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45 Cards in this Set
- Front
- Back
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Antibiotics are:
produced by: |
substances to kill other microorgs
produced by microorgs also: semi-synthetic, synthetic Most drugs semi synthetic |
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5 Desirable Properties of Ideal Antibacterial Drug
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Stability - PEN G v. PEN V.
Solubility Diffusibility - access BBB Slow Excretion - Protein binding/Drug combinations Large Therapeutic Indix -- SELECTIVE |
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Prophylaxis Def:
% drugs prophylatic? When are these used? |
temporarily decrease number of pathogens below critical level required to cause infection.
1/4 - 1/2 drugs do this Prevent epidemics Prosthetics Surgery Transplants |
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Empiric Therapy
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giving antibiotics before etiology of infectious is known -- time too precious to waste
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Minimum Inhibitory Concentration (MIC)
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lowest concentration of drug which completely inhibits growth at 24 hrs
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Minimum Bactericidal Concentration
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lowest concentration to kill all bacteria
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Disk Diffusion Assay
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Put different antibiotics on different parts of petri dish with pathogen smeared on -- big clear zone means its a good one!
MIC -- corresponds to not clear, not spotty but just kinda green? zone |
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Location of infection effects antibiotic choice because:
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CSF -- BBB (difficult to treat)
abscess -- pH/stability + no blood supply circulation limitations |
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Pharacokinetics:
ADMET 3 Types of "T" |
Absorption
Distribution Metabolism Excretion Toxicity: nephrotoxic, ototoxic, hypersensitity |
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Synergism
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more than additive effects when using drugs that have different mechanisms of action
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5 Possible Mechanisms of actions of antibacterials
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Nucleic Acid Synthesis Inhibition
DNA Damaging Agents Cell Wall Synthesis Inhibition Cell Membrane Damaging Agents Protein Synthesis Inhibitors |
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Inhibitors of Nucleic Acid Synthesis
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Sulfonamides/Trimethoprim - inhibit folic acid synthesis
Rifampin - inhibit RNA synthesis |
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DNA Damaging Agents
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Quinolones - DNA Gyrase, Topoisomerase IV inhibitors
Nitrofurantoin -- free radical generator Metronidazole -- anaerobic enzymatic reduction, then metabolite binds to DNA Methenamine -- breaks down to form formaldehyde which alkylates DNA and protein |
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Antifolate antibiotics (2):
Idea behind them: |
sulfonamides
trimethoprim Bacteria needs to synthesize own folate but humans get it from diet, so by inhibiting its production we selectively target bacteria cells |
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Sulfonamides:
Mech Selectivity |
Mech: binds dihydropteroate synthetase/competitive inhibitor of pABA --> inhibits folic acid synthesis
Selectivity: bacteria need to make own folate but we get it from diet |
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Sulfonamides:
Spectrum/resistance Clinical Uses |
Spectrum: both Gram + and -
There exist many resistant strains Clinical: simple UTI's (due to E. Coli) toxoplasmosis malaria prophylatic for burns; AIDS patients for prevention of Pneumocystis jirovecii |
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Sulfonamides:
Absorption Distribution Excretion |
A -- Good orally; some forms worse and used on purpose to decrease colonization density before surgery
D -- wide, gets to CSF E -- renal -- need patient well hydrated |
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Sulfonamides:
Toxicity (dose related v unrelated) |
Dose Related:
0.**Kernicterus** = sulfa drug displaces albumin bound bilirubin; free bilirubin passes BBB in newborn, deposits in CNS --> leads to encephlalopathy 1. Crystalluria (rare) -- why you need well hydrated patient 2. Hematipoetic: agranulocytosis, anemia 3. GI upset Dose Unrelated: Hypersensitivity Rxns includind **Stevens Johnson Syndrome** |
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Kernicterus
Steven Johnson Syndrome |
Toxic Rxs to Sulfaamides
bilirubin displacement by sulfa --> CNS deposition hypersensitivity rxns |
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Trimethoprim
Mech Selectivity |
Inhibits DHFR (dihydrofloate reductase)
Structural analogue to pteridine Bacteria DHFR inhibited with much much lower concentration than human DHFR |
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Trimethorprim:
Spectrum/resistance Clinical |
Spectrum: Broad like sulfonamides.
Resistance: altered DHFR Clinical: Used in Synergistic combo with sulfonamides to treat: UTIs intestinal infections prostatitis prevention/treatment in AIDS patients of pneumocystis jarovecii |
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Trimethorprim:
Absorption Distribution Excretion |
A -- oral, good
D -- Wide, CNS E -- renal |
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Trimethorprim:
Toxicity |
Slight
Blood dyscrasias associated with sulfa cobo Anemia if patient already folate deficient |
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Is Sulfonamide baceriacidal or static?
Trimethoprim Combo of both? |
static
static cidal! -- combo used for gram neg UTIs |
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Is sulfonamide used in all age groups?
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Not newborns -- Kernicterus!
