Download Antimicrobials

Antimicrobials:
How to reduce unnecessary Use
Thomas M File, Jr MD MSc MACP FIDSA FCCP
Chair, Infectious Disease Division
Summa Health System
Akron, Ohio;
Professor of Internal Medicine,
Chair ID Section
Northeast Ohio Medical University
Rootstown, Ohio
Antimicrobial Resistance:
Public Health Crisis
 Antibiotic
resistance:
a threat to global
health security
May,
2013
Perhaps the single most
important action needed to
greatly slow down the
development and spread of
antibiotic-resistant infections
is to change the way
antibiotics are used..”
IDSA Call-to-Action:
Bad Bugs, No Drugs
No. of new antimicrobials
As resistance increases . . . number of new antimicrobials
diminishes
IDSA. Infectious Diseases Soc. Of Am. Bad Bugs, No Drugs.
Available at: www.idsociety.org/badbugsnodrugs.html.
The Impact of Antimicrobial
Resistance
 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
File TM, Jr. Chest. 1999;115(suppl):3S-8S.
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
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.
Promise of vaccines for reducing bacterial
infections and enhancing Antimicrobial
Stewardship
•
Prevention of infections will reduce antibiotic use and resistance
•
In 2000 Conjugate 7 valent pneumococcal vaccine introduced in
US for children
6
Kyaw et al, NEJM, 2006,354,1455-63
ACTUAL
GAP
BEST
PRACTICE Variance of Care PRACTICE
Guidelines
reduce variance; improve care
STEWARDSHIP
Optimal Practice for
Best Patient
Outcomes
March, 2015
Diagnostic Tests for Etiology
in Management of CAP
• Standard culture methods (blood,
sputum)
– Low yield, time to results
• Gram stain, urinary antigen testing
– S pneumoniae, Legionella spp
• Newer molecular tests (PCR, MALDITOF)
– Potential for more rapid diagnosis, greater sensitivity
– Allows for pathogen-directed therapy
• Biomarkers (Procalcitonin)
• Differentiate Bacterial vs virus
• Timely response to bacterial load
PCR, polymerase chain reaction; MALDI-TOF, matrix-assisted laser desorption/ionization Time of Flight mass spectrometry
9
Diagnostic testing: Time to ID
 Rapid diagnostic tests
 PNA FISH, PCR, MALDI-TOF
Goff DA, et al. Pharmacother. 2012;32:677-88.
Who are Using Antimicrobials?
11
From Hicks L et al. Clin Infect Dis. 2015
Who are Using Antimicrobials?
12
From Hicks L et al. Clin Infect Dis. 2015
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 DE-ESCALATION
 Right DURATION
Who of the following patients
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 nonexudative 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
NQF PERFORMANCE MEASURE:
ACUTE BRONCHITIS
NQF=National Quality Forum
www.qualtiyforum.org/Measures_List.aspx
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.
Interventions to Improve
Appropriate Antibiotic Use
for Acute Respiratory Tract Infections
“Watchful Waiting Strategy”
Electronic Decision Support
clinic-based education interventions
multifaceted intervention that combined
a clinical
 algorithm, clinical tutor training, and
provider education




Agency for Healthcare Research and Quality; 2015
19
From American/s Knowledge of and Attitudes towards Antimicrobial Resistance. From Pew Health Group
20
21

A cough and sneeze; NO antibiotics please!!

Antibiotics cure bacterial infections, NOT viral infections such as: colds
and flu, most coughs and runny noses

Antibiotics are the only drug where use in one patient can impact the
effectiveness in another

If everyone does not use antibiotics well, we will all suffer the
consequences

Antibiotics are a shared resource (and becoming a scarce resource)
Get Smart: Know When Antibiotics Work. Available at: www.cdc.gov/getsmart. Accessed 5 July 2012.
CDC: Division of Healthcare Quality Promotion
Antibiotic Prescriptions: US
Title: Setting a national goal to reduce antibiotic overuse in the United States 2016
Authors: Katherine Fleming-Dutra, Adam Hersh, Daniel Shapiro, Monina Bartoces, Eva
Enns, Thomas File, Jonathan Finkelstein, Jeffrey Gerber, Jeff Linder, Ruth Lynfield, David
Margolis, Larissa May, Linda McCaig, Dan Merenstein, Josh Metlay, Jason Newland, Jay
Piccirillo, Rebecca Roberts, Guillermo Sanchez, Katie Suda, Ann Thomas, Teri Woo, Lauri
Hicks
Interventions to Improve
Appropriate Antibiotic Use
for Acute Respiratory Tract Infections
“Watchful Waiting Strategy”
Electronic Decision Support
clinic-based education interventions
multifaceted intervention that combined
a clinical
 algorithm, clinical tutor training, and
provider education




Agency for Healthcare Research and Quality; 2015
PROCALCITONIN (PCT):
Viral vs. Bacterial infection
 Peptide precursor of calcitonin
 ‘Hormokine’
 Expressed by neuroendocrine cells (e.g. thyroid)
• Healthy individuals, non detected
 Released like a cytokine by variety of parynchymal cells (e.g. liver,
monoctes) in response to microbial toxins and proinflammatory
mediators (IL-1, TNF-α, IL-6)
• Increased in bacterial infection
• Inhibited by TNF-ϒ in response to variety viral infections
• Distinguishes Bacterial from viral infection
 Levels change rapidly in response to bacterial
infection
 Rapid response to treatment of bacterial infection
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.
Use of Procalcitonin for Antimicrobial
Stewardship for RTIs
PCT < 0.1
ug/ml
Bacterial
Infection
VERY
UNLIKELY
NO
ANTIMICROBIALS
Consider repeat 6-24hrs
based on clinical status
PCT 0.10.25 ug/ml
Bacterial
infection
UNLIKELY
NO
ANTIMICROBIALS
Use of ABX based on
clinical status (‘unstable’)
& judgment
YES
ANTIMICROBIALS
Repeat PCT day 3, 5, 7 (for
Duration)
Bacterial
YES
infection
ANTIMICROBIALS
VERY LIKELY
CONSIDER STOP ABX
when 80=90% decrease; if
PCT remains high consdier
treatment failure
PCT > 0.25- Bacterial
0.5 ug/ml
infection
LIKELY
PCT > 0.5
ug/ml
File TM Jr. Clin Cherst Med. 2011; modified from
Schuetz P. et al. Eur Respir J 2011;37(2): 384–92.
Hospital Stewardship-CDC
 Incorrect prescribing and
variability in current usage
patterns suggest that
improvements are needed and
will benefit patients.
 CDC recommends all hospitals
implement antibiotic stewardship
 Urgent action needed to ensure
these lifesaving drugs work in the
future.
Hospital Antimicrobial Stewardship:
Definition
“An ongoing effort…to optimize antimicrobial use in
order to improve patient outcomes, ensure costeffective therapy, and reduce adverse sequelae of
antimicrobial use (including antimicrobial resistance)”
Secondary goal: Reduce costs
Dellit T, et al. Clin Infect Dis. 2007;44:159-177.
Common Principles of
Antimicrobial Stewardship

Avoid Antimicrobials if not warranted


? Value of delayed prescription for RTIs
Appropriate agent (based on susceptibility)

Avoid discordant therapy

De-escalation

Dose Optimization

Based on renal function, weight, MIC

Stop ABX if not warranted

Reduce duration

Switch to oral
What is appropriate therapy for a 55 year
old asymptomatic diabetic female with >105
E. coli in urine culture?
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
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
You are evaluating a 58 y/o female with who
weighs 45 kg and has a creatinine of 1.5. She
has cystitis due to Klebsiella sp. susceptible
to ciprofloxacin and nitrofurantoin Which of
the following is most appropriate?
a. Ciprofloxacin 750 mg BID
b. Ciprofloxacin 250 mg BID
c. Nitrofurantoin 100 mg BID
Calc Cr Cl = 30
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.
82 y/o female transferred from LTCF with fever, decrease
mental status; WBC-15,000. Exam unremarkable. Has longterm 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.
B.
C.
D.
Cefepime
Ampicillin
Piperacillin/tazobactam
Imipenem
Fosfomycin (Monuril™)
 Phosphonic acid derivative, approved in US for single
dose Rx of UTI
 Inhibits cell wall synthesis (cidal) by inactivating pyruvyl
transferase (critical cell wall synthesis)
 Active against many GNB (not Pseudomonas)
 Available as sachet containing 3 g fosfomycin to be
dissolved in H2O
 Bioavailability: 30% (fed) - 37% (fasting)
 Pregnancy Category B
 Dose (cost $37/dose)
 Uncomplicated cystitis: 3 gm as single dose
 Complicated UTI: 3 gm every 2-3 days for 3 doses
 Prostatitis: 3 gm every 2-3 days for 21 days
Etiology and sensitivity of uropathogens in
uncomplicated UTI in women
 Multicenter study, 803 woman
 E. coli 80%; S saprophyticus 4.4%; P
mirabilis 4.3%; enterococcus 3.2%; K
pneumoniae 2.3%
 Susceptibility E coli:
• Fosfomycin 97%; nitrofurantoin 94%; cipro
88%; cotrimoxazole 66%; amox/clav 75%;
ampicillin 45%;
Pigrau et al. Med Clin Oct 2010
Azithromycin and Cardiovascular
events (QT effect)
 NEJM 2012 (Ray et al. Tennessee, USA)
 Older population; Azithro associated with higher mortality
 NEJM 2013 (Svanstrom et al. Denmark)
 General population; no association with mortality
 JAMA 2014 (Mortensen et al. VA database, USA)
 Azithro associated with slight increase of MI but overall reduced
mortality in hospitalized patients
 J AM Coll Cardiology 2015 ( Cheng et al)
 Metaanalysis: higher risk sudden cardiac death
 MY TAKE: Risk small; Azithro safe for general
population and associated with better outcomes for
hospitalized patients. Need to consider risk-benefit for
patients with CV disease (QT prolongation). Avoid 2
39
drugs that prolong QT
Augmentin XR™
 Pharmacokinetic design
 Bilayer tablets with immediate release layer of amoxicillin and
clavulanate, and extended release layer of amoxicillin
 Each tablet contains 1 gm amox and 62.5 gm clavulanate
• Increases daily dose of amoxicillin—2000 mg BID = 4000 mg/day
• Maintains daily dose of clavulanate—125 mg BID = 250 mg/day
 Extends coverage to include S. pneumoniae with elevated
amoxicillin MICs
• Indications (When PRSP is a concern): CAP; Acute Bacterial
Sinusitis
 Tolerability
 Similar to Augmentin 875 (clavulanate dose is the same)
 Diarrhea approx 10% (most are mild)
Pharmacokinetic Profile
Comparison: Augmentin XR™ vs.
Amox/Clav 875/125
Amox/Clav 875/125
Mean amoxicillin
concentration (µg/mL)
20
Augmentin XR 1000/62.5 mg, 2 tabs
Augmentin XR
15
Maintains extended plasma concentrations
875mg
10
5
0
S. pneumoniae with amox
4.8 hours
7.2 hours
40%
60%
MIC = 2 µg/mL
Goal= 4.8 hours
0
1
2
3
4
5 6 7 8
Time (hours)
40% of 12-hour dosing interval = 4.8 hours
9
10 11 12
Duration of Therapy: How
low to go (Clinically resolving)
Infection
Duration (days)
Meta-analysis
Duration (days)
Guideline
Cystitis (uncomplicated)
3 = 5-10 for clin cure; 5-10
better bact erad (Milo et al
3 days (Gupta et al. IDSA 2009)
Cochrane 2004)
Pyelonephritis(uncomplicated)
≤7 = longer (Eliakim-Raz J
7 (Gupta et al IDSA 2009)
Antim Chem 2013)
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
CAP
AECOPD
7-8 days (? 14 for
Pseudomonas) [ATS/IDSA
2005]
5-7 days (IDSA/ATS 2007)
5 days = 7-10(Falagas.
J
Antimicrob Chemother 2008)
Cellullitis (uncomplicated)
Sinusitis (Max)
5 days (IDSA 2014)
≤7 = >7, adults ( Falagas.
Cochrane 2009)
5-7days (IDSA 2012)