Antimicrobial Stewardship

Thomas M. File, Jr, MD, MSc, MACP, FIDSA, FCCP

Chair, Infectious Disease Division

Paula A. Politis, PharmD, BCPS

Clinical Lead Pharmacist, Antimicrobial Stewardship

Antimicrobial Stewardship:

Dellit T, et al. Clin Infect Dis. 2007;44:159-177.

Definition

“An ongoing effort…to optimize antimicrobial use in

order to improve patient outcomes, ensure cost-

effective therapy, and reduce adverse sequelae of

antimicrobial use (including antimicrobial resistance,

C difficile)...Effective antimicrobial stewardship

programs can be financially self-supporting and

improve patient care”2

File TM Jr, et al. Clin Infect dis. 2014; 59 (Supple 3): S93-96.

MMWR. August 14, 2015 / Vol. 64 / No. 31 / Pg. 837 - 864; ND 544 – 561.

PART OF SOLUTION

“If best infection control practices and antibiotic

stewardship were nationally adopted, more than

600,000 infections and 37,000 deaths could be

prevented over 5 years.” — MMWR Aug 2015

Summa Health among first four Institutions to receive Center of Antimicrobial Stewardship Designation*

• Impact of ASP at Summa

• Reduction:Doses/Days of ABX

LOS

Readmission Rate

Mortality in ICU

Resistance

Cost

4

Hospital Stewardship-HOW?

•Antimicrobial restriction•Prospective evaluation and feedback►Avoid unnecessary antibiotics►Appropriate agent (based on susceptibility)

►Avoid discordant therapy

►De-escalation

►Stop if no antimicrobial warranted

►Stop MRSA therapy if no MRSA

►Colonization; Asymptomatic bacteruria

►Dose Optimization

►Based on renal function, weight, MIC

►Switch to oral

►Reduce duration

►Allergy Assessment

5

Drug Allergy

•Reported in 20-40% of patients

• Impact often negativeoFrequently leads to less optimal or more toxic agents.oIncreased cost, LOS, Delays, Adverse events, DeathoRecent study: “Penicillin allergy leads to increase MRSA and C difficile” due to

overuse of beta lactam alternatives. (Blumenthal et al. BMJ, June 2018)

•While a reaction related to drug allergy is an adverse event, avoidance of a more appropriate antimicrobial because of ‘fear’ of allergy can be associated with even worse effects

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• Penicillin allergy is reported by 8-25% of patients across inpatient and outpatient settings

• Only 10% of patients with reported penicillin allergy are skin test positive

• Most common reaction is a cutaneous eruption

• Prevalence of life-threatening anaphylactic reaction to penicillin is estimated between 0.02% and 0.04%

• Key Point – Among all patients with a reported allergy to penicillin, up to 90% are able to tolerate penicillins after complete evaluation either because they were never allergic or an earlier allergy has resolved

Penicillin Allergy (most common drug allergy)

7

Summa protocol8

45 y/o female admitted with diverticulitis confirmed on CT. History of PCN allergy. Started empirically on ciprofloxacin + metronidazole. When questioned about her PCN allergy, she states she was told she had an allergic reaction (unknown what it was) to penicillin by her mother when she was 8 years old. She does not recall taking a penicillin or cephalosporin recently. Course of action?

a) Continue ciprofloxacin + metronidazoleb) Change therapy to piperacillin/tazobactamc) Change ciprofloxacin to ceftriaxone

Case

9

82 y/o female transferred from LTCF with chest pain; has acute MI. Has foley catheter. Afebrile; + pyuria; Culture: 105

Klebsiella pneumoniae

Course of action?

A. Start antimicrobial

B. Await susceptibility test and choose most cost effective agent for therapy

C. No antimicrobial therapy warranted

D. Methenamine

Case

• CULTURE SHOULD NOT BE PERFORMED FOR ASYMPTOMATIC RESIDENTS!!!!![A-I]1

o10-50% or residents have >105 cfu/ml

oProspective studies have shown no benefit to treat

• In catheterized patients, reserve U/A and culture for those with symptoms [A-II] 1

oPyuria or positive dipstick for leukocyte esterase not helpful unless negative

• Methenamine not recommended in patients with long-term catheterization2

1. High K. et al. Clin Infect dis. 2009; 48: 149-71; can access via www.idsociety.org

2. Hooton et al. Clin Infect Dis. 2010

UTI in LTCF

From: Massachusetts Infection Prevention PartnershipMassachusetts Coalition for the Prevention of Medical Errors, Massachusetts Department of Public Health, Massachusets Senior Care Association, Masspro

Asymptomatic Bacteriuria: Fact or Fiction

From: Massachusetts Infection Prevention PartnershipMassachusetts Coalition for the Prevention of Medical Errors, Massachusetts Department of Public Health, Massachusets Senior Care Association, Masspro

82 y/o female transferred from LTCF with fever, decrease mental status; WBC-15,000. Exam unremarkable. Has long-term foleycatheter: + pyuria; Treated initially with ciprofloxacin. Day #3 lab reports culture with > 100,000 E. coli resistant to ciprofloxacin but susceptible to all other agents tested. What is the appropriate choice now? Stop ciprofloxacin and start

A. Cefepime

B. Ampicillin

C. Piperacillin/tazobactam

D. Imipenem

Case

14

• Susceptibility results used to more specifically target microbiological results; narrowing the antibiotic spectrum by changing from a broad spectrum agent to a narrow spectrum agent or by eliminating a drug from combination therapy.

• Should ideally occur as soon as possible, but within 48 hours of the availability of culture results.

• Benefits include

• reduced bacterial resistance,

• decreased incidence of bacterial, viral, and fungal superinfections,

• limited exposure to unnecessary drug therapy and the associated risks of adverse effects (e.g. C diff)

• decreased costs.

De-escalation

CASE: A 45 y/o healthy male presents to the ED with one

day of fever and painful red leg. Temp 100.4F; BP 130/80;

P 84; What is most appropriate therapy?

a. Piperacillin/tazobactam + Vancomycin

b. Cefazolin

c. Vancomycin

d. Vancomycin + piperacillin/tazobactam

e. Daptomycin

Photo courtesy T File MD

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Skin Infections: messages• Non-suppurativeoBeta strep most likelyoConsider MRSA if any drainage, recent

antimicrobials without improvement, prior MRSA infection

oGNR unlikely unless chronic ulceroTreat with antibacterial for 5 days if

response at 2-3 days (IDSA guideline)

• SuppurativeoStaph

• MSSA-treat with beta lactam• MRSA- trim/sulfa, clindamycin,

tetracyclines, linezolid; vancomycin, ceftaroline, daptomycin, tigecycline

17

18

RESULTS

Pasquale TR, et al. Am J Health Syst Pharm. 2014;71:1136-9. 19

Duration of Therapy: How low to go (Clinically resolving)Infection Duration (days)

Meta-analysisDuration (days) Guideline

Cystitis (uncomplicated) 3 = 5-10 for clin cure; 5-10 better bact erad (Milo et al

Cochrane 2004)

3 days (Gupta et al. IDSA 2009)

Pyelonephritis(uncomplicated) ≤7 = longer (Eliakim-Raz J

Antim Chem 2013)

7 (Gupta et al IDSA 2009)

Intra-ABD (surgical drainage) 4-7 days (Afebrile, WBC normalizing, Bowel

sounds)[IDSA 2010]

VAP 7-8 = 10-15 (Dimopoulos Chest

2013; Pugh et al. Cochrane 2011-except Non Fermenters

7 days [ATS/IDSA 2016]

CAP 5-7 days (IDSA/ATS 2007)

AECOPD 5 days = 7-10 (Falagas J.

Antimicrob Chemother 2008)

Cellullitis (uncomplicated) 5 days (IDSA 2014)

Sinusitis (Max) ≤7 = >7, adults ( Falagas.

Cochrane 2009)

5-7days (IDSA 2012)

20

PROCALCITONIN (PCT)

• Peptide precursor of calcitonin

• ‘Hormokine’

oExpressed by neuroendocrine cells (e.g. thyroid)• Healthy individuals, non detected

oReleased like a cytokine by variety of parynchymal cells (e.g. liver, monocytes) in response to microbial toxins and proinflammatory mediators (IL-1, TNF-α, IL-6)• Increased specifically in bacterial infection

• Inhibited by TNF-ϒ in response to variety viral infections

• Levels change rapidly in response to bacterial infectiono Rapid response to treatment of bacterial infection

• Guideline supported for duration of antimicrobial therapy

oSepsis (2013); AM Stewardship (2016); HAP/VAP (2016)

Brunkhorst FM, et al. Intensive Care Med. 1998 Aug;24(8):888-889.

Gilbert D. Clin Infect Dis. 2011 May;52 Suppl 4:S346-350. 21

Use of Procalcitonin for Antimicrobial Stewardship

PCT < 0.1 ug/ml

Bacterial Infection VERY UNLIKELY

NO ANTIMICROBIALS Consider repeat 6-24hrs based on clinical status

PCT 0.1-0.25 ug/ml

Bacterial infection UNLIKELY

NO ANTIMICROBIALS Use of ABX based on clinical status (‘unstable’) & judgment

PCT > 0.25-0.5 ug/ml

Bacterial infection LIKELY

YES ANTIMICROBIALS Repeat PCT day 3, 5, 7 (for Duration)

PCT > 0.5 ug/ml

Bacterial infection VERY LIKELY

YES ANTIMICROBIALS CONSIDER STOP ABX when 80=90% decrease; if PCT remains high consdiertreatment failure

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• Observational, historical control to assess impact of PCT in ICU

• 50 patients with PCT at initial suspicion of infection and 48 hrs 50 Control pts--same time frame, diagnosis, gender, age, APACHE II

• Active ASP in place

• Findings:

o Duration of ABX decreased by 3.3 days (p=0.0238)

o Duration in hospital decreased by 4.3 days (p=0.029)

o Readmission to hospital decreased by 16% (p=0.055)

o Mortality 2% vs 4% (p=0.5)

23

CASE• 63 y/o female; history HTN, COPD

• smoker

• Admitted general ward, 2 days SOB, NP cough

• Afebrile; BP 118/62, P-88, R-24; Decreased BS bilat

• WBC, 3,900; CXR-no acute process

• Influenza/RSV PCR neg.; PCT 0.14

• DX: Pneumonia

• TX: Levofloxacin in ED

• ASP recommended test

Admission

24

CASE

• + for Human Metapneumovirus

• Intervention: Stopped ABX (only one dose received);

• Discharged without ABX

Follow up

25

CAP(empiric ABX )

+ Viral PCR

YES

PCT <0.1

YES NO

NO

PCT < 0.1

YES NO

STOP ABX

SUMMA Stewardship

Individualize Individualize Cont. ABX

Panel Bacteria viruses Fungi Parasites

Blood Enterococcus, Listeria, Staph sp, S aureus, S.agalactiae, S pneumoniae, Listeria,S pyogenes, A baumanii, H influenzaeN meningitidis, PseudomonasE cloacae, E coli, Koxytoca/pneumoniae, Proteus,S marcescensRESIST GENES: mecA, vanA/B, KPC

Candida- 5 sp

Encephalitis/meningitis

S pneumoniae, S agalactiae, Listeria, H influenzae, E coli

CMV, HSV, VZV,Enterovirus, parechovirus

Cryptococcus

GI Campylobacter (3 sp), C diff, Pleisiomonas, Salmonella, Yersinia (3 sp), V cholerae, E coli-5 spincluding O157, Shigella

Adenovirus,Astrovirus, Norovirus, Rotavirus, Saporvirus

Cryptosporidium cyclospora, Giardia,Entamoeba

Multiplex PCR Panels (FDA Approved)

Source: biofiredx.com27

Blood Cx Contaminant Example

The Future: Game Changers??LRTI multiplex PCR panels

Curetis UnyveroBioFire

US FDA Issues New Warnings [Posted 05/12/2016]

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm500665.htm

Fluoroquinolone Antibacterial Drugs: Drug Safety Communication – FDA Advises Restricting Use for Certain Uncomplicated Infections

ISSUE:

•FDA is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options.

– For patients with these conditions, fluoroquinolones should be reserved for those who do not have alternative treatment options

•An FDA safety review has shown that fluoroquinolones when used systemically (i.e. tablets, capsules, and injectable) are associated with disabling and potentially permanent serious side effects that can occur together

– These side effects can involve the tendons, muscles, joints, nerves, and central nervous system

– C diff; Prolonged QT (arrythmias); Fluoroquinolone Assoc Disability Synd(FADS)-often nneurocognitive issues in elderly

30

FDA Issues Newer Warnings [07/10/2018]

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm500665.htm

• Manufacturers of fluoroquinolone antibiotics must

update their labeling to warn about mental health

issues and potential low blood sugar adverse

reactions

• includes "disturbances in attention, disorientation,

agitation, nervousness, memory impairment and

delirium.”

• new warnings won't come with the black border

signifying the most serious types of risks.

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Impact of Fluoroquinolone reduction on CDI

• Summa CDI Reduction Task Force

oSystem-Wide Initiative

• Coordinated by Infection Control and ASP

oGoal: Reduce hospital acquired C.difficile for the 2016 year by 10%

• April 2016 – April 2017

o612 total recommendations, 95% acceptance rate

o40% reduction ciprofloxacin use, 54% reduction levofloxacin use (2015 v 2016)

o33% reduction CDI

32

• 52 y/o male in ICU on ventilator 5 days post surgery for colon CA

• Develops fever, pulmonary infiltrates

• T: 38.5°C; P: 110/min; BP: 130/90 mmHg; Lungs: bilateral rhonchi

• WBC: 18,000/mm3

• Chest x-ray: new infiltrates

• ET aspirate: moderately purulent secretions

• “Allergic to Penicillin (unknown reaction, told by mother age 8)

• What Antimicrobial Therapy

Case Study

Ibrahim EH et al. Chest 2000; 118: 146-155; Alvarez-Lerma F et al. Intensive Care Med 1996; 22: 387-394; Rello J et al. Am J Respir Crit Care Med 1997; 156: 196-200

Inadequate Antimicrobial Therapy Associated with Increased Mortality

• Basic principles

oRecognize variability in bacteriology from

hospital to hospital, and modify therapy to

local data

• Know local antibiogram

oBalance the potential benefits of starting

adequate antibiotics early (eg, decreased

mortality) with the harms of superfluous

coverage (eg, adverse drug effects, C. difficile

infection, and increased antimicrobial

resistance

• Initial broad-spectrum therapy; De-escalation

ANTIMICROBIAL THERAPY

Which of the following is your choice

for empiric antimicrobial therapy?

A. Aztreonam+ Vancomycin

B. Cipro + Vancomycin

C. Cefepime* + vancomycin

D. Piperacillin* + vancomycin

*+/- Aminoglycoside

Clin Infect Dis July 14, 2016

• Know your local data• Goal:

• VAP to cover 95% of possible pathogens• HAP: patients tend to be less severely ill than VAP

patients and, therefore, the negative consequences of initial inappropriate antibiotic therapy are likely less severe than with VAP patients

Clin Infect Dis. July 14, 2016

37

Know Your PathogensMost common Causes of VAP US

Sievert DM, et al.Infect Control Hosp Epidemiol 2013; 34(1): 1-14

Resistant Gram Negative Infections:Treatment Options

• Optimize PK/PD

o Extended infusion; Continuous Infusionfor Beta-lactams1-3

• Use of old drugs: colistin IV

• New drugs:

oceftolozane/tazobactam; ceftazadime/avibactam; meropenem/vaborbactam

• Combination therapy

oVariable combinations (colistin, carbapenems, tigecycline, rifampin….)

• Aerosolized drugs (aminoglycosides, colistin)4

1.Lodise TP Jr et al. Clin Infect Dis. 2007;44:357-363. 3. Chastre J et al. Crit Care Med. 2008;36:1089-1096; 4

Betrosian AP et al. Scand J Infect Dis. 2007;39(1):38-43 ; 4 Palmer L . Curr Opin Crit Care 200941

Optimizing Beta-lactam Therapy: Maximizing Percent T>MIC

• Increased duration of infusion

o Prolonged infusion

• Same dose and dosing interval, however, change duration of infusion (0.5 hr 3-4hr)

42

Co

nce

ntr

atio

n

(mg

/L)

Time Since Start of Infusion (h)

MIC

32

16

8

4

2

10 642 8 10 12

Slide courtesy of D. Nicolau

Pharmacodynamic Dose Optimization Piperacillin/Tazobactam

Empiric TherapyClcr >20 ml/min – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 8 hrs

Clcr < 20 ml/min – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 12 hrsHD & PD – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 12 hrs

CRRT patients– Piperacillin/tazobactam 3.375 g IV over 4 hrs every 8 hrs

Clcr >20 ml/min – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 8 hrsClcr < 20 ml/min – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 12 hrs

HD & PD – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 12 hrsCRRT patients– Piperacillin/tazobactam 3.375 g IV over 4 hrs every 8 hrs

