inhibitors of protein synthesis 1.30s directed: irreversible=cidal aminoglycosides selective...
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Inhibitors of Protein SynthesisInhibitors of Protein Synthesis1.1. 30S directed: irreversible=cidal30S directed: irreversible=cidal
aminoglycosidesaminoglycosides• selective toxicityselective toxicity: active transport into bacteria, requires oxid/phos and is affected by pH, O2, : active transport into bacteria, requires oxid/phos and is affected by pH, O2,
cations, no penetration into animal cellscations, no penetration into animal cells
2.2. 50S directed: reversible=static50S directed: reversible=staticchloramphenicol, erythromycin, (clarithromycin), clindamycin, quinupristin/dalfopristin, chloramphenicol, erythromycin, (clarithromycin), clindamycin, quinupristin/dalfopristin,
linezolidlinezolid• selective toxicityselective toxicity: do not penetrate mito/ poor binding to mitochondrial and animal ribosomes: do not penetrate mito/ poor binding to mitochondrial and animal ribosomes
3.3. 30S directed: reversible=static30S directed: reversible=statictetracyclines (doxycycline, minocycline)tetracyclines (doxycycline, minocycline)
• selective toxicityselective toxicity:energy dependent uptake by sensitive bacteria, animal ribosomes sensitive :energy dependent uptake by sensitive bacteria, animal ribosomes sensitive to high dose but no active transportto high dose but no active transport
Folic Acid Pathway InhibitorsFolic Acid Pathway Inhibitorssulfonamides, trimethoprimsulfonamides, trimethoprim– selective toxicityselective toxicity: :
• sulfonamides: animal cells do not make folate, we sulfonamides: animal cells do not make folate, we absorb it absorb it from the environment from the environment
• trimethoprim: has much higher affinity for the bacterial trimethoprim: has much higher affinity for the bacterial DHFR than the mammalian DHFRDHFR than the mammalian DHFR
Pathway of tetrahydro-Pathway of tetrahydro-folate cofactor synthesisfolate cofactor synthesisand role in DNA, RNA,and role in DNA, RNA,and protein synthesisand protein synthesis
Trimethoprim inhibitsTrimethoprim inhibits
Sulfonamides inhibitsSulfonamides inhibits
Folic Acid
DHFRDHFR
thymidylate synthetasethymidylate synthetase
Synergistic combinations of Synergistic combinations of Trimethoprim & SulfamethoxazoleTrimethoprim & Sulfamethoxazole
(Bactrim®, Septra®) (Bactrim®, Septra®) Staph sensitivityStaph sensitivity
Sulfamethoxazole MIC = 3 ug/mlSulfamethoxazole MIC = 3 ug/ml Trimethoprim MIC = 1 ug/mlTrimethoprim MIC = 1 ug/ml combo MIC = 0.3 Sulf & 0.015 Trimcombo MIC = 0.3 Sulf & 0.015 Trim
• 20:1 ratio most effective20:1 ratio most effective
AdvantagesAdvantages more likely to be cidalmore likely to be cidal broader spectrumbroader spectrum decreased resistancedecreased resistance lower doses = lower toxicitylower doses = lower toxicity
Other mechanismsOther mechanisms
Membrane disrupters: Membrane disrupters: DaptomycinDaptomycin
• lipopeptide that binds bacterial lipopeptide that binds bacterial membranesmembranes
• causes ion leakage and causes ion leakage and membrane depolarizationmembrane depolarization
• leads to cell death (cidal) leads to cell death (cidal)
Daptomycin actionDaptomycin action
active against gram+ including methicillin resistant Staph A active against gram+ including methicillin resistant Staph A (MRSA) and vancomycin resistant enterococcus (VRE)(MRSA) and vancomycin resistant enterococcus (VRE)
alternative to vancomycin for MRSA (especially important alternative to vancomycin for MRSA (especially important as vancomycin resistant MRSA emergesas vancomycin resistant MRSA emerges other alternatives: linezolid, quinupristin/dalfopristin, other alternatives: linezolid, quinupristin/dalfopristin,
Other mechanismsOther mechanisms RNA synthesis inhibitors:RNA synthesis inhibitors:
rifampin--binds bacterial RNA Polymerase and rifampin--binds bacterial RNA Polymerase and inhibitsinhibits
selective toxicity: little binding to human RNA selective toxicity: little binding to human RNA polymerasepolymerase
DNA gyrase/topoisomerase inhibitorsDNA gyrase/topoisomerase inhibitors prototype: nalidixic acidprototype: nalidixic acid fluoroquinolonesfluoroquinolones
• ciprofloxacin, norfloxacin: broad spectrum, low toxicityciprofloxacin, norfloxacin: broad spectrum, low toxicity• newer derivatives: trovafloxacin, moxifloxacin, levofloxacin newer derivatives: trovafloxacin, moxifloxacin, levofloxacin
have expanded spectrum, longer half life, high oral have expanded spectrum, longer half life, high oral bioavailability bioavailability
REPLICATIONREPLICATION
TRANSCRIPTIONTRANSCRIPTION
TOPO IVTOPO IVGYRASEGYRASE
Function of DNA gyrase and topoisomerase Function of DNA gyrase and topoisomerase IV in replication and transcriptionIV in replication and transcription
Mechanism of actionof ciprofloxacin and otherDNA gyrase/topoisomerase
IV inhibitors
N
NH
CH3N
O
OH
O
F
OCH3
N
O
OH
O
N
NH
F
N
NH
N
O
OH
O
F
CH3
N N
O
OH
O
CH3
CH3
Gatifloxacin
CiprofloxacinNalidixic acid
Norfloxacin Levofloxacin
Moxifloxacin
N
N
O
OH
O
F
O
N
CH3CH3
S
N
O
OH
O
F
NNH
H
H
OCH3
S
S
Quinolones
Metronidazole--mechanism of actionMetronidazole--mechanism of action
Anaerobic organisms Anaerobic organisms contain ferredoxins that can contain ferredoxins that can activate metronidazole to activate metronidazole to form a reactive nitro radical form a reactive nitro radical anion that kills by targeting anion that kills by targeting DNA/other biomoleculesDNA/other biomolecules
Treatment examples:Treatment examples: Giardiasis (protozoal infection)Giardiasis (protozoal infection) also used to treat Clostridium also used to treat Clostridium
difficiledifficile
Giardia lamblia
Risk of Giardia in the mountains?Risk of Giardia in the mountains?