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Rifampin: a semisynthetic analog of a natural prodcut from Streptomyces
bacteriocidal or static? |
Really?!?
bacteriocidal |
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Rifampin:
Mech Selectivity |
Mech: Binds to and inhibits RNA polymerase --> kills bacteria
Doesn't bind human RNA poly |
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Rifampin:
Spectrum/Resistance Clinical |
Spectrum: ***potent against M. tuberculosis at both intra and extracellular sites***; some activity against staphycocci.
Rapid induction of resistance -- never used alone Clinical: first line TB drug used in combo with other first line TB drugs; some use with for endocarditis due to prosthetics, resistant staph infections, prophylaxis against meningococcal disease and meningitis |
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Rifampin:
Absorption Distribution *Metabolism Excretion |
A -- oral
D -- ***WIDELY*** distributes to organs, tissues, body fluids, CSF. gives red/orange color to all fluids M -- ***Liver P450 enzyme-mediated deacetylation**** E -- Elimination rapidly in Bile |
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Rifampin:
*Toxicity *Don't use with what patients? Why? *Use what instead in this case? |
T -- ***Liver Damage***, jaundice
Don't use with HIV patients (with TB infection): when processed by liver, drug retains full activity but it also impairs intestinal reabsorption inducing hepatic enzymes that increase metabolism. This decreases half-life of HIV protease and reverse transcriptase inhibitors! Substitute with Rifabutin -- less induction of enzymes |
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Other Anti-TB drugs:
1. isoniazid 2. pyrazinamide 3. etyhambutol Mech? Static/Cidal? Toxicity? |
None of these effect DNA
1. interferes with cell envelope integrity: bacteriostatic. Side effect: hepatotoxic 2. inhibits ETC: bacteriosidal intracellularly rapidly. Side efftect: hepatotoxic, hyperuricemia/gout 3. inhibit cell wall synth: bacteriostatic. Side effect: decrease color vision |
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DNA Damaging Agents (4)
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Quinolones
Nitrofurans Methenamine Metronidazole |
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Quinolones -- bacteriocidal/static?
Mech Selectivity |
Bacteriocidal
Mech: Poisons DNA gyrase (which normally relieves torsional stress) -- inhibits it from uncoiling DNA ahead of replication fork Inhibits DNA topoisomerase IV -- inhibits separation and re-formation of newly replicated DNA from old strand Selectivity: Mammallian DNA topoisomerase not inhibited to same extent |
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Quinolones:
Spectrum/Resistance Clinical |
both Gram + and -
Resistance: Mutations in Gyrase, topoisomerase. Altered porins. Increased efflux pumps. Clinical: UTI's respiratory tract infections anti-TB |
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Nalidix Acid (gram pos or neg or both?)
Ciprofloxin (gram pos or neg or both?) Levofloxacin (gram pos or neg or both?) Moxifloxacin (gram pos or neg or both?) |
1st generation no longer used
Cipro-- used against pseudomonas aeruginosa = gram negative bacterium. no longer used against gram + because of resistance! Other two: Gram + : used to treat community acquired pneumonia |
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Quinolones:
Absorption Distribution Metabolsim Excretion Toxicity |
A -- oral, rapid -- no milk!
D -- cipro penetrates into prostatic fluid so good for prostatitis M -- high concenrtations in kidney and urine E -- renal, rapid T -- insomnia (cipro) -- don't use cipro in children because it can cause tendon ruptures |
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Nitrofurans:
Mech Selectivity |
reduction of nitro group causes DNA damage by formation of oxygen free radicals
Bacteria cause reductive activation more extensively, but can only use low serum concentrations. |
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Nitrofurans:
Spectrum Clinical |
Broad spectrum -- gram +/-
Not effective for P. aeruginosa **Only used for UTI's** |
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Nitrofurans:
Absorption Excretion High concentrations where? Toxicity |
A -- oral, rapid
E -- renal High concentration in urine and renal fluids T -- Acute fever, rashes, urticaria (itching, hives) Acute Pleural effusions **Pulmonary Fibrosis** if chronic toxicity |
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Methenamine:
Used a lot or not a lot? For? Mech |
Rarely used. Prophylatic
At acidic pH, it is hydrolyzed and forms formaldehyde which denatures proteins (and possibly damages DNA). Increase selectivity by acidifying urine |
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Methenamine:
Clincal Use |
Prophylaxis for UTI.
Only Gram - Not effective against Pseudomonas b.c they keep pH basic |
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Methenamine:
Pharacokinetics Toxicity |
PK -- oral, well distributed
T -- gastric distress, bladder irritation, crystalluria if inadequate urine flow |
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Metronidazole: a prodrug for... what type of infections?
Cidal or Static? Mech |
Anaerobic infections only.
Cidal! *reductive activation* of nitro group specifically in anaerobic bacteria leads to Free Radical Species binding to DNA. *pro-drug --> requires metabolic activation |
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Metronidazole:
Spectrum |
Spectrum -- obligate anaerobic gram + or -
No good against aerboes/faculatives but active against protozoa |
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Metronidazole:
Absorption Distribution Excretion Toxicity |
A -- oral, well absorbed
D -- Wide, CSF E -- renal --> metabolites T -- Metallic taste; no alcohol because inhibits its metabolism leading to GI distress, nausea, vomiting if drinking |
