OPTO 6434 General Pharmacology
Antibacterial Agents III
Inhibitors of Bacterial Protein Synthesis
Dr. Alison McDermott
Room 254 HBSB, Phone 713-743 1974
Email [email protected]
Fall 2015
Reading:
Chapter 47 Brody’s Human Pharmacology by Wecker et al. 5th edition.
1. Introduction
Aminoglycosides
Tetracyclines
Chloramphenicol
Macrolides & Ketolides
Clindamycin
Streptogramins
Oxazolidinones
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Aminoglycosides are bactericidal, others mainly bacteriostatic
Most effective against both Gram +ve and Gram –ve, and organisms without proper cell wall
Several more toxic ∴ more restricted use
Resistance a problem
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2. Mechanism of Action
3. Aminoglycosides
Streptomycin
Gentamicin (Gentak)
Kanamycin
Neomycin (Neosporin)
Tobramycin (TOBI, Tobrex)
Amikacin
3.1 General Information and Mechanism of Action
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Bactericidal (because disrupt cell membrane as well as inhibit protein synthesis)
Gram-ve more than Gram +ve. Uptake is oxygen dependent so not active against anaerobes
Mechanism of Action:
Bind to 50s / 30s / interface of ribosomes
Interferes with protein synthesis by:
Stops binding of fMet-tRNA (always the first to bind during protein synthesis)
Restricts polysome formation (reduces amount of proteins produced)
Distorts codon and causes misreads (incorrect proteins produced)
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Resistance due to:
Mutation in ribosomal protein (not common)
Decreased drug entry (not common)
Structural modification of drug by phosphorylation, adenylation or acetylation which
reduces ability to bind to ribosomes (major mechanism)
3.2 Pharmacokinetics and Uses
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NOT absorbed orally so given parenterally, also topically
Renal elimination
Major activity against Gram -ve bacilli and Pseudomonas, but also against Staphylococci
Systemically ONLY used for serious infections and often in combined therapy
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Gentamicin - preferred aminoglycoside, used for e.g. intra-abdominal & gynaecological
infections
Ocular uses:
Systemic gentamicin for Pseudomonas keratitis, endophthalmitis, prophylactic after
penetrating eye injury
Topical tobramycin, gentamicin, neomycin for keratitis & conjunctivitis
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3.3 Adverse effects (systemic administration)
• Renal toxicity
Up to 25% of patients
Damages renal tubules (reversible) – internalized and blocks prostaglandin production,
mitochondrial and ribosomal function leading to proteinuria, reduced GFR etc
Older female patients with liver disease & hypotension, patients also receiving
cyclosporine or amphotericin B (an antifungal) or having split doses are at increased risk
of developing toxicity
• Ototoxicity
Up to 25%
Auditory:
Hair cell loss in organ of Corti
High frequency range first affected then auditory range
Vestibular:
Damage to hair cells in ampullar cristae
Vertigo, headache, nausea
Concomitant loop diuretics or split doses increase risk of auditory toxicity
Streptomycin & gentamicin cause more vestibular toxicity, amikacin causes more
auditory
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Neuromuscular paralysis
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4. Tetracyclines
Tetracycline (Achromycin)
Minocycline (Dynacin, Minocin)
Doxycycline (Monodox, Vibramycin)
Oxytetracycline (Terramycin)
Demeclocycline (generic)
Tigecycline (Tygacil)
4.1 General information and Mechanism of Action
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Bind to 30s subunit, prevent attachment of incoming tRNA-amino acid so elongation of
amino acid chain cannot occur
Resistance:
Bacteria have plasmid or transposon that codes for protein that facilitates transport of
drug OUT of organism
Mutations in bacterial genome give altered membrane proteins which prevent drugs
entering organism
Bacteria have plasmid that codes for protein that prevents binding of drug to ribosome
Tigecycline (newest) has higher (x5) affinity for 30s and best resistance
4.2 Pharmacokinetics and Uses
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Variable oral absorption
Widely distributed, only Minocycline reaches adequate levels in brain
Metabolised then renal or biliary excretion
Wide spectrum: aerobic and anaerobic Gram +ve and -ve, mycoplasmas, chlamydiae but
NOT effective against Strep. Staph. E. coli, Shigella, Pseudomonas due to resistance
Used for:
Rickettsial diseases (Gram -ve infection from flea/tick bites)
Doxycycline is used to treat chlamydia, acne, prophylaxis of malaria
Minocycline used for MRSA and prophylaxis of meningitis
Ocular uses:
Oxytetracycline (combined with other antibacterials) used topically for ocular infections
Systemic doxycycline or tetracycline for chlamydia conjunctivitis
Systemic doxycycline/minocycline for blepharitis/meibomian gland dysfunction
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4.3 Adverse effects
• Allergy
• Photosensitivity
• Bind to bone and tooth enamel so NEVER GIVEN TO CHILDREN < 8 YEARS OF AGE
OR PREGNANT WOMEN
• GI - nausea, ulcers
• Hepatotoxicity
• Aggravate existing renal dysfunction
• Oral or vaginal candidiasis
5. Chloramphenicol
5.1 General information and Mechanism of Action
• Binds to 50s subunit and prevents attachment of incoming tRNA-amino acid so elongation of
growing amino acid chain cannot occur
• Resistance:
Bacteria have plasmid that codes for enzyme that acetylates the drug and so prevents it from
binding to the ribosome
Alterations in cell wall limit entry of the drug
Modified ribosomal subunits to which the drug cannot bind
5.2 Pharmacokinetics and Uses
