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Antimicrobial Resistance Where Do We Stand? Hannah R Palmer, PharmD, BCPS Infectious Diseases Clinical Coordinator St. Luke’s Episcopal Hospital Houston, TX Disclosures I have no conflicts of interest in relation to this program Objectives Become familiar with current challenges in infectious diseases pharmacotherapy Become familiar with the changing trends in resistance rates to antimicrobials Understand the goals of antimicrobial stewardship programs Understand the role pharmacists can play in optimizing the use of antimicrobials http://www.youtube.com/watch?v=QKaTlqOQTnw Significance of infectious diseases • #1 cause of mortality worldwide – 26% of worldwide mortality in 2003 • $120 billion spent annually in the U.S. on infectious diseases medical care • 3rd most common reason for US hospital admissions www.nih.gov www.who.gov Mortality due to infectious diseases www.cdc.gov Defining Antimicrobial Resistance • Acquired ability of a pathogen to withstand an antibiotic that kills off its sensitive counterparts • Arises from – – – – www.cdc.gov Random mutations Horizontal gene transfer Exposure to antibiotics Replication “The struggle against antibiotic resistance is a war we will never win. The strength of trillions upon trillions of microorganisms, combined with the ancient force of evolution by constant, unrelenting variation, will inevitably overpower our drugs” - American Academy of Microbiology Challenges • Hospital – 50 – 75% of patients who present to the ER receive antimicrobials • Up to 99% of these may be inappropriate – St. Luke’s: 71% of patients admitted > 48hrs receive antibiotics (2008) • Lack of new antibiotics in the pipeline Am J Med 2006;119:S53-61 JAMA 1997;278:875 Br Med J 1997:315:1211 Arch Intern Med 2003;163:601 Number of new antibiotics approved by the FDA Clin Infect Dis 2009; 48:1–12 • • • • • • Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumanii Pseudomonas aeruginosa Enterobacter spp. Clin Infect Dis 2009; 48:1–12 Challenges • Community – 75% of pts with ARTIs receive antibiotics • Only 1/5th may require therapy – Over 38 million prescriptions annually for ARTIs alone • 12 million of these unnecessary • Increasing resistance with most commonly prescribed antibiotics to most common pathogens Am J Med 2006;119:S53-61 JAMA 1997;278:875 Br Med J 1997:315:1211 Arch Intern Med 2003;163:601 Challenges Antibiotic prescriptions during ARTI visits Grijalva cg, et al JAMA 2009;302(7):758 Antibiotic Prescription Rates for Acute Respiratory Tract Infections in US Ambulatory Settings Grijalva cg, et al JAMA 2009;302(7):758 Prescribing habits for acute otitis media among children: 1998 - 2004 Broad spectrum Amoxicillin/clavulanate Macrolides Cephalosporins Quinolones Coco AS. BMC Pediatr. 2009 Jun 24;9:41 Changing Habits: Antibiotic Prescriptions during ARTI visits 1995-1996 2005-2006 70 60 ↑ 620%! 50 40 ↑ 540%! 30 20 10 Grijalva cg, et al JAMA 2009;302(7):758 ol on es qu in as su l fa s/ te tr in az ith ro m yc m ac ro lid es s or in ce ph al os p ox -c la v Am Am ox i ci llin 0 Resistance to respiratory tract bacteria in respect to previous antibiotic prescribing BMJ 2010;340:2096 Streptococcus pneumoniae Resistance Rates of high-level penicillin resistance (MIC 2 mg/mL): 1986–2001 respiratory tract–infection seasons Karchmer AW. Clin Infect Dis 2004; 39:S142–50 Influence of penicillin resistance Karchmer AW. Clin Infect Dis 2004; 39:S142–50 Levofloxacin for CAP • Remains Level I recommendation – Evidence from well-conducted, randomized controlled trials – Should be used with caution when Pseudomonas aeruginosa a concern • ↑ hospital resistance (SLEH ICUs – 56% resistant) • Resistance – S. pneumoniae • Increases with PCN resistance – H. influenzae – remains rare – Atypical bacteria – rare • Moxifloxacin resistance - lower? – In one study*, 13.3% levo R vs. 8.9% moxi Mandell LA et al. Clin Infect Dis 2007;44:S27 *Ho PL, et al. JAC. 2001;48:659 Levofloxacin use and outpatient E. coli UTI resistance versus