Infectious Diseases Bootcamp 1

P702

What is the primary goal of antimicrobial stewardship?

To optimize outcomes for infected patients.

What is empiric antimicrobial therapy?

Therapy started BEFORE the causative organism is known, based on likely pathogens and expected susceptibilities.

What is definitive antimicrobial therapy?

Targeted therapy that is selected AFTER the causative organism and susceptibility results are available.

What is the MIC?

The lowest concentration of an antimicrobial that inhibits growth, producing a static effect in the test tube.

What does a susceptible result mean?

The antimicrobial’s PK/PD target is expected to be achievable with common dosing, making clinical success likely.

What does an intermediate result mean?

The MIC is elevated, but clinical success may be possible with dose optimization.

What does a resistant result suggest?

The antimicrobial’s PK/PD target is not reliably attainable with clinically used doses.

If multiple agents are active against the pathogen and all other factors are equal, which agent should generally be selected?

The narrowest spectrum agent that covers the pathogen.

Cefazolin

1st generation cephalosporin

Cefuroxime

2nd generation cephalosporin

Ceftriaxone

3rd generation cephalosporin

Cefepime

4th generation cephalosporin

Ceftaroline

5th generation cephalosporin AND covers MRSA

When choosing between cephalosporins, which is best for EMPIRIC therapy?

Broad spectrum, 4th/5th gen; Cefepime, Ceftaroline

When choosing between cephalosporins, which is best for DEFINITIVE therapy?

Narrowest spectrum, 1st gens typically; Cefazolin, Cephalexin

What factors must be considered in addition to susceptibility when selecting an antimicrobial?

Infection site penetration, patient-specific factors, efficacy, safety, collateral damage, local susceptibilities, severity, and formulary considerations.

Why is the lowest MIC not automatically the best antibiotic?

MIC has to be interpreted with organism susceptibility category, PK/PD target attainment, patient PK factors, infection site, safety, and spectrum; LOTS of factors to consider.

In a critically ill patient with severe gram-negative infection, why is empiric combination therapy considered?

To increase the likelihood that at least one empiric agent is active; increase spectrum to gram (-).

What should happen to empiric combination therapy once cultures and susceptibilities are available?

Reassess and de-escalate to the narrowest effective regimen when appropriate.

A patient is not responding to antimicrobial therapy and resistance is suspected. What type of therapy modification may be needed?

Escalation - increase the antimicrobial spectrum.

Culture results identify a susceptible pathogen that can be treated with a narrower agent than what the patient was started on. What should occur?

De-escalation - since definitive causes are now known.

Cultures and the clinical picture do not support a bacterial infection. What antimicrobial modification should be considered after the patient was started on empiric therapy.

Discontinuation of antimicrobial therapy.

A patient has pneumonia. What pharmacologic property should highly influence antimicrobial selection?

Adequate penetration into lung tissue and site of infection.

Can you use Daptomycin in this pneumonia patient? Why or why not?

No, because lung surfactant inactivates daptomycin, even though it does penetrate into the lung.

Why might using the same antimicrobial not be appropriate for both cystitis and meningitis?

Drug distribution and penetration differ by infection site, so one drug may not be able to be cleared or penetrated into the other site as well.

What antimicrobial considerations are important for cystitis?

urine elimination

What antimicrobial considerations are important for meningitis?

CSF penetration

Which type of antimicrobial benefits from maintaining concentrations above the MIC for a greater portion of the dosing interval?

Time-dependent (T>MIC) antimicrobials

What dosing strategies can optimize a time-dependent antimicrobial?

More frequent dosing and prolonged or continuous infusions when appropriate.

Which agents should we know are time-dependent antimicrobials?

Beta lactams

What are examples of beta lactams?

Penicillins, Cephalosporins, Carbapenems, Monobactams

Penicillins?

Penicillin G and V, Methicillin, Nafcillin, Pxacillin, Cloxacillin, Dicloxacillin, Ampicillin, Amoxicillin, Piperacillin, Pivmecillinam

1st gen Cephalosporins?

Cephazolin, Cephalexin, Cefadroxil

2nd gen Cephalosporins?

Cefuroxime, Cefotetan

3rd gen Cephalosporins?

[IV: Cefotaxime, Ceftriaxone, Ceftazidime], [Oral: Cefixime, Cefdinir]

4th gen Cephalosporin?

Cefepime

5th gen Cephalosporins?

Ceftaroline, Ceftobiprole, Cefiderocol

Carbapenems?

Meropenem, Imipenem-Cilastatin, Ertapenem, Sulopenem + Probenecid

Monobactam?

Aztreonam

What is the relevant PK/PD concept for time dependent agents

We want free drug concentrations to remain above the MIC for longer.

What PK/PD exposure is typically relevant for aminoglycosides?

Cmax/MIC or concentration-dependent.

Why can patient-specific pharmacokinetics affect antimicrobial dosing?

The needed total exposure or AUC/MIC depends on how the individual patient’s ADME works.

What are 3 major mechanisms of antimicrobial resistance?

1. Drug-modifying enzymes

2. Target-site alterations

3. Decreased antimicrobial concentration at the site of activity

What are examples of antimicrobial modifying enzymes?

Beta lactamases and aminoglycoside-modifying enzymes

What are two mechanisms that decrease antimicrobial concentration at the site of activity?

1. Efflux pumps

2. Porin downregulation

What is a target-site alteration example?

Modification of penicillin-binding proteins.