Let’s Really Implement Antimicrobial Stewardship Chris Gentry, Pharm.D., BCPS Clinical Coordinator and Clinical Specialist, Infectious Diseases Oklahoma City VA Medical Center

Unintended consequences Pt seen for approval of piperacillin/tazobactam, linezolid, daptomycin. 79 yo MALE w/ h/o CKD, CHF, DM originally transferred from outside hospital 12/31 with ARF, new onset A.fib, and right pleural effusion. Hospital course complicated by development of HCAP, HIT, NSTEMI, solar keratosis with hemorrhage. – HCAP treated empirically with pip/tazo 1/12-1/22; no opportunity to de-escalate due to lack of microbial etiology necessitating broad-spectrum therapy

Unintended consequences Transferred to MICU 1/29 for altered mental status, GPC bacteremia & presumed nosocomial pneumonia. Pip/tazo and ciprofloxacin added to vancomycin. Trach aspirate and BAL culture grew a pip/tazo-resistant Enterobacter cloacae. Patient's GPC bacteremia was found to be vancomycin- resistant Enterococcus faecium. – Vancomycin changed to daptomycin & linezolid for Gram positive bacteremia & pneumonia. Patient also has purulent UA with culture growing Candida albicans.

Unintended consequences Recommended dc pip/tazo since E. cloacae was pip/tazo-resistant. Given good MIC of the E. cloacae to ciprofloxacin, treated with ciprofloxacin monotherapy, increasing dose to 400 mg IV q12hr. Recommended treating VRE bacteremia with either linezolid or daptomycin, but not both. In this circumstance either was appropriate but linezolid has confirmed activity against this isolate. Recommended starting fluconazole for Candida albicans in urine.

Effect of broad-spectrum antibiotics on microbial ecosystems Green = susceptible/nice Red = resistant/mean

Effect of narrow-spectrum antibiotics on microbial ecosystems Light Green = susceptible/nice Dark Green = resistant/nice Red = resistant/mean

Inactive pipeline

Lack of unique classes From: Extendingthecure.org, RW Johnson Foundation, 2007

Gram negative antibiotic pipeline

Nada

Gram negative antibiotic pipeline Nada Nothing

Gram negative antibiotic pipeline Nada Nothing Zilch

Gram negative antibiotic pipeline Nada Nothing Zilch Non-existent

Why Antimicrobial Stewardship ? Resistant organisms lead to poorer outcomes in efficacy: – Vancomycin-resistant enterococci – Glycopeptide intermediate or resistant Staphylococcus aureus – Penicillin-resistant Streptococcus pneumoniae – Extended-spectrum beta-lactamase producing Klebsiella pneumoniae and E. Coli – Multidrug-resistant Acinetobacter sp and Pseudomonas aeruginosa – Candidemia

Why Antimicrobial Stewardship ?  Resistant organisms lead to poorer outcomes in safety, leading to ↑ use of: Aminoglycosides Carbapenems Colistin Linezolid Voriconazole Amphotericin

Why Antimicrobial Stewardship ? Resistant organisms lead to increased lengths of stay

Why Antimicrobial Stewardship ? Resistant organisms lead to more broad- spectrum antibiotic use – Which, in turn, leads to more resistant organisms

Multi-drug resistant Gram negative infections ESBL-producing Klebsiella sp. and E Coli Acinetobacter sp. and Pseudomonas sp. – Cases being seen that are PAN-resistant Necessitating the rapid increase in use of carbapenems, tigecycline, and colistin

ICU Gram negative bacilli bloodstream infections Wisplinghoff H, et al. Clin Infect Dis 2004;39:

2009 ICU Gram negative bacilli susceptibilities Bertrand, Dowzicky. Clin Ther 2012;34:

ESBL-producing K. pneumoniae and E. Coli Susceptibility & Resistance Characteristics Resistant to: – All penicillins Questionable activity for piperacillin/tazobactam – First, second and third generation cephalosporins Questionable activity for cefepime – Aztreonam – Fluoroquinolones Susceptibility rates of ~25% – TMP-sulfamethoxazole – Aminoglycosides Tobramycin and amikacin can be susceptible

ESBL-producing K. pneumoniae and E. Coli Susceptibility & Resistance Characteristics Susceptible to: – Carbapenems Some level of concern for ertapenem – Tigecycline – Colistin

ESBL incidence Klebsiella sp. ESBL rates increased from ~10% in 2003 to ~15% thru E.coli ESBL rates increased from ~3% in 2003 to 7% thru 2008 Proteus mirabilus ESBL rates have been ~4%. Castanheira M, et al. American Society for Microbiology General Meeting. May San Diego, CA

KPCs Susceptibility & Resistance Characteristics Resistant to: – Penicillins – Cephalosporins – Aztreonam – Carbapenems Usually Carbapenemase activity may not provide resistance if other mechanisms are not present – Fluoroquinolones Usually

KPCs Susceptibility & Resistance Characteristics Susceptible to: – Tigecycline – Colistin – Aminoglycosides