time Johnson L, et al. Am J Med 2008;121:876 Urinary isolates in the ED – St. Luke’s E.coli (n=123) Enterococcus (n=71) Klebsiella (n=30) Pseudomonas (n=17) Proteus (n=16) Ampicillin 80 (65%) 11 (15%) NA NA NA Levofloxacin 47 (38%) NA 6 (20%) 13 (76%) 5 (31%) Ciprofloxacin 47 (38%) NA 6 (20%) 13 (76%) 7 (44%) Cotrimoxazole 46 (37%) NA 5 (17%) NA 8 (50%) Nitrofurantoin 12 (10%) 9 (13%) 23 (77%) NA 16 (100%) Over half of these patients required follow up with an intervention, switching the original antibiotic prescribed Covey R, et al. 2009, Unpublished data Correlation of levofloxacin resistance and alternative agents among E. coli UTIs Clin Infect Dis 2010; 51(3):280–285 Fosfomycin: The Not-So-New, New Kid on the Block • Phosphonic acid derivative • FDA approved in 1996 for uncomplicated UTIs • Only available as oral sachet in U.S. – Available in IV formulation in Europe • Retains excellent activity against urinary pathogens (so far) even among MDR pathogens • Use is increasing! Monurol (fosfomycin) Package Insert [2007]. Forest Pharmaceuticals, St. Louis, MO Fosfomycin (Monurol) Class Phosphonic acid inhibitor; bactericidal Activity Most aerobic Gram-positive, Gram-negative pathogens Penetration Excellent into kidneys/bladder/urine Cmax urine > 1000 mg/mL (>128 mg/mL at 48hrs) Side effects GI – diarrhea (~10%), nausea (~5%) Availability Oral 3g sachet (US) Dose 3g sachet x 1 – uncomplicated UTIs 3g sachet qod x 3 doses – MDR urinary pathogens Cost $50/sachet Drug Interactions Metoclopramide (↓ fosfomycin concentrations) Int J Antimicrob Agents 2009;34:206-515 Monurol (fosfomycin) Package Insert [2007]. Forest Pharmaceuticals, St. Louis, MO Fofsomycin versus Comparators Comparative agent Study population Outcome Amoxicillin single doses of fosfo and amox Eradication, recurrence, reinfection no difference; persistence less in F group single dose of fosfo, mult doses amox/clav No difference in efficacy nor side effects Single dose fosfo vs. 7d nitro at multiple different (RCT) No differences in efficacy; higher relapse in nitro group Single dose fosfo vs. differing doses FQs No difference in efficacy; higher rate of SEs in F group Single dose fosfo vs. differing doses/days No differences in efficacy; diarrhea higher in F group Chemotherapy 1990aa; 36:19 Amox-clav Chemotherapy 1990; 36:24-26 Nitrofurantoin Infection 1990; 18:S94-S97 Pharm World Sci 1993; 15:257 Clin Ther 1999; 21(11):1864-1872 Oflox/norflox Chemotherapy 1990; 36:46-49 Infection 1990b; 18:S70-S76 TMP-SMX Infection 1990; 18:S70-S76 St. Luke’s ED isolates – fosfomycin susceptibility Pathogen (n) No. of pathogens % susceptible E. coli 24 100 Enterococcus spp. 9 78 (2 VRE INT) Staphylococcus spp 4 100 Klebsiella pneumoniae 3 100 Proteus spp. 2 100 Streptococcus spp 2 100 Enterobacter cloaecae 1 100 Citrobacter koseri 1 100 Pseudomonas aeruginosa 1 100 Morganella spp. 1 0 Chabria et al. 2010, Unpublished data What’s new with the flu? hwww.cdc.gov/flu/weekly/ New CDC recommendations: Antivirals • • • • Confirmed or suspected influenza PLUS Severe, complicated, or progressive illness AND/OR Require hospitalization AND/OR Outpatients with underlying medical conditions AND/OR • No known risk factors for severe illness if treatment can be initiated within 48 hours of illness onset AND/OR • Based on clinical judgment www.cdc.gov Antiviral Resistance Adamantadines • Agents – Amantadine (Symmetrel, generic) – Rimantidine (Flumadine, generic) • Resistance – Influenza B inherently resistant – Influenza A resistance • 1995 – 0.8% • 2004 – 12.3% • 2005 – 96 % • **No longer recommended** www.cdc.gov J Inf Dis 2007; 196: 249-57 Antiviral resistance Neuraminidase inhibitors • Available agents – Oseltamivir (Tamiflu) – oral only – Zanamavir (Relenza) – inhaler only – Peramivir (Phase III studies) – IV • Oseltamivir resistance – H274Y mutation seen in 2010 seasonal H1N1 and avian H5N1 viruses – Through June 2010, 300 oseltamivir-resistant novel H1N1 viruses detected worldwide • Remain drugs of choice for Influenza www.cdc.gov J Inf Dis 