Updates in Antimicrobial Stewardship

Meghan Brett, MDMedical Director, Antimicrobial Stewardship Program

UNMH Hospital EpidemiologistAssistant Professor, Infectious Diseases

APIC NM Meeting – 4.6.18

Disclosures

• None

Objectives

• Describe key/informative articles and topics regarding antimicrobial stewardship which also tie into infection control

• Discuss the implications of increasing antimicrobial resistance for antimicrobial stewardship and infection preventionists

• Learn about how infection preventionists and antimicrobial stewardship team members can support each other/combine forces

Highlights from 2017 Clostridium difficile Guidelines

McDonald LC et al. CID 2018.www.idsociety.org

What’s Different? Testing Recommendations

Clinicians + Lab agree to not submit

specimens for patients on laxatives AND only

specimens with unexplained, new onset ≥ 3 unformed stools in

24 hours for CDI testing

Stool toxin test as part of multiple step

algorithm*(specific)

NAAT alone ORStool toxin test as part

of multiple step algorithm*(sensitive)

No

Yes

*GDH + toxin arbitrated by NAAT or NAAT + toxin

No repeat testing in 7d Note: Yield ~2% more casesNPV of NAAT or tiered algorithm > 99%)

What’s Different? Definitions & Associated Treatment

• Classification of C difficile infections

– Initial episode then recurrences

– Initial episode: severe, non-severe, vs. fulminant* infection

– First vs. second/subsequent recurrences

• Antibiotic recommendations for initial and recurrent episodes

*Hypotension or shock, ileus, or megacolon

Treatment - It’s Mostly Vanco…

Clinical Definition RxRec Strength/

Quality of Evidence

Initial, non-severeVanco 4x/d for 10d, ORFDX 2x/d for 10dAlt: metronidazole

Strong/HighStrong/HighWeak/High

Initial, severeVanco 4x/d for 10d, ORFDX 2x/d for 10d

Strong/HighStrong/High

Initial, fulminant

Vanco 4x/d (oral/NGT) plusMetro IV q8 hoursIf +ileus, consider rectal instillation

Strong/Mod

Weak/Low

Why? Additional RCTs suggest better cure rates with vanco >> metro and lower risk of C diff recurrence as well.

Treatment - It’s Mostly Vanco…Clinical Definition Rx Rec Strength/

Quality of Evidence

First recurrence

Vanco 4x/d for 10d if metro for 1st

episode, OR

Prolonged tapered/pulsed regimen with vanco if vanco for 1st episode, OR

FDX 2x/d for 10d if vanco for 1st

episode

Weak/Low

Weak/Low

Weak/Mod

Second/subsequent recurrence

Prolonged tapered/pulsed regimen with vanco, OR

Vanco x 10d then rifaxamin 3x/d for 20d, OR

FDX 2x/d for 10d, OR

Fecal microbiota transplantation*

Weak/Low

Weak/Low

Weak/Low

Strong/Mod

ASP’s Role in C difficile?

C diff and… PPIs? Probiotics?

• Proton pump inhibitors (PPIs)

– Although linked, insufficient evidence for discontinuation

• Probiotics for 1o prevention?

– Insufficient data (no recommendation)

For a patient with C diff still on ABX?

• No recommendations to extend length of C diff treatment OR empiric restarts of C diff therapy while on other ABX

Highlights from 2017 Clostridium difficile Guidelines

• Many other recommendations for infection control in these guidelines

Other Notable ASP Literature for IPs and Pharmacists

Shorter is More Common

• “The Antibiotic Course has had its Day” from BMJ July 2017

• Stopping early does NOT increase resistance

• What increases/causes resistance?– Inadequate dosing

– Monotherapy where multiple drugs are required

– Collateral selection

• Where did the idea of completing the full prescription for ABX come from?

https://en.wikipedia.org/wiki/Alexander_Fleming#/media/File:Synthetic_Production_of_Penicillin_TR1468.jpg

Fear of undertreatment persists…

Few Controlled Trials – What’s Too Short of a Course?

Take Away Points About Shorter Antimicrobial Courses

• Some infections require long treatment

– Endocarditis, osteomyelitis, TB

• However most common infections have limited data regarding outcomes for varying lengths of antibiotic courses

Antibiotic Selection and SSI Prevention

• Evaluation of patients undergoing surgery at 1 hospital– THA, TKA, hysterectomy, colon surgery, and CABG

• 4 year period: 8385 pts with 9004 procedures– 11% (922) reported PCN allergy– 2.7% (241) had an SSI

• AOR of 1.51 for developing an SSI

• Why? – Use of non-beta-lactam antibiotics such as vanco, clinda, gent, FQs

and metro– Vancomycin – challenges with infusion preincision

• >90% of patients tested will not have a true allergy… challenge is sorting this out in clinical practice

Blumenthal KG et al. CID 2018.

Antibiotics Increase Risk of Sepsis?

