Antibacterials 4 Flashcards
List Protein Synthesis Inhibitors antibiotics?
- Tetracyclines
- Glycylcyclines
- Aminoglycosides
- Macrolides
- Chloramphenicol
- Clindamycin
- Streptogramins
- Linezolid
- Mupirocin
General Idea of protein synthesis inhibitors?
• Bind to and interfere with ribosomes
• Bacterial ribosome (70S) differs from mammalian
(80S) but closely resembles mammalian mitochondrial
ribosome
• Bacterial ribosome made of 30S and 50S subunits
• Mostly bacteriostatic
3 types of tetracyclines and decribe?
Doxycycline, Minocycline, Tetracycline • Broad-spectrum • Bacteriostatic • Activity against many aerobic and anaerobic Grampositive & Gram-negative organisms
Tetracycline MOA?
• Entry via passive diffusion & energy-dependent
transport unique to bacterial inner cytoplasmic
membrane
• Susceptible cells concentrate drug intracellularly
• Bind reversibly to 30S subunit of ribosome, preventing
attachment of aminoacyl tRNA
Describe tetracycline resistance and 3 main mechanisms?
• Widespread resistance (usually plasmid mediated)
• 3 main mechanisms:
• Impaired influx or increased efflux by active
(plasmid-encoded) protein pump
• Production of proteins that interfere with binding to
ribosome
• Enzymatic inactivation
Tetracycline Clinical applications?
• Most common use = severe acne & rosacea
• Used in empiric therapy of community-acquired
pneumonia (outpatients)
• Can be used for infections of respiratory tract,
sinuses, middle ear, urinary tract, & intestines
• Useful at treating atypical pneumonias (Mycoplasma,
Chlamydia, Legionella)
• Syphilis (patients allergic to penicillin)
Describe Tetracycline PK?
• Variable oral absorption (decreased by divalent &
trivalent cations)
• Doxycycline (lipid soluble) = preferred for parenteral
admin. and good choice for STD’s and prostatitis
• Concentrate in liver, kidney, spleen & skin
• Excreted primarily in urine except doxycycline (primarily
via bile)
• TERATOGENIC – all cross placenta & are excreted into
breast milk (FDA category D)
Tetracyclines AE?
• Gastric effects / superinfections (nausea, vomiting, diarrhea)
• Discoloration & hypoplasia of teeth, stunting of
growth (generally avoided in pregnancy & not given in
children under 8y)
• Fatal hepatotoxicity (in pregnancy, with high doses,
patients with hepatic insufficiency)
• Exacerbation of existing renal dysfunction
• Photosensitization
• Dizziness, vertigo (esp. doxycycline & minocycline)
Describe Glycylcyclines and antibacterial spectrum?
Tigecycline
Antibacterial spectrum
Broad-spectrum against multidrug-resistant Grampositive,
some Gram-negative & anaerobic organisms
Describe Glycylcyclines resistance?
• Little resistance
• Not subject to same resistant mechanisms as
tetracyclines (exceptions = efflux pumps of Proteus &
Pseudomonas species)
Glycyclines Clinical applications and black box warning?
• Treatment of complicated skin, soft tissue and intraabdominal
infections
• Increased risk of mortality has been observed with
tigecycline compared with other antibiotics when
used to treat serious infections
• FDA recommends considering the use of alternative
antimicrobials when treating patients with serious
infections
Glycylcyclines PK, AE, and Contraindications?
• IV only • Excellent tissue & intracellular penetration • Primarily biliary/fecal elimination Adverse effects • Well tolerated • AE similar to tetracyclines Contraindications • Pregnancy & children <8y
List the 5 Aminoglycosides?
Amikacin, Gentamicin, Tobramycin, Streptomycin,
Neomycin
Describe Aminoglycosides? Relevant Pharmacodynamic effect?
• Bactericidal • Associated with serious toxicities • Largely replaced by safer antibiotics Postantibiotic effect \+Concentration-dependent killing= Once-daily dosing
What are concentration dependent vs time dependent antibiotic examples?
- Concentration-dependent (aminoglycosides)
* Time-dependent (penicillins, cephalosporins)
Aminoglycoside MOA?
• Passively diffuse across membranes of Gram negative organisms
• Actively transported (O
2-dependent) across cytoplasmic membrane
• Covalently bind to 30S ribosomal subunit prior to
ribosome formation leading to irreversible inhibition of
initiation complex :
• misreading of mRNA, &
• blockade of translocation
Antibacterial spectrum of Aminoglycosides?
- Most active against aerobic Gram-negative bacteria
* Anaerobes lack O2-dependent transport
What are the 3 principle mechanisms of aminoglycoside resistance?
3 principal mechanisms:
• Plasmid-associated synthesis of enzymes that
modify and inactivate drug by acetylation,
phosphorylation and adenylation
• Decreased accumulation of drug
• Receptor protein on 30S ribosomal subunit may be
deleted or altered due to mutation
Aminoglycoside Clinical Applications?
• Used mostly in combination
• Once organism is identified aminoglycosides are normally discontinued in favor of less toxic drugs
• Empiric therapy of serious infections eg, septicemia,
nocosomial respiratory tract infections, complicated
UTI’s, endocarditis etc
• Neomycin for bowel surgery and hepatic
encephalopathy, as well as topically
Drugs of choice for:
• Empiric therapy of infective endocarditis in
combination with vancomycin
Aminoglycoside PK?
- Parenteral admin. only (except neomycin - topical)
- Once-daily admin.
- Well distributed (excluding CSF, bronchial secretions)
- High levels in renal cortex & inner ear
- 99% excreted in urine (reduce dose in renal insufficiency)
AE of Aminoglycosides?
