Micro Exam 2: Antibiotics – Flashcards
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Unlock answers| differential toxicity |
| based on the concept that the drug is more toxic to the infecting organism than the host |
| minimal inibitory concentration (MIC) |
| minimum concentration of antibiotic required to inhibit growth of test organism |
| Minimum Bactericidal Concentration |
| minimal concentration of antibiotic needed to kill the test organism |
| prophylaxis |
| antimicrobial agents are administered to prevent infection |
| treatment |
| antimicrobial agents are administered to cure existing or suspected infection |
| therapeutic index; which drugs have a low one? |
= toxic dose (TD)/effective dose (ED) drugs with low may require therapeutic drug monitoring (TDM)
-- aminoglycosides and vancomycin |
| Ideal antibioitic? |
| low toxicity, low development of resistance, no hyper-sensitivity to host, rapid and extensive distribution, long half-life, free of drug interations, convenient and cheap |
| synergy |
1+1=10 more than added |
| antagonism |
1+1 = 0.5 does not add; less |
| only bacteria that emergence of resistance can be prevented by combination therapy? |
1. mycobacterium tuberculosis 2. S. aureus (fluroquinonlone, rifampin) |
| Empiric Therapy |
immediate treatment prior to identification - prior to growth, identification, or susceptibility reports - based on epidemiology (most probable etiologies) - severity of disease and local rates of disease Can narrow the original broad therapy once we know. |
| Define Resistance |
inability to kill or inhibit organism with clinically achievable drug concentrations
- may be innate (mutation) or acquired (acquisition of foreign DNA) |
| What are the mechanisms of resistance gene transfer? |
| Transformation - take up naked DNA Conjugation - 2 cells sharing DNA Transduction - introduction of new DNA via bacteriophage. |
| Penicillin Binding Proteins (PBP) |
- transglycosylases: transver of nascent peptidoglycan to growing backbone - carboxypeptidases/transpeptidases: similar function as above, cleave the terminal D-ala from pentapeptide; ratio determines extent of cross-linking (influences cell shape) |
| glycopeptides |
-vancomycin/teicoplanim -gram positive agents
bind to terminal D-ala of nascent cell wall peptides and prevents cross-linking of these peptides to form mature peptidoglycan |
| mechanisms of vancomycin action |
| inhibits peptidoglycan synthesis in bacterial cell wall by complexing with D-alanyl-D-alanyl portion of cell wall precursor |
| B-lactam resistance |
1. production of B-lactamase (most common) 2. altered penicillin binding proteins (s. pneumoniae) 3. novel penicillin binding proteins (MRSA) 4. altered permeability |
| glycopeptide resistance |
- primary concern = enterococcus/S. aureus - altered target, bacteria substitutes D-lac for D-ala; vancomycin can no longer bind |
| Beta-lactamase inhibitors |
- clavulanate (w/ amoxicillin or ticarcillin) - tazobactam (w/ piperacillin)
|
| Inhibitors of protein synthesis (drugs) |
-macrolids, lincosamides, streptogramins (MLS), tetracyclines, aminoglycosides, linezolid -binding may be reversable or irreversable |
| Macrolids (4) |
1. erythromycin 2. clarithromycin 3. azithromycin 4. telithromycin (ketolide) |
| Macrolides |
exert antibacterial effect by inhibiting protein synthsis - bind to 50s subunit of bacteria ribosomes
1. block growth of nascent peptide chain by stimulating dissociation of peptidyl-tRNA from ribosome 2. inhibit assembly of new large ribosomal subunits (depletion of functional ribosomal subunits in cell) |
| Macrolide-Resistance |
1. Efflux pump mef(A) 2. Target Site Modification erm(B)
S. pneumoniae |
Where should you use macrolides? (1st and 2nd choice)
|
First Choice: - community acquired pneumonia - pertussis - chlamydia trachomatis infections - mycoplasma infections
