48 th Annual Meeting. Microbiology 101: What You Wish You Had Learned in Pharmacy School. Disclosures. Objectives. Susceptibility Testing 7/19/2014

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48 th Annual Meeting Microbiology 101: What You Wish You Had Learned in Pharmacy chool Lindsey Childs-Kean, PharmD, MPH, BCP Clinical Assistant Professor University of Florida College of Pharmacy t.

William tewart, United tates urgeon General pellberg B. Infect Dis Poverty 2013;2:3.

1 48 th Annual Meeting Microbiology 101: What You Wish You Had Learned in Pharmacy chool Lindsey Childs-Kean, PharmD, MPH, BCP Clinical Assistant Professor University of Florida College of Pharmacy t. Petersburg, FL Navigating the Oceans of Opportunity The time has come to close the book on infectious diseases. We have basically wiped out infection in the United tates. -attributed to Dr. William tewart, United tates urgeon General pellberg B. Infect Dis Poverty 2013;2:3. Disclosures I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation If current trends continue unabated, the future is easy to predict. ome experts say we are moving back to the pre-antibiotic era. No. This will be a post-antibiotic era. -Dr. Margaret Chan, Director-General of the World Health Organization World Health Organization Objectives By the end of the presentation, learners should be able to: Discuss susceptibility testing and how it impacts treatment Compare and contrast the mechanisms of antimicrobial resistance Explain the role of antibiograms in clinical practice Given a patient case, determine which antimicrobial agent(s) would be most effective for treatment usceptibility Testing 1

Definitions Types of usceptibility Testing Term Minimum Inhibitory Concentration (MIC) usceptible () usceptible-dose Dependent (DD) Intermediate (I) esistant () Definition

used MIC at concentration expected with higher antibiotic dosing MIC higher than concentration expected with therapeutic doses Broth Dilution Tests Antimicrobial Gradient

Principles and Practices of Infectious Disease. Ch. 17, 2009. Jorgenson J. Clin Infect Dis 2009;49:1749-1755.

year old diabetic male presents with foot wound He describes 3 days of erythema and pain at the site of the wound and subjective fever The physician empirically places the

Principles and Practices of Infectious Disease. Ch. 17, 2009. taphylococcus spp. Gram Negative Organisms Cocci Neisseria, Moraxella Gram Negative Lactose Fermenter E.

2 Definitions Types of usceptibility Testing Term Minimum Inhibitory Concentration (MIC) usceptible () usceptible-dose Dependent (DD) Intermediate (I) esistant () Definition Lowest concentration that inhibits bacterial growth MIC at or below concentration expected with usual antibiotic dosing usceptibility is dependent on dose of antibiotic used MIC at concentration expected with higher antibiotic dosing MIC higher than concentration expected with therapeutic doses Broth Dilution Tests Antimicrobial Gradient Method Disk Diffusion Test Automated Instrument ystems Jorgenson J. Clin Infect Dis 2009;49: Clinical and Laboratory tandards Institute Murray P. Principles and Practices of Infectious Disease. Ch. 17, Jorgenson J. Clin Infect Dis 2009;49: Gram Positive Organisms Gram Positive Bacilli Cocci Bacillus, Listeria, Corynebacterium, Lactobacillus Pairs & Chains Clusters treptococcus Enterococcus taphylococcus 44 year old diabetic male presents with foot wound He describes 3 days of erythema and pain at the site of the wound and subjective fever The physician empirically places the patient on clindamycin He had wound cultures taken and preliminary reports show Gram positive cocci in clusters What organism(s) should you suspect at this point? Murray P. Principles and Practices of Infectious Disease. Ch. 17, taphylococcus spp. Gram Negative Organisms Cocci Neisseria, Moraxella Gram Negative Lactose Fermenter E. coli, Klebsiella, Enterobacter, erratia, Citrobacter Bacilli Lactose Nonfermenter Pseudomonas Morganella, Proteus, Acinetobacter Murray P. Principles and Practices of Infectious Disease. Ch. 17, Lewis J. Clin Infect Dis. 2005;40:

