Let’s Really Implement Antimicrobial Stewardship

Chris Gentry, Pharm.D., BCPSClinical Coordinator and Clinical Specialist, Infectious DiseasesOklahoma 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/niceRed = resistant/mean

Effect of narrow-spectrum antibiotics on microbial ecosystems

Light Green = susceptible/niceDark Green = resistant/niceRed = resistant/mean

Inactive pipeline

Lack of unique classes

From: Extendingthecure.org, RW Johnson Foundation, 2007

Gram negative antibiotic pipeline

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;39:309-317

2009 ICU Gram negative bacilli susceptibilities

Bertrand, Dowzicky. Clin Ther 2012;34:124-137

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

ESBL-producing K. pneumoniae and E. ColiSusceptibility & 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 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

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

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

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%

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 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).

Antimicrobial Stewardship Program: Personnel

ASP

ID MD

ID PharmD

Micro

IT ICP

Epi

Pharmacist level of impact

Education IV to PO Renal dosing

Clinical practice guidelines

Resistance & Case-specific expertise

STAFF

GENERALCLINICAL

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 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

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

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.