2007; 196: 249-57 Clostridium-difficile associated diarrhea NAP1/ribotype 027 Arch Surg 2007;142:624-631 Clostridium-difficile associated disease treatment timeline 1935 1980 1983 1995 2000 2010 2007 First randomized, prospective, doubleblinded, placebo-controlled trial comparing vancomycin and metronidazole C. difficile-associated diarrhea A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile-Associated Diarrhea, Stratified by Disease Severity Fred A. Zar, Srinivasa R. Bakkanagari, K.M. L. S. T. Moorthi, and Melinda B. Davis University of Illinois at Chicago, Chicago, and Saint Francis Hospital, Evanston, Illinois Severe CDAD: > 2 points 1 point 2 points Age > 60 years ICU Tmax > 38.3°C albumin < 2.5 mg/dL WBC > 15,000 cells/mm3 Endoscopic evidence of pseudomembraneous colitis Clin Infec Dis 2007;45:302-7 Rate of cure by disease severity and treatment .006 Clin Infec Dis 2007;45:302-7 Changing paradigm in C. difficile St. Luke’s – specific data 144 Evaluable patients with 1st or 2nd episode – Pre-implementation Mild-moderate disease 85 (59%) metronidazole 77 (91%) vancomycin 8 (9%) Severe Disease 59 (41%) metronidazole 51 (86%) vancomycin 8 (14%) 82 Evaluable patients with 1st or 2nd episode of C. diff – Post-implementation Mild-moderate disease 47 (57%) metronidazole 30 (64%) vancomycin 17 (36%) Severe Disease 35 (43%) metronidazole 7 (20%) vancomycin 28 (80%) Antibiotic Use: A balancing act Appropriate & Adequate Initial Antimicrobial Treatment ↓ mortality Avoid unnecessary Antimicrobial Use ↓ drug resistance Antimicrobial Stewardship • Limit inappropriate use of antimicrobials • Optimize selection, dose, route, and duration of antimicrobial therapy to maximize clinical cure or prevention of infection • Limit emergence of resistance, adverse drug events, and cost Antimicrobial Stewardship Programs (ASPs) • Collaboration of a multi-disciplinary team – – – – – – ID physician Clinical pharmacist** Clinical microbiologist Information system specialist Infection control professional/epidemiologist Support from hospital administration • St. Luke’s – Center for Antimicrobial Stewardship and Epidemiology (CASE) What can we do? Quality of Care Committee Medical Executive Committee Pharmacy, Nutrition, and Therapeutics Committee CASE Advisory Board CAS Medical Director Infectious Disease Pharmacists Infection Control Practitioner Clinical Microbiologist Nursing Information Management Medical Staff Members from, but not limited to: Infectious Disease Internal Medicine Emergency Medicine General Surgery Cardiovascular Surgery Orthopedics Pathology CASE Research Collaborative St. Luke’s UH College of Pharmacy CASE Medical Director CASE Team Infectious Disease Pharmacists Infectious Disease Physician Pharmacy ID Fellow Dir. Infection Control CASE initiatives • Bug-drug mismatch lists – Bug-drug – Gram-positive Gram negative – Daptomycin-linezolid • • • • • Sterile site list review Daptomycin policy Clostridium-difficile treatment policy Pharmacokinetic service/consults 24-hour pager ASP opportunities • • • • • • • • • • • • • • • Medical Staff Education Prospective audit of antimicrobial use with feedback Antimicrobial Restrictions and Controls Antimicrobial Support Teams Pharmacokinetics/pharmacodynamics Therapeutic Substitutions Dose/drug optimization Automatic Stop Orders Antibiotic Order Forms Cost savings Interventional Pharmacists Reduction of Pharmaceutical Promotion? Rotational or Cyclic Antimicrobial Use? Promotion of Combination Therapy? Etc How ASPs can alter prescribing habits Antibiotics for HAP 70 Pre Post 60 50 40 30 20 10 0 Fluoroquinolone Hanzelka K, et al. Ann Pharmacother (submitted) Aminoglycoside Zosyn+Cipro+Vanc Impact of an ASP on Sepsis Pre Post p value Adequacy of empiric antibiotics 68% 85% < 0.05 28-day mortality 32% 24% NS Chest 2006;130:787-93 Impact on outcomes Clin Infect Dis 2001;33:289 www.IDsociety.org Antimicrobial Resistance Where Do We Stand? Hannah R Palmer, PharmD, BCPS Infectious Diseases Clinical Coordinator St. Luke’s Episcopal Hospital Houston, TX