Antibiotics Over-prescribing and New Antibiotics · •acute pharyngitis, rhinosinusitis, acute bronchitis, or AECOPD •4 groups •Patient-led prescription strategy •Prescription

Antibiotics Over-prescribing and New Antibiotics

Sept 18, 2018

Paul Bonnar, FRCPC

paule.bonnar@nshealth.ca

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

• Most antimicrobials are used in:

a) Hospital

b) Community

c) Long-term Care

• 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

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

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)

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.

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

producing

animals

medicine

Canadian Integrated Program for Antimicrobial

Resistance.

Annual Report 2014.

• 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

26% amoxicillin

9% azithromycin

8% ciprofloxacin

Patterns in antimicrobial use by age group, as dispensed by

Canadian Pharmacies, 2010-2014

65% Canadians filled Rx

Ciprofloxacin was the most commonly recommended antimicrobial

agent used to treat 46% of lower UTIs in women

Management of UTIs

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

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

Metronidazole

Cefazolin

Ceftriaxone

Piptazo

Ciprofloxacin

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

• How common are antibiotic side-effects?

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

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

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

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 in the IV

Conversion

Policy given IV

Orders with

an indication

Orders with

duration or

reassessment

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

Txfailure

C diff

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

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

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

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.

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

HPI: LK presents with 3 days of cough productive for green sputum. Also increasing dyspnea. Some sweats and chills. She did not measure temperature.

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

- 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)

Rhinosinusitis - management

Amoxicillin*Amox-clav recommended by IDSA: (weak, low)

Allergy• Doxycycline or

fluoroquinolone

Duration

• 5-7 days (weak, low-moderate)

Kaplan. Can Fam Physician. 2014 Mar; 60(3): 227-234.

Rhinosinusitis - management

Amoxicillin*Amox-clav recommended by IDSA

Allergy• Doxycycline or

fluoroquinolone

Duration

• 5-7 days

Kaplan. Can Fam Physician. 2014 Mar; 60(3): 227-234.

Sinusitis is over treated

Bacterial Viral

70% resolve spontaneously

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

• 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

Antibiotics Over-prescribing and New Antibiotics · •acute pharyngitis, rhinosinusitis, acute bronchitis, or AECOPD •4 groups •Patient-led prescription strategy •Prescription

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