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Flashcards in Drugs- protein syn inhibitors Deck (28):
1

Tetracyclines

spectrum:

mech of action:

very broad spectrum

Enter gram (-) bacteria by diffusion thru porins

Minocycline and Doxycycline more lipophilic and cross outer membrane, great affinity for gram -

Mech: Bind 30S subunit of ribosome, preventing access of aminoacyl tRNA to acceptor (A) site on mRNA-ribosome complex

2

Tetracyclines: Mech of resistance

Numerous, important ones are:

- decreased influx into bacteria thru altered membrane porin proteins

- increase efflux thru actice transport out of cell by pump proteins

3

Tetracyclines

absorption:

Distribution:

elimination:

administration methods:

absortion: dairy products and divalent cations interfere

Distribution: distribute to bones and teeth, can cross placenta where they can stain developing teeth

elimination: glucuronidation, with urinary excretion (most) and minor biliary excretion

EXCEPT: doxycycline is almost entirely excreted in bile, safe in renal failure

Doxycycline PO and IV

Minocycline and tetracycline PO only

4

tetracycline adverse effects

gastric discomfort: irritating mucosal tissues (gastritis, esophagitis)- remain upright 45-60 min after dose.

Bone/teeth: may interfere with bone depostition; stains teeth (dont use before age 9)

Phototoxity: skin rashes with light exposure

Vestibular problems: dizziness with minocycline

Associated with liver failure at high dose, and in pregnancy

super infection

5

Uses of tetracyclines

Pneumonia "atypical pathogens"

STDs (Chlamydia, PID, LGV)

Rickettsial infection

Prophylaxis against malaria

CA-MRSA

P.Acnes

6

Tigecycline

mech:

administration:

spectrum:

uses:

Bacteriostatic inhibitor of 30S ribosome, blocking aminoacyl-tRNA

IV only (hospital infections only)

Broad spectrum of Action

Gram + (including MRSA and VRE)

Gram - (includes MDR acinetobacter, excluding Pseudomonas)

Anaerobes

Indicated for soft tissue infection, complicated intraabdominal infection, CA pneumonia

Recent warning about increased mortality for nosocomial pneumonia

7

Aminoglycosides

mech of action:

 

from a mold

First bind to outer membrane, displacing cations

causes disruption of outer membrane

Transport across cytoplasmic membrane

- depends on electrochem enviroment

- gradient depends on oc phos

- No gradient in anaerobic condition

- not active in abcesses

Once inside bacterial cell, disrupt translation:

- bind 30S ribosome (primarily)

- interfere with formation of initiaition complex

- cause misreading of mRNA, missence mutations, incorporation of wrong amino acid

- interfere with translocation

8

Aminoglycoside activity pharmodynamics

Exhibit concentration dependent killing: bacteriacidal activity is proportional to peak concentration

Post antibiotic effect is prolonged (10 hrs)

Toxicity is less with once daily dosing

Multiple dosing may be needed to achieve synergy with cell wall active agents

9

Aminoglycosides

spectrum of action:

effective primarily against aerobic gram - bacteria including pseudomonas

- amikacin>tobramycin>gentamicin

Some acitivity against gram +

- most strep, staph

- used with penicillin or vancomycin in synergistic regiment for enterococcal, and some staph infections

10

Macrolides : adverse events

adverse drug interactions:

epigastric distress, greatest with erythromycin

Cholestatis jaundice

Ototoxicity (rare, transient, seen in high doses)

Cardiac conduction: QT prolongation

Contrainications: hepatic dysfunction

Adverse drug interactions

- interfere with cytochrome P450 clearance

- Theophylline, cyclosporin, digoxin, others

11

Linezolid

mech:

sprectrum:

First and onlye member of oxazolidinone class

interferes with intiatiation of translation, preventing formation of 70s comples

Active against S. aureus (inclduing MRSA), strep, enterococcus faecium, enterococcus faecalis including VRE strains

 

12

Linezolid

pharmcokinetics:

adverse events:

pharmokokinetics: very well absorbed orally, BID dosing (IV, PO)

85% excreted in urine

Adverse effects: diarrhea, nausea, vomiting

bone marrow suppression (usually platelets after ~2 wks)

Weak MAO inhibitor (can cause serotonin syndrome with SSRIs, maybe fatal)

13

Protein synthesis inhibitors key points:

tetracyclines:

aminoglycosides:

chlorampheicol:

macrolides:

clindamycin:

Tetracyclines
- Widely available, wide spectrum, resistance common, bacteriostatic

Aminoglycosides
- Active against aerobic organisms only; usually bactericidal
- Oto-, nephrotoxic
- Used in synergistic therapy for enterococci

Chloramphenicol
- Seldom used in the U.S. due to hematopoetic toxicities, very broad spectrum

Macrolides
- Broad spectrum, respiratory tract and skin infections
- Erythromycin causes most GI upset

Clindamycin
- Spectrum: anaerobic bacteria and gram + (including CA-MRSA)
- Classic pseumomembranous enterocolitis risk

14

Drugs with anaerobic infections:

Protein synthesis inhibitors:

Clindamycin

Chloramphenicol

Tigecycline

 


Beta-lactamase inhibitor/penicillin combinations:
Penicillins
Piperacillin/tazobactam
Ampicillin/sulbactam
Amoxicillin/clavulanate
2nd gen cephalosporins (cefoxitin, cefotetan)
Carbapenems

Moxifloxacin (fluoroquinolone)

15

Metronidazole

- NOT A PROTEIN SYN INHIBITOR

Acts as an electron acceptor; once activated by reduction, it damages DNA and other macromolecules

Very well absorbed orally. Available IV and PO.
Penetrates well into all tissues.

