Download How To Treat Infections Without Using Antibiotics

How To Treat Infections Without
Using Antibiotics
Dr. W. A. Ciccotelli
Infectious Diseases & Medical Microbiology
Grand River & St. Mary’s General Hospitals
Nov. 4, 2009
Disclosures
No drug company interactions
 Slides are my own
 Reflect my perspective on “best/useful”
evidence
 I am an antibiotic minimalist
 Don’t fully understand the ins & outs of
family practice

My Objectives
Review rationale for less Abx use
 Introduction to Abx stewardship
 Exemplify areas in outpatient ID where

◦ Less antibiotics can be used
◦ No antibiotics are required
◦ Provide some 1st principles

Not to steal too much from Dr. Low’s talk
Your Objectives

Reflect on the myths
◦ Abx are risk free
◦ Abx efficacy is untouchable
◦ Practices patterns in ID stable
Examine your Abx prescribing as it relates
to the evidence
 Find ways to reduce unnecessary Abx use
(“practical stewardship”)

Bottom of the R&D Barrel

No novel Abx classes
◦ Cross resistance
Big pharma disinterested
 Nothing anticipated for 10
years
 Abx efficacy under siege
 Multi-drug R gram negative
era emerges

Spelberg et al. Clin Infect Dis 2008; 46:156-164
Talbot et al. Clin Infect Dis 2006; 42:657-68
Nosocomial Menace

“ESKAPE” (IDSA)
◦
◦
◦
◦
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◦
◦
VRE
MRSA
ESBL producing E. coli & Klebsiella
Carbapenemase producing Klebsiella
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter sp.
Boucher et al. Clin Infect Dis 2009; 48:1-12
Community Menace
CA-MRSA
 Penicillin/MDR S. pneumoniae
 EBSL E. coli (CTX type)
 C. difficile
 Spread of classic hospital acquired
antibiotic resistant bacteria

◦ Quicker discharges
◦ More “advanced” community care
◦ IV antibiotic therapy
Darwin and the Microbes

Evolutionary forces favour microbes
◦ Generation time permits rapid adaptation
◦ Abx pressure = ongoing mutant selection

Precedent for quick adaptation
◦ E. coli R to penicillin
◦ S. aureus R to penicillin/methicillin

Resistance costs organism
◦ Cellular energy to run machinery
◦ Decreased fitness to replicate
Playing for Stalemate
Spelberg et al. Clin Infect Dis 2008; 46:156-164
Ecological Burden of Resistance

Genes are the “currency”
◦ Inter- & intra species trade
◦ Survival advantage

The “markets”
◦ Individual - colon
◦ Community – water, soil, biofilms
◦ Hospitals – synergistic mix of both

Less Abx use  less evolution
◦ Favour wild-type strains
◦ Decrease resistance gene acquisition
Increasingly Resistant Bacteria
New Infection
Abx Stopped
Self amplifying cycle
New Resistance Emerges
“Treatment
Stenosis”
Fewer Abx Options
More use of fewer effective Abx
Abx Therapy
Clinical Cure
New Selection Pressure
Basic Tenants of Stewardship

Patient safety initiative
◦ Too much Abx use with no clear benefit
◦ Too much harm with no clear reason
◦ Abx benefit plateaus at some point
 Risks exceed benefit

Prevent/control antibiotic resistance
◦ Patient or population focus

Moving target for application
◦ Severity of illness
◦ Clinical uncertainty
Antibiotic Balance - Patient

Proper empiric Abx
◦ Common bacteria for
syndrome
◦ Patient co-morbidities
◦ Previous culture results
◦ Unique exposures
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
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Occupation/hobbies
Animal
Travel
Previous Abx

Avoid Abx harm
◦ Protect health flora
◦ Eliminate unnecessary
combinations
◦ Evidence based durations
◦ Narrow spectrum
◦ Avoid/reduce IV catheter
days
Antibiotic “Co-lateral Damage”

The 7 C’s
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Colonization with AROs
C. difficile
Candidemia
Continuing need for IVs
Cytochrome 450 drug-drug interactions
Catastrophic adverse reactions
Cost
Antibiotic Balance - Population

Increasing Abx needs
◦ Advances in transplant/oncology
◦ More chronic illness
◦ Longevity

Quality assurance around use has not
advanced
◦ When/if to treat
◦ Helpful diagnostics
◦ Overtreatment is ubiquitous
Antibiotic “Co-lateral Damage”

The 7 8 C’s
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Colonization with AROs
C. difficile
Candidemia
Continuing need for IVs
Cytochrome 450 drug-drug interactions
Catastrophic adverse reactions
Cost
“Community” impact
Antibiotic Stewardship