Both time- and concentration-dependent
• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade (myasthenia gravis =
contraindicated)
• Pregnancy (contraindicated unless benefits outweigh risks
– FDA Category D)
Describe oral Neomycin?
• Used as adjunct in treatment for hepatic encephalopathy Alternative treatment options for hepatic encephalopathy: • Lactulose • Oral vancomycin • Oral metronidazole • Rifaximin
Lactulose MOA
• Nonabsorbable disaccharide MOA • Degraded by intestinal bacteria ->lactic acid + other organic acids -> acidification of gut lumen -> favors formation of NH 4+ from NH3 -> NH4 \+ is trapped in colon effectively reducing plasma ammonia concentrations
Other effects and adverse effects of lactulose?
Other Effects • Prebiotic (suppression of urase producing organisms) • Osmotically active laxative Adverse Effects • Osmotic diarrhea • Flatulence • Abdominal cramping
Name 4 Macrolides
Erythromycin, Clarithromycin, Azithromycin, Telithromycin
Describe Macrolides?
- Mainly used to treat Gram-positive infections
* Bacteriostatic (bactericidal at high conc.)
Macrolides MOA?
• Reversibly bind to the 23S rRNA of the 50S subunit
blocking translocation
• Binding site is identical or close to that for clindamycin & chloramphenicol
Macrolides Resistance(last 2 most important?
3 main mechanisms (usually plasmid encoded):
• Reduced membrane permeability or active efflux
• Production of esterase that hydrolyze drugs (by
enterobacteriaceae)
• Modification of ribosomal binding site (by
chromosomal mutation or by methylation)
• Complete cross-resistance between erythromycin,
azithromycin, & clarithromycin
• Partial cross-resistance with clindamycin & streptogramins
Describe Macrolide antibacterial spectrum?
• Most active against Gram-positive bacteria (some activity against Gram-negatives)
• Spectrum is slightly wider than that of penicillins
• Azithromycin, clarithromycin & telithromycin have broader
spectrum than erythromycin
Macrolides Clinical Applications?
• Used in empiric therapy of community-acquired
pneumonia (outpatient & in combination with beta-lactam for inpatients)
• Useful at treating atypical pneumonias (Mycoplasma,
Chlamydia, Legionella)
• Treatment of upper respiratory tract & soft-tissue
infections
• Erythromycin = DOC for whooping cough (B.pertussis)
• Common substitute for patients with penicillin allergy
Macrolides PK?
• Clarithromycin, azithromycin, telithromycin = improved
oral absorption, longer t1/2, increased bioavailability
compared to erythromycin
• Erythromycin, clarithromycin & telithromycin = CYP P450
inhibition (NOT azithromycin)
Macrolides AE?
- GI irritation
- Hepatic abnormalities (erythromycin & azithromycin)
- QT prolongation
- Severe reactions are rare (anaphylaxis, colitis)
Macrolide Contraindications?
• Statins (due to macrolides inhibiting CYP P450)
• Telithromycin – fatal hepatotoxicity, exacerbations of
myasthenia gravis, & visual disturbances
-> don’t use for
minor illnesses
Describe Chloramphenicol?
• Potent inhibitor of protein synthesis
• Broad-spectrum (aerobic & anaerobic Gram-positive & -
negative organisms)
• Bacteriostatic (usually)
• Toxicity limits use to life-threatening infections with
no alternatives
Chloramphenicol MOA?
• Enters cells via active transport process
• Binds reversibly to 50S ribosomal subunit (site adjacent
to site of action of macrolides & clindamycin), inhibiting
peptidyltransferase
• Can inhibit protein synthesis in mitochondrial ribosomes
-> bone marrow toxicity
Chloramphenicol Resistance?
• Presence of factor that codes for chloramphenicol
acetyltransferase (inactivates drug)
• Changes in membrane permeability
Chloramphenicol antibacterial spectrum?
• Very broad spectrum
• Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes
• N.meningitidis, H.influenzae, Salmonella & bacteroides =
highly susceptible
• Never given systemically for minor infections (due to
adverse effects)
Chloramphenicol Clinical Applications?
• Serious infections resistant to less toxic drugs
• When chloramphenicol’s penetrability to site of
infection is clinically superior to other drugs
• Active against many VRE
• Topical treatment of eye infections (mainly outside
US)
Chloramphenicol PK?
- Oral, IV or topical
- Wide distribution (readily enters CSF)
- Inhibits hepatic oxidases (3A4 & 2C9)
Chloramphenicol AE?
• GI distress • Bone marrow depression • dose-related reversible depression • severe irreversible aplastic anemia • Gray baby syndrome (cyanosis), due to drug accumulation
Clindamycin MOA and uses?
• MOA = same as macrolides (binds to 50S subunit and
blocks transolcation)
• Mainly bacteriostatic
• Primarily used against Gram-positive anaerobic
bacteria.
• Also active against bacteroides and Gram-positive
aerobes
Clindamycin Resistance?
Due to: • mutation of ribosomal receptor site • modification of the receptor • enzymatic inactivation of drug • Most Gram-negative aerobes & enterococci are intrinsically resistant • Cross-resistant with macrolides
Clindamycin clinical applications?
• Anaerobic infections (eg, bacteroides infections,
abscesses, abdominal infections)
• Skin and soft tissue infections (streptococci and
staphylococci, and some MRSA)
• In combination with primaquine as an alternative in PCP
• In combination with pyrimethamine as an alternative
treatment for toxoplasmosis of brain
• As an alternative for prophylaxis in penicillin-allergic patients
Clindamycin PK?
- Oral or IV
* Good penetration (including abscesses and bones)
Clindamycin AE?
• Potentially fatal pseudomembranous colitis
(superinfection of C.difficile)
• GI irritation (~ 20% people experience diarrhea)
• Skin rashes (~10 %)
• Neutropenia & impaired liver function
