Antimicrobials II

Question 1

Describe three aminoglycosides.

Answer 1

Gentamicin is an older drug.

Tobramycin is newer, and useful in gentamicin-resistant infections.

Amikacin is newest, and is useful in gentamicin/tobramycin-resistant infections (use limited).

Question 2

Aminoglycosides

What is their mechanism of action?

How are they administered?

Are they time, concentration, or AUC/MIC dependent?

Answer 2

Aminoglycosides

Bind the 30S (and 50S) bacterial ribosomal subunit to cause RNA misreads and premature release. Note that the bacteria transport them in a fashion that is dependent on aerobic metabolism.

IV/IM, topical. Not oral!

Concentration dependent.

Question 3

Aminoglycosides

What are their indications?

Why are they synergistic with β-lactams?

What is the “post-antibiotic effect”?

Answer 3

Aminoglycosides

They are bacteriocidal against many gram-negative aerobic bacilli–eg Pseudomonas–and can affect some gram-positives as an adjunct.

Cell wall inhibitors increase the permeability of bacteria to aminoglycosides (which act intracellularly). However, they don’t mix well in vitro.

Aminoglycosides adhere well to ribosomes, sustaining their activity well after serum levels have fallen.

Question 4

Aminoglycosides

What are their side effects?

Why is their use limited to serious infections only?

Answer 4

Aminoglycosides

Nephrotoxicity (reversible), ototoxicity (usually irreversible), and neuromuscular blockade (worse with abdominal admin).

The therapeutic window for these drugs is quite narrow. These side effects are seen in a high percentage of cases.

Question 5

Tetracyclines

What is their mechanism of action?

How are they resisted?

How are they administered?

Answer 5

Tetracyclines

They are carried into the cell where they prevent ribosomal 30S from interacting with aa-tRNA.

Usually by drug efflux pumps. Cross-resistance is observed.

Orally or parenterally (NOTE: Calcium binding, can’t be taken with food or drink).

Question 6

Tetracyclines

Name two examples.

What are their indications?

What are their side effects?

Answer 6

Tetracyclines

Doxycycline and Minocycline.

Useful against “atypical” bugs: Rickettsial infections, myco/ureaplasma, chlamydia, and gonorrhea (adjunctive).

GI disturbance & enterocolitis, Candida infection of colon, rash w/ photosensitization, and teeth discoloration in children.

Question 7

Tigecycline

What is its mechanism of action?

What are its indications?

How is it administered?

Answer 7

Tigecycline

Pretty much identical to tetracyclines, but with more binding interactions.

Skin, intra-abdominal, and pneumonial infections. G+/G-/Anaerobes. (“E. Coli, Citrobacter, Klebsiella, Enterobacter, Staph, Strep, Bacteroides, C. Perfringens”)

IV only.

Question 8

Chloramphenicol

What is its mechanism of action?

What are its indications?

What are its side effects?

Answer 8

Chloramphenicol

Binds ribosomal 50S and stops it from associating with aa-tRNA (like tetracyclines, but with 50S).

Only serious infections: Meningitis, abscesses.

Bone marrow suppression (fatal aplastic anemia), grey baby syndrome, optic neuritis and blindness, oh and more GI upset/enterocolitis.

Question 9

Macrolides

What is their mechanism of action?

Name 3 of them.

Answer 9

Macrolides

Binds the ribosomal 50S to stop translocation (halts translation).

Erythromycin (natural product), clarithromycin, azithromycin.

Question 10

Erythromycin

What are its indications?

What are its side effects?

Answer 10

Erythromycin

Mostly useful against G+ (MSSA, strep, listeria) as well as the “atypicals” (chlamydia, myco/ureaplasma, bordetella).

Enhanced GI mobility > N/V, CYP3A inhibition. Increased risk of cardiac arrhythmia & arrest (long QT syndrome).

Question 11

Clarithromycin

What are its indications?

What are its side effects?

Describe its duration of effect.

Answer 11

Clarithromycin

Same as erythromycin, plus: Haemophilus, Moraxella, penicillin-resistant Strep, atypical mycobacteria, and Helicobacter (part of triple therapy).

As erythromycin’s, but with less GI motility.

Longer than erythromycin’s (HL: ~4hrs vs 2hrs)

Question 12

Azithromycin

What are its indications?

What are its side effects?

Describe its duration of effect.

Answer 12

Azithromycin

Outpatient respiratory tract infections. Chlamydia & Gonorrhea (adjunctive).