Hospitals based
◦ Multidisciplinary team
◦ Controlled prescribing
◦ Quality assurance
cycle

Non acute care
◦ Hard to replicate
◦ Education (non bias)
◦ Taper therapy
Deresinski et al. Clin Infect Dis 2007; 45(suppl 3):S177-S183
Summary 1
Antibiotic resistant organism on the rise
are unchecked
 New Abx not the answer (per se)
 Abx use fuels selection pressure
 Stewardship a logical start

◦ Patient safety
◦ Protect Abx efficacy (population level)

Community stewardship model needs
different emphasis
Strategies for Outpatients
Avoid prescribing
 Fix the underlying problem
 Do not over value non sterile site
cultures
 Make the diagnosis
 Taper to or use narrow spectrum Abx
 Shorter duration
 Non bias education/CME

Infectious Syndromes to Target
Acute pharyngitis
 Acute otitis media
 Acute sinusitis
 Acute bronchitis
 AECOPD (mild)
 Cellulitis
 Outpatient pneumonia
 Asymptomatic bacteriuria
 UTIs (cystitis)

Viral or
self limited bacteria
Excessive Abx use
AVOID ANTIBIOTIC
PRESCRIBING
Avoid Prescribing When Safe

Abx have no/little effect on natural
history
◦ Mild illness
◦ Minimal risk of complications if untreated
◦ Common etiological agents are viral

“False disease” from micro tests
◦ Colonization
Sinusitis

United Kingdom
◦ 90% get Abx
◦ £10 million pounds/year

USA
◦ 85-98% get Abx
◦ $2.4 billion/year

Placebo effect 60-85%
◦ Benefit for Abx from non 1˚ care settings
Ashworth et al. Br J Gen Pract 2005; 55(517):603-608
Hickner et al. Ann Intern Med 2001; 134(6):498-505
Osguthorpe et al. Med Clin North Am 1999; 83(1):27-41
Williams et al. Cochrane Database Syst Rev 2003; 2:CD000243
Sinusitis – Primary Care RCT
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Amox 500 mg3 x 7 days
Block randomized (ITT)
Healthy >15 yr
Median 7 days symptoms
No difference at day ≥10
◦ Symptom duration
◦ Symptom severity

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No severe complications at 6
wks
No interactions
◦ Factorial trial with nasal steroids
Williamson et al. JAMA 2007; 298(12):2487-2496
Sinusitis – Meta-analysis
15 pts treated before 1 addition pt benefits
 Common clinical features can not

◦ Differentiate viral from bacterial
◦ Determine “Abx beneficial” subgroup(s)

65% pts cured at 2 wks on placebo
◦ 1/1381 placebo pt serious complication
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Antibiotics not useful despite
◦ Symptoms >7-10 days
◦ Severe symptoms in absence of complications

Symptomatic relief and time for healthy adults
Young et al. Lancet 2008; 371:908-914
Asymptomatic Bacteriuria

Lack cystitis/pyelonephritis S&S
◦ Pyuria is not a “symptom”
◦ Cloudy or smelly urine not diagnostic
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>105 cfu/mL single species
◦ Female – 2 consecutive samples
◦ Male – 1 sample
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>102 cfu/mL single species
◦ Single catheterized sample

Exclude
◦ Pregnant women
◦ Pre TURP/other urological procedures
Nicolle et al. Clin Infect Dis 2005; 40:643-654
Asymptomatic Bacteriuria

No treatment benefit
◦ Premenopausal non pregnant
women
◦ Diabetic women
◦ Male/female elderly
 Community or LTCF
◦ Spinal cord injuries
◦ Short/long term Foley

May benefit - bacteriuria >48 hr
post short term Foley removal

No long term risk of not treating
◦ Short term sterilization
◦ Drug side effects
◦ Resistance with subsequent
infections
Nicolle et al. Clin Infect Dis 2005; 40:643-654
Otitis Media
15 million Rx per year in USA
 Spontaneous resolution common
 Complication rate similar treated &
untreated
 UK guidelines for Tx

◦ Age <2 yr with bilateral acute otitis media
◦ Otorrhea on presentation
◦ No/delay Tx for all else
Spiro et al. JAMA 2006; 296(10):1235-1241
Vouloumanou et al. JAC 2009; 64:16-24
Otitis Media

