Antimicrobial Stewardship: Strategies for Appropriate

Antimicrobial Use

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

Chair, Infectious Disease Division

Summa Health System;

Professor of Internal Medicine, Master

Teacher, Chair ID Section NEOMED

IDSA Call-to-Action: Bad Bugs, No Drugs

IDSA. Infectious Diseases Soc. Of Am. Bad Bugs, No Drugs.

Available at: www.idsociety.org/badbugsnodrugs.html.

As resistance increases . . . number of new antimicrobials diminishes

No

. o

f n

ew a

nti

mic

rob

ials

‘Drug resistance follows the drug like a faithful

shadow’. Paul Erhlich 1854-1915

“It is not difficult to make microbes resistant to penicillin in

the laboratory by exposing them to concentrations not

sufficient to kill them….there is the danger that the

ignorant man may easily underdose himself and

by exposing his microbes to non-lethal quantities

of the drug make them resistant.” Alexander Fleming Nobel Prize lecture Dec 11, 1945

Clin Infect Dis. 2011 “Antimicrobial resistance is a major public health crisis.” Clin Infect Dis 2011

Antibiotics Should Be Assigned to a Special Drug Class to

Preserve Their Power, Says Alliance for the Prudent Use of

Antibiotics S. Levy 2010

The Impact of Antimicrobial Resistance

File TM, Jr. Chest. 1999;115(suppl):3S-8S.

Affects clinical outcomes

Associated with higher mortality

Results in higher healthcare costs

Leads to prolonged hospitalization

Increase challenge for appropriate

management

Empiric therapy

Directed therapy

Clinical Practice Guidelines

"Clinical practice guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances" (Institute of Medicine, 1990).

Bringing scientific evidence into daily clinical routines

“Evidence-based”

IDSA > 50 guidelines (www.idsociety.org)

“…guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment…” (IDSA guidelines)

From Pirates of the Caribbean Curse of the Black Pearl 2003

Jack Sparrow: I thought you were supposed to keep to the code

(referring to the pirates code that “Any man that falls behind stays behind”… when the Black Pearl waits for him to escape)

Mr. Gibb: We figured they were more like guidelines rather than actual rules

CMS Measures and Stewardship

Core Measures--Effort to improve care of

patients1

Based on Process of care recommendations (within control of HCP) or

outcomes

Should be complementary to Stewardship

• Unintended consequences

Effects reimbursement

Stewardship Strategies Avoid Antimicrobials if not warranted Stop in not warranted

Appropriate agent (based on susceptibility) Stop MRSA therapy if no MRSA

Avoid discordant therapy Reduce Duration

De-escalation Dose Optimization

Switch to oral ID consult

1. File TM Jr. et al. Clin Infect Dis. 2011; 53: S15-S22

2. File TM Jr, Gross PA. Clin Infect Dis. 2007;44:942-944;

Link Between Evidence-based Guidelines, Core Measures, & Outcomes

Actual

Practice

Ideal

Practice

GAP Individual

factors justify

variance

of care

CORE MEASURES

& GUIDELINES Reduce variance

Improve care

Reasons to Target Antimicrobials

Increased rates of bacterial resistance result in part

from antimicrobial drug use

50% antimicrobial use is inappropriate

Improvements in antimicrobial use have been shown

to improve patient outcomes and reduce rates of

resistance

Pt with resistant infection is 15% more likely to die

Stimulus for Antimicrobial Stewardship

“The primary goal of antimicrobial stewardship is to optimize clinical

outcomes while minimizing unintended consequences of antimicrobial

use, including toxicity, the selection of pathogenic organisms (such as

Clostridium difficile), and the emergence of resistance…..Effective

antimicrobial stewardship programs can be financially self-supporting

and improve patient care. ….”

Guidelines for Developing an Institutional Program to Enhance Antimicrobial

Stewardship: Dellit T et al. Clin Infect Dis. 2007;44:159-77

Appropriate antimicrobial usage: For optimal outcomes and reduce resistance

‘Antimicrobial Avoidance’ when not

indicated

3 ‘Ds’

Right DRUG

• Guidelines

• Local resistance patterns

• Patient risk stratification

Right DOSE

• Pharmacokinetics/Pharmacodynamics (PK/PD)

Right DURATION

• Compliance

Who of the following patients are likely to warrant antibacterial therapy?

1. 35 year old afebrile, non-smoking male with

mild nasal congestion and non-productive

cough for three days

2. 20 year old afebrile college student with non-

exudative acute sore throat

3. 35 year old afebrile female with signs of acute

sinusitis of three days duration

4. 55 year old smoking male with diabetes and

acute fever cough and localised rhonchi

5. All of the above

1MacKay DN. J Gen Inter Med. 1996;11:557-562. 2Bent S, et al. Am J Med.

1999;107:62-67. 3. Smith et al. Cochrane Systematic Review 2012

9 studies reviewed (placebo versus ATMB)1 – Antibiotics had no benefit

– Albuterol better than antibiotics (2 studies)

– “Treating a condition that is largely viral in origin with antibiotics” promotes

resistance

Meta-analysis, 8 studies2 – “Small” benefit (? clinically significant)

– “As the benefit must be weighed against the risk of side effects and the

societal cost of increasing antibiotic resistance, we believe that the use of

antibiotics is not justified in these patients”

– Cochrane systematic review (2012)3 – “the current update provides clearer evidence on the lack of effectiveness of

antibiotics for acute bronchitis.”

Antibiotics and Acute Bronchitis

File TM Jr. Up-To-Date 2012

Clinical

Cough (50% scant sputum; often green or yellow); occasional

wheezing, chest wall discomfort; assoc with common cold

Procalcitonin-low if viral

Etiology

90% viral; 10%-Mycoplasma, Chlamydophila; B. pertussis

CXR-negative

Therapy

No antimicrobials for viral

Antimicrobial only if bacterial (Pertussis > 3 wks cough; treatment to

reduce transmission, not for acute resolution)

Symptomatic

NSAIDS, Aspirin, Ipratroprium (Atrovent)

Delayed prescription

Acute Bronchitis

Procalcitonin for Antimicrobial

Stewardship for RTIs

File TM Jr. Clin Cherst Med. 2011; modified from

Schuetz P. et al. Eur Respir J 2011;37(2): 384–92.

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 consdier

treatment failure

NQF PERFORMANCE MEASURE: ACUTE BRONCHITIS

NQF=National Quality Forum

www.qualtiyforum.org/Measures_List.aspx

Acute respiratory infection

Case: 40-year-old male with non-productive

cough x 4 days; non-smoker;

no comorbidity

Exam: Afebrile; P-72; R-20; lungs –

no localized findings

Survey of PCPs:

No Yes

Should antibiotics be used? 90% 10%

Would antibiotics be used? 12% 88%

Antimicrobials for Colds—Why?

“Patient pressures”

Patient satisfaction correlates with

quality of patient-doctor

intervention,

not prescription1 “Prevent bacterial superinfection”

Several controlled studies showed

no benefit for URI/colds2

1Hamm RM, et al. J Fam Pract. 1996;43:56-62.

2Rosenstein N, et al. Pediatrics. 1998;101:181-184.

Overuse of antibiotics

Receiving an antibiotic reinforces the

patients’ belief that antibiotics are warranted

when a similar situation arises

Patients may continue to consult for acute

RTIs and expect antibiotics to be prescribed

Doctors may also prescribe antibiotics rather

than educate patients

Most patients and many doctors view

‘unnecessary’ antibiotic prescribing as a

neutral intervention that is, one that cannot harm but may help

File T. Curr Opin Infect Dis. 2002;15:149–50

Reduce use by reducing demand

Primary care: acute bronchitis (> 200 patients)

Antibiotics used by:

Prescription alone (no leaflet) 62% (P = 0.04)

Prescription plus explanatory leaflet 47%

Macfarlane et al. BMJ 2002; 324:1–6

Primary care: acute bronchitis (> 2,000 patients)