• Good oral absorption, very well distributed reaching CSF and eye. Also crosses placenta
• Conjugated in liver to glucuronide, eliminated by kidney
• Wide spectrum of activity: aerobic and anaerobic Gram +ve and -ve, chlamydiae, rickettsiae
and mycoplasmas
• Bacteriostatic with most, Bactericidal to H. influenzae, N. meningitides
• BUT due to toxicity always considered a "last resort" drug e.g. bacterial meningitis, brain
abscesses
5.3 Adverse effects
• Affects mitochondrial membrane enzymes cytochrome oxidase, adenosine triphosphatases
• Myelosuppression - inhibition of blood cell production in bone marrow. Most cases develop
during treatment and are reversible but may get fatal aplastic anaemia or acute leukemia after
treatment has stopped
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Gray baby syndrome - ability to metabolise/eliminate drug not fully developed in neonates so
may build up to toxic levels causing pallor, cyanosis, flaccidity, abdominal distention and
circulatory collapse
Optic neuritis in children
6. Macrolides and Ketolides
Erythromycin (Erythrocin)
Clarithromycin (Biaxin)
Azithromycin (Zithromax, Azasite)
Telithromycin (Ketek)
6.1 General Information and Mechanism of Action
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Bind to 50s ribosomal subunit and inhibit translocation
Resistance of Macrolides due to:
Bacteria have MLSB phenotype i.e. have plasmid carrying “erm (erythromycin ribosome
methylation) gene” that codes for an enzyme that methylates the ribosome so drug cannot
bind
Increased efflux due to “mef (macrolide efflux) gene” which codes for a pump
Alteration in components of outer membrane in Gram -ves limits drug entry
Production of esterase enzymes that hydrolyse and inactivate drug
Bacteriostatic or bactericidal depending on organism
6.2 Pharmacokinetics and Uses
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Absorbed orally and well distributed
Most excreted in bile
All primarily against Gram +ve cocci, bacilli. Mycoplasmas, Chlamydiae, Legionella,
Bordetella pertussis
NOT very effective against Gram -ve aerobes due to resistance
Telithromycin (a ketolide) concentrates in phagocytes so good for killing intracellular
pathogens. Higher affinity for ribosomes than the macrolides. Activity not affected by erm or
mef resistance genes.
Uses:
Alternative drug of choice in penicillin allergic patients
Often used for community acquired pneumonia
Ocular uses:
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Erythromycin as topical for superficial ocular infections, prophylaxis of gonococcal or
chlamydial conjunctivitis in newborns
Systemic erythromycin or azithromycin for chlamydial conjunctivitis
Topical azithromycin for bacterial conjunctivitis
6.3 Adverse Effects
• Erythromycin
Most common: GI - Abdominal cramps, neausea
Less common: hepatoxoicity, transient deafness
Inhibits p450 so e.g. prolongs half-life of theophylline which can lead to seizures and
dysrhythmias
• Clarithromycin
GI - Abdominal cramps, nausea (but less than erythromycin)
Inhibits p450 so e.g. prolongs half-life of theophylline which can lead to seizures and
dysrhythmias
• Azithromycin (2nd most commonly prescribed antibacterial)
Least adverse effects
No inhibition of p450 so less drug interactions
• Telithromycin
Most common – GI and nausea
Inhibits p450
7. Clindamycin
7.1 General Information and Mechanism of Action
• Cleocin, Clindets
• Mechanism of Action:
Binds to 50s subunit and prevents attachment of incoming tRNA-amino acid so
elongation of amino acid chain cannot occur
Also prevents translocation
• Resistance due to plasmid having erm gene i.e. that codes for an enzyme that methylates the
ribosome so drug cannot bind
7.2 Pharmacokinetics and Uses
• Good oral absorption
• Well distributed, reaches high enough level in CSF for toxoplasmosis but not meningitis
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Metabolised to demethyl and sulphoxide metabolites which also have activity
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Eliminated in kidney and bile
Active against most Gram +ve cocci, many anaerobes but NOT aerobic Gram -ves
Uses: Intra-abdominal and gynaecological infections (e.g. Bacteroides), anaerobic pulmonary
infections
Alternative to penicillin
7.3 Adverse Effects
• Pseudomembranous colitis due to C. difficile in 3-5% patients
8. Streptogramins
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Quinupristin and dalfopristin (30:70 mix for IV is Synercid)
Mechanism of action – 50s is target
quinupristin inhibits "late phase" get incomplete protein chains
dalfopristin inhibits "early phase" – elongation
Several mechanisms leading to resistance: erm gene, increased efflux
Metabolised in liver, metabolites also have activity
Together the two drugs have synergistic activity against variety of organisms
Used for life-threatening vancomycin resistant Enterococcus faecium bactremia, also skin
and skin structure infections due to Staph. aureus
Adverse effects:
Inflammation. Pain, thrombophlebitis at injection site
Pseudomembranous colitis due to C. difficile overgrowth
Inhibits metabolism of other drugs e.g. cyclosporine, protease inhibitors (for HIV)
9. Oxazolidinones
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Linezolid (Zyvox)
Binds to 50s subunit and stops it interacting with 30s, so functional 70s never formed
Resistance (not common) due to mutated 23s rRNA gene which alters binding site
Oral or IV
Most effective against Gram +ve aerobes
Used for nosocomial pneumonia, skin and skin structure infections due to staph and strep
Adverse effects:
Myelosupression (particularly low platelets)
Lactic Acidosis
Peripheral and optic neuropathy (long term use)
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