21 22 principles of antimicrobial therapy

8/6/2019 21 22 Principles of Antimicrobial Therapy

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Principles of

antimicrobial therapy

Marvin J. Bittner MD MSc

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Results of inappropriate use

Antimicrobials

Resistance Might spread

Affects other

patients

Other drugs

No No

No


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Key points:

Inappropriate antimicrobials

More resistance

Costlier antimicrobialsRisk: no antimicrobials

Toxicity: allergy, C. difficile

colitis, other reactions Wasted money


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This lecture is controversial

Much antimicrobial use is

inappropriatebut Imchallenging it

Im naming names by

pointing out barriers to goodantimicrobial use


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Key issues

Why is appropriate antimicrobialuse important?

What pharmacology concepts dowe use?

How do we choose drugs?

How do we overcome barriers toappropriate use?


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Key points 1: Appropriate use

Resistance: Minimize broad-

spectrum drugs that increaserisk of selection of resistance

Other reasons for parsimony

Less toxicityLess cost


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Key points 2: Pharmacology

Review general concepts

AbsorptionHalf-life, etc.

Explain antimicrobial issues

MIC vs. MBC

Static vs. cidal


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Key points 3: Drug choice

Hierarchy: Bug, body, billfold

Practical approachWhats the problem?

Special patient issues:

Renal, allergy, pregnancy Prophylactic antibiotics


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Key points 4: Barriers

Physician advertising

Lawsuit fears Patient demands

Culture of prescribing


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General concepts:

Absorption, bioavailability

Absorption: rate, extent

leaves administration site Bioavailability: fraction

reaching systemic circulation

in active form (afterabsorption & first pass effect)


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Absorption problems-1

Vomiting patient

Ketoconazole needs acidPatients on proton pump

inhibitors (PPI), H2 blockers

Take with Coca Cola


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Absorption problems-2

Quinolones (ciprofloxacin)

Bind to antacids, sucralfateSolution: PPI or H2 blocker

Didanosine (ddI) unstable in

acid; so: antacid in the tablet Drugs taken with(out) food


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General concepts:

Volume of distribution

Vd Volume of distribution

Volume to containadministered dose A if evenlydistributed at plasma

concentration Cp


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Concentration Cp =

Dose A/Volume of distribution Vd

Dose AVd Cp


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Changing Vd

Gentamicin distributes intospace resembling extracellular

fluid (ECF) ECF larger in shock, drops with

recovery

Gentamicin levels lower inshock, rise with recovery

Assume 0.3 L/kg ICU, 0.25 floor


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Limited distribution-1 Most antibiotics well distributed,

but . . .

Not always intracellular

Not always to:

Central nervous systemEye Prostate Bone

Placenta Breast milk


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Limited distribution-2

Meningitis: Higher doses to

get adequate CNS levels Prostatitis: Prefer

trimethoprim-

sulfamethoxazole,quinolones


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Distribution to

placenta & breast milk

Hard to predict

Practical matter: look updata on a drug


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General concept:

Protein bindingx x x x x xx x x

x x x

x x x

x x x


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Extensive protein binding Good: Allows slow, steady

release of heavily bound drug,

e.g. ceftriaxone Bad: since less free drug

available for bacteria, e.g.

ceftriaxone Reality: Only one factor


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Protein binding perinatal issue Sulfonamide displaces

unconjugated bilirubin from

serum protein Perinatally, high unbound

bilirubin causes kernicterus &

brain damage Dont use sulfonamides in 3rd

trimester, neonate


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General concept:

Biotransformation

Synonym: metabolism

Body alters drug to othercompounds


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Biotransformation: CYP 450

Often hepatic microsomal

enzymes (CYP 450) Rates vary up to 6-fold from

one person to the next

Enzymes geneticallydetermined


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Biotransformation: HIV &T

B Rifampin (forTB) induces

CYP450 3A4 & reduces levels of

indinavir (for HIV) Indinavir inhibits CYP450 3A4 &

increases levels of rifampin

Solution: Low dose rifabutin,high dose indinavir


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Biotransformation:

ketoconazole, erythromycin

Ketoconazole, erythomycin

inhibit CYP450 3A4 Slows metabolism of

cisapride, levels rise, causes

torsade de pointes, death Cisapride highly restricted


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G

eneral concept: Clearance

Quantitative measure of

bodys ability to eliminate thedrug

Includes various forms of

excretion


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General concept:

Elimination t1/2

Half-life

Time for serum concentrationto fall 50%

Constant IF a person is stable

Varies from person to person


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G

eneral concept: Serum levels

Therapeutic serum levels

Plateau after about 4 t1/2

Rate to steady state dependson t1/2

Levels depend on Vd, dose


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T

raditional gentamicin dosing Problem

Therapeutic levels close totoxic levels

Unpredictable individual

variation in levels. Why? Solution: Monitor levels


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ConcentrationT

ime Curve


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T

raditional gentamicin dosing Target peak level Cp x estimated

Vd

= initial dose D

Measure levels after peak todetect rate of change & know t

Adjust dose to get peak Adjust interval to 2-3 x t


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T

raditional gentamicin dosing Eliminated through kidney. How

would 50% renal function affect

initial dose size? Give larger loading dose &

smaller maintenance dose?