3 Drug MIC Interpretation (mg/ml) Benzylpenicillin > 16 Oxacillin < 2 Erythromycin > 8 Clindamycin > 8 Tetracycline < 1 Trimethoprim/ < 10 ulfamethoxazole Vancomycin 1 Cefepime- -DD Category for Enterobacteriaceae Prior to 2014, Intermediate Category Method usceptible Intermediate esistant MIC < 8 mcg/ml 16 mcg/ml > 32 mcg/ml Zone Diameter > 18 mm mm < 14 mm Now, usceptible-dose Dependent Category Method usceptible* usceptible-dose Dependent esistant MIC < 2 mcg/ml 4-8 mcg/ml > 16 mcg/ml Zone Diameter > 25 mm mm < 18 mm *usceptible based on cefepime dose of 1 gram every 12 hours Clinical and Laboratory tandards Institute WHEN DOE MIC MATTE? Antibacterial esistance Vancomycin For taphylococcus sp.: usceptible range: < 2 mcg/ml Clinical failures seen with MICs > 1mcg/mL Why Do Bacteria Become esistant to Antibiotics? We are trying to kill them. They are trying to eat and reproduce What would YOU do if someone was trying to kill you while you were trying to eat and/or reproduce? -tephen B. Brecher, Ph.D. oriano A. Clin Infect Dis 2008;46: Murray KP. Clin Infect Dis 2013;56: Brecher B. Microbiology for tewardship June

Types of Bacterial esistance Beta-Lactamases Intrinsic Extrinsic (acquired) olution: Add beta-lactamase inhibitor Amoxicillin/clavulanic acid Ampicillin/sulbactam Ticarcillin/clavulanic acid

4 Types of Bacterial esistance Beta-Lactamases Intrinsic Extrinsic (acquired) olution: Add beta-lactamase inhibitor Amoxicillin/clavulanic acid Ampicillin/sulbactam Ticarcillin/clavulanic acid Piperacillin/tazobactam olution: Use beta-lactam that is stable olution: Use alternate class(es) of antibiotics Mechanisms of Bacterial esistance Clinical Pearl Most beta-lactamases produced by anaerobes are inhibited by beta-lactamase inhibitors No need for double anaerobic coverage! Levy. Nat Med 2010;10: Enzymatic Alteration Other Enzymatic Alteration Classic Example: Beta-lactamase Hydrolyze beta-lactam ring Ambler Class Enzyme Type(s) Antibiotic(s) Affected Examples A Penicillinases EBLs Carbapenemases PCNs, narrow cephs PCNs, most cephs All beta-lactams TEM, HV, CTX KPC B Carbapenemases All beta-lactams IMP, VIM, PM, NDM C Cephalosporinases Most cephalosporins AMP C D Oxacillinases EBLs Carbapenemases PCNs, narrow cephs PCNs, most cephs All beta-lactams OXA PCNs: penicillins, Cephs: cephalosporins, EBLs: Extended-spectrum beta-lactamases Aminoglycoside esistance-modifying Enzymes Chloramphenicol Acetyltransferase Macrolide Inactivation Tetracycline Inactivation 4

Alteration of Target ite Other Efflux Change in site of action of antibiotic Example: Change in ribosomal binding sites Macrolides, Lincosamides, treptogramins Gram positive bacteria Mediated by

5 Alteration of Target ite Other Efflux Change in site of action of antibiotic Example: Change in ribosomal binding sites Macrolides, Lincosamides, treptogramins Gram positive bacteria Mediated by erythromycin ribosome methylation (erm) genes Constitutive or inducible olution: ecognize inducible resistance in micro olution: Increase concentration of drug olution: Use alternate antibiotic class Macrolides and treptogramins Beta-lactams Fluoroquinolones Other Target Alterations Decreased Permeability Beta-lactams Fluoroquinolones Aminoglycosides Oxazolidinones Glycopeptides ulfonamides Ceccarelli M. Frontiers in Bioscience 2009;14:3222. Efflux Decreased Permeability Membrane transport system removing antibiotic Major mechanism of resistance in Gram negatives to tetracyclines Inner membrane protein produced by tetracyclineresistance determinant (tet) Inducible by low concentrations of tetracyclines olution: Ensure adequate concentrations olution: Use alternate antibiotic class Not primary mechanism of resistance Present in resistance to many antibiotic classes Beta-lactams Aminoglycosides Macrolides Fluoroquinolones olution: Use alternate antibiotic class 5

Bacteria Can Mix and Match Goal Multi-drug resistant bacteria can have multiple mechanisms of resistance Guide practitioners in selection of appropriate antimicrobials for EMPIIC management May

6 Bacteria Can Mix and Match Goal Multi-drug resistant bacteria can have multiple mechanisms of resistance Guide practitioners in selection of appropriate antimicrobials for EMPIIC management May require unique combinations of antibiotics May require pharmacokinetic/pharmacodynamic optimization Can also be used to track resistance rates over time Infectious Disease Consult (+ Infectious Disease Pharmacist) Clinical and Laboratory tandards Institute Example Antibiograms Duke University Medical Center Clinical Microbiology Laboratory, Basics Clinical cenario ummary of susceptibilities of local isolates hould be done at least annually Include only species with at least 30 isolates Only diagnostic cultures (no screening cultures) Only first isolate included eport percent susceptible (%) Your Pharmacy Clinical Coordinator asks you to reevaluate your preferred aminoglycoside for empiric use. He wants to ensure the greatest efficacy against Pseudomonas aeruginosa. Clinical and Laboratory tandards Institute

