Basic Principles of Infectious Disease and Antimicrobials

What is considered when choosing an antibiotic?

- the bug

- the drug

- the patient

- the disease state

What Antimicrobial Properties are considered when choosing an antibiotic?

- Spectrum of activity (broad vs narrow)

- Dose (indication matters)

- Pharmacokinetics/Dynamics

- Adverse Effect Profile

- Cost

- Bactericidal vs Bacteriostatic

Bactericidal vs bacteriostatic is not nearly as important as we thought but __________________ is recommended for deep seated infections such as endocarditis.

bactericidal

What host (patient) factors are considered when choosing an antibiotic?

- Allergy history (Most critical!)

- Age

- Special populations (pregnancy, pediatrics, immunocompromised)

- organ function (renal dysfunction -- most antibiotics are cleared really -- and hepatic dysfunction)

What antimicrobial (bug) factors are considered when choosing an antibiotic?

- the normal flora (where the bacteria normally resides in the body)

- the antibiogram

What is an antibiogram?

An overall summary report of antimicrobial susceptibility test results. It shows the percentage of specific bacterial or fungal strains that are inhibited or killed by various tested antibiotic drugs.

Antibiograms are especially important in ___________ therapy and they are always __________________ specific!

empiric; local/institution

What disease state factors are considered when choosing an antibiotic?

- physical exam findings

- signs/symptoms (septic shock patients)

- laboratory findings

- culture and susceptibility testing

Not all patients with positive cultures are considered infected! What are examples of when this is the case:

- Asymptomatic Bacteriuria: bacteria growing in the urine but no symptoms so we won't treat these patients unless they are pregnant

- Contaminated Blood Culture (Coagulase Negative Staph): contamination by a bacteria normally fund on the skin

Generally, choosing antibiotics depends on:

- the disease states, bugs, and drugs

- practice specific information: local epidemiology (organism and resistance trends), formularies, and cost

- patient specific information: exposure history, risk factors for specific bugs, allergies, organ dysfunction, interacting medications, weight, and height

Important resources for ID information:

- the Sanford Guide

- Antibiotics Simplified by J Gallagher

- IDSA Guidelines

- Social Media

What are the three ways that antibiotics are used?

Prophylaxis, empiric, and definitive.

Prophylaxis therapy

The use of a drug before a patient gets the infection.

Examples of medical prophylaxis:

- patients with exposure to virulent pathogens (HIV (PrEP) and N. meningitis)

- immunocompromised patients (HIV with CD4

Procedural prophylaxis

Short course of antibiotics recommended/preferred prior to surgery (ancef/cefazolin is the most commonly used)

Empiric therapy

treatment of an infection before specific culture information has been reported or obtained; usually lasts up to 72 hours

Empiric therapy is chosen based on:

- likely pathogen

- local susceptibility trends

- patient specific factors (allergies, organ dysfunction)

It is important to get cultures ________________ the start of antibiotics in empiric therapy so that growth in the culture is not suppressed.

prior to

It is important to start appropriate antibiotics ASAP in empiric therapy especially for the following conditions:

- sepsis (start within an hour)

- meningitis (start within 45 minutes)

______________ dosages are most appropriate for empiric therapy.

Higher

Definitive therapy

antibiotic therapy tailored to treat organism identified with cultures

Definitive therapy for T. palladium (it is susceptible to this drug) is

penicillin

Caveats to susceptibility testing:

- interpretation of mIC as S, I, or R is bug-drug specific (relative to concentrations of drug in body)

- one cannot just pick the one with the lowest MIC (MIC's are not comparable)

- CLSI and FDA determine breakpoints

MIC

minimum inhibitory concentration; the lowest concentration of an antibiotic that stops visible growth of a bacterium in a lab test

S

susceptible

I

Intermediate

R

resistant

S-DD

Susceptible but dose dependent

Sometimes we want to suppress the results to some broad spectrum agents because we want more narrow coverage drugs to be used when available. This is called _________________.

Cascaded reporting

E-test

A manual test that will get you an MIC. It is used as an additional test when the drug does not have established breakpoints or the drug is a new ABX that is not on the automated panels.

What is the goal of definitive therapy?

To use the most effective, least toxic, narrowest spectrum, and most cost effective agent aka the drug of choice.

The drug of choice may actually be...

a combination of drugs (e.g. ampicillin and gentamicin for enterococcal endocarditis)

It is important to know the ________________________ to the drug of choice especially when the patient is allergic to the DOC.

alternatives

After finding the drug of choice, one must understand that the dose, route, intervals, and duration are all _________________________________.

disease state and patient specific

What is the duration of treatment for antibiotics?

It is not well defined but generally shorter courses are better for most infections so its usually less than 7-10 days (such as in CABP, ABSSSI, Uncomplicated Cystitis).

For which disease states are longer durations with antibiotics necessary?