MIC 24 & 32Clcr > 40 ml/min – 4.5 g IV every 6 hrs over 3 hoursClcr 20-39 ml/min – 4.5 g IV every 8 hrs over 4 hoursClcr < 20 ml/min (inc. intermittent HD) – 2.25 g IV every 6 hrs over 3 hoursPeritoneal Dialysis – 3.375 g IV every 12 hrs over 4 hoursCRRT patients (i.e.. CVVHD) – 4.5 g IV every 8 hrs over 3 hours*

MIC <16

43

Efficacy, Safety, and Cost of Pharmacodynamic Dose Optimization of Beta-Lactam Antibiotics

Variable PDOP Group n = 41 (%)

Non-Optimized Groupn = 38 (%)

p value

In-Hospital Mortality 6 (14%) 15 (39%) 0.025

30-day All Cause Mortality

6 (14%) 16 (42%) 0.013

Avg. Time on Ventilator (days)

11.7 15.0 0.171

Avg. ICU LOS (days) 14.4 19.7 0.087

44

• 52 y/o male in ICU on ventilator 5 days post surgery for Colon CA

• Develops fever, new pulmonary infiltrates, purulent sputum, WBC 18,000/mm3, Procalcitonin 5

• Initial ABX therapy: Piperacillin/tazobactam, gentamicin,vancomycin

• 3 days later: Patient improved; Procalcitonin 2; culture=Klebsiella pneumoniae susceptible to all drugsstested except ampicillino Continue same therapy or change??o What is appropriate duration?

Case Study: Nososcomial Pneumonia

45

De-escalation/Duration of VAP

• De-escalation in ICU1

o20 ICUs; 398 pts with VAP (MRSA, Pseudomonas most frequent pathogens)

oMortality• No De-escalation (62%): 24%• Escalation 43%• DE-ESCALATION 17% (P=0.001)

• De-escalation for VAP in Surgical ICU2

oRetrospective evaluationo138 of 1596 patients (8.7%) developed VAPoMortality

• De-escalation: 35.1; No de-escalation: 42.1% (P=0.324)

• IMPORTANCE OF CULTURE• DURATION: 7 daysoFor all pathogens; based on response

• (ATS/IDSA Guidelines 2016)

1. Kollef MH et al. Chest. 2006;129:1210-1218. 2. Eachempati SR et al. J Trauma. 2009;66:1343-1348. 46

Duration of Therapy: How low to go (Clinically resolving)Infection Duration (days)

Meta-analysisDuration (days) Guideline

Cystitis (uncomplicated) 3 = 5-10 for clin cure; 5-10 better bact erad (Milo et al

Cochrane 2004)

3 days (Gupta et al. IDSA 2009)

Pyelonephritis(uncomplicated) ≤7 = longer (Eliakim-Raz J

Antim Chem 2013)

7 (Gupta et al IDSA 2009)

Intra-ABD (surgical drainage) 4-7 days (Afebrile, WBC normalizing, Bowel

sounds)[IDSA 2010]

VAP 7-8 = 10-15 (Dimopoulos Chest

2013; Pugh et al. Cochrane 2011-except Non Fermenters

7 days [ATS/IDSA 2016]

CAP 5-7 days (IDSA/ATS 2007)

AECOPD 5 days = 7-10 (Falagas J.

Antimicrob Chemother 2008)

Cellullitis (uncomplicated) 5 days (IDSA 2014)

Sinusitis (Max) ≤7 = >7, adults ( Falagas.

Cochrane 2009)

5-7days (IDSA 2012)

47

Appropriate antimicrobial usage:For optimal outcomes and reduce resistance

• ‘Antimicrobial Avoidance’ when not

indicated

•3 ‘Ds’

oRight DRUG• Guidelines

• Local resistance patterns

• Patient risk stratification

oRight DOSE• Pharmacokinetics/Pharmacodynamics (PK/PD)

oRight DURATION

48

Importance of Normal Microbiome

• Gut microbiome plays a role o Digestion

o Metabolism

o Immunity

o Mood.

• Balanced, diverse microbiome contributes to better overall healtho Specific biochemical functions of

normal bacteria effect immune response

• Antimicrobials cause Disruption of microbiome

oResults in less diversity

Belkaid and Hand. Role of the microbiome in immunity and inflammation. Cell 2014; 157: 12149