As erythromycin and azithromycin, but even lesser (still QT prolongation).

It has a 3-day half-life.

Question 13

Clindamycin

What is its mechanism of action?

What are its indications?

What are its side effects?

Answer 13

Clindamycin

Same as the macrolides (yet, it’s not a macrolide).

G+ Cocci (staph/strep, including necrotizing fasciitis), anaerobes other than C. Diff.

GI upset/enterocolitis (major cause), heptatotoxicity.

Question 14

Linezolid

What is its mechanism of action?

What are its indications?

What are its side effects?

Answer 14

Linezolid

Prevents formation of the 70S ribosome (binds 50S).

Mostly for G+ (resistant skin infections, nosocomial pneumonia)

MAO inhibition, Gi upset & enterocolitis, “superinfection”, headache, and bone marrow suppression.

Question 15

Sulfonamides

What is their mechanism of action?

What are its indications?

What are its side effects?

Answer 15

Sulfonamides

They are ρ-aminobenzoate analogs, and inhibit dihydropteroate synthase.

Mostly adjunctive treatments.

Rash w/ photosensitivity, GI upset, renal damage (crystalluria), and CYP2C9 inhibition.

Question 16

Distinguish between sulfamethoxazole and sulfadiazine-Ag.

Answer 16

Sulfamethoxazole is the sulfonamide most typically paired with trimethoprim.

Silver sulfadiazine is often used as a topical in burn patients (silver contributes most of the antibiotic effect).

Question 17

Trimethoprim

What is its mechanism of action?

What are its indications?

What are its side effects?

Answer 17

Trimethoprim

It is a DHF analog and inhbits DHF reductase.

When mixed with sulfamethoxazole, forms TMP/SMX–a bactericidal useful for UTIs (UTEC/S. Saprophyticus), upper RT/ear (Haemophilus, Moraxella, Strep Pneumoniae), GI infections (Salmonella/Shigella), and pneumocystis jiroveci.

N/V/Diarrhea, bone marrow suppression, rash.

Question 18

Describe four categories of antibacterial use.

Which is most ideal?

Answer 18

Prophylactic, empiric, pathogen-directed, and susceptibility-guided.

Susceptibility-guided is preferable, since we can expect that the drug will affect the infection.

Question 19

When is empiric therapy appropriate?

Describe empiric therapy in treating a simple UTI.

Answer 19

When the exact identity of the bug is not known. Typically, empiric treatment will be started while definitive tests or diagnoses are processing.

TMP/SMX is the preferred choice, as it covers most of the organisms that cause cystitis. Nitrofurantoin and fosfomycin are also options.

Question 20

Why might an antibacterial treatment fail?

What other factors should be considered when selecting an antibiotic?

Answer 20

Incorrect choice of drug (wrong spectrum of coverage, poor penetrance, resistance)

Host factors (immuocompromisation, foreign bodies, abscesses, lack of adherence)

Consider patient’s age, renal/liver function, and the route of administration, as well as resistance patterns.

Question 21

What factors are contributing to the rise of antibiotic resistances?

Answer 21

Overuse and/or improper prescription. 11mil kg per year in medical contexts (even more in agricultural)!

Question 22

Describe the emergence of multidrug resistance in gonorrhea, and how it is treated today.

C. Difficile is very resistant to many drugs. What can treat it?

What organisms are becoming carbapenem-resistant?

Answer 22

Ceftriaxone is currently the only truly effective agent left. It is co-administered with doxycycline/azithromycin to help prevent selection against it.

Only vancomycin and metronidazole, although it is developing resistances to them.

Klebsiella and E. Coli. Acinetobacter is also largely resistant.

Question 23

What is the source of vancomycin resistance in bugs like Staph Aureus?

What immunities does ESBL expression confer? What bugs express it?

Answer 23

Resistant strains of Enterococcus (VRE).

Resistance to penicillins and cephalosporins, maybe carbapenems and monobactams too. Watch out for Klebsiella, E. Coli, Enterobacteriaceae.

Question 24

What treatments exist for HA-MRSA?

What treatments exist for CS-MRSA?

Answer 24

Linezolid, vancomycin, daptomycin, tigecycline (all IV; linezolid also oral).

Linezolid, Doxy/minocycline, clindamycin, TMP/SMX (all oral). HA-MRSA treatments too.

Note that most of these drugs are seriously powerful and/or risky.