Second Choice: - pyogenic streptococcal infections - C. jejuni gastroenteritis
|
| Fluroquinolones - static or cidal? Time or concentration dependent? |
concentration-dependent and highly bactericidal
|
| Evolution of Fluoroquinolones |
1st: nalidixic acid 2nd: ciprofloxacin - broader spectrum, anti-pseudomonal 3rd: moxifloxacin - enhanced gram (+), +/- anaerobic activity |
| Fluoroquinolones mechanism of action |
Inhibit DNA Gyrase (gyrA) Topoisomerase IV (parC) |
| Development of Fluoroquinolone resistance |
- spontaneous mutation in gyrA and parC - efflux pumps (pump it out) - down regulation of porin channels (don't let it in) ; ; ; |
| Aminoglycosides |
- natural/semi-synthetic antibiotics (streptomycin - 1944) - excellent gram (-) activity (pseudomonas) - good gram (+) activity - bactericidal/concentration dependent
ex. Gentamicin, Tobramicin, Amikacin |
| Aminoglycosides mechanism of action |
gain entry through inner membrane via energy dependent transport (dependent on electron transport) -- this step is rate limiting and blocked by divalent cations and anaerobiosis
CANNOT work in anaerobic environments (abscess)
they irreversibly bind to 30S ribosomal subunit through energy dependent process; perturbs elongation of nascent polypeptides by impairing proofreading process; aberrant/truncated proteins --can interfere with mammalian protein synthesis at high concentrations |
| Aminoglycosides - mechanisms of resistance |
1. altered ribosome binding sites (streptomycin only!) 2. reduced uptake or decreased cell permeability 3. enzymatic modification - most common form (>70 ezymes); different substrate specificities and plasmid mediated |
| Inhibitors of Metabolic Pathways |
|
| Mechanisms of action of TMP-SMX |
PABA --> Dihydofolic Acid (by sulfonamides) Dihydofolic Acid --> Tetrahydrofolic Acid (Trimethoprim) |
| TMP/SMX |
- commonly used as 1st line antibioitc in uncomplicated UTIs - gastro-intestinal infections - management of penicillin resistant protein pneumonia - very active anti-Staphylococcal agent (CA-MRSA)
|
| Metronidazole (mechanism of action and side effects) |
|
| Uses of Metronidazole |
|
| Bacteriostatic vs. bacteriocidal |
| Stalls growth vs. Kills |
| Time Dependent |
| Once you reach a concentration, no further increase in concentration will make a difference. Time exposure is key factor. Multiple doses per day. |
| Concentration Dependent |
| Higher the concentration, the more bactericidal. Give once a day |
| Targets of Antibiotics |
| Folic Acid metabolism, Cell wall synthesis, DNA gyrase, topoisomerase IV, protein synthesis (50s 30s) |
| Do ATBX cause resistance? |
| NO, they select for pre-existing mutations. Darwinian |
| What are the general mechanisms of resistance? |
| Altered permeability, Inactivation/destruction of ATBX, altered binding site (PBP), new binding sites, efflux pumps |
| What are the types of Beta- Lactam drugs? |
| Penicillins, Cephalosporins, Carbapenems |
| Mechanism of action of Beta-Lactam drugs? |
| Inhibition of transpeptidases, disinhibition of autolysins. Cell swells and ruptures due to high osmotic pressure inside the cell. Transpeptidase creates the cross links between peptidoglycan polymer strands. BIND TO PBP (transpep, and autolysins) |
| Piperacillin |
| Effective against pseduomonas |
| Cloxacillin |
| effective against staphylococcus(produce beta lactamases), with the exception of MRSA. |
| Penicillins are normall active against which type of organisms? |
| Gram Positive, Outer membrane of gram negative organisms is difficult to penetrate. |
| Carbapenems |
| Reserved for hospital use. Very broad spectrum. Kills everything |
| Ampicillin affective against? |
| E. Coli, H. Influenzae, Salmonella, Shigella. Broad spectrum penicillin. |
| What is often combined with beta lactam drugs to boost effectiveness? |