• Risk of sepsis assessed within 90d of discharge after previous hospital stay

• From large national database, identified a hospitalized cohort (516 hospitals), 7 year period

• Exposure: antibiotics more strongly associated with clinically important microbiome disruption

• Assessed subsequent hospitalization for discharge diagnosis of severe sepsis or septic shock– 0.17% patients developed sepsis– Higher risk for pts whose index visit related to infection (0.3%

vs. 0.13%) or CDI (1.0% vs. 0.16%)– Greater risk for pts exposed to high-risk ABX during index visit

Baggs J et al. CID 2018.Prescott HC et al. Am J Respir Crit Care Med 2015.

Antibiotic Risk for Microbiome Disruption

High Risk Low Risk Control Exposures

3rd/4th generation cephalosporin

1st/2nd generationcephalosporins

Aminoglycoside

Fluoroquinolones Macrolide Penicillin

Lincosamides Tetracycline IV vancomycin

β-lactam/β-lactamase inhibitors

Metronidazole (No high or low risk ABX)

Oral vancomycin Sulfa

Carbapenems (No high risk ABX)

Baggs J et al. CID 2018.

Baggs J et al. CID 2018.

Why Does Gut Microbiome Disruption Change Sepsis Risk?

• Hypothesis 1: loss of colonization resistance against more virulent/pathogen microbes

• Hypothesis 2: impacting the immune-regulatory dampening functions of the gut microbiome

• Hypothesis 3: loss of gut mucosal barrier function (lose microbes reduce short chain fatty acids impact health of large intestinal enterocytes integrity impacted)

• Antibiotic Exposure Matters…

• Encourage Antimicrobial Stewardship to Save Patient’s Microbiome!!!

Antibiotic Pressure and Generation of Antibiotic Resistance

Jernberg C et al. Microbiology 2010

How Frequent Are Adverse Effects from Antibiotics?

• Retrospective cohort of ~1,500 adult inpatients• Admitted to general medicine wards• Single academic medical center• Reviews for adverse drug event (ADE) 30d after at least 24 hours of

any parenteral or oral ABX– GI, derm, MSK, heme, hepatobiliary, renal, cardiac and neurologic– 90d follow-up: C difficile or new MDR infection

• Findings– 20% experienced at least 1 ADE– Of these ~300 patients, 56 (20%) were not clinically indicated– Every additional 10d of ABX had a 3% increased risk for ADE– GI (42%), renal (24%), and hematologic (15%) were most common– Notable differences for ADEs associated with specific ABX

Tamma PD et al. JAMA Internal Medicine 2017.

Increased Risk of AKI with Pip/Tazo(Zosyn) + Vancomycin?

• 3 studies to date:

– Metanalysis: aOR 3.11 for AKI with combo1

– Incidence with Vanco + Zosyn (21.4%) vs. with Vanco + cefepime (12.5%)2

– AKI incidence with Vanco + Zosyn (16.3%) vs. 8.1% with Vanco alone3

1Hammond DA, et al. Clin Infect Dis. 2017; 64:666-674.2Rutter WC, et al. Antimicrob Agents Chemother. 2017; 61:e02089-16.3Burgess DL, et al. Pharmacother. 2014;34:670-676.

https://www.cdc.gov/drugresistance/pdf/8-2013-508.pdf

Langdon A, Crook N, Dantas G. Genome Medicine 2016.

Health Consequences of MicrobiomeDisruption Across a Lifetime

Vanco for VAPs Not Always Needed

• Assess likelihood that patients with negative MRSA nasal swabs develop subsequent MRSA infection– Bacteremia, +sputum cx with signs/sx pneumonia, CSF or

intraabdominal fluid, skin/bone/joints

• Secondary Goal: assess avoidable vancomycin days• 6 ICUs in tertiary care hospital, ~1.5y period• 11,441 patients with negative nasal swabs• Low overall number of MRSA infections• Subsequent MRSA infection 0.22%

– Rates of MRSA infection with and without MRSA nasal colonization were 27.4% vs. 22.7%

– Note: 31% of patients did not have nasal swabs upon admission

• NPV 99.4%• Vancomycin use in patients with negative nasal swabs amounted to

7,364 vancomycin days

Chotiprasitsakul D et al. ICHE 2018.

Cochrane Review of Procalcitonin for Acute Respiratory Tract Infections (ARIs)

• Procalcitonin– Marker for bacterial infections– FDA approved for sepsis but has utility for antibiotic deescalation

(ARIs)

• Update from 2012 analysis• 18 new trials with 32 trials overall• Data pooled from 26 trials• Mortality: 8.6% for PCT-guided participants vs. 10.0% in controls

(AOR 0.83, 95% CI 0.70 to 0.99, P = 0.037)• Treatment failure: not significantly lower (23.0% PCT vs. 24.9%

controls, P =0.068)• Antibiotic exposure: 2.4 day reduction (5.7 vs. 8.1 days)• Length of stay or ICU stay: no impact

Scheutz P et al. Cochrane 2017.