Highly bactericidal for anaerobic bacteria, no activity against other  Gram + or Gram -

Also used to treat wide array of protozoans
Trichomoniasis, Giardiasis, Amebiasis

Disulfiram-like reactions with alcohol.
Sensory neuropathy with prolonged use.

16

TX of anaerobic infections

anarobic strep:

GI tract or oropharyngeal:

Intestinal:

abscesses:

 

Anaerobic streptococci:  Penicillin

Gastrointestinal tract infections
Oropharyngeal:  (e.g head and neck abscess)
Clindamycin
Penicillin
Penicillin class + beta lactamase inhibitor

Intestinal:   (e.g ruptured appendix) 
Metronidazole
Cefoxitin/Cefotetan
Carbapenem
Penicillin class + beta lactamase inhibitor

Clindamycin

Abscesses


Metronidazole
Chloramphenicol     

17

Aminoglycosides

Much of action:

Decreased influx into bacteria

- altered uptake mechanisms

Altered target

- mutation in 30s subunits

Enzymatic modification

- phosphorylated, adenylated,, acetlyated by bacteria

18

Aminoglycosides

absorption:

distribution:

elimination:

Absorption: poor across GI tract. IV, IM or topical

Distribution: Highly polar, poor CSF penetration

Elimination: urinary excretion, achieve very high levels in urine. 

EFfective for UTIs

19

aminoglycosides

toxicity:

adverse effects:

Nephrotoxicity

- acute tubular necrosis

- prolonged high trough levels is a risk factor

 

Otoxicity (vestibular and cochlear)

- problems with balance, high freq hearing loss

- recommendations for audiograms before and after

 

Neuromuscular blackade- caution with myasthenia gravis

20

Macrolides

eythro-, clarithro-, azithromycin

mech:

resistance:

Mech: bind 50S ribosomal subunit

- binding site overlap with those lincosamides (clindamycin) and streptogramins

- Block translocation step of protein syn

- bacteriostatic for most organisms

 

Resistance:

- decreased penetration across membrane

- alterations of 50S RNA targets, usually rRNA methylation

- Macrolide hydrolysis (seen in gram -)

- drug efflux pumps

21

Macrolides

Spectrum:

Most of the same organisms as Penicillin G (except anaeurobes), used in Penicillin allergic patients

Respiratory pathogens (S. pneumoniae, H. Influenzae, Legionella)

Active against Chlamydia, mycoplasma, rickettsia (cell wall deficient organisms)

Clarithromycin and azithromysin highly active against many mycobacteria

H.Pylora

Diptheria and PErtussis

22

Differences between Erythromycin vs. Azithromycin and Clarithromycin-

More GI upset in erthromycin

Less frequent dosing with Azithro-/clarithro-

Shorter courses with Azithromycin (long 1/2 life)

Wider spectrum with Azithro-/clarithro

Azithro has no hepatic metabolism, elimination 1/2 life of 68hrs due to tissue sequestration

Erythro and azithromycin PO and IV

Clarithromycin only PO

23

Clindamycin

Mech:

spectrum:

Distribution:

toxicities:

Major uses:

Clindamycin and lincomycin are lincosamides

MEch: Bind sites on 50s ribosome similar to macrolides and chloramphenicol

Spectrum: Active against gram + anaerobes

Distribution: Poor CSF penetration, penetrates bone

Toxicities: allergic skin rashes, pseudomembranous enterocolitis

Major uses: Staph and anaerobic infections, especially odotogenic infection

24

Chloramphenicol

mech:

Spectrum:

 

Not used in US

mech: Bidn to 50S subunit of ribosome, preventing access of aminoacyl tRNA to acceptor (A) site.

- binds near same site of macrolides and clindamycin, and may antagonize their activity

 

Spectrum: very broad, widely distributed

25

Chloramphenicol

Key adverse events:

Hematopoetic

- bone marrow suppression

- aplastic anemia (bone marrow aplasia)

- idiosyncratic rxn, led to avoidance of use in US

 

Drug interactions: inhibits cyp 450 metabolism of many other drugs

 

Grey baby syndrome

- lack of glucuronidation of chloraphenicol, metabolites

- vomiting, ashen color, cyanosis, ciculatory collapse

26

Rifampin

Mech

spectrum

metabolism

admin

semisynthetic derived from mold

MEch: inhibits DNA-dependent RNA polymerase in bacterial cells, preventing ts (mRNA syn)

Spectrum: active against gram + (S.aureus), mycobacteria

Metabolism: hepatic metabolism

administration: PO, IV

 

27

Rifampin

adverse events:

hepatotoxicity (cholestatic), nausea, vomiting

Extensive drug interactions (enhances clearence of coumadin, digoxin, azole antifungals, antiretrovirals)

Stains red-orange (urine, sweat, teats, soft contacts)

28

Mupirocin (Bactroban)

spectrum:

mech:

Distribution:

Uses:

also known as Pseudomonic acid A from P. fluorescens

spectrum: Active against most gram +, including MRSA

Mech: bind bacterial isoleucyl-tRNA synthetase

distribution: topically only

Uses:

- prophylaxis and tx of skin infections caused by gram + organisms

- clearence of nasopharyngeal colonization with MRSA

- emerging resistane