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Protein Synthesis Inhibitors
Selectively inhibit bacterial protein synthesis
by binding to and interfering with ribosomes
Basis for selective toxicity against microorganisms without causing major effects on mammalian cells
not identical
Protein synthesis in microorganisms is ___ to mammalian cells
70S
ribosomes in bacteria
80S
ribosomes in mammalians
Bacteriostatic
They do not kill the bacteria but instead slow down the production of their proteins
Bactericidal
They kill the bacteria
the charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70S ribosome
Step 1
Transpeptidation: peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino acid 6
Step 2
uncharged tRNA left at the donor site is released
Step 3
Translocation:
new 6-amino acid chain with its tRNA shifts to peptidyl site
Step 4
Chloramphenicol & Macrolides
inhibit the transpeptidation
bind to the 50S subunit
Macrolides, telithromycin, lincosamides
block the translocation of your peptidyl tRNA from the acceptor
Tetracyclines
bind to the 30S subunit
prevent step 1
Streptogramins
constrict the exit channel
Linezolid
block the formation of the tRNA ribosomes and the mRNA complex
blocks the binding of the mRNA and tRNA to the ribosome
difficult to form the peptide bonds
Active against both aerobic and anaerobic gram-positive and gram negative organisms
Antimicrobial Activity
Plasmid-mediated - chloramphenicol acetyltransferases
Resistance
Rickettsial infections
typhus and Rocky Mountain spotted fever
Alternative to a β-lactam antibiotic
treatment of bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin
50-100 mg/kg/day divided every 6 hours
usual dosage
chloramphenicol succinate (prodrug)
IV formulation
conjugation with glucuronic acid
reduction to inactive aryl amines
Inactivated by
Active chloramphenicol + inactive degradation products
Excretion: urine
small amount of active drug
Excretion: bile and feces
Gray baby syndrome
Lacks effective glucuronic acid conjugation mechanism for the degradation and detoxification
gram-positive and gram-negative
Antimicrobial Activity
impaired influx or increased efflux
ribosome protection
enzymatic inactivation
Resistance
Mycoplasma pneumoniae
Chlamydiae Rickettsiae
Borrelia sp.
Vibrios some spirochetes
Anaplasma phagocytophilum
Ehrlichia sp
Primary Clinical Uses
community-acquired pneumonia (CAP)
syphilis
Chronic bronchitis
Leptospirosi
Acne
Secondary Clinical Uses
Tetracycline
Selective Uses: gastrointestinal ulcers caused by H. pylori
Demeclocycline
Selective Uses: ADH-secreting tumors; inhibits the renal actions of antidiuretic hormone (ADH)
Minocycline
Selective Uses: meningococcal carrier state
Doxycycline
Lyme disease
Malaria prophylaxis
amoebiasis
Tigecycline
MRSA strains
VRE strains
60–70%
Oral Absorption: tetracycline and demeclocycline
95-100%
Oral Absorption: doxycycline and minocycline
Tigecycline and Eravacycline
poorly absorbed orally and must be administered intravenously
breast milk
Cross the placental barrier and excreted in ___
Doxycycline and tigecycline: feces
Excreted mainly in bile and urine except
Tetracycline (oral) - 6-8 hours
Short-acting
Demeclocycline (oral) - 12 hours
Intermediate-acting
Doxycycline & Minocycline (IV & Oral) - 16-18 hours
Long-acting
Tigecycline and Eravacycline
require twice daily dosing to maintain adequate serum concentrations
Omadacycline
dosed once daily after an initial loading dose
Nausea, vomiting, diarrhea
most common reasons for discontinuing tetracyclines
Fanconi syndrome: outdated
tetracyclines
Renal toxicity
Tetracycline + diuretic
Tetracycline and Minocycline
Nephrotoxicity
Demeclocycline
Photosensitivity
Doxycycline & Minocycline
Vestibular toxicity
Macrolides
moderate spectrum
macrocyclic lactone ring with attached sugars
good oral bioavailability
hepatic metabolism
Erythromycin
Prototype
Clarithromycin and azithromycin
Semisynthetic derivatives of erythromycin
Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA
Mechanism of Action
torsades de pointes arrhythmia
Macrolide antibiotics prolong the electrocardiographic QT interval due to an effect on potassium channels
2 hours (Oral & IV)
Half Life
Reduced permeability of the cell membrane or active efflux
Production (by Enterobacteriaceae) of esterases that hydrolyze macrolides
Modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolideinducible or constitutive methylase
Resistance
Food
interferes with absorption
bile
Excretion
polymorphonuclear leukocytes and macrophages
Taken up by ___
penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci
Clinical Use
Clarithromycin
More active against Mycobacterium avium complex
6 hours (Oral)
Half-life
14-hydroxyclarithromycin with antibacterial activity
eliminated in the urine
patients with creatinine clearances less than 30 mL/min
Dosage reduction
Azithromycin
Spectrum of activity, mechanism of action, and clinical uses are similar to those of clarithromycin
M avium complex, T gondii, H influenzae, Chlamydia sp
2-4 days (Oral & IV)
Half-life
Aluminum and magnesium antacids
do not alter bioavailability but delay absorption and reduce peak serum concentrations
Clindamycin
Chlorine-substituted derivative of lincomycin (Streptomyces lincolnensis)
Gram-negative aerobes are intrinsically resistant
6-8 hours (Oral & IV)
Half-life
severe anaerobic infections
Bacteroides, Fusobacterium, and Prevotella
Backup drug against gram-positive cocc
Community-acquired strains of MRSA
Toxic shock syndrome
with penicillin G
Penetrating wounds of the abdomen and gut
combined with aminoglycoside or cephalosporin
endocarditis in valvular disease
patients allergic to penicillin
P. jiroveci pneumonia in AIDS patients
In combination with primaquine alternative
AIDS-related toxoplasmosis
In combination with pyrimethamine
Quinupristin-Dalfopristin
Combination streptogramins
gram-positive cocci
active against ___
0.85 hours
Quinupristin half-life
0.7 hours
Dalfopristin half-life
feces
Excretion
Linezolid
Active against gram-positive organisms
Bacteriostatic but bactericidal against streptococci
binds to 23S ribosomal RNA of the 50S subunit
4-6 hours (Oral & IV)
Half-life
thrombocytopenia
most common manifestation
Tedizolid
Active moiety of the prodrug tedizolid phosphate
High potency against gram-positive bacteria
Plasma concentrations
good indicator for tissue concentrations as it penetrates well into muscle, adipose, and pulmonary tissues
12 hours
Half-life
Pleuromutilins
discovered in the 1950s but previously it was only used in veterinary medicine.
Lefamulin
Approved only for the treatment of adult patients with community acquired pneumonia
lower respiratory tract infections
in vitro activity against most aerobic gram-positive organisms
hepatic metabolism (CYP3A4)
Excretion
8 hours, 2x daily
Half-life
Note
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