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75 Cards in this Set
- Front
- Back
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Tetrahydrofolate
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Product of folic acid metabolism. Humans can use exogenous forms, but bacteria must synthesize de novo.
Synthesis begins with GTP |
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Sulfonamides
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Inhibit Dihydropteroate Synthase
Part of folic acid metabolism Absent in humans Competitive inhibitors and alternate substrates Mimic PABA Sulfamethoxazole Bacteriostatic |
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Diaminopyrimidines
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Inhibit dihydrofolate Reductase
Part of folic acid metabolism Trimethoprim Methotrexate Bacteriostatic |
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TMP-Sulfa
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Co-trimoxazole
Bactericidal unlike individual classes Most side effects come from sulfa drugs here |
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Cationic Peptide Antibiotics
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Amphophilic.
Form pore in membrane of gram NEGATIVE bacteria to allow stuff to leak out Have positively charged amines on outside Gramacidin Polymyxin B1 Colistin High toxicity |
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Daptomycin
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Complexes with Ca2+ which causes membrane disruption
Gram POSITIVE only |
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ESKAPE Pathogens
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Enterococcus Faecium
Staphylococcus Aureus Klebsiella Pneumoniae Acinetobacter Baumanii Pseudomonas Aeroginoa Enterobacter |
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Oleandomycin
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Glucosylation of oleandomycin to inactivate it
Then exported by OleB pump to reactivate it Effective against macrolides Example of producer immunity |
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Types of Beta Lactamases
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A, C, D = Serine
B = Zinc |
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Aminoglycoside resistance
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Modify 16S rRNA of 30S ribosomal subunit
3 routes. Acetylation, Phosphorylation, Adenylation |
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Main Gram Positive Efflux Pump
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MFS
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Main Gram Negative Efflux Pump
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RND
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Types of efflux pumps in bacteria?
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H+ driven rather than the ATP driven ones in eukaryotes
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MRSA
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MRSA has new PBP called PBP2A
PBP2A has low affinity to B-lactams Treat by adding large hydrophobic groups Make less immunogenic by having it release the toxic side chain when binding PBP2a |
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S. Pneumoniae Resistance
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Altered PBPs with reduced B-lactam affinities
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Macrolide resistance
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Modification of 23s RNA of 50S ribosome subunit.
Modification is Methylation of A2058!! Telithromycin (a ketolide) maintains activity after methylation due to long arm going towards A752! |
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MLSb Resistance
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Macrolides, Lincosamides, Streptogramin B all share binding sites
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Vancomycin resistance
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3 phenotypes. VanA, B, C.
Converts D-Ala-D-Ala to D-Ala-D-Lac Teicoplanin does not trigger VanB transcription, so it still works. Via Two Component System, much like Gram + Quorum Sensing |
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Adhesins
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Structures that extend out from the bacterial cell surface.
Pili |
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Exotoxins
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Type 1: Superantigens
-Stimulate host cells and lead to extensive inflammatory reactions Type 2: Cytolytic exotoxins (enzymes) -Toxins that disrupt integrity of cells and tissues Type 3: A-B -A inactivates host cell target or signaling pathway -B binds to receptor on host cell Inhibit via transcriptional level or receptor mimics |
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Quorum Sensing 4 step process
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1. Production of signaling autoinducer
2. Release of signaling molecules 3. Recognition of signaling molecules by receptor 4. Changes in gene expression |
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Gram Negative Quorum Sensing
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Luxl synthesizes autoinducers
Autoinducers bind to LuxR to drive transcription of target genes Autoinducers have Acyl Homoserine lactone |
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Gram Positive Quorum Sensing
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Two component system
Autoinducers bind to histidine kinase which phosphorylates response regulator |
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Vibrio Cholerae Quorum Sensing
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In low cell density, Qrr1-4 made which deactivate HapR
In high cell density Qrr1-4 are cut up which allows HapR to lead to quorum sensing target genes |
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Quorum Sensing Therapy
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Inhibitors of LasR cause weak and poorly formed biofilms that are more sensitive to antibiotics.
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Probenacid in combos?
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Probenacid inhibits renal secretion of most Beta lactams
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Statins
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May inhibit staphyloxanthin in cell membrane.
Show benefit in S. Aureus infections |
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Vanco/Dapto + ?
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+ Rifampin
Good for deep foci of infection where large antibiotics cant penetrate well |
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Methods of determining antibiotic synergy
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Checkerboard testing
Agar Dilution Dynamic Kill Curve |
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Checkerboard
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Used to assess combination IN VITRO
Fractional Inhibitor Concentration (FIC) <0.5 synergy. <1 Additivity, >2 antagonism |
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Agar Dilution
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Disk or Etest Diffusion
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B-Lactam + B-Lactamase inhibitors better for what?
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Gram negative
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Vanco + B-Lactams
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Example of multiple targets along one pathway for synergy.
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Daptomycin + B-Lactams
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Both target membrane/Cell Wall
B-Lactams increase DAp binding to membrane |
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Gentimicin + Penicillin
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Penicillin opens up membrane, Gentimicin goes on in!
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Main Bactericidal antibiotics?
