10/9/2012. Unprecedented success of antibiotics in 1960s. Infectious diseases are #1 cause of mortality worldwide

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1 I have no conflicts of interest in relation to this program Whitney Jones, PharmD Antimicrobial Stewardship Pharmacist Vanderbilt University Medical Center October 25, 2012 Understand the epidemiology associated with gramnegative resistance Discuss changing trends in resistance to antimicrobials Recognize current challenges in infectious diseases pharmacotherapy Understand the goals of antimicrobial stewardship programs and the role pharmacists may play in optimizing the use of antimicrobials Unprecedented success of antibiotics in 1960s [It] is time to close the book on infectious diseases and declare the war against pestilence won - US Surgeon General William H. Stewart Infectious diseases are #1 cause of mortality worldwide 3 rd most common reason for hospitalization in U.S. Dellit TH. Clin Infect Dis2007;44: Accessed September 12, Accessed September 12, Rice LB. J Infect Dis2008;197: Widespread use of antibiotics inevitably leads to resistance Definition Acquired ability of a pathogen to withstand an antibiotic that kills off its sensitive counterparts Multidrug-resistant (MDR) bacteria No consensus definition > 3 antimicrobial classes ~ 70% of bacteria causing hospital-acquired infections are resistant to > 1 antibiotic 89% of A. baumannii isolates resistant to > 3 antibiotic classes Antipseudomonal cephalosporins Antipseudomonal carbapenems Piperacillin/ tazobactam Ciprofloxacin Levofloxacin Ticarcillin/ clavulanate Aminoglycosides Pandrug Extensively Drug Susceptible Susceptible Gaynes R. Clin Infect Dis2005;41:

2 E cloacae (n = 704) K pneumoniae non-esbl (n = 931) K pneumoniae ESBL (n = 78) P aeruginosa (n = 1,054) A baumannii (n = 486) P-T TAZ CFP MER AMK LVX MIN TIG NA* NA Data are % susceptible. ESBL = extended-spectrum β-lactamase; P-T = piperacillin-tazobactam; TAZ = ceftazidime; CFP = cefepime; MER = meropenem; AMK = amikacin; LVX = levofloxacin; MIN = minocycline; TIG = tigecycline. P-T = piperacillin-tazobactam; TAZ = ceftazidime; IMP = imipenem; TOB = tobramycin; CIP = ciprofloxacin. Dowzicky MJ, et al. Clin Ther. 2008;30: Rhomberg PR, et al. Diagn Microbiol Infect Dis. 2009;65: Financial impact in U.S. $21 34 billion spent annually > 8 million additional hospital days Outcome OR (95% CI) P Length of stay Cost of hospitalization Clinical impact P-T = piperacillin-tazobactam; TAZ = ceftazidime; IMP = imipenem; TOB = tobramycin; CIP = ciprofloxacin. Rhomberg PR, et al. Diagn Microbiol Infect Dis. 2009;65: Schwater MJ. Antimicrob Agents Chemother 2006;50: ESBL production associated with increased mortality Organism to Mortality LOS Enterobacter P aeruginosa Acinetobacter 3rd-generation cephalosporins imipenem MDR 5.02 ( ) 1.94 ( ) 2.6 ( ) 1.47 ( ) 15.5 vs9 days* (P =.02) 2.5 ( ) * Mean LOS post-culture Schwaber MJ, et al. J Antimicrob Chemother. 2007;60: Cosgrove SE, et al. Arch Intern Med. 2002;162: Lautenbach E, et al. Infect Control Hosp Epidemiol. 2006;27: Sunenshine RH, et al. Emerg Infect Dis. 2007;13:

3 Ahead of the curve 3.5 billions years to adapt Genetic plasticity Rapid replication minutes to replicate Gram-negative pathogens Possess features of particular concern Highly efficient up-regulation or acquisition of genes that code for resistance mechanisms Plethora of resistance mechanisms Multiple mechanisms at once Single mechanism may affect multiple antibiotics Inactivating Enzyme Altered Target Decreased Permeability β-lactams Aminoglycosides Fluoroquinolones Sulfonamides ++ Trimethoprim ++ + Efflux Tetracyclines Tigecycline + ++ Polymyxins ++ ++: most common mechanism +: other mechanism Adapted from: Opal SM. Mandell, Douglas, and Bennett s Principles and Practices of Infectious Diseases. 7 th ed. Philadelphia, PA: Churchill Livingstone Elsevier;2010: Changes in or protection of target Binding site mutations in topoisomerase II and IV Most common for fluoroquinolones Overproduction of the target Nicasio AM, et al. Pharmacotherapy. 2008;28: Drug- or class-specific efflux pumps May recognize broad range of agents MexAB-OprMpump: meropenem, fluoroquinolones, tetracyclines and tigecycline AcrAB-ToICpump: fluoroquinolones, ampicillin, tigecycline, macrolides and oxazolidinones MexXY-OprMpump: adaptive resistance to aminoglycosides in P. aeruginosa Loss of outer membrane proteins OprD: imipenem resistance One of most common mechanisms Aminoglycoside-modifying enzymes Acetyltransferases Adenyltransferases phosphoryltransferases β-lactamase production Nicasio AM, et al. Pharmacotherapy. 2008;28: Poole K. J Antimicrob Chemother. 2005;56:

