Aminoglycosides (Name 2)*, tetracyclines, chloramphenicol,

erythromycin

Streptomycin and Gentamycin

inhibit bacterial protein synthesis.

(* exception to rule: aminoglycosides are bactericidal).

Quinolones, fluoroquinolones, sulfonamides

inhibit bacterial DNA synthesis.

inhibits microbial RNA synthesis

Think Rifampin=RNA pol inhibitor

In general, cell wall-active agents are bactericidal or fungicidal, and drugs that inhibit protein synthesis are bacteriostatic.

MOA of Amphotericin B

Toxicity

It is a polyene that will span lipid bilayer of fungus by binding to ergosterol and forms a pore.

Permanent loss of some renal function.

Erythromycin.

Binds to the 50s bacterial Ribosomal subunit, and prevents translocation of the nascent polypeptide from the A site to the P site.

Think: Macro=Big so, it binds to the 50s

1. Drug efflux by active pumps.
2. Ribosomal protection by methylation (methylases)

Bind to where the mRNA binds on the 30s subunit, and they prevent the tRNA from binding to the A-site.

Think: Tetra=4, so if it binds to the 30s and blocks aa entry into A site of the 50s, then 3,4,5

1. Decreased accumulation of tetracycline through decreased influx, and increased efflux.
2. There is also a protection protein that displaces the drug from the 30s
3. Enzymatic inactivation.

MOA of aminoglycosides.

Examples?

1. Bind to 30s and interferes with the initiation of protein synthesis at the start codon (bacteriostatic)
2. Also promotes misreading of the mRNA: leads to premature termination or detachment or incorporation of incorrect amino acids producing aberrant proteins  (bactericidal).
3. Streptomycin and Gentamycin

MOR of aminoglycosides.

Toxicity

1. Failure of the antibiotic to penetrate intracellularly
2. Low affinity for the ribosome.
3. Main one: inactivation of the drug by microbial enzymes.

MOA of trimethoprim and sulfamethoxazole.

Mutations in dihydropteroate synthase or DHFR.

It is rare to have a defect in both.

These drugs are usually given together for G-. 

DNA gyrase inhibitors in G- Bacteria and topoisomerase IV inhibitors in G+bacteria (humans have topoisomerase I and II)

Bacteriostatic.

Mutations in gyrase or toposiomerase.

Efflux pump.

Inhibits DNA dep RNA pol in mycobacteria and other microbes.

Inhibits the initiation of chain formation (elongation)

Induces many of the liver's cytochromes, therefore reducing the half-life of many drugs - especially those in HIV patients.

Would give rifabutin to and AIDS patient (less induction of cyt)

Think: ampin' up the activity of cyt p450

Mutations of target molecules: altered D-Ala-D-Ala peptides (vancomycin),

enzymes in involved in cell wall synthesis, resistant PBPs produced that do not

bind β-lactam antibiotics (produced by homologous recombinations of PBPs

from different bacterial species), lack of porin channels in gram-negative bacteria.

Multidrug efflux pumps traverse both the inner and outer membranes of G- bacteria. The pumps are composed of a minimum of three proteins and are energized by ATP pumps. Have accessory proteins and an outer-layer channel. Increased expression of these pumps is an important cause of antibiotic resistance.

This tends to select for highly-resistant bacteria. You mainly just try and use a broad-spectrum antibiotic, and use more specific drugs later if you need to.

Also, you run the risk of wiping out normal flora.

There is occasionally antagonism between bactericidal and bacteriostatic drugs.

If it is less than 1, there is a synergism between two drugs given simultaneously.

If it is greater than 1, there is antagonism. 

1 is additive

Penicillin, vancoymcin and cephalosporin.

Strep and Staph get the PVC treatment

Streptomycin, gentamycin, tetracyclin and doxycyclin 

It's the plague, so you get all of them.

Cleave the Beta ring on drugs like penicillin.

Betalactams are more important for treatment of G+ than G-

Clavanulate, tazabactam and sulfbactam

Think: Beta-lactamase -> Bactamase -> tazabactam and sulfbactam

Interferes with cell wall synthesis:

Blocks 1-3 β D-Glucan Synthase

What do you use to treat Candida presenting as:

1. Cutaneous or vaginal thrush
2. Oral Thrush
3. Deep infection

1. Fluconazole, Clotrimazole and nystatin (Itraconazole 2nd choice)
2. Fluconazole, Clotrimazole and nystatin (Itraconazole 2nd choice)
3. Amphotericin B (Fluconazole 2nd, Caspofungin 3rd)

1. Voriconazole, posaconazole and liposomal amphotericin B
2. Itraconazole
3. Caspofungin

With what do you treat cryptococcus neoformans presenting as:

1. Nonmeningeal
2. Meningitis 

1. None/Amphotericin B
2. Amphotericin B, Flucytosine and Fluconazole

(Ambisome, ABCD) is one of the best treatments for systemic fungal infection.

Given IV

Got rid of the renal toxicity of amphotericin deoxycholate

What is amphotericin B typically given in combination with?

How does it work?

What is the toxicity of Flucytosine?

Inhibits human p450s, and reduces the production of sex hormones,

Also inhibited the liver microsomal p450 drug metabilizing enzymes

Still has some hepatotoxicity

Is teratogenic.

What are the benefits of posaconazole?

What do you use to treat dermatophytes?

Name 5

Topical agents such as

Griseofulvin (oral, absorbed)

terbinafine (oral, absorbed)

nystatin (oral, not absorbed)

myconazole and clotrimazole

Some of these are oral, but localize in keratin precursor cells in hair, skin and nails

What is the MOA of Griseofulvin?

What are its toxicities

Binds to tubulin, and inhibits fungal mitosis

Will induce human p450s to metabolize anticoagulants such as warfarin

What is the MOA of Terbinafine?

Toxicities?

Inhibits squalene epoxidase to block ergosterol synthesis

It does not induce the cyt p450s

Contraindicated in pregnancy

How is nystatin administered?

What is its MOA

Orally by mouthwash or troche.

Does not get absorbed

It is a polyene - so it forms pores like amphotericin B