Decline in antibiotic use associated with

education of patient and prescriber

(74% to 48%, P = 0.003) Gonzales et al. JAMA 1999; 281:1512–1519

Restricting antibiotics reduces resistance

Finland – reduced erythromycin use led to

reduced Streptococcus pyogenes

resistance1

Iceland – reduced antibiotic use led to

reduced penicillin-nonsusceptible S.

pneumoniae2

Alaska – reduced antibiotic use led to

reduced penicillin-resistant S. pneumoniae3

1 Seppala et al. N Engl J Med. 1997; 337:441–446 2 Arason et al. BMJ 1996; 313:387–391

3 Petersen et al. 37th IDSA Meeting 1999 [Abstract 62]

Hospital 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)”

Common interventions in pilot programs at SUMMA

Avoid Antimicrobials if not warranted

Appropriate agent (based on susceptibility)

Avoid discordant therapy

Dose Optimization

Based on renal function, weight, MIC

De-escalation

Stop if no antimicrobial warranted

Stop MRSA therapy if no MRSA

Reduce duration

Switch to oral

a. Trimethoprim/Sulfamethoxazole (e.g.

Septra, Bactrim) three DS tablets as a

single dose

b. Ciprofloxacin (Cipro) 250 mg po b.i.d. for

6 doses

c. Nitrofurantoin (e.g. Macrobid) 100 mg po

b.i.d. for three days

d. None of the above; no therapy is required

What is appropriate therapy for a 55

year old asymptomatic diabetic

female with >105 E. coli in urine

culture?

ASYMPTOMATIC BACTERIURIA

SCREENING AND TREATMENT NOT INDICATED

Premenopausal, Nonpregnant or Diabetic Women1

Older persons whether living in Nursing Homes or in the

community 2

Spinal cord Injury 2

Catheterized patients 2

1 ACOG Bulletin #91. Obstet Gynecol 2008;111:785

2 Nicolle et al. IDSA Guidelines. Clin Infect Dis 2005;40:643-50.

ASYMPTOMATIC BACTERIURIA

DEFINITION

Single Catheter Specimen with > 105 Bacteria

Women: 2 CCU Specimens with same Bacteria (> 105 )

Men: Single CCU specimen with > 105 Bacteria

SCREENING AND TREATMENT INDICATED

Urologic Surgery (Including TURP)

Pregnancy

Nicolle et al. IDSA Guidelines. Clin Infect Dis 2005;40:643-50

Prevalence of Asymptomatic

Bacteriuria Population Prevalence

Healthy premenopausal women 1-5%

Pregnant women 2-10%

Postmenopausal women (50-70) 3-9%

Diabetic women/men 9-27/4-19%

Elderly (>70) in community: W/M 25-50/15-40%

Spinal cord injuries 23-90%

Indwelling catheters

short term 9-23%

Long term 100%

Nicolle L et al. Clin Infect Dis 2005; 40: 643-54

(IDSA Guidelines for asymptomatic bacteriuria in adults)

ASYMPTOMATIC BACTERIURIA

in Young Women RCT of 673 young women (18-40)

No therapy vs antimicrobial (based on culture)

RESULT:

Recurrence: No therapy 13% vs Therapy 47% (p<

0.001)

CONCLUSION: No benefit to treat. AB should not

be treated in young women and it may play a

protective role in preventing symptomatic

recurrence

Cai T et al. Clin Infect Dis 2012; early access July

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 chose most

cost effective

agent for therapy

C. No antimicrobial

therapy warranted

D. Methenamine

UTI in LTCF

CULTURE SHOULD NOT BE PERFORMED FOR

ASYMPTOMATIC RESIDENTS!!!!![A-I]1

10-50% or residents have >105 cfu/ml

Prospective studies have shown no benefit to treat

In catheterized patients, reserve U/A and culture

for those with symptoms [A-II] 1

Pyuria 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

82 y/o female transferred from LTCF with fever, decrease mental status; WBC-15,000. Exam unremarkable. Has long-term foley catheter: + 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

De-escalation

• 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

• decreased costs.