4 Amber classification Class β-lactamases Amino Acid Examples A penicillinases serine TEM, SHV, KPC, CTX-M B zinc IMP, VIM C cephalosporinases serine AmpC D oxacillinases serine OXA Nicasio AM, et al. Pharmacotherapy. 2008;28: Commonly found in Enterobacteriaceae Confer resistance to penicillins, cephalosporinsand aztreonam Cephamycins, cefepime and piperacillin-tazobactam may appear susceptible Revised susceptibility breakpoints Additional plasmid-mediated resistance Aminoglycosides and fluoroquinolones Carbapenems Drugs of choice to ESBL hydrolysis Nicasio AM, et al. Pharmacotherapy. 2008;28: Jacoby GA, et al. N Engl J Med. 2005;352: Paterson DL, et al. Clin Microbiol Rev. 2005;18: Mushtaq S, et al. Antimicrob Agents Chemother. 2004;48: Chromosomal production Common bacteria Enterobacter Citrobacter Serratia marcescens A. baumannii P. aeruginosa Selection following β-lactam exposure Primarily 3 rd generation cephalosporins Confer resistance to penicillins, cephalosporins and aztreonam Generally including β-lactamase inhibitor combinations and cephamycins Possible resistance to cefepime and carbapenems Jacoby GA. Clin Microbiol Rev. 2009;22: Livermore DM, et al. Trends Microbiol. 2006;14: Chow JW. Ann Intern Med1991;115: Broad terminology Ambler Class Class β-lactamases Examples B A metallo-βlactamases metallo-βlactamases Serine carbapenemases IMP, VIM, SPM KPC, IMI, SME D oxacillinases OXA, PSE Carbapenem-resistant Enterobacteriaceae to carbapenems, antipseudomonal cephalosporins and antipseudomonal penicillins Increased MICs, usually requiring additional mechanism (e.g. porinloss) to become fully resistant Klebsiella pneumoniae carbapenemases (KPC) First identified in 1996 in North Carolina Widespread Aztreonam May resist hydrolysis by carbapenemases Poor clinical efficacy 4

5 First reported in India (2006) Plasmid mediated Easily transferrable Associated bacteria K. pneumoniae E. coli E. cloacae Susceptible to colistin and tigecycline Colistin-resistant isolated detected Among the most significant multidrug-resistant (MDR) pathogens in hospitals Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumanni Pseudomonas aeruginosa Enterobacter species Rice LB. J Infect Dis. 2008;197: Boucher HW, et al. Clin Infect Dis. 2009;48:1-12. CB is a 56 year old WF who presents to ED Chief complaint Dyspnea and cough with nonpurulent sputum Afebrile WBC 6K Culture results Many Enterobacter aerogenes PMH: COPD, DM, HTN, hypothyroidism Admitted to pulmonary internal medicine floor for management of COPD exacerbation Physical exam Cellulitis of LLE - erythematous, warm to touch and weeping Patient started on vancomycin and purulent fluid collected for culture. Medical resident plans to order ceftriaxone Is this appropriate given the potential mechanisms of resistance? Severity of illness Prolonged hospital length of stay (LOS) Prolonged intensive care unit (ICU) LOS Transfer from another hospital or nursing home Invasive procedure or device Immunocompromise Prior antibiotic therapy BB, an 78 yo AAM, presents to ED CC: fever and chills x 24 hrs SH: lives with son in Lexington, SC PMH: type II diabetes, CKD, HTN, obesity, recurrent UTIs Safdar N, et al. Ann Intern Med. 2002;136: Maragakis LL, et al. Clin Infect Dis. 2008;46: Virk A, et al. Mayo Clin Proc. 2000;75:

6 CXR no infiltrates seen UA cloudy, positive nitrite/leukocytes, TNTC bacteria Blood, urine and sputum cultures obtained Blood cultures Lactose-fermenting gram-negative bacilli (2 of 2) $400 -$800 million per approved agent Lower return on investment Short course therapy Need to limit use of new, broad-spectrum antibiotics Decreased efficacy with increased use Lack of available research guidance Boucher HW, et al. Clin Infect Dis2009; 48: DiMassa JA. J Health Econ2003;22: Projan SJ. Curr Opin Microbiol2003;6: Spellberg B. Clin Infect Dis2008;46: Patient and clinician education Infection control Antimicrobial stewardship Multifaceted approach Limit inappropriate use of antimicrobials Optimize selection, dose, route, and duration Limit emergence of resistance, adverse drug reactions and minimize cost McDonald LC, et al. ClinInfect Dis2006; 42: S DellitTH, et al. ClinInfect Dis2007; 44:

7 Education Prospective audit and feedback Medical/pharmacy staff education Multidisciplinary approach Antimicrobial Support Teams Pharmacy Infectious Diseases physicians Microbiology Hospital Epidemiology Surveillance of resistance and antibiotic use Bug-drug mismatch Sterile site list review Review of antibiograms Institutional vs. location-specific Management of antibiotic use Prospective audit and feedback Institution of antibiotic restrictions Therapeutic substitutions Automatic stops Antimicrobial order forms Antibiotic dose optimization Extended infusions Pharmacokinetic services provided by pharmacists 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 Whitney Jones, PharmD Antimicrobial Stewardship Pharmacist Vanderbilt University Medical Center October 25,

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