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![Page 1: Let’s Really Implement Antimicrobial Stewardship Chris Gentry, Pharm.D., BCPS Clinical Coordinator and Clinical Specialist, Infectious Diseases Oklahoma.](https://reader036.fdocuments.net/reader036/viewer/2022062315/5697bfbc1a28abf838ca1b09/html5/thumbnails/1.jpg)
Let’s Really Implement Antimicrobial Stewardship
Chris Gentry, Pharm.D., BCPSClinical Coordinator and Clinical Specialist, Infectious DiseasesOklahoma City VA Medical Center
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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
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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.
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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.
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Effect of broad-spectrum antibiotics on microbial ecosystems
Green = susceptible/niceRed = resistant/mean
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Effect of narrow-spectrum antibiotics on microbial ecosystems
Light Green = susceptible/niceDark Green = resistant/niceRed = resistant/mean
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Inactive pipeline
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Lack of unique classes
From: Extendingthecure.org, RW Johnson Foundation, 2007
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Gram negative antibiotic pipeline
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Gram negative antibiotic pipeline
• Nada
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Gram negative antibiotic pipeline
• Nada• Nothing
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Gram negative antibiotic pipeline
• Nada• Nothing• Zilch
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Gram negative antibiotic pipeline
• Nada• Nothing• Zilch• Non-existent
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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
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Why Antimicrobial Stewardship ?
Resistant organisms lead to poorer outcomes in safety, leading to ↑ use of:• Aminoglycosides• Carbapenems• Colistin• Linezolid• Voriconazole• Amphotericin
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Why Antimicrobial Stewardship ?
• Resistant organisms lead to increased lengths of stay
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Why Antimicrobial Stewardship ?
• Resistant organisms lead to more broad-spectrum antibiotic use– Which, in turn, leads
to more resistant organisms
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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
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ICU Gram negative bacilli bloodstream infections
Wisplinghoff H, et al. Clin Infect Dis 2004;39:309-317
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2009 ICU Gram negative bacilli susceptibilities
Bertrand, Dowzicky. Clin Ther 2012;34:124-137
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ESBL-producing K. pneumoniae and E. ColiSusceptibility & 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
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ESBL-producing K. pneumoniae and E. ColiSusceptibility & Resistance Characteristics
• Susceptible to:– Carbapenems• Some level of concern for ertapenem
– Tigecycline– Colistin
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ESBL incidence
• Klebsiella sp. ESBL rates increased from ~10% in 2003 to ~15% thru 2008.
• 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 2010. San Diego, CA
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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
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KPCs Susceptibility & Resistance Characteristics• Susceptible to:– Tigecycline– Colistin– Aminoglycosides
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MDR P. aeruginosa, Acinetobacter sp., and other non-fermenters
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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
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Colistin and Tigecycline
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ColistinBack to the Future
• Polymixin E – look at your triple antibiotic ointment tube
• 2.5-5 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%
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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
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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
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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).
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IDSA/SHEA Guidelines: Executive Summary
2. Collaboration between the antimicrobial stewardshipteam and the hospital infection control and pharmacy andtherapeutics 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).
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Antimicrobial Stewardship Program: Personnel
ASP
ID MD
ID PharmD
Micro
IT ICP
Epi
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Pharmacist level of impact
Education IV to PO Renal dosing
Clinical practice guidelines
Resistance & Case-specific expertise
STAFF
GENERALCLINICAL
ID-TRAINED
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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)
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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?
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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
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Anti-infective spectrum funnelGram positiveGram positive/ Gram negative Fungal
DaptomycinLinezolid Telavancin Quinopristin/ Dalfopristin
Vancomycin
CefazolinNafcillin
Penicillin
Meropenem, Imipenem & Doripenem
Piperacillin/tazobactamCefepime & Ceftazidime
Fluoroquinolones
ErtapenemCeftriaxone
Amp/sulbactamCefoxitin
CefazolinAmpicillin
Amphotericin
VoriconazolePosaconazole
Echinocandins
Itraconazole
FluconazoleNONE
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Types of interventions
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 effect Cost effectiveness
Little effect Little effect
Large effect Large effect
Large effect Enormous effect
Large effect Large effect
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Antibiotic outcome timeline
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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
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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.
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