| Clavulanic acid - beta lactamase inhibitors. |
| Broad spectrum penicillins(amoxicillin ampicillin) are more effective because? |
| ability to penetrate gram-negative cell envelope. Ineffective against staph aureus because of beta lactamase. |
| Staph Aureus difficult to treat because? |
| Produces beta lactamase. |
| If a history of a rash exists with penicillin use, which other class can be used? |
| Cephalosporins. |
| Ticarcillin and Piperacillin - special because? |
| Antipseudomonals |
| How does vancomycin/teicoplanin work? |
| Against gram positive, binds to D-ala, D-ala ending on premature glycopeptides so they can't be cross-linked. |
| Bugs that produce Beta Lactams? |
| S. Aureus, H. Influenzae, Neisseria, Bacteroides Fragilis, E. coli, Klebsiella. |
| Protein Synthesis Inhibitors target what? |
| Ribosomes, may be reversible or irreversible. |
| Protein Synthesis inhibitors include which ATBX? |
| Macrolides, aminoglycosides, tetracyclines etc. |
| Protein Synthesis inhibitors include which ATBX? |
| Macrolides, aminoglycosides, tetracyclines etc. |
| What are the primary drugs in the macrolide class? |
| Erythromycin, clarithromycin, azithromycin, ketolide. |
| How do macrolides exert antibacterial effects? |
| Bind to 50s ribosomal subunit. |
| Mechanism of macrolide resistance? |
| Efflux pump - Mef gene. Low level of resistance. Target site modification - erm gene. High level of resistance These are acquired genes, not normally present. |
| Where should you use macrolides? |
| 1st choice - community acquired pneumonia, chlamydia, mycoplasma(no cell wall, penicillin won't work), pertussis. Lower Respiratory tract infections. |
| Mechanism of action of fluoroquinolones - concentration dependent. |
| Action against gram negative. Interfere with DNA replication. Target Gyrase(enzyme responsible for supercoiling, without which replication can't take place) and topoisomerase (separates daughter strands during cell division). |
| Ciprofloxacin is important because ________? |
| antipsuedomonal activity. |
| Uses of aminoglycosides? |
| Gram negative activity, including antipseudomonals. Good gram positive activity. |
| Examples of Aminoglycosides and uses? |
| Gentamicin - most commonly prescribed. Tobramicin - anti-pseudomonal. |
| Pseudomonas? |
| bacteria, gram negative, found in hospitals, multidrug resistance, causes life threatening infections. |
| Aminoglycosides and abscesses |
| Amino's need energy to be transported into the cell, require oxygen. Do not work in anaerobic environments such as abscess. |
| Aminoglycosides inhibit protein synthesis how? |
| Bind to the 30s ribosome. |
| Aminoglycoside mechanisms of resistance? |
| 1. Altered ribosome binding site. 2. Reduced uptake or decreased cell permeability. 3. Enzymatic modification. * most common. |
| Inhibitors of metabolic pathways (Trimethoprim and sulfonamides) - mechanism of action? |
| Inhibit folic acid production, which is required by cells to synthesize DNA RNA and proteins. Humans take up folic acid from food and don't synthesize it. Block at two different points. Usually used to treat UTI, GI, treats STAPH!. Gram negative drug. |
| Metronidazole - mechanism of action? |
| taken up into cell and converted into active form (free radicals) that damage DNA and other macromolecules. |
| Metronidazole other points? |
| Available PO, long half life. CAN"T DRINK ALCOHOL. Best for anaerobic organisms (and CLINDAMYCIN). Resistance is slow to develop. CHEAP. |
| Best drugs for anaerobes? |
| Clindamycin and metronidazole. |
| Ciprofloxacin (fluoroquinolone) action against? |
| Antipsuedomonals. |
| Excellent use for anaerobics? |
| Metronidazole |
| Protein synthsis inhibitors - 50s? |
| Macrolides, clindamycin |
| Protein synthesis inhibitors - 30s? |
| Aminoglycosides, tetracyclines |
