Intro to Antimicrobials week 4 Flashcards
Explain the difference btwn a bactericidal and bacteriostatic agent.
In what clinical situations would you prefer one over the other?
A bacteriostatic agent inhibits the growth of bacteria; a bactericidal agent kills the bacteria. In circumstances where there is a generalized or local decrease in the immune response infection, a bactericidal agent is preferred.
a. Sequestered focus of infection - endocarditis and meningitis.
b. Generalized: bacteremia in a patient with peripheral blood neutrophil count < 500 cells/mm3.
What is the difference btwn broad spectrum and narrow spectrum antibiotics (abx)?
The classical definition of broad spectrum refers to an antibiotic, which has activity against both gram-positive and gram-negative bacteria. A narrow spectrum agent has activity against only gram-positive bacteria - i.e. penicillin. The inherent assumption is that broad spectrum has more side effects than narrow spectrum. This may not be true for newer agents.
Buy AT 30, CCEL (sell) at 50
30S inhibitors:
A: Aminoglycosides (bactericidal)
T: Tetracyclines (bacteriostatic)
50 S inhibitors:
C: Chloramphenicol, Clindamycin (bacteriostatic)
E: Erythromycin (macrolