antibiotics over-prescribing and new antibiotics · •acute pharyngitis, rhinosinusitis, acute...
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Antibiotics Over-prescribing and New Antibiotics
Sept 18, 2018
Paul Bonnar, FRCPC
http://www.cdha.nshealth.ca/nsha-antimicrobial-stewardship
No disclosures
• Off-label antibiotic recommendations will be declared
• Receiving evaluations is critical to the accreditation process.
Please provide feedback
Learning objectives
• To understand the state of antibiotic resistance and
antibiotic use patterns
• To be aware of new antibiotics in the pipeline
• To understand treatment of common community-acquired
syndromes
• To become stewards of antimicrobials
MCQ
• Most antimicrobials are used in:
a) Hospital
b) Community
c) Long-term Care
MCQ 2
• What % of antibiotics are used unnecessarily?
a) 10%
b) 30%
c) 60%
d) 90%
pewtrusts.org
Each year in Canada, >18,000 hospitalized patients acquire
infections that are resistant to antimicrobials
WHO: Antimicrobial Stewardship for Hospitals Training Workshop
Antimicrobial resistance is an
urgent global public health threat
Carbapenemase-producing Enterobacteriaceae
Canadian Antimicrobial Resistance
Surveillance System Report 2016
WHO priority list
Lancet Infect Dis. 2017 Dec 21
N Engl J Med 2005;352:380-91
Vancomycin-resistant Enterococcus infections
Canadian Antimicrobial Resistance
Surveillance System Report 2016
BSAC 2018
Resistant microorganisms are expensive
http://sitn.hms.harvard.edu
Used for short
duration
Priced low
Held in reserve
LESS REWARD
LONGER
DEVELOPMENT
Ceftazidime / Avibactam
IDSA
IndicationFDA
Approval date
Dalbavancin Lipoglycopeptide
(1953)Dalvance IV SSTIs May 2014
Tedizolid
phosphate
Oxazolidinone
(1955)Sivextro PO/IV SSTIs June 2014
Oritavancin
diphosphate
Lipoglycopeptide
(1953)Orbactiv IV SSTIs Aug 2014
Delafloxacin
meglumineBaxdela IV/PO SSTIs June 2017
Ceftolozane and
tazobactam
Ceph (1928)
+ BLIZerbaxa IV
cIAI (+metronidazole)
cUTIDec 2014
Ceftazidime and
avibactam
Ceph (1928)
+ BLIAvycaz IV
cIAI (+metronidazole)
cUTI
HAP/VAP
Feb 2015
Meropenem and
vaborbactamVabomere IV cUTI Aug 2017
Isavuconazonium
sulfateCresemba IV/PO
Invasive aspergillosis
Invasive mucormycosisMarch 2015
Secnidazole Solosec PO Bacterial vaginosis Sept 2017
GAINS FDA report
Jan 2010-2015
CeftarolineCephalosporin
(1928)IV SSTI, CAP
FidaxomicinMacrolide
(1948)PO C. diff
Bedaquiline Diarylquinoline (1997) PO MDR-TB
Ann Intern Med. 2016 Sep 6;165(5):363-72.
2009
Telavancin Lipoglycopeptide IV SSTI, CAP
pewtrusts.org
• Surveillance
• Infection prevention and
control
• Antimicrobial Stewardship
• Research and innovation
ANTIBIOTIC USE PATTERNS
Medically important
antimicrobials in Canada
• 2014
Food-
producing
animals
82%
Human
medicine
18%
Canadian Integrated Program for Antimicrobial
Resistance.
Annual Report 2014.
MCQ
• Most antibiotics are used in the community to treat:
a) Urinary tract infections
b) Skin infections
c) Respiratory infections
d) Gastrointestinal infections
• 23 million Rx dispensed
• 93% dispensed from community pharmacies
• $786M
• 65% Canadians received abx
• Most often for respiratory tract infections
Antibiotic use in the community
2014
Canadian Antimicrobial Resistance
Surveillance System Report 2016
Canadian Antimicrobial Resistance
Surveillance System Report 2016
26% amoxicillin
9% azithromycin
8% ciprofloxacin
Patterns in antimicrobial use by age group, as dispensed by
Canadian Pharmacies, 2010-2014
Canadian Antimicrobial Resistance
Surveillance System Report 2016
65% Canadians filled Rx
Ciprofloxacin was the most commonly recommended antimicrobial
agent used to treat 46% of lower UTIs in women
Management of UTIs
Canadian Antimicrobial Resistance
Surveillance System Report 2016
Canadian Antimicrobial Resistance
Surveillance System Report 2016
Ambulatory care
antibiotic use in US
Overall
• 506 antibiotic prescriptions/1000 pop/year
• >30% are unnecessary
• 50% if include selection, dosing, duration
• Top 3: sinusitis, otitis media, pharyngitis
Acute respiratory conditions
• 221 antibiotic prescriptions/1000 pop annually
• 50% unnecessary
Fleming-Dutra. JAMA. 2016;315(17):1864-1873
CDC
A Point Prevalence Survey of Antimicrobial Use at
Hospitals in Nova ScotiaEmily Black, Heather Neville, Mia Losier, Megan Harrison, Kim Abbass, Kathy Slayter, Lynn Johnston, and
Ingrid Sketris
11.1%
10.9%
8.9%
8.0%
7.4%
5.5%
4.4%
3.6%
3.3%
3.0%
2.6%
2.1%
2.0%
2.0%
Metronidazole
Cefazolin
Ceftriaxone
Piptazo
Ciprofloxacin
Vanco
Cephalexin
SMX/TMP
Fluconazole
Levofloxacin
Imipenem
Moxifloxacin
Amoxclav
Ampicillin
30% NS inpatients
on antimicrobials
47% ICU
~2/3 IV
Black E, Neville H, Losier M, Harrison M, Abbass K, Slayter K, Johnston
K, Sketris I. CPJ. 2017;150(4):S35. (abstract)
OPTIMIZE ANTIBIOTIC USE
MCQ
• How common are antibiotic side-effects?
a) 5%
b) 20%
c) 40%
d) 60%
Misuse of antibiotics
• An antibiotic is not used when it could improve healthUnderuse
• An antibiotic is not indicated e.g. non bacterial infections
Unnecessaryuse
• Incorrect timing, choice, dose, route, or duration
Inappropriate use
Dose /
frequencyChoice
Duration /
timingRoute
Optimal
use
WHO: Antimicrobial Stewardship for Hospitals Training Workshop
Empiric vs targeted therapy
• Empiric therapy
– Treating an infection without knowing
the causative pathogen
– Relying on experience and precedent
• Prophylaxis
– Prevention of disease
Both rely on
- Knowledge of
location of disease
in the body
- Local epidemiology
• Targeted therapy• Antibiotic regimen determined by identity and antibiotic sensitivities
• More refined and specific compared to empiric therapy
WHO: Antimicrobial Stewardship for Hospitals Training Workshop
Classes of infective agents• Commensal
– an organism in a co-operative relationship in which the person
derives some benefit while remaining unaffected by its presence
– do not cause disease when in their usual location
• Staphylococcus epidermidis on skin, Escherichia coli in
gastrointestinal tract
• Pathogen
– an organism that causes disease
– some organisms are always regarded as pathogenic
• Mycobacterium tuberculosis, Salmonella typhi, influenza virus
- some sites are normally sterile
• e.g. blood, cerebrospinal fluid (CSF), bladder
• any organisms in these sites are usually thought of as pathogenic
What is Antimicrobial Stewardship?
Coordinated interventions designed to improve and measure the
appropriate use of antimicrobials
Barlam. Clin Infect Dis. 2016;62(10):e51–e77
Tamma CID 2017;64(5):537–43
Right drug
Right dose
Right duration
Right route
SUMMARY OF ACTIVITIES
Prospective
audit and
feedback
IV to PO policy
Obtaining
antimicrobial
use data
Presentations /
education
Handbook &
guidelines
Research /
QI projects
Point Prevalence
Surveys
Redundant
therapy policy
Public
engagement:
Antibiotic
Awareness Week
Website
Cascading
sensitivitiesAntibiograms
Beta-lactam
allergy
algorithm
Formulary
review
Outpatient
Academic
Detailing
• Don’t prescribe antibiotics
• in adults with bronchitis/asthma
• in adults and children with uncomplicated sore throats
• for upper respiratory infections that are likely viral in origin, such as influenza-like
illness, or self-limiting, such as sinus infections of less than 7 days of duration
• adult cough with antibiotics even if it lasts more than 1 week, unless bacterial
pneumonia is suspected (mean viral cough duration is 18 days)
• asymptomatic bacteriuria (ASB) in non-pregnant patients
• Don’t routinely prescribe IV forms of highly bioavailable antimicrobial
agents
• Don’t prescribe alternate 2nd
line antimicrobials to patients reporting non-
severe reactions to penicillin when beta-lactams are the recommended 1st
therapy
Clinical question
• Do you you use delayed prescriptions?
a) Yes
b) No
Barriers in community stewardship
• Knowledge gaps
• best practices and clinical practice guidelines
• Clinician perception of patient expectations
• Pressure to see patients quickly
• Clinician concerns about decreased patient satisfaction with clinical
visits when antibiotics are not prescribed
Sanchez. MMWR Recomm Rep 2016;65(No. RR-6):1–12
Nudge, nudge
• RCT 5 primary care clinics
• Acute respiratory infections
• Poster: signed commitment letter
• Posted in exam rooms for 12 weeks
• 20% absolute reduction in inappropriate abx (p=.02)
Meeker. JAMA Intern Med. 2014;174(3):425-431
DELAYED PRESCRIPTIONS
• UK > 50% of ARI prescriptions are delayed
• RCT, multicenter in Spain• acute pharyngitis, rhinosinusitis, acute bronchitis, or AECOPD
• 4 groups• Patient-led prescription strategy
• Prescription collection strategy
• Immediate abx
• No abx
Abad. JAMA Intern Med. 2016;176(1):21-29
DELAYED PRESCRIPTIONS
Patient-led prescription strategy
• 32%
Prescription collection strategy
• 23%
Immediate abx
• 91%
No abx
• 12%
Abad. JAMA Intern Med. 2016;176(1):21-29
DELAYED STRATEGIES
P<.001
Duration
Inappropriate use in hospitals
1. CDC Get Smart for Healthcare in Hospitals and Long Term Care https://www.cdc.gov/getsmart/healthcare/2. Antimicrobial prescribing practice in Australian hospitals. December 2016
0.00% 5.00% 10.00% 15.00% 20.00% 25.00% 30.00%
Spectrum too narrow
Microbiology mismatch
Incorrect dose
Incorrect duration
Spectrum to broad
Antimicrobial not indicated
30 - 50% inpatient use inappropriate
or suboptimal1
Common problems
Spellberg. JAMA Intern Med. 2016 Sep 1;176(9):1254-5.
Patients on
abx
Abx in the IV
PO
Conversion
Policy given IV
Orders with
an indication
Orders with
duration or
reassessment
date
TOTAL 34% 41% 77% 44%
Central 34% 30% 83% 34%
Western 29% 30% 87% 53%
Northern 37% 44% 79% 47%
Eastern 42% 55% 58% 39%
Sept 2017
Antibiotic time outs
Followup on sensitivity
results
“Drug-Bug mismatch”
73% of interventions were narrowing antimicrobial therapy
Handbook
• S. aureus
• Candidemia
• Meningitis
• ASB/cystitis
• Vancomycin
Beta-lactam allergy
Cost
Txfailure
MDRO
C diff
LOS
Peni
cilli
n
Am
oxic
illin
Am
pici
llin
Clox
acill
in
Pipe
raci
llin
Ceph
alex
in
Cefa
zolin
Cefa
drox
il
Cefo
xiti
n
Cefu
roxi
me
Cefp
rozi
l
Cefa
clor
Cefo
taxi
me
Ceft
riax
one
Cefi
xim
e
Ceft
azid
ime
Ceft
oloz
ane
Penicillin X X X X X
Amoxicillin X X X X X X X X
Ampicillin X X X X X X X X
Cloxacillin X X X X
Piperacillin X X X X
Cephalexin X X X X X
Cefazolin
Cefadroxil X X X X X
Cefoxitin X X
Cefuroxime X X X X
Cefprozil X X X X X
Cefaclor X X X X X
Cefotaxime X X
Ceftriaxone X X
Cefixime
Ceftazidime X
Ceftolozane
X=Risk of cross reaction due to identical or similar side chains
http://www.cdha.nshealth.ca/nsha-antimicrobial-stewardship
SYNDROMES
Symptom free pee…
• 82 year old female admitted for nausea & vomiting
• Cloudy urine, foul smelling
• Urine culture: Pseudomonas aeruginosa
https://www.ammi.ca/?ID=127
Practice Points
• Asymptomatic bacteriuria is a colonization state NOT an infection
• Antibiotics are NOT indicated
• Bacteriuria and pyuria are expected findings in the elderly
• Symptomatic UTI is much less common than asymptomatic
bacteriuria
68
Nicolle LE. Infect Dis Clin North Am 1997;11(3):647-62
Nicolle LE. Infect Control Hosp Epidemiol 2001;22(3):167-75
NITROFURANTOIN
•1st line by IDSA
•Beers: previously ‘high’ severity risk• ‘potential for renal impairment’• ’safer alternatives available’
•NOT nephrotoxic• Excreted by kidneys
• Low eGFR: less drug in urinary tract; risk of non-renal toxicities
69
Beers - update
• Avoid if ClCr <30mL/min
• Avoid long term use
(also should avoid if interstitial lung disease)
• Low quality of evidence
• Strong strength of recommendation
J Am Geriatr Soc. 2015 Nov;63(11):2227-46
Cystitis:
• Nitrofurantoin 5 days (A-I)
• Fosfomycin 3g 1 dose (A-1)
• TMP/SMX 1DS po BID 3 days (A-I) (off label)
• Amoxclav 875/125mg BID 5-7days (B-I)
(MOXIFLOXACIN does not get into urine)
CID, Volume 52, Issue 5, 1 March 2011, Pages e103–e120
• Ciprofloxacin was the most commonly recommended antimicrobial agent used to treat 46% of lower UTIs in women
Management of UTIs
Canadian Antimicrobial Resistance Surveillance System Report 2016
Respiratory infections
Respiratory syndromes
Acute bronchitis
Pneumonia
Case: LK with coughID: LK, 45 yo female, weight 90kg
CC: Cough with productive sputum
HPI: LK presents with 3 days of cough productive for green sputum. Started after runny nose and sore throat. No dyspnea, sweats, or chills. She did not measure temperature.
PMHx: Hypertension, coronary artery disease
Meds: ASA, Perindopril, metoprolol, atorvastatin
Allergies: Penicillin allergy
Social Hx: Lives with husband. Nonsmoker
Vitals 120/70 mmHg, 90bpm, RR 20, afebrile
Phx Normal
Case: LK with coughID: LK, 45 yo female, weight 90kg
CC: Cough with productive sputum
HPI: LK presents with 3 days of cough productive for green sputum. Started after runny nose and sore throat. No dyspnea, sweats, or chills. She did not measure temperature.
PMHx: Hypertension, coronary artery disease
Meds: ASA, Perindopril, metoprolol, atorvastatin
All: Penicillin allergy
SocialHx:
Lives with husband. Nonsmoker
Vitals 120/70 mmHg, 90bpm, RR 20, afebrile
Phx Normal
Acute Bronchitis
Nasal congestion, rhinitis, sore throat, malaise
⬇Acute cough +/- sputum
10d to >3weeks
Inflammation large and mid airways
No signs of pneumonia
Principles and Practice of Infectious Diseases 2014
Most commonly viruses• Rhinovirus• Influenza• RSV
• Metapneumovirus• Coronaviruses• Adenovirus
• <10% M. pneumoniae, C. pneumoniae, B. pertussis
No antibiotics(but 60-80% of patients
receive abx)
Pt reassurance, Vaccinations , smoking cessation
Antibiotics for bronchitis
Endpoint RR (95% CI)
Clinical improvement at follow-up
1.07 (0.99 – 1.15)NNT for an additional beneficial outcome (NNTB)= 22
Adverse effects in the antibiotic group
1.20 (1.05 to 1.36)
Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database of Systematic Reviews 2014,Issue 3. Art. No.: CD000245. DOI: 10.1002/14651858.CD000245
Canadian Antimicrobial Resistance Surveillance System Report 2016
Case: LK with coughID: LK, 89 yo female, weight 90kg
CC: Cough with productive sputum
HPI: LK presents with 3 days of cough productive for green sputum. Also increasing dyspnea. Some sweats and chills. She did not measure temperature.
PMHx: Hypertension, coronary artery disease
Meds: ASA, Perindopril, metoprolol, atorvastatin
Allergies: Penicillin allergy
Social Hx: Lives with husband. Nonsmoker
Vitals 120/70 mmHg, 100bpm, febrile
Phx Crackles left lower base
Invest. Chest Xray: Left lower lobe opacity
MANAGEMENT OF OUTPATIENT PNEUMONIA
Controversial
S. pneumoniae
most common bacterial pathogen
Amoxicillin:
best oral beta-lactam against S.
pneumoniae
Doxycycline:
less pneumoresistance than
macrolides
Macrolides:
increasing pneumococcal
resistance
Role of “atypical pathogens” debatable
Clinical Infectious Diseases ; 2007 ; 44 : S27 -S72
CAP requiring hospitalization among US adults
NEJM 2015; 373:415-27
http://www.antimicrobialstewardship.com/
BTS / NICE
• CAP treated in community: amoxicillin 500mg po TID x 5days [1a]
• Alternative: doxycycline [4b] or clarithromycin [1b]
Thorax 2009; 64 (Suppl III):iii1–iii55
• afebrile for 48 hours• no more than one clinical instability factor
• defined as HR >100 beats/min• RR >24 breaths/min• SBP ≤90 mmHg• Sats < 90% on room air
• Success at 30 days was 92.6% (long) and 94.4% (short); p=.54
Uranga et al. JAMA Intern Med. 2016;176(9):1257-1265
Minimizing collateral damage
• Acute bronchitis is usually VIRAL
• Use as narrow a spectrum agent as possible
• Evidence supports amoxicillin for mild CAP
• Use as short a course as necessary
• Evidence supports azithromycin for 3 days
• Evidence supports levofloxacin 750 mg for 5 days
Sinusitis
• 38 year old with a history of asthma
• Facial congestion x 5days
• Feverish x 24hours, now resolved
• Rhinorrhea: “yellow”
Clinical Manifestations
Viral
- 5-10 days
-peak d3-6
-nasal d/c and congestion are prominent
-mild fever 1st 48 h
Bacterial
1) Persistent symptoms
2) Onset of severe symptoms
3) “Double sickening”
Chow. Clin Infect Dis. 2012 Apr;54(8):e72-e112
Bacterial Rhinosinusitis
• Symptoms 10 days without improvement (strong, low-mod)
• Severe symptoms: fever >39°C + purulent nasal discharge or facial pain for at least 3-4 days (strong, low-mod)
• Initial viral infection that improved with subsequent worsening: new fever, headache, nasal discharge (strong, low-mod)
Chow. Clin Infect Dis. 2012 Apr;54(8):e72-e112
Rhinosinusitis - management
Amoxicillin*Amox-clav recommended by IDSA: (weak, low)
1
Allergy• Doxycycline or
fluoroquinolone
2
Duration
• 5-7 days (weak, low-moderate)
3
Kaplan. Can Fam Physician. 2014 Mar; 60(3): 227-234.
Chow. Clin Infect Dis. 2012 Apr;54(8):e72-e112
Rhinosinusitis - management
Amoxicillin*Amox-clav recommended by IDSA
1
Allergy• Doxycycline or
fluoroquinolone
2
Duration
• 5-7 days
3
Kaplan. Can Fam Physician. 2014 Mar; 60(3): 227-234.
Sinusitis is over treated
10%
90%
Bacterial Viral
70% resolve spontaneously
Chow. Clin Infect Dis. 2012 Apr;54(8):e72-e112
Canadian Antimicrobial Resistance Surveillance System Report 2016
Skin and soft tissue infections
Cellulitis
Gp A streptococcus
Gp C/G streptococcusGp B streptococcus
S. aureus
Adding clindamycin Does Not improve outcomes Doubles the risk of diarrhea
Brindle R, et al. BMJ Open 2017;7:e013260
http://foottalk.blogspot.ca/2005/09/trench-foot-and-katrina.html
Improvement takes time
Bruun. CID. 2016;63(8):1034–41
Improvement takes time
Antibiotic escalation in 34%, usually within 2 days of
initiation
Bruun. CID. 2016;63(8):1034–41
C. difficile
CDC
TIPS
• Not all lab results are relevant
• Fever is not always infection
• Watch for sensitivity results
• Allergy assessments, allergy is harmful
• Side effects are common
• A complete prescription requires an INDICATION
• Use resources: Academic detailing, NSHA ASP
Summary
• Antibiotics are widely used in outpatients, resistance is a major concern
• Techniques to optimize antibiotic usage
• Approach to common syndromes
sick source bug treatment duration outcome