Antibiotic Are Needed…

• Not only for treatment of common infections– Pneumonia– UTIs– Gonorrhea

• But also to support other advances in healthcare– Chemotherapy for cancer– Increasing immunosuppression for autoimmune

diseases– Solid organ and stem cell transplantation– Complex surgeries– Patients on dialysis/end stage renal disease

http://www.pewtrusts.org/~/media/assets/2016/05/ascientificroadmapforantibioticdiscovery.pdf

“New” Antibiotics

• Ceftazidime/avibactam (Avycaz)

• Ceftolozane/tazobactam (Zerbaxa)

• Meropenem/vaborbactam (Vabomere)

• Delafloxacin (Baxdela)

A Review of the Pipeline

• Sept 2017

• 48 drugs listed

– 38% would have activity against drug-resistant gram-negatives (ESKAPE)

– 25% might impact treatment of various carpabenem-resistant organisms (CRE, CRPA or CRAB)

• Note: only 1 in 5 infectious disease products that enter human testing (phase 1 clinical trials) will be approved for patients

http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development

Worldwide Antibiotic Consumption by Country Income Classification 2000-2015

Klein EY et al. PNAS 2018.

Projected Total Antibiotic Consumption

Klein EY et al. PNAS 2018.

Source: Dr. Brad Spellberg

A Few Words About Antibiotic Resistant Organisms…

IVABX

HC environment

HC equipment

Links between ABX and IC

Gram-Positives

Antibiotic-Resistant Organisms

Gram-Negatives

• MRSA (Methicillin-resistant Staphylococcus aureus)

• VISA (Vancomycin-intermediate S.aureus)

• VRSA (Vancomycin-resistant S. aureus)

• VRE (Vancomycin-resistant enterococci)

• MRSP (Multidrug-resistant Streptococcus pneumoniae)

• MDROs (Multidrug-resistant organisms)

• AmpC-producing SPACE bacteria

• ESBL (extended spectrum beta-lactamase)-producing bacteria

• CRE (Carbapenem-resistant Enterobacteriaceae)

• MDR/XDR Pseudomonas aeruginosaor Acinetobacter baumanii

Antibiotic Susceptibility Report for CRE E. coli

Ahmed-Bentley J, et al. Antimicrob Agents Chemother. 2013.

Antibiotic Name MIC (µg/mL) Interpretation

Aztreonam > 16 Resistant

Cefoxitin > 32 Resistant

Ceftriaxone > 32 Resistant

Ceftazidime > 16 Resistant

Tobramycin > 8 Resistant

Ciprofloxacin > 2 Resistant

Ertapenem > 4 Resistant

Imipenem > 8 Resistant

Meropenem > 8 Resistant

Pip/tazo > 64/4 Resistant

SMX/TMP > 2/38 Resistant

2001

Source: CDC

CP CRE (KPC)

2013

Source: CDC

CP CRE (KPC)

No one is safe from CRE (KPC)…

And NDMs are Closing in…

Uncharacterized Transmission Events for CRE—Denver, 2012-2016

Janelle SJ et al. MMWR 2016.

Trends of CRE vs. ESBLs, US

MMWR 2018 (Vital Signs).

Synergies of ASP pharmacists and IPs

Combating C. difficile Infections (CDI)

• Hospital-onset CDI (Community-onset healthcare facility associated [HCFA])

• Sharing data about rates

• Joining forces

– Prioritizing hospital-level interventions

– Combined case reviews by pharmacists and infection preventionists to glean local factors

Antibiotic Resistant Organisms

• Sharing data regarding trends (IPs) or unusual clusters (pharmacists)

• Alerting each other to more highly drug-resistant organisms– Are prescribers using most appropriate

antibiotics? (pharmacists)

– Are providers/nursing following infection control practice? (IPs)

– If carbapenem-resistant Enterobacteriaceae, reported the patient’s case to NM DOH? (IPs)

Surgical Site Infections (SSIs)

• Antibiotic prophylaxis for surgical site infections– Appropriate antibiotic use

– Limiting antibiotic overuse (stop at time of incision)

– Managing penicillin allergies

– Limiting high risk antibiotics

• Sharing data regarding surgical site infections and consider case reviews

• Developing a clinical pathway for management of specific surgical site infections (SSIs) and assess impact on outcomes

Summary

• Much opportunity exists for ASPs and IPs to work together

– Data sharing

– Case reviews

– Prioritized interventions for preventing healthcare associated infections and limiting antibiotic resistant infections among our patients

A Pitch for Antimicrobial Stewardship ECHO Clinic

Antimicrobial Stewardship ECHO

• ECHO is telementoring instead of telemedicine• Improve networks of providers and provide real-time

feedback/education

• Started in June 2017– Great collaboration between NM DOH and UNM SOM/COP and

the entire ASP ECHO community

• Acute care hospitals in New Mexico (focus)• Pharmacists and IP participation

– CPE and CME available

• Interested in joining? antimicrobialecho@salud.unm.edu

QUESTIONS?

THANK YOU!