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B-Lactams, Vanco, Daptomycin
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Aminoglycosides + Static Antibiotics
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Inihibits active transport mechanisms necessary for aminoglycoside uptake
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Static Antibiotics
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Tetracyclines, MLS antibiotics, Linezolid
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Pharmacodynamics of Beta Lactams
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Time > MIC
Do NOT have PAE |
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Pharmacodynamics of Aminoglycosides
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Cmax/MIC
Single dose better to increase Peak. Have good PAE Lower troughs should improve safety |
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Pharmacodynamics of Macrolides
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AUC/MIC
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Pharmacodynamics of Fluoroquinolones
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AUC/MIC
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Pharmacodynamics of Glycopeptides
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AUC/MIC
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Types of Fungi
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Filamentous fungi (molds)
-Reproduce by asexual spores -Form longer chains Yeast -Grow as single cells and reproduce by budding. Resemble little groups of circles Dimorphic Fungi -Filamentous at room temp -Yeast at body temp |
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Example of dimorphic fungi
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Cryptococcus Neoformans
Encapsulated -Prevents neutrophils inhibiting |
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Most common opportunistic Fungal infections
and strains causing/location |
Candidiasis - Candida albicans (normal part of human flora)
Aspergillosis - Aspergillus via respiratory tract Cryptococcosis - Primary infection in lungs Zygomycosis - Histoplasmosis, Blastomycosis. Sinopulmonary Pneumocystic carinii (Use TMP Sulfa to treat) |
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Azoles
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Inhibit ergosterol biosynthesis by inhibiting 14-alpha-sterol-demethylase.
Ergosterol regulates membrane fluiditity. Fungicidal! |
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Polyenes
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Bind ergosterol and form pores
have hydrophobic and hydrophilic part Amphotericin B Resistance quite rare |
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Allylamines
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Inhibit Lanosterol biosynthesis (earlier step of ergosterol synthesis) by inhibiting squalene epoxidase.
Damage is due to squalene accumulation rather than ergosterol deficiency Fungistatic most of the time No resistance so far Terbinafine |
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Pyrimidines
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Inhibit DNA/RNA synthesis
5-FdUMP Inhibits thymidylate synthase 5FC is prodrug 5FU Fungistatic |
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Candins
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Inhibit Glucan biosynthesis noncompetitively. Affect cell wall.
Not orally Bioavailable Suffix is -Fungin Act on B-(1,3)-glucan synthetase Fungicidal Resistance due to target mutation Safest class!! |
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Azoles resistance
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Alteration in drug target via mutations
Reduction of azole entering cell due to efflux pumps |
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Amphotericin formulations
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Fungizone is oldest and cheapest, has highest toxicity, lowest Cmax
Fungizone has SERIOUS nephrotoxicity Must give all of these IV Highest concentration found in spleen and liver VERY long half life |
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Abelcet
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Amphotericin in phospholipid ribbons
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Amphotec
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Amphotericin in cholesterol disks
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Ambisome
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Amphotericin in liposomes
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Which candin has unique PK?
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Anidulafungin. Non-enzymatic elimination
No drug-drug intx or PK differences! |
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Pyrimidine resistance
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1. 5FC uptake (loss of permease activity)
2. Loss of enzyme activities to convert 5FC to 5-FUMP |
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Example of antifungal antagonism
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Azoles deplete ergosterol, which removes the targest for polyenes.
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Example of antifungal synergy
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Pretreatment with Amphotericin B leads to pores which ease access of azoles to inside
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Ribavirin
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Inhibits RNA polymerase for non-retroviral viruses
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Stribild
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5 drug combo for HIV
Cobicistat is used as a 3A4 inhibitor to allow lower doses of elvitegravir, rather than to act by itself |
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Acyclic Nucleoside Phosphonates
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Acyclovir is prototype. Bottleneck is first phosphorylation.
Adefovir has first phosphorylation already done so it works much faster. P-O-C sensitive to esterases P-C-O is resistant to esterases |
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Cidofovir
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Chain terminator of viral DNA polymerase
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Nucleoside RT inhibitors
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Lamivudine, Abacavir, Tenofovir (prodrug)
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Nonnucleoside RT inhibitors
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Only hit HIV-1, bind to non-active site.
Efavirenz, Nevirapine |
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HIV protease inhibitor
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Phenylalanine and proline mimics
Transition state analogs All have hydroxyethylene core Saquinavir, Lopinavir, Ritonavir |
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Raltegravir
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HIV integrase inhibitor
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Valacyclovir
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Prodrug for acyclovir. DNA polymerase inhibitors
Substrate for intestinal peptide transporters |
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RNA non-retrovirus parts
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Hemaglutinin helps get into cell
Neuraminidase helps get out of cell |
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M2 Blockers
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Amantadine, Rimantadine.
Inhibit viral uncoating process |
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Neurominidase Inhibitors
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Sialic Acid mimics.
Oseltamivir Peramivir |
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Tamiflu
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Oseltamivir
Neuraminidase inhibitor |
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Peramivir
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Emergency for H1N1
Neuraminidase inhibitor |
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Viramidine
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Prodrug converted to ribavirin
Inhibits IMP dehydrogenase which is necessary for RNA synthesis |