When to draw 1st levels? 1stdose? Wait til steady state?


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General concept:

Kinetics vs. dynamics

Pharmacokinetics: What the

body does with a drug(results in levels of drug)

Pharmacodynamics: What

the drug does to the body(and the microorganism)


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General concept:

Bioequivalence

Chemical: in vitro chemical,

physical tests Biological: concentrations in

blood, tissues

Therapeutic: results inclinical trials


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Antimicrobial concept:

MIC, MBC

MIC: Minimum inhibitory

concentration (to inhibitgrowth in vitro)

MBC: Minimum bactericidal

concentration (to kill in vitro) MIC90: Inhibits 90% of strains


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Time 0

few bacteria, no antibiotic* *


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Time 0 + 18 hr

many bacteria

***

***

***


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Time 0

few bacteria, antibiotic* *


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Time 0 + 18 hr

few bacteria (inhibited)* *


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Time 0

* * * * * *

0 mcg/ml 0.5 1.0


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Time 0 + 18 hr. MIC?

***

***

****** * *

0 mcg/ml 0.5 1.0


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Time 0 + 18 hr. MBC?

***

***

***

*** * *

0 mcg/ml 0.5 1.0


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What is MIC90

?

Strain MIC

1 0.252 0.25

3 0.50

4 0.505 0.50

Strain MIC

6 0.507 0.50

8 0.50

9 0.5010 4


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MIC, MBC, MIC90

MIC: Minimum concentrationto inhibit growth

MBC: Minimumconcentration to kill bacteria

MIC90: MIC for 90% of strains New methods, new results!


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Antimicrobial concept:

bacteriostatic/bacteriocidal Bacteriostatic drug: Inhibits

growth, need host immune

system to kill bacteria Bacteriocidal drug: Kills

bacteria

Distinction may be dubious(methods influence results)


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Key message:

Selective toxicity

Kill bacteria, dont hurt host

Penicillin acts on bacterialcell walls; but human cellslack cell walls

Better therapeutic index


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Key message:

Post-antibiotic effect Persistence of effect

(inhibition of growth orkilling) after drug removed (orlevel below MIC)

PAE + pharmacokineticsaffects dosing strategy


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Post-antibiotic effect 1

Nutrient broth

*

*

Bacteria

* A

* A

Antibiotics


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Centrifuge Decant

*

*

Resuspend

A A

* * * *


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Exposed

*

*

*

*

No growth

****

****

*

*

Unexposed Grows


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New gentamicin dosing

Higher peak, better killing

Higher peak, host toxicitysaturable

Antibiotic effect persists

hours after washing drug outof media (PAE)


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Predict: High peaks, longintervals

Better control of infection

No more toxicity to host

Animals: confirm prediction Humans: equivocal, but . . .


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Higher peaks, longer

intervals meansFewer doses to give

Less monitoring of levels

I.e., cheaper


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Combinations: Synergy

Gent 0 0.2 0.5 1.0 2.0 mcg/mlO O O O O


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Gent 0 0.2 0.5 1.0 2.0 mcg/ml** ** ** ** O

MIC = 2.0 mcg/ml


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Amp

0 O0.2 O0.5 O1.0 O2.0 O



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Amp

0 **0.2 **0.5 **1.0 **2.0 OMIC 2.0 mcg/ml



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Gent 0 0.2 0.5 1.0 2.0

Amp0 O O O O O0.2 O O O O O0.5 O O O O O1.0 O O O O O2.0 O O O O O


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Gent 0 0.2 0.5 1.0 2.0

Amp0 ** ** ** ** O0.2 ** ** ** O O0.5 ** ** O O O1.0 ** O O O O2.0 O O O O O


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Key points: Drug choice

Ideally, lots of time, information,and money available when

choosing Reality: Consider key issues re:

Effectiveness, host factors

Therapeutic, empiric, orprophylactic strategies


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Hierarchy of concerns

#1: Effectiveness vs. bug: Just

broad enough to succeed#2: Body: How body handles

drug & vice versa

#3: Cost: Low cost irrelevant ifnot effective, safe


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Effectiveness: Narrow focus

Less flora disruption(diarrhea)

Less resistance selection

Often

Less toxicityLess cost


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Effectiveness: Combinations

Broader spectrum

Mixed infectionEmpiric

Synergy (uncommon), e.g.,

enterococcal endocarditis &ampicillin-gentamicin


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Effectiveness: Combinations

Theory of risk of antagonism

with cidal + static (ampicillin+ doxycycline)

Possibilities: synergy,

antagonism, indifference Synergy helps in endocarditis


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Effectiveness: Dose, duration

Usually limited data

Theory: High dose & shortcourse to cut resistance

Longstanding question:

Staphylococcus aureusbacteremia duration


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Host factors

Oral route possible?

Traditional: IV if serious Reality: Bacteria dont know

how the drug got thereby

mouth or by vein


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Antimicrobial Request 2000

Lung transplant with

pneumonia, can swallow Levofloxacin 500 mg

iv qd x 3, then po qd x 10

About $15 daily vs. $2 daily


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Need parenteral (IV or IM)

Vomiting

Shock, other gastrointestinaldysfunction interfering withabsorption

Cant get adequate oral levels


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Ciprofloxacin costs

Oral

About $0.10/day

Intravenous

About $3/day

+ Pharmacy time

+ Nursing time

+ IV bag/tubing

+ Infection risk

+ Discomfort


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Host factors

Change dose

Renal

Hepatic

Avoid drug

Allergy

Pregnancy

Childhood


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Therapeutic

Rare . . . but the ideal way

Have time to get cultureresult before selecting drug

Just broad enough, suited to

patient, least expensive


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Example: Therapeutic

Red, tender, swollen area ofskin. Gram stain Gram-positive cocci. Blood cultureGroup G streptococci.

Group G strep: penicillin Reality: Start empirically


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Empiric therapy

Before culture

Site?

Host factors?

Organisms?

Susceptibility? Barrier?

Example: CNS

Meningitis

Skull fracture

S. pneumo

Pen resistant Blood-brain


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Types of prescribing

Therapeutic: Documentedinfection

Empiric: Suspect infection,lack cultures

Prophylactic: No infection,want to prevent (pre-op)


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Prophylactic antibiotics

Traditional surgical approach

Cost-effective approach Key points for surgery

Other types of prophylaxis


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Traditional thinking (obsolete)

Whats risk?

Clean

Clean-contam

Contaminated

Dirty

Need antibiotic?

No

Maybe

Yes

Definitely


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Surgical prophylaxis

By operation, not category

Antibiotic cost, toxicity

Chance of infection

Impact of infection

Mastectomy,venticuloperitoneal shunt


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Surgical prophylaxis now

Drug in tissue at time ofincision

Longer duration questioned

Cefazolin popular choice


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Other types of prophylaxis

At risk? Give antibiotics

Example: Dental, heart valve,endocarditis (evidence??)

Many other, from

meningococcal to malaria


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Barriers: Physician advertising

Physicians Desk Reference

Generics vs. brands

Gifts

Appropriate informationsources


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Why not the PDR?

Prescribing info submitted bycompanies, okayed by FDA

Companies maximize salesFDA covers its tail

Companies pay for inclusion

Excludes if not worth studying(endocarditis prophylaxis)

OK for noncontroversial info


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Generics vs. Brands

Brand names (Bactrim) areeasier than generic names(trimethoprim-sulfamethox-azole)but on the billfold?


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Professional perspectives vary

Dentists: OK to work onfamily (objective procedures)

Physicians: Not OK toprescribe for family (bias)


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Gifts from pharmaceutical

manufacturers Scientific physician: I

decide on science, regardlessof gifts.

Attorney: I argue for

whoevers paying me. AMA: Ethical guidelines


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Why The Medical Letter?

Offshoot ofConsumer Reports

Brief reviews of new drugs,some summary reviews

No advertising

Doesnt permit commercial use Very cautious


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Why the Sanford guide?

Pocket guide withoutadvertising

The Sanford Guide toAntimicrobialTherapyisoften distributed bypharmaceuticalrepresentatives


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Peer review journals

Examples: NEngl J Med,Ann Intern Med

Author writes manuscript

Reviewers scrutinize

Editors decide


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Reality on info sources

Often from trusted colleagues

(Diplomatically) find out:

Makes sense in terms ofprinciples of antimicrobial

prescribingBased on reliable sources


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Better information sources

The Medical Letter

Sanford guide Peer review journals

Some guidelines

Colleagues, but . . . .


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Barriers: Lawsuit fears

MD: Gotta do thator youll getsued.

MB: Doesnt make sense.MD: Law often doesnt make

sense.

Can use law as an argument fordoing anything!


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Epidemiology of torts

Brennan (Harvard School ofPublic Health), NEngl J Med

1991;324:370


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Overcoming lawsuit fears

More prescribing does notequal less legal trouble

Adverse events risk withmore prescribing

Fight fear with knowledge


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Practical advice on torts

Provide information aboutmedical malpractice

Put you in a better position torespond to argument toPrescribe heavily or get sued

Controversial: Some people saywe shouldnt talk about practicalaspects of malpractice suits


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Torts

Legal framework

Quality improvement Practical steps to take


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Torts claim: Legal framework

Concept

Duty

Breach

Damages Causation

Example

No penicillin if penallergy history

Gave penicillin

Got rash, died Due to penicillin


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Lawsuit argument

for bad prescribing Duty to prescribe drug X.

Its the standard of care. So . . . why doesnt the

medical literature support

drug X?


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Quality improvement:

Accident theory Complex systems with many

shields, e.g. drug allergy

(physician, pharmacy, nurse,records)

Shields have holes, sometimes

they line up Consistent with anesthesiology:

safety, cut malpractice premiums


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Sulfa-allergic patient got sulfa

MD phoned order, didnt seechart with warning


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Sulfa-allergic patient got sulfa

MD phoned order, didnt seechart with warning

RN missed warning

Pharmacy allergy files

incomplete Administering RN missed it


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Losses

Hazards

The Swiss cheese model of how defences, barriers, andsafeguards may be penetrated by an accident trajectory.

Reason J. BMJ2000(Mar 18);320:768-70


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Practical steps to take

Change the big picture

Advice from Mother

Plaintiffs lawyer

Records

Depositions Authoritative


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Change the big picture

When you become powerful,encourage safety

Join the American MedicalAssociation and your state

and county medical societies Exercise your political rights


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Torts: Advice from Mother

If you dont have anything niceto say, dont say anything

Always tell the truth

Be friendly and polite

Dont lose your temper Dont talk to strangers


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Torts: Plaintiffs lawyer

Hes not your friend. He maybe friendly to get you to makea damaging admission. If

you want a friend, get a dog! Dont try to talk him out of it

Anything you say can andwill be used against you

Your office is off limits


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Torts: Records & your lawyer

Dont even think about alteringrecords

To avoid discovery, make notes& reports only for your lawyer &discuss the case only with yourlawyer

Choose a lawyer with whom youcan work effectively


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Torts: Depositions

They are as serious as court

Dont bring any notes Be truthful, but be brief and

dont volunteer additional

information


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Torts: Authoritative

Can you name anauthoritative source,doctor?

No, if authoritative means

reliably correct; medicine isuncertain & changing.


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B i P ti t d d f


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Barriers: Patient demand for

inappropriate antimicrobials Less paternalism, more

patient autonomy

Physician report cards thatmeasure patient satisfaction

Direct-to-patient advertising

O i th b i f


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Overcoming the barriers of

patient demands: Assertive If you prescribe

inappropriately to keep yourpatients happy, youll build apractice filled with patients

who are only happy when youprescribe inappropriately

O i th b i f


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patient demands: Trust Travel Clinic

Info mailed in advance

Cite CDC (authoritative)

Good patient relationship:

Example of family relationscalling me

O r mi th b rri rs f


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patient demands: Education Advising non-antibiotic cold

medicine

Public awareness campaigns


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Barriers: Culture of prescribing

HO: New patient, amlodipine

MB: Switch to VAs felodipineHO: Medically, could switch

MB: So why not switch?

HO: SJH ProfRxd amlodipine



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culture of prescribing: Trainee Role as trainee

Cave in to inappropriate use(or forget about yourevaluations)

Try to ask why

Ultimately: professionalism

Key points: Consequences of


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Key points: Consequences of

misuse of antimicrobials Resistance

Need to use more costlydrugs

Toxicity, including

Clostridium difficile colitis


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Key points: General concepts

Absorption, bioavailability,distribution, protein binding

Biotransformation, clearance Serum levels

Pharmacokinetics vs.

pharmacodynamics Bioequivalence


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Key points: Antimicrobials

MIC vs. MBC

Bacteriostatic vs. cidal Selective toxicity

Post-antibiotic effect


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Key points: Drug choice

Bug, then body, then billfold

Narrow focus desirable

Combinations, synergy?

Oral preferred

Renal, hepatic: dose

Allergy, pregnancy, child


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Key points: MD advertising

The Medical Letter, otherreliable sources

AMA ethical guidelines re:gifts from pharmaceutical

manufacturers


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Key points: Lawsuit fears

More prescribing doesnt equalfewer lawsuits

Potential for more claims, resultsnot based on care

Swiss cheese theory: Accidentreflect alignment of multiple defects


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Key points: Lawsuits

Dont alter records

Dont get friendly

Dont get angry

Care in depositions:

authoritative, standard ofcare


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Key points: Patient demands

Establish expectations

Education Alternative medications

Key points:


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Key points:

Culture of prescribing As trainee, ask why

(diplomatically)

Professionalism