MDR P. aeruginosa, Acinetobacter sp., and other non-fermenters

Susceptible to: – Colistin Use with an anti-pseudomonal carbapenem or rifampin may produce synergistic killing and reduce emergence of colistin resistance – Amikacin – Acinetobacter sp. may be susceptible to: Ampicillin-sulbactam Minocycline Tigecycline

Colistin and Tigecycline

Colistin Back to the Future Polymixin E – look at your triple antibiotic ointment tube mg/kg/day, divided into 2 or 3 doses Revived due to ICU outbreaks of multidrug resistant P. aeruginosa and Acinetobacter sp. infections Should use in combination with carbapenem or rifampin to minimize emergence of colistin resistance Nephrotoxicity in ~20-30% Neurotoxicity (NMB) in ~10%

Tigecycline New class: Glycylcycline – similar to tetracyclines without similar resistance Very unique – good AND bad - microbiologic profile – Gram negative bacilli EXCEPT for: Pseudomonas aeruginosa Proteus mirabilus Providencia sp. Serratia marcescens – Gram positive cocci INCLUDING: MRSA VRE MDR Streptococcus pneumoniae – Anaerobic activity

Tigecycline 100 mg IV load, then 50 mg IV q12h Very low serum concentrations – Limits role in serious infections (along with being bacteristatic) Reasonable volume of distribution Primarily biliary excreted – Limits role in UTI’s High rate of nausea (20-30%) and vomiting (10%) – Limited primarily to first couple of days

IDSA/SHEA Guidelines: Executive Summary 1. Core members of a multidisciplinary antimicrobial stewardship team include an infectious diseases physician and a clinical pharmacist with infectious diseases training (A-II) who should be compensated for their time (A-III), with the inclusion of..... Because antimicrobial stewardship, an important component of patient safety, is considered to be a medical staff function, the program is usually directed by an infectious diseases physician or codirected by an infectious diseases physician and a clinical pharmacist with infectious diseases training (A-III).

IDSA/SHEA Guidelines: Executive Summary 2. Collaboration between the antimicrobial stewardship team and the hospital infection control and pharmacy and therapeutics committees or their equivalents is essential (A- III). 4. The infectious diseases physician and the head of pharmacy, as appropriate, should negotiate with hospital administration to obtain adequate authority, compensation, and expected outcomes for the program (A-III).

Antimicrobial Stewardship Program: Personnel ASP ID MD ID PharmD Micro ITICP Epi

Pharmacist level of impact Education IV to PO Renal dosing Clinical practice guidelines Resistance & Case-specific expertise STAFF GENERAL CLINICAL ID-TRAINED

Stewardship Strategies – Restriction enforcement model Prospective audit Maintains prescriber autonomy Avoids potential delays in timely therapy Recommendations may be optional By drug, by culture, by disease state Preauthorization Use of “experts” at outset of therapy May delay initiation of therapy 24/7/365 unless exceptions for after-hours are in place (ie, first dose sent)

Stewardship Strategies, cont’d. Education – Not very effective when used alone IV to PO – Traditionally big bang-for-the-buck intervention, but physicians are doing this better on their own. Clinical practice guidelines – Development – Dissemination – Enforcement – Updating Antimicrobial order forms – Good for initial empiric therapy, but then what?

Stewardship Strategies, cont’d. De-escalation – Most effective with good quality, positive cultures – What about empiric therapy? – What if there are no culture data? Dose optimization – Optimizes outcomes? – Doesn’t alter broad-spectrum activity Antimicrobial cycling – Largely dismissed now, no real effect on resistance

Anti-infective spectrum funnel Gram positiveGram positive/ Gram negativeFungal Daptomycin Linezolid Telavancin Quinopristin/ Dalfopristin Vancomycin Cefazolin Nafcillin Penicillin Meropenem, Imipenem & Doripenem Piperacillin/tazobactam Cefepime & Ceftazidime Fluoroquinolones Ertapenem Ceftriaxone Amp/sulbactam Cefoxitin Cefazolin Ampicillin Amphotericin Voriconazole Posaconazole Echinocandins Itraconazole Fluconazole NONE

Types of interventions Day 1Days 2-3Days 4-5Days 7-14 Trade one broad-spectrum regimen for another Narrow the spectrum based on culture and susceptibility results Patients doing well; change to po and/or discharge Patient cured; discontinue therapy Resistance effectCost effectiveness Little effect Large effect Enormous effect Large effect

Antibiotic outcome timeline

Conclusions MDR bacteria threaten our ability to treat outpatient infections with oral antibiotics and our ability to treat inpatient infections with intravenous antibiotics Totality of evidence points only to increasing trends in the prevalence of MDR bacteria with current practices

Conclusions, cont’d The antibiotics we are forced to use to treat MDR bacterial infections are: – limited in number – potentially less effective – generally less safe – generally more broad-spectrum (feeds vicious cycle) The antibiotic pipeline looks dismal for the foreseeable future Efforts need to focus on preventing infections and maximizing the durability of available treatment options with antimicrobial stewardship.