Antimicrobial Stewardship: Strategies for Appropriate Antimicrobial - - PowerPoint PPT Presentation

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. of new antimicrobials

‘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

• f 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
• utcomes
• 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

• f 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
• utcomes 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

• rder 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)

• r

Antipseudomonal carbapenem (imipenem, meropenem)

• r

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) Concentration (mg/L) Time Since Start of Infusion (h) MIC

32 16 8 4 2 1 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 10 15 15 20 20 25 25 Persistent >3 but ≤7 Days Persistent >7 Days Relapse Bacteriologic Failure Nafcillin (n=18) Vancomycin (n=70) 6 21 21 11 11 7 19 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
• f 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)