RCT – Standard vs. Wait & See
◦ Well 6-12 mos old seen in ER
◦ Co intervention with analgesia
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Wait & see (statistical significance):
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49% less Abx use
Fever & otalagia triggers to fill Rx
0.5 day more fever/otalagia (relevant?)
15% less diarrhea
Spiro et al. JAMA 2006; 296(10):1235-1241
Otitis Media
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Meta analysis favour Abx
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Clinical cure (RR = 1.13)
Symptoms at day 2 to 4 of Tx (RR = 0.68)
More diarrhea (RR = 1.5)
No difference in severe complications
Margin of benefit very narrow
◦ Parental relief & less absenteeism
◦ Side effects & resistant bacteria

RCT F/U Amox vs. placebo
◦ 20% more recurrences in Abx group
Vouloumanou et al. JAC 2009; 64:16-24
Bezakova et al. BMJ 2009; 339:b2525
FIX THE UNDERLYING
PROBLEM
Infection as a “Symptom”

Predisposition from other disease
◦ Unknown or known
◦ 1 condition repeatedly
◦ Multiple infectious syndromes
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Fix underlying cause
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Global health improvement
Reduced infections & repeat visits
Reduced Abx need (therefore risks)
Prevent resistant flora development
Avoid lure of chronic prophylaxis
Case Example - Cellulitis
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38 yr M outdoor construction worker
◦ Healthy
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Classic GAS
◦ Lymphadenitis/fever  cellulitis

3 standard 14 day 1st gen cephalosporin
courses
◦ Fully resolution each time
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Relapses within 30 day each time
Inpatient admission 2 to 3 day/episode
Cause?
Case Example - Cellulitis
Courtesy of Center for Disease Control and Prevention Image Library
Case Controlled Studies
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Risk factors at least partially
reversible
Not prospectively tested
More frequent cellulitis likely
will benefit more
Prevent multiple Tx courses
or prophylaxis
Big 2
 Tinea pedis
 Chronic venous
insufficiency
Bjornsdottir et al. Clin Infect Dis 2005; 41:1416-22
Dupuy et al. BMJ 1999; 318:1591-4
Prophylaxis Pitfalls
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Recurrent UTI risk
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Severe vesicoureteral reflux
Abx prophylaxis no effect
Controversial – no Abx
prophylaxis for at least mild
disease
Abx resistant infections

Prophylaxis exposure
Fix the problem
 Repeated Abx creates new
problems

Conway et al. JAMA 2007; 298(2):179-186
DO NOT OVER VALUE
NON STERILE SITE
CULTURES
Non Sterile Site Cultures

Clinical impression your guide
◦ When to test and its interpretation
◦ Not vice versa

Avoid unnecessary testing
◦ During or post Abx with clinical improvement
◦ Asymptomatic state
◦ Low probably of helping (e.g. cellulitis)

Leads to “bug – drug – kill” mentality
◦ Colonization not a disease
◦ Can not sterilize these sites

Polymicrobial results ≠ multiple pathogens
Non Sterile Site Sample
Sterile Site Sample
More
Less
Clinical Correlation to Culture Results
Skin Flora – Low Virulence
(e.g. CoNS, Corynebacterium sp., Viridans Group Strep)
Skin Flora – Moderate Virulence
(e.g. Staphylococcus aureus, E. coli, Pseudomonas)
Professional Pathogen - High Virulence
(e.g.M.tuberculosis, Brucella, Franciella)
Colonization
Contamination
Invasion
Disease
A Typical Case
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Longstanding DM2
Acute foot ulcer – S. aureus
◦ Better with cefazolin
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Non infected non healing ulcer
◦ Re swabbed – cefazolin R E.coli
 Ciprofloxacin added
◦ Re swabbed – cipro R P. aeruginosa
 Piperacillin-tazobactam subbed in
◦ Re swabbed – multiple R GNBs, E. faecium

“Survivor phenomena” of non sterile sites
DM Foot Discordance
Abx not recommended for non
infected/non healing ulcers
 Chronic osteomyelitis
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◦ Bone biopsy gold standard
◦ Non bone specimen poor correlation
 52% false negative
 36% false positive
 28% concordance with bone biopsy
Zuluaga et al. BMC Infect Dis 2002; 2:8
Lipsky et al. Clin Infect Dis 2004; 39:885-910
MAKE THE DIAGNOSIS
Death to Empiric Therapy

Clinical exam has limitations
◦ Bacterial vs. viral
◦ Infectious vs. non infectious

Diagnostic test can confirm/refute clinical
impression
◦ Abx needed?
◦ Understand why if empiric Tx fails
◦ Risk benefit alignment
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Avoid repeated rounds of Abx
Not always convenient for Family MDs
Community Acquired Pneumonia
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No symptom can rule in/rule out
Signs with modest likelihood ratios
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Temp >37.8˚C LHR+ 2.4-4.4
Dullness to percussion LHR+ 2.2-4.3
Decreased breath sound LHR+ 2.2-2.5
Crackles LHR+ 2.6-2.7
Bronchial breath sounds LHR+ 3.5
Egophony LHR+ 5.3-8.6
No sign can rule out
◦ Lack of any vital abnormalities reduces probability
LHR- 0.16