up to 35% of children in daycare test positive forGiardia in stool samples! most asymptomatic
Oral Absorption of AntibioticsOral Absorption of Antibiotics
Good:Good: sulfonamideschloramphenicolclindamycintrimethoprimisoniazid, pyrazinamideciprofloxacindoxycyclinecycloserinemetronidazolelinezolid
Bad or variable:Bad or variable: penicillins (some are, many aren’t)cephalosporins (few are, most are
not)erythromycin (estolate conjugate)
(clarithromycin is better)
Ugly:Ugly: aminoglycosides:gentamicintobramycinamikacinnetilmicin
vancomycinquinupristin/dalfopristinmeropenem
Therapeutic levels in the CSF?Therapeutic levels in the CSF?
Good:Good: ciprofloxacinsulfonamides, trimethoprimchloramphenicolsome 3rd generation cephalosporins
(e.g. ceftriaxone, ceftizoxime)meropenemcycloserine, metronidazolepyrazinamide, isoniazidlinezolid
OK:OK: (esp. when meninges inflamed)ampicillin, ticarcillinvancomycinrifampin
Poor:Poor:aminoglycosidesaminoglycosidestetracyclinestetracyclinesclindamycinclindamycinerythromycinerythromycincefaclorcefaclorquinupristin/dalfopristinquinupristin/dalfopristin
(synercid)(synercid)
Distribution of drug into human cells?Distribution of drug into human cells?
Pathogens can enter cells Pathogens can enter cells Require intracellular phaseRequire intracellular phase
• Rickettsia (cytoplasm)Rickettsia (cytoplasm)• Chlamydia (phagosomes)Chlamydia (phagosomes)
Can survive both intra and extracellular environmentCan survive both intra and extracellular environment• Mycobacteria (cytoplasm & phagosomes)Mycobacteria (cytoplasm & phagosomes)• Legionella (phagosomes)Legionella (phagosomes)• Listeria (cytoplasm)Listeria (cytoplasm)• Salmonella (phagosomes)Salmonella (phagosomes)
Question: Do antibiotics need to penetrate animal cell Question: Do antibiotics need to penetrate animal cell to kill these pathogens?to kill these pathogens? probably not but it may helpprobably not but it may help
Antibiotic metabolism and excretionAntibiotic metabolism and excretion
1.1. excreted unchanged via kidneyexcreted unchanged via kidney
2.2. metabolized by liver metabolized by liver metabolites excreted by kidneymetabolites excreted by kidney metabolites excreted thru bilemetabolites excreted thru bile
Affected by renal/hepatic disease, developmental Affected by renal/hepatic disease, developmental state, pharmacogenetic traits, and drug/drug state, pharmacogenetic traits, and drug/drug interactionsinteractions
Drug Metabolism and ExcretionDrug Metabolism and Excretion
Excretion by Kidney (primarily)Excretion by Kidney (primarily)penicillins/cephalosporins
(both kidney and liver for some)
aminoglycosidestetracyclines (except
doxycycline)sulfonamidesvancomycinciprofloxacintrimethoprimpyrazinamide
Metabolized by Liver (primary)Metabolized by Liver (primary)doxycyclinechloramphenicolerythromycinclindamycinisoniazidrifampinmetronidazolelinezolidquinupristin/
dalfopristin
Chloramphenicol is metabolized in liver andChloramphenicol is metabolized in liver andthen excreted by kidneythen excreted by kidney
age 1-2 daysage 1-2 days
age 1-11 yearsage 1-11 years
Application of pharmacokinetic Application of pharmacokinetic principlesprinciples
Bactrim: 400mg sulfamethoxazole + 80 mg Bactrim: 400mg sulfamethoxazole + 80 mg trimethoprim in fixed dose---does this make trimethoprim in fixed dose---does this make sense?sense? what basic properties of these two drugs are what basic properties of these two drugs are
relevant?relevant?• optimal plasma ratio and concentrationoptimal plasma ratio and concentration• t1/2t1/2• oral bioavailabilityoral bioavailability• volume of distributionvolume of distribution• drug interactionsdrug interactions
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