- Endocarditis and Osteomyelitis often require 6 weeks

- Prostatitis often requires 4 weeks

- Staphylococcus aureus Bacteremis often require >/= 14 days via IV

When a patient is put on an antibiotic, it is important to...

track the number of days of therapy in progress notes and set an endpoint

Prolonged unnecessary antibiotic therapy increases...

the risk of resistance, adverse effects, and cost

List some gram positive organisms:

- Staph Aureus

- Enterococcus species (E. faecaliss and E. faecium)

- Strep Pneumoniae

How is staph aureus empirically treated?

as Methicillin-Resistant Staph Aureus (MRSA)

What is the Methicillin susceptible staph aureus drug of choice?

Cefazolin (preferred) and Nafcillin (can cause significant kidney injury)

What is the community acquired methicillin resistant staph aureus drug of choice (if uncomplicated)?

- Trimethoprim/Sulfamethoxazole

- Clindamycin

- Doxycycline and Minocycline

What are the primary enterococcus species?

E. faecalis and E. faecium

What is the drug of choice for Enterococcus species?

Ampicillin (or amoxicillin) or vancomycin

What can be used to treat a UTI caused by Enterococcus species?

Nitrofurantoin, Ampicillin, or Vancomycin

Vancomycin resistant Enterococci (VRE) is primarily ________________ and primary options for treatment include ____________________________________.

E. faecium isolates; daptomycin and linezolid

Which antibiotic class has ZERO coverage vs enterococci?

Cephalosporins

Strep Pneumoniae îs the primary pathogen for...

- community acquired bacterial pneumonia

- acute sinusitis

- bacterial meningitis

What is the regimen of choice for strep pneumoniae infections in the CNS is....

High dose (HD) Ceftriaxone (2g IV Q12H) + Vancomycin

What is special about the dose of Ceftriaxone for the treatment of strep pneumoniae infections in the CNS?

Ceftriaxone is usually dosed once a day but is dosed twice a day in strep pneumoniae CNS infections because it is difficult for drugs to penetrate the CNS.

What is the drug of choice for strep pneumoniae infections OUTSIDE thee CNS (outpatient):

High dose amoxicillin (PO)

What is the drug of choice for strep pneumoniae infections OUTSIDE thee CNS (inpatient):

- Ceftriaxone

- Respiratory Flouroquinolones if at risk for resistance or step-down for secondary bacteremia (high bioavailability)

List some gram negative organisms:

- E. coli

- Pseudomonas Aeruginosa

Where is E.coli commonly found?

In urine

Which drugs are the drugs of choice for E.coli infections?

- Trimethoprim/Sulfamethoxazole

- Flouroquinolones such as Ciprofloxacin and Levofloxacin

Which flouroquinolone is not recommended for E.coli infections and why?

Moxifloxicin because very little is excreted in the urine

What are the best drugs for treating Pseudomonas aeruginosa infections?

- Piperacillin/Tazobactam

- Cefepime

- Meropenem (reserve)

What are the "less effective" drugs (50-70% susceptible) used to treat Pseudomonas aeruginosa infections?

- Aztreonam

- Levofloxicin and Ciprofloxacin

How are ahminoglycosides used in Pseudomonas aeruginosa infections?

as second drugs in combination with the best drugs or the "less effective" drugs unless the infection is a UTI

Which anaerobes are gram positive?

Peptostreptococcus and Clostridium

Which anaerobes are gram negative?

Bacteroides

Which medications in general are used to treat anaerobe infections?

- amoxicillin/clavulanate

- ampicillin/sulbactam

- piperacillin/tazobactam

- carbapenems

Any Penicillin with __________________________ has excellent anaerobic coverage.

beta-lactamase inhibitor

Which type of anaerobes commonly affect the mouth and lungs and which antibiotic is best to treat that infection?

Gram positive anaerobes are most likely to infect the mouth/lungs and this infection is best treated with clindamycin.

Which type of anaerobes commonly affect the abdomen and GU and which antibiotic is best to treat that infection?

Gram negative anaerobes are most likely to infect the abdomen/GU and this infection is best treated with Metronidazole.

List atypical organisms:

- legionella

- mycoplasma

- chlamydia

Which antibiotics best treat atypical organisms?

- macrolides

- tetracyclines

- respiratory fluoroquinolone

Why do macrolides, tetracyclines, and respiratory fluoroquinolones work well on atypical organisms?

Because these antibiotics do not work by attacking cell walls and atypical organisms do not have cell walls (aka beta lactams won't work on them).

Which antibiotics work by attacking the peptidoglycans in the cell wall of an organisms?

- penicillins +/- beta lactamase inhibitors

- cephalosporins

- imipenem

- aztreonam

Which antibiotics work by attacking precursor molecules and decreasing peptidoglycans needed for the cell walls of an organism?

vancomycin

Which antibiotics work by affecting DNA gyrase and Topoisomerase 4?

Fluoroquinolones

Which antibiotics work by affecting the 30S protein in ribosomes?

Tetracylines

Which antibiotics work by affecting the 50S protein in ribosomes?

Macrolides

Which antibiotics work by affecting the 30S and 50S proteins in ribosomes?

Aminoglycosides

Which antibiotics work by affecting folate metabolism?

Trimethoprim/Sulfamethoxazole

What are mechanisms of resistance used by antibiotics?

- alteration of targets such as PBPs: an absolute change will cause no binding (e.g. MRSA which is resistant to all beta lactams) while a relative change will cause decreased binding and increased MICs (e.g. drug resistant s. Pneumoniae)

- destruction by enzymes such as beta lactamases: penicillinase in MSSA, H.influenzae, and anaerobes (but can be combated by adding a beta-lactamase inhibitor or changing structure) and Cephalosporinase (ESBL) in E.coli/Klebsiella species

Which antibiotics have great PO absorption?

- fluconazole

- fluoroquinolones (be careful of drug interactions)

- metronidazole

- TMP/SMX

- doxycycline

Which antibiotics are IV only?

- vancomycin (except when treating c.difficile)

- all antipseudomonal agents except for fluoroquinolones

- 3rd and 4th generation cephalosporins (may give IM)

- aztreonam (only for severe beta-lactam allergies)

- aminoglycosides (gentamicin et al; may give small doses MI or may be used oral for gut disinfection (rare))

- Clindamicin (also used orally at times)

Why is the IV dose for Clindamycin much higher than the oral dose?

Because clindamycin is hard to tolerate orally (bad side effects at high doses).

Which antibiotics have excellent CNS penetration?

metronidazole, chloramphenicol, fluconazole, TB drugs

Which antibiotics have adequate CNS penetration with high doses?

Ceftriaxone, ceftazidime, ampicillin

Which antibiotics have problematic CNS penetration?

Vancomycin (huge molecule) and Amino-glycosides (very polar and water soluble)

Which antibiotics have good lung penetration?

Fluoroquinolones, Macrolides, and Beta-lactams

Which antibiotics have modest lung penetration?

Aminoglycosides

How do you adjust for renal dysfunction for antibiotics?

using ClCr via Cockcroft Gault

Why can you use lower doses of some antibiotics for UTIs?

because most antibiotics are really excreted so they would have good levels in urine despite lower doses

What considerations for the liver must be made for antibiotics?

- dose adjustments for liver dysfunction (not exactly clear how this is done yet)

- potential for drug interactions

MDRD (Modification of Diet in Renal Disease) Levey equation

a mathematical formula used to estimate the glomerular filtration rate (eGFR) to assess kidney function; can be done on medcalc

Cockcroft-Gault equation

Estimates a person's creatinine clearance (CrCl) to measure kidney function (140-age) x IBW/(72xScr) (x 0.85 if female) -- would round SCreen up if

If a patient's ClCr < 50-60 mL/min, adjust the interval +/- dose of the following antibiotics:

- penicillins (not nafcillin or oxacillin)

- cephalosporins (not ceftriaxone)

- aztreonam

- vancomycin

- ahminoglycosides

Miscellaneous agents that require adjusted dosing in renal dysfunction:

- TMP/SMX (generally avoid)

- fluconazole

- acyclovir

- ganicyclovir

- most nucleoside RTIs

Which antibiotic is avoided in renal dysfunction due to being nephrotoxic?

Amphotericin B but the liposomal formulations have less toxicity

Which antibiotics need dosing adjustments in hepatic dysfunction but generally don't need to be adjusted for renal dysfunction?

- Ceftriaxone

- Nafcillin

- Clindamycin

- Metronidazole

- Macrolides

- Tetracyclines

- Rifampin

- Isoniazid

What are some common drugs cleared by CYP450?

Statins, Cyclosporins, Benzodiazepines, Theophylline, Anticonvulsants, Oral hypoglycemics

Which antibiotics inhibit metabolism of CYP450 enzymes and thus increase the levels of drugs cleared by CYP450 enzymes?

- Macrolides (erythromycin/clarithromycin BUT NOT azithromycin)

- Azoles (Fluconazole, Itraconazole)

- Protease inhibitors

- Ciprofloxacin

Which antibiotics induce metabolism by CYP450 enzymes and thus decrease the levels of drugs cleared by CYP450 enzymes?

- Rifampin

- Rifabutin

Levels of oral contraceptives are decreased with ________________________.

rifampin and nafcillin

Vitamin K is made by bacteria in the colon so the use of the following antibiotics can profoundly increase a patient's INR if they are on warfarin:

- trimethoprim/sulfamethoxazole

- metronidazole

- erythromycin/clindamycin

Vitamin K is made by bacteria in the colon so the use of the following antibiotics can significantly increase a patient's INR if they are on warfarin:

Fluconazole +/- ciprofloxacin/levofloxacin

Vitamin K is made by bacteria in the colon so the use of the following antibiotics can decrease a patient's INR if they are on warfarin:

Rifampin/Rifabutin