PROTEIN SYNTHESIS INHIBITORS Flashcards
PROTEIN SYNTHESIS INHIBITORS
- 1) Tetracyclines
- 2) Glycylcyclines
- 3) Aminoglycosides
- 4) Macrolides
- 5) Chloramphenicol
- 6) Clindamycin
- 7) Streptogramins
- 8) Linezolid
- 9) Mupirocin
Bind to and interfere with ribosomes
- Bacterial ribosome (70S) differs from mammalian (80S) but closely resembles mammalian mitochondrial ribosome
- Mostly bacteriostatic
DOXYCYCLINE
MINOCYCLINE
TETRACYCLINE
TETRACYCLINES
“DMT” binds to the THIRTY-S subunit
- broad spectrum
- bacterioSTATIC
- activity against many aerobic and anaerobic Gram +ve and -ve organisms
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 binding of aminoacyl tRNA
TETRACYCLINS - RESISTANCE
3 main mechanisms:
- Impaired influx or increased efflux by active protein pump
- Production of proteins that interfere with binding to ribosome
- Enzymatic inactivation
TETRACYCLINS - 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
- Syphilis (patients allergic to penicillin)
TETRACYCLINE IS DOC FOR
DOC FOR
- Chlamydia
- Mycoplasma pneumoniae
- Lyme disease
- Cholera
- Anthrax prophylaxis
• Rickettsia (Rocky Mountain Spotted Fever, typhus)
Used in combination for:
- H.pylori eradication
- Malaria prophylaxis and treatment
- Treatment of plague, tularemia, brucellosis
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
- Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state)
- 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)
TIGECYCLINE
is a GLYCYLCYCLINE
- is STRUCTURALLY similar to tetracyclines
- antibacterial spectrum: Broad-spectrum against multidrug-resistant Gram- positive, some Gram-negative & anaerobic organisms
RESISTANCE:
Little resistance
• Not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)
CLINICAL APPLICATIONS:
Treatment of complicated skin, soft tissue and intra- abdominal infections
GLYCYLCYCLINES - TIGECYCLINE
BLACK BOX WARNING
1) 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
GENTAMICIN
AMIKACIN
NEOMYCIN
TOBRAMYCIN
STREPTOMYCIN
“G-ANTS” - AMINOGLYCOSIDES
fight against AEROBIC gram -NEGATIVE
- Bactericidal
- Associated with serious toxicities
- Largely replaced by safer antibiotics
MOA:
- Passively diffuse across membranes of Gram-negative organisms
- Actively transported (O2-dependent) across cytoplasmic membrane
–> therefore are most active against AEROBIC GRAM -VE BACTERIA
• Bind to 30S ribosomal subunit prior to ribosome formation leading to:
- 1) misreading of mRNA, &
- 2) inhibition of translocation
PHARMACODYNAMICS;
Postantibiotic effect + Concentration-dependent killing
= Once-daily dosing
–> Concentration-dependent (aminoglycosides)
GLYCYLCYCLINES - PK/AE
IV only
• Excellent tissue & intracellular penetration • Primarily biliary/fecal elimination
Adverse effects
• Well tolerated
• AE similar to tetracyclines
Contraindications
• Pregnancy & children <8y
AMINOGLYCOSIDES - RESISTANCE
3 principal mechanisms:
1) Plasmid-associated synthesis of enzymes that
modify and inactivate drug
2) Decreased accumulation of drug
3) Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation
CONCENTRATION DEPENDENT VS TIME-DEPENDENT KILLING
- Concentration-dependent (aminoglycosides)
- Time-dependent (penicillins, cephalosporins)
AMINOGLYCOSIDES - CLINICAL APPLICATIONS
-Used mostly in COMBINATION
- Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc
- Once organism is identified aminoglycosides are normally
discontinued in favor of less toxic drugs
DOC:
1) Empiric therapy of infective endocarditis in combination with either a penicillin or (more commonly) vancomycin
2) Streptomycin is the drug of choice for Plague (Y.Pestis)
TREATEMENT FOR THE PLAGUE
-the plague (yersinia pestis) is treated with STREPTOMYCIN
ORAL NEOMYCIN
AMINOGLYCOSIDE
• Used as adjunct in treatment for hepatic encephalopathy
Alternative treatment options for hepatic encephalopathy:
1) Lactulose
2) Oral vancomycin
3) Oral metronidazole
4) Rifaximin
HEPATIC ENCEPHALOPATHY
-treated with ORAL NEOMYCIN
Alternative treatment options for hepatic encephalopathy:
- Lactulose
- Oral vancomycin
- Oral metronidazole
• Rifaximin
LACTULOSE
-Nonabsorbable disaccharide
MOA
• Degraded by intestinal bacteria lactic acid + other organic acids
–> acidification of gut lumen
–> favors formation of NH4+ from NH3
–> NH4+ is trapped in colon effectively reducing plasma ammonia concentrations
Other Effects
- Prebiotic (suppression of urase producing organisms)
- Osmotically active laxative
Adverse Effects
- Osmotic diarrhea
- Flatulence
- Abdominal cramping
AMINOGLYCOSIDES PK + AE
Like sticking the “sai” from sketchy into your EAR as well as KIDNEY
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:
Both time- and concentration-dependent
• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade (myasthenia gravis =
contraindicated)
• Pregnancy (contraindicated unless benefits outweigh risks – FDA Category D)
ERYTHROMYCIN
CLARITHROMYCIN
AZITHROMYCIN
TELITHROMYCIN
Mainly used to treat Gram-positive infections
• Bacteriostatic (bactericidal at high conc.)
MOA:
- Reversibly bind to 50S subunit inhibiting translocation
- Binding site is identical or close to that for clindamycin & chloramphenicol
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 - RESISTANCE
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 a methylase)
- Complete cross-resistance between erythromycin, azithromycin, & clarithromycin
- Partial cross-resistance with clindamycin & streptogramins
MACROLIDES - CLINICAL APPLICATION
- Used in empiric therapy of community-acquired pneumonia (outpatient & in combination with B-lactam for inpatients)
- DOC for Mycoplasma pneumoniae
- Treatment of upper respiratory tract & soft-tissue infections (eg, Staph, H.influenzae, S.pneumoniae, enterococci)
- Erythromycin = DOC for whooping cough (B.pertussis)
Is a common substitute for patients with penicillin allergy
WHOOPING COUGH TREATMENT
ERYTHROMYCIN (macrolide)
Mycoplasma Pneumonia treatment
macrolide
MACROLIDES PK + AE
PK:
- Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer t1/2, increased bioavailability compared to erythromycin
- Azithromycin & telithromycin = greater tissue penetration compared to other macrolides
- Erythromycin, clarithromycin & telithromycin = CYP P450 inhibition (NOT azithromycin)****
AE:
- GI irritation
- Hepatic abnormalities (erythromycin & azithromycin) • QT prolongation
- Severe reactions are rare (anaphylaxis, colitis)
MACROLIDE CONTRAINDICATIONS
Macrolides always standing on the static (statins) telephone poles (TELI) –> fatal hepatotoxicity, exacerbation of myasthenia gravis
CONTRAINDICATIONS:
1) Statins (due to macrolides inhibiting CYP P450)
2) Telithromycin – fatal hepatotoxicity, exacerbations of myasthenia gravis, & visual disturbances –> *don’t use for minor illnesses*
CHLORAMPHENICOL
Potent inhibitor of protein synthesis
• VERY Broad-spectrum (aerobic & anaerobic Gram-positive & -
negative organisms)
- Bacteriostatic (usually)
- Toxicity limits use to life-threatening infections with no alternatives
MOA:
Enters cells via ACTIVE TRANSPORT process
• Binds reversibly to 50S ribosomal subunit (site adjacent
to site of action of macrolides & clindamycin)
• Can inhibit protein synthesis in mitochondrial ribosomes
ADVERSE EFFECTS
–> bone marrow toxicity –> reversible or APLASTIC ANEMIA
CHLORAMPHENICOL ANTIBACTERIAL SPECTRUM + CLINICAL APPLICATIONS
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)
CLINICAL APPLICATIONS:
1) Serious infections resistant to less toxic drugs
2) When chloramphenicols penetrability to site of
infection is clinically superior to other drugs
3) Active against many VRE
4) Topical treatment of eye infections (mainly outside US)
CHLORAMPHENICAL PK + AE
Chloram”chemical” –> inhibits hepatic oxidases, and does BONE MARROW DEPRESSION b/c is such a strong chlorine chemical, also TURNS YOU GREY!!!
• Oral, IV or topical
• Wide distribution (readily enters CSF)
• Inhibits hepatic oxidases (3A4 & 2C9)
AE:
- GI distress
- Bone marrow depression
- dose-related reversible depression
- severe irreversible aplastic anemia
• Gray baby syndrome (cyanosis), due to drug accumulation
CLINDAMYCIN
“give it to 50 (for 50S subunit) y/o’s and then they get C diff
–> used for gut anaerobic bact
MOA = same as macrolides (binds to 50S subunit)
- Mainly bacteriostatic
- Primarily used against Gram-positive anaerobic bacteria. Also active against bacteroides
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
1) Anaerobic infections (eg, bacteroides infections, abscesses, abdominal infections)
2) Skin and soft tissue infections (streptococci and staphylococci, and some MRSA)
3) In combination with primaquine as an alternative in PCP (pneumocystis pneumonia)
4) In combination with pyrimethamine as an alternative treatment for toxoplasmosis of brain
5) Prophylaxis of endocarditis in valvular patients allergic to penicillin
CLINDAMYCIN - PK + AE
- Oral or IV
- Good penetration (including abscesses and bones)
AE:
• Potentially fatal pseudomembranous colitis (superinfection of C.difficile)
• GI irritation (~ 20% people experience diarrhea)
- Skin rashes (~10 %)
- Neutropenia & impaired liver function
QUINUPRISTIN
DALFOPRISTIN
PRISTIN = STREPTOGRAMINS
• Given as a combination (act synergistically to have
bactericidal action)
• Long postantibiotic effect
Mechanism of action
- Bind to separate sites on 50S bacterial ribosome
- Resistance is uncommon
ANTIBACTERIAL SPECTRUM:
1) Gram-positive cocci
2) Multi-drug resistant bacteria (streptococci, PRSP, MRSA, E.faecium)
QUINUPRISTIN
DALFOPRISTIN
CLINICAL APPLICATIONS:
STREPTOGRAMINS
Restricted to treatment of infections caused by drug- resistant
1) Staphylococci or
2) VRE
STREPTOGRAMINS PK + AE
- IV only
- Penetrates macrophages & polymorphonucleocytes
• Inhibitors of CYP 3A4
AE:
• Infusion related (venous irritation, arthralgia & myalgia)
- GI effects
- CNS effects (headache, pain)
LINEZOLID
LINEZOLID –> LINE –> looks like a 7, so know it that it binds to the 70S and the Z looks like a “+” sign so for gram +ve species. Line’s are STATIC
• Bacteriostatic (cidal against streptococci & Clostridium perfringens)
Mechanism of action
- Inhibits formation of 70S initiation complex
- Binds to unique site on 23S ribosomal RNA of 50S subunit
RESISTANCE:
- Decreased binding to target site
- No cross-resistance with other drug classes
ANTIBACTERIAL SPECTRUM:
Most Gram-positive organisms (staphylococci, streptococci, enterococci, Corynebacterium, Listeria monocytogenes)
• Moderate activity against mycobacterium tuberculosis
LINEZOLID CLINICAL APPLICATIONS
treatment of MULTI-DRUG RESISTANT INFECTIONS
LINEZOLID PK + AE
PK:
-Oral (100% bioavailable) & IV
• Widely distributed (including CSF)
• Weak reversible inhibitor of MAO
AE:
• Well tolerated for short admin. (GI, nausea, diarrhea, headaches, rash)
Long-term admin. can cause:
- _Reversible myelosuppression*****_
- _Optic & peripheral neuropathy, & lactic acidosis***_
LINEZOLID CONTRAINDICATIONS
Reversible, nonselective inhibitor of MAO
–> potential to interact with adrenergic and serotonergic drugs
FIDAXOMICIN
“FEDEX”-OMI-SIN –> if you want to fedex you sin, only a narrow time (narrow spectrum) for you to do that. Is anaerobic inside the fedex box, binds to the RNA polymerase to get delivered –> treats C DIFF!!! and you MUST BE 18 Y/O to use credit card to ship!!!
- Narrow spectrum macrocyclic antibiotic
- Activity against Gram-positive aerobes and
anaerobes especially _Clostridia_
• No activity against Gram-negative bacteria
MOA: Inhibits bacterial protein synthesis by binding to RNA polymerase
CLINICAL APPLICATOINS: treatment of C. diff colitis (in adults)
-when administered orally, systemic absorptoin is negligible but fecal concentrations are high
AE:
Main effects appear to be gastrointestinal disorders
• The safety and effectiveness of fidaxomicin in patients _< 18 years of age have not been established. *** watch this age_
TREATMENT OF C. DIFF COLITIS IN AN ADULT
FIDAXOMICIN
-patient must be AT LEAST 18 y/o
MUPIROCIN
MUCOUS IS IN!!! –> use it for INTRANASAL MRSA, or topically applied for impetigo, binds to bacterial isoleucyl transfer-RNA synthetase
Antibiotic belonging to monoxycarbolic acid class
• Activity against most Gram-positive cocci, including
MRSA and most streptococci (but not enterococci)
• Only topical/intranasal agent with activity against MRSA
MOA:
Binds to bacterial isoleucyl transfer-RNA synthetase resulting in the inhibition of protein synthesis
CLINICAL APPLICATIONS:
A) Intranasal:
• Eradication of nasal colonization with MRSA in
B) Topically:
adult patients and healthcare workers
• Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes
AE:
- Resistance develops if used for long periods of time
- Mainly local and dermatologic effects (eg, burning,
edema, tenderness, dry skin, pruritus)
MUPIROCIN
CLINICAL APPLICATIONS
Intranasal:
- Eradication of nasal colonization with MRSA in adult patients and healthcare workers
Topically:
- Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes
TREATMENT OF IMPETIGO or secondary infected traumatic skin lesion d/t S. aureus or S. pyogenes
MUPIROCIN
