butterfield@parallon.com