52 y/o male in ICU; 5 days post abdominal surgery

Develops fever, pulmonary infiltrates, purulent sputum, leukocytosis

Principles: Nosocomial Pneumonia* Recognise variability in bacteriology from

hospital to hospital, and customise therapy to local data

Avoid untreated or inadequately treated patients by using prompt and appropriate therapy

Avoid the overuse of antibiotics: accurate diagnosis, tailor therapy to culture data, shorten duration of therapy as much as possible (7-8 days unless Pseudomonas)

• De-escalation

Case Study: Nososcomial Pneumonia

CXR courtesy of T File

* ATS/IDSA Guidelines Am J Resp Crit Care Med. 2005

VAP: Empiric Treatment Patient at Risk for MDR*

Potential Pathogens

Core pathogens +

MDR pathogens

P. aeruginosa

ESBL

Acinetobacter spp

MRSA

Legionella

Combination Therapy

Antipseudomonal cephalosporin (cefepime, ceftazidime) or Antipseudomonal carbapenem (imipenem, meropenem) or Piperacillin-tazobactam PLUS Antipseudomonal fluoroquinolone (levofloxacin, ciprofloxacin) or aminoglycoside PLUS linezolid or vancomycin (if MRSA risk)

*Multidrug Resistance; Adapt to local patterns of resistance.

American Thoracic Society, Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171:388-416.

Case Study: Patient Initially Treated with Cefepime and Vancomycin. Day #3 Patient Improved and ETA culture reveals Klebsiella sp. (pan susceptible). What therapy?

1. Continue present therapy

2. Continue cefepime; stop

vancomycin

3. Continue cefepime; add

gentamicin

4. De-escalate to cefazolin or

ceftriaxone

ETA: endotracheal aspirate.

Strategy for Optimization:

De-escalation De-escalation in ICU1

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

Mortality • No De-escalation (62%): 24%

• Escalation 43%

• DE-ESCALATION 17% (P=0.001)

De-escalation for VAP in Surgical ICU2

Retrospective evaluation

138 of 1596 patients (8.7%) developed VAP

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

IMPORTANCE OF CULTURE

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

72 y/o male in ICU on ventilator; New Fever, Purulent ET secretions, Leukocytosis

Endotracheal aspirate culture reveals: MRSA (vancomycin MIC 1.5 μg/mL by E-test) and Acinetobacter:

Gentamicin-R; Amikacin-R; Cipro-R;

Cefepime-R; Amp/Sulb-

R;Pip/tazob-R

Ertapenem-R; Meropenem-R;

Doripenem-R

VAP: Case Study, Senerio 2

CXR Courtesy of T File

Resistant Gram Negative Infections: Treatment Options

Optimize PK/PD

Extended infusion; Continuous Infusion; Higher doses for Beta-lactams (e.g., Cefepime, Amp/sulb)1-3

Use of old drugs: colistin IV

New drugs: (tigecycline; doripenem)

Combination therapy

Variable 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 2009

Optimizing Beta-lactam Therapy: Maximizing Percent T>MIC

Increased duration of infusion Prolonged infusion

• Same dose and dosing interval, 100-250 mL, however, change duration of infusion (0.5 hr 3-4hr)

Co

nce

ntr

atio

n

(mg

/L)

Time Since Start of Infusion (h)

MIC

32

16

8

4

2

1 0 6 4 2 8 10 12

Slide courtesy of D Nicolau

Empiric Therapy

CrCl > 40 ml/min – Piperacillin/tazobactam 4.5 g IV over 3 hrs every 6 hrs CrCl 20-40 ml/min – Piperacillin/tazobactam 4.5 g IV over 4 hrs every 8 hrs CrCl < 20 ml/min (inc. intermittent HD) – Piperacillin/tazobactam 2.25 g IV over 3 hrs every 6 hrs CRRT patients (ie. CVVHD) – Piperacillin/tazobactam 4.5 g IV over 4 hrs every 8 hrs

CrCl > 20 ml/min – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 8 hrs CrCl < 20 (inc. intermittent HD) – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 12 hrs CRRT patients (i.e. CVVHD) – Piperacillin/tazobactam 3.375 g IV over 4 hrs every 8 hrs

