How To Treat Infections How To Treat Infections Without Using AntibioticsWithout Using Antibiotics

DisclosuresDisclosuresNo drug company interactionsSlides are my own Reflect my perspective on

“best/useful” evidenceI am an antibiotic minimalist Don’t fully understand the ins &

outs of family practice

My ObjectivesMy ObjectivesReview rationale for less Abx useIntroduction to Abx stewardshipExemplify 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 ObjectivesYour ObjectivesReflect 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 BarrelBottom of the R&D Barrel

No novel Abx classes◦ Cross resistance

Big pharma disinterestedNothing anticipated for

10 yearsAbx efficacy under siege

Multi-drug R gram negative era emerges

Nosocomial MenaceNosocomial Menace“ESKAPE” (IDSA)

◦VRE◦MRSA◦ESBL producing E. coli & Klebsiella◦Carbapenemase producing Klebsiella◦Acinetobacter baumannii◦Pseudomonas aeruginosa◦Enterobacter sp.

Community MenaceCommunity MenaceCA-MRSAPenicillin/MDR S. pneumoniaeEBSL E. coli (CTX type)C. difficileSpread of classic hospital

acquired antibiotic resistant bacteria◦Quicker discharges◦More “advanced” community care◦IV antibiotic therapy

Darwin and the MicrobesDarwin and the MicrobesEvolutionary 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 StalematePlaying for Stalemate

Ecological Burden of Ecological Burden of ResistanceResistanceGenes 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

“TreatmentStenosis”

“TreatmentStenosis”

New Infection

Abx TherapyClinical Cure

Abx Stopped

More use of fewer effective Abx

Self amplifying cycle

Basic Tenants of Basic Tenants of StewardshipStewardshipPatient 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 benefitPrevent/control antibiotic resistance

◦Patient or population focusMoving target for application

◦Severity of illness◦Clinical uncertainty

Antibiotic Balance - Antibiotic Balance - PatientPatientProper empiric

Abx◦ Common bacteria for

syndrome◦ Patient co-morbidities◦ Previous culture

results◦ Unique exposures

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 Antibiotic “Co-lateral Damage”Damage”The 7 C’s

◦Colonization with AROs◦C. difficile◦Candidemia◦Continuing need for IVs◦Cytochrome 450 drug-drug

interactions ◦Catastrophic adverse reactions◦Cost

Antibiotic Balance - Antibiotic Balance - PopulationPopulationIncreasing 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 Antibiotic “Co-lateral Damage”Damage”

Antibiotic StewardshipAntibiotic StewardshipHospitals based

◦ Multidisciplinary team

◦ Controlled prescribing

◦ Quality assurance cycle

Non acute care◦ Hard to replicate◦ Education (non

bias)◦ Taper therapy

Summary 1Summary 1Antibiotic resistant organism on

the rise are uncheckedNew Abx not the answer (per se)Abx use fuels selection pressureStewardship a logical start

◦Patient safety◦Protect Abx efficacy (population

level)Community stewardship model

needs different emphasis

Strategies for OutpatientsStrategies for OutpatientsAvoid prescribingFix the underlying problemDo not over value non sterile site

culturesMake the diagnosisTaper to or use narrow spectrum

AbxShorter durationNon bias education/CME

Infectious Syndromes to Infectious Syndromes to TargetTargetAcute pharyngitisAcute otitis mediaAcute sinusitisAcute bronchitis AECOPD (mild)CellulitisOutpatient pneumoniaAsymptomatic bacteriuriaUTIs (cystitis)

Viral or self limited bacteria

Excessive Abx use

AVOID ANTIBIOTIC AVOID ANTIBIOTIC PRESCRIBINGPRESCRIBING

Avoid Prescribing When Avoid Prescribing When SafeSafeAbx 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

SinusitisSinusitisUnited 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

Sinusitis – Primary Care Sinusitis – Primary Care RCTRCT

Amox 500 mg3 x 7 daysBlock randomized (ITT)Healthy >15 yrMedian 7 days symptomsNo difference at day ≥10

◦ Symptom duration◦ Symptom severity

No severe complications at 6 wks

No interactions◦ Factorial trial with nasal

steroids

Sinusitis – Meta-analysisSinusitis – Meta-analysis15 pts treated before 1 addition pt

benefitsCommon 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

Antibiotics not useful despite◦ Symptoms >7-10 days◦ Severe symptoms in absence of complications

Symptomatic relief and time for healthy adults

Asymptomatic BacteriuriaAsymptomatic BacteriuriaLack cystitis/pyelonephritis S&S

◦Pyuria is not a “symptom”◦Cloudy or smelly urine not diagnostic

>105 cfu/mL single species◦Female – 2 consecutive samples ◦Male – 1 sample

>102 cfu/mL single species◦Single catheterized sample

Exclude◦Pregnant women◦Pre TURP/other urological procedures

Asymptomatic BacteriuriaAsymptomatic 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

Otitis MediaOtitis Media15 million Rx per year in USASpontaneous resolution commonComplication rate similar treated

& untreatedUK guidelines for Tx

◦Age <2 yr with bilateral acute otitis media

◦Otorrhea on presentation◦No/delay Tx for all else

Otitis MediaOtitis MediaRCT – Standard vs. Wait & See

◦Well 6-12 mos old seen in ER◦Co intervention with analgesia

Wait & see (statistical significance): ◦49% less Abx use◦Fever & otalagia triggers to fill Rx◦0.5 day more fever/otalagia

(relevant?)◦15% less diarrhea

Otitis MediaOtitis MediaMeta analysis favour Abx

◦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

FIX THE UNDERLYING FIX THE UNDERLYING PROBLEMPROBLEM

Infection as a “Symptom”Infection as a “Symptom”Predisposition from other disease

◦Unknown or known◦1 condition repeatedly◦Multiple infectious syndromes

Fix underlying cause◦Global health improvement◦Reduced infections & repeat visits◦Reduced Abx need (therefore risks)◦Prevent resistant flora development◦Avoid lure of chronic prophylaxis

Case Example - CellulitisCase Example - Cellulitis38 yr M outdoor construction worker

◦HealthyClassic GAS

◦Lymphadenitis/fever cellulitis3 standard 14 day 1st gen

cephalosporin courses◦Fully resolution each time

Relapses within 30 day each timeInpatient admission 2 to 3

day/episodeCause?

Case Example - CellulitisCase Example - Cellulitis

Courtesy of Center for Disease Control and Prevention Image Library

Case Controlled StudiesCase Controlled Studies

Bjornsdottir et al. Clin Infect Dis 2005; 41:1416-22Dupuy et al. BMJ 1999; 318:1591-4

Risk factors at least partially reversible

Not prospectively tested

More frequent cellulitis likely will benefit more

Prevent multiple Tx courses or prophylaxis

Big 2Tinea pedisChronic venous

insufficiency

Prophylaxis PitfallsProphylaxis PitfallsRecurrent UTI risk

Severe vesicoureteral reflux

Abx prophylaxis no effect

Controversial – no Abx prophylaxis for at least mild disease

Abx resistant infections Prophylaxis exposure

Fix the problemRepeated Abx creates

new problems

DO NOT OVER VALUE DO NOT OVER VALUE NON STERILE SITE NON STERILE SITE CULTURESCULTURES

Non Sterile Site CulturesNon Sterile Site CulturesClinical 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

ColonizationContamination

DiseaseInvasion

Non Sterile Site Sample Sterile Site Sample

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)

More LessClinical Correlation to Culture Results

A Typical CaseA Typical CaseLongstanding DM2Acute foot ulcer – S. aureus

◦Better with cefazolinNon 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 DiscordanceDM Foot DiscordanceAbx not recommended for non

infected/non healing ulcersChronic osteomyelitis

◦Bone biopsy gold standard◦Non bone specimen poor correlation

52% false negative 36% false positive 28% concordance with bone biopsy

MAKE THE MAKE THE DIAGNOSISDIAGNOSIS

Death to Empiric TherapyDeath to Empiric TherapyClinical 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

Avoid repeated rounds of AbxNot always convenient for Family

MDs

Community Acquired Community Acquired PneumoniaPneumoniaNo symptom can rule in/rule outSigns with modest likelihood ratios

◦ 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- 0.16CXR infiltrate recommended for

diagnosis

Acute BronchitisAcute Bronchitis9th most common outpatient issue

◦5% of adults annuallyViral etiology predominatesAntibiotics 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

TAPER TO (OR USE) TAPER TO (OR USE) NARROW SPECTRUM NARROW SPECTRUM THERAPYTHERAPY

Less is MoreLess is MoreBroad 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 Community Acquired PneumoniaPneumonia

Outpatient ◦ PSI I to III◦ Benign disease

Broader therapy (quinolones) no effect◦ Mortality◦ Treatment success◦ Microbiological eradication

for S. pneumoniaeEquivalent to -lactams or

macrolidesWhy the over coverage?

COPD ExacerbationsCOPD 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

SHORTER DURATIONSSHORTER DURATIONS

Longer Is Not BetterLonger Is Not BetterLength 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 - Shorter Duration - CellulitisCellulitisDouble blinded RCT

◦All patients - 5 days of levofloxacin◦Randomized - 5 days placebo or

levofloxacinNo 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

Shorter Duration - CystitisShorter Duration - CystitisWell studied in women3 = 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

Shorter Duration - CAPShorter Duration - CAP 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

Summary 2Summary 2Multiple “mild” conditions over

treatedPractical 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