7 Clinical cenario Duke University Medical Center Clinical Microbiology Laboratory, Duke University Medical Center Clinical Microbiology Laboratory, Clinical cenario Which aminoglycoside do you recommend to your Clinical Coordinator? A. Amikacin B. Gentamicin C. Tobramycin Which of the following is TUE regarding the empiric use of sulfamethoxazole/trimethoprim in this patient? A. ulfamethoxazole/trimethoprim local resistance is less than 20%; therefore, it is an option. B. ulfamethoxazole/trimethoprim should not be used empirically as resistance is greater than 20%. Continued TG is a 32 year old non-pregnant female who presents to clinic with dysuria but is afebrile and denies flank pain. he is able to tolerate oral medication and has no known allergies. he is diagnosed with an uncomplicated urinary tract infection (UTI). The 2010 IDA Uncomplicated UTI Guidelines state that sulfamethoxazole/trimethoprim is an option if local resistance rate is not greater than 20%. Gupta K. Clin Infect Dis 2011;52:e103-e120. TG s urine culture came back as shown below: Organism: E. coli Drug Ampicillin Cefazolin Cefepime Ceftriaxone Ciprofloxacin Ertapenem Gentamicin Meropenem Nitrofurantoin ulfamethoxazole/trimethoprim Interpretation 7

8 Continued eferences Which of the following is TUE regarding TG s urine culture? A. Ciprofloxacin is the preferred regimen for this patient. B. ulfamethoxazole/trimethoprim is an option based on urine culture results. C. The isolate is only susceptible to IV antibiotics. D. Nitrofurantoin is the only oral antibiotic option. Levy B, Marshall B. Antibacterial resistance worldwide: causes, challenges, and responses. Nat Med 2004;10: Lewis J, Jorgensen JH. Inducible clindamycin resistance in staphylococci: should clinicians and microbiologists be concerned? Clin Infect Dis 2005;40: Murray KP, Zhao JJ, Davis L, et al. Early use of daptomycin versus vancomycin for methicillin-resistant taphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration > 1mg/L: a matched cohort study. Clin Infect Dis 2013;56: Murray P, Witebsky FG. The Clinician and the Microbiology Laboratory. In Mandell, Douglas, and Bennett s Principles and Practice of Infectious Diseases. 7 th ed Opal M, Pop-Vicas, A. Molecular Mechanisms of Antibiotic esistance in Bacteria. In Mandell, Douglas, and Bennett s Principles and Practice of Infectious Diseases. 7 th ed oriano A, Marco F, Martinez J, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant taphylococcus aureusbacteremia. Clin Infect Dis 2008;46: pellberg B, Taylor-Blake B. On the exoneration of Dr. William H. tewart: debunking an urban legend. Infect Dis Poverty 2013;2:3. World Health Organization. Antimicrobial resistance in the European Union and the world. March Accessed April 27, 2014 at ummary Questions? There are 4 main mechanisms of antibiotic resistance usceptibility testing is the mainstay of directing antibiotic therapy Antibiograms help guide clinicians in choosing appropriate empiric antibiotic therapy Lindsey Childs-Kean, PharmD, MPH, BCP Lmchilds000410@gmail.com eferences Brecher B. Microbiology for tewardship. Powerpoint presentation. Antimicrobial tewardship Task Force Monthly Webinar. June 26, Ceccarelli M. imulating transport properties through bacterial channels. Frontiers in Bioscience 2009;14: CLI. Analysis and Presentation of Cumulative Antimicrobial usceptibility Test Data; Approved Guideline- Fourth Edition. CLI document M39-A4. Wayne, PA: Clinical and Laboratory tandards Institute; CLI. Cefepime Breakpoint Change for Enterobacteriaceae and Introduction of the usceptible- Dose Dependent (DD) Interpretation Category. July Accessed March 30, 2014 at Enterobacteriaceae_-Intro-of-DD-For-Labs.pdf Duke University Medical Center Clinical Microbiology Laboratory. ummary of antimicrobial susceptibility testing February Accessed April 27, 2014 at Gupat K, Heoton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Disease ociety of American and the European ociety for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52:e103-e120. Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: a review of general principles and contemporary practices. Clin Infect Dis 2009;49:

Microbiology Basics and Applications to Clinical Practice

Microbiology Basics and Applications to Clinical Practice LINDSEY CHILDS-KEAN, PHARMD, MPH, BCPS CLINICAL ASSISTANT PROFESSOR UNIVERSITY OF FLORIDA COLLEGE OF PHARMACY ST. PETERSBURG, FL Disclosures I