CXR infiltrate recommended for diagnosis
Metlay et al. JAMA 1997; 278(17):1440-1445
Mandell et al. Clin Infect Dis 2007; 44(suppl 2):S27-S77
Acute Bronchitis
 9th
most common outpatient issue
◦ 5% of adults annually
Viral etiology predominates
 Antibiotics not recommended

◦ Reduce cough by 0.6 of a day
◦ Trend towards Abx adverse events
◦ B. pertussis an exception
 Reduce transmission
 Decrease cough duration (given) in 1st week
Wenzel & Fowler. NEJM 2006; 355:2125-2130
TAPER TO (OR USE)
NARROW SPECTRUM
THERAPY
Less is More

Broad spectrum therapy
◦ Risk and/or uncertainty
◦ Culture & wait

Narrow spectrum therapy generally
equivalent
 With results (based on CLSI)
 Safer for patient

Best hints for empiric therapy
◦ Know the common pathogens by syndrome
◦ Previous culture results
◦ Previous Abx use
Community Acquired Pneumonia

Outpatient
◦ PSI I to III
◦ Benign disease

Broader therapy (quinolones)
no effect
◦ Mortality
◦ Treatment success
◦ Microbiological eradication for S.
pneumoniae


Equivalent to -lactams or
macrolides
Why the over coverage?
Konstantinos et al. CMAJ 2008; 179(12):1269-1277
COPD Exacerbations
50/50 viral & bacterial
 Problems studying Abx benefit

◦ Study design flaws
◦ Bacterial colonization in stable
disease
◦ Small benefit overall
Atypical bacteria no clear role
 P. aeruginosa advanced disease
 Avoid overly broad coverage

◦ Mild exacerbations
◦ Uncomplicated COPD
Wedzicha & Seemungal. Lancet 2007; 370:786-96
Sethi & Murphy. NEJM 2008; 359:2355-2365
SHORTER DURATIONS
Longer Is Not Better

Length of therapy generally too long
◦ Poorly studied
◦ Shorter therapy equivalent when studied
 Especially for outpatients
 Risk of progressing to severe disease less
 VAP – CAP example

Longer therapy
◦ Does not prevent resistance
◦ Harms healthy flora
◦ Raises risk of adverse events
Shorter Duration - Cellulitis

Double blinded RCT
◦ All patients - 5 days of levofloxacin
◦ Randomized - 5 days placebo or levofloxacin

No difference
◦ Day 14 for clinical endpoints
◦ Day 28 for recurrence

Levofloxacin likely overkill
◦ S. aureus, -hemolytic Streptococcus
◦ Cephalexin could of been used but no evidence
exists
 Rapid improvement duration should be <10 days
Hepburn et al. Arch Intern Med 2004; 164:1669-74
Morris. ACP Journal Club 2005; 142:45
Shorter Duration - Cystitis


Well studied in women
3 = 5-10 days for
symptomatic improvement
◦ Most relevant outcome


5-10 > 3 days for
microbiological eradication
Balance
◦ 5-10 day group
 More side effects
 More drug resistance (possible)
◦ Risk of recurrence with 3 day
group
 Pyelonephritis extremely rare
Warren et al. Clin Infect Dis 1999; 29:745-58
Katchman et al. The Cochrane Database of Systematic Review 2009; Issue 1
Shorter Duration - CAP


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Recommended 7-14 days ?evidence
RCTs with various Abxs
Peds (2-5 yr) non severe
◦ 3 = 5 days of therapy
 Clinical cure
 Tx failure or relapse

Adults (admitted) mild-mod severe
◦ 3 = 8 days Amoxicillin
 Treatment success, symptoms, radiographic,
adverse effects
◦ Improved at day 3 needed

Adults outpatient
◦ 3 = 5 days respiratory quinolone
◦ Clinical, microbiological, radiographic
Moussaoui et al. BMJ 2006; 332:1355
Haider et al. Cochrane Database of Systematic Reviews 2008, Issue 2
File et al. JAC 2007; 60:112-120
Summary 2
Multiple “mild” conditions over treated
 Practical tips

◦ Treat bacterial infections
 Not colonization or viruses
◦ Understand value of culture results
◦ Use less Abx when possible
◦ Establish Dx & fix reversible risk factors

Ongoing ID education provides the
evidence