CrCl > 40 ml/min – Piperacillin/tazobactam 4.5 g IV over 30 min every 6 hrs CrCl 20-40 ml/min – Piperacillin/tazobactam 4.5 g IV over 30 min every 8 hrs CrCl < 20 ml/min (inc. intermittent HD) – Piperacillin/tazobactam 2.25 g IV over 30 min every 6 hrs CRRT patients (ie. CVVHD) – Piperacillin/tazobactam 4.5 g IV over 30 min every 8 hrs

MIC 32

MIC 8**

Summa Health System Pharmacodynamic Dose Optimization for Pip/tazob

CrCl > 40 ml/min – Piperacillin/tazobactam 4.5 g IV over 3 hrs every 6 hrs CrCl 20-40 ml/min – Piperacillin/tazobactam 4.5 g IV over 4 hrs every 8 hrs CrCl < 20 ml/min (inc. intermittent HD) – Piperacillin/tazobactam 2.25 g IV over 3 hrs every 6 hrs CRRT patients (ie. CVVHD) – Piperacillin/tazobactam 4.5 g IV over 4 hrs every 8 hrs

MIC <16

8/2010 – Ref: Shea KM, et al. Annals of Pharmacother 2009;43:1747-54. Kim A, et al. Pharmacother 2007;27:1490-97.

CrCl > 20 ml/min – Piperacillin/tazobactam 4.5 g IV over 30 min every 8 hrs CrCl < 20 ml/min (inc. intermittent HD) – Piperacillin/tazobactam 2.25 g IV over 30 min every 6 hrs CRRT patients (ie. CVVHD) – Piperacillin/tazobactam 4.5 g IV over 30 min every 8 hrs

MIC < 4** ** Only If no IV access for extended infusion

Case Study SENARIO 2a: Pt on Cefepime, Vancomycin, gentamicin. ETA culture reveals Heavy growth MSSA. You D/C cefepime and gentamicin. Choice of therapy for MSSA?

1. Vancomycin 15 mg/kg q 8-12 h

2. Vancomycin + rifampin

3. Linezolid

4. Nafcillin

Outcomes in MSSA Bacteremia Nafcillin vs Vancomycin

5

10

15

20

25

Persistent

>3 but ≤7 Days

Persistent

>7 Days

Relapse Bacteriologic

Failure

Nafcillin (n=18)

Vancomycin (n=70)

6

21

0

11

0

7

0

19

Chang et al. Medicine (Baltimore). 2003;82:333-339.

Prospective Observational Study With 6 Months Follow-up

Duration: 8 vs 15 days of ABX for VAP

Prospective, R,D-B RCT in 51 French ICUs

401 pts diagnosed by quant culture results

Results Mortality: 8 vs 15 no difference (18.8% vs 17.2%)

Recurrent infections: No difference (28.9% vs 26.0%)

Antibiotic-free days less with 8 d; Resistance LESS

NO difference in # ventilator-days, Organ dysfunction

Infection caused by non-fermenting GNR had higher pulm-infection-recurrence

Conclusion: Comparable clinical effectiveness against VAP was obtained. Reduction in days of antibiotics could help control costs and contain the emergence of resistance

Chastre et al. JAMA Med 2003; 290: 2588-2598

2013 Measures and Timing: 20 Measures for FFY 2013

Weighted

70%

Experience of Care

Measures Encompassing 8

Key Topics

• Communication with nurses

• Communication with

doctors

• Responsiveness of staff

• Pain management

• Communication about meds

• Cleanliness and quietness

of hospital environment

• Discharge information • Overall rating of hospital

Weighted

30%

FFY, Federal Fiscal Year.

Medicare Program; Hospital Inpatient Value-Based Purchasing Program. Available at:

https://www.federalregister.gov/articles/2011/05/06/2011-10568/medicare-program-hospital-inpatient-value-based-

purchasing-program. Accessed June 5, 2012.

17 Clinical Process

Measures

• Acute Myocardial

Infection

• Heart Failure

• Pneumonia

• SCIP (SCIP 1,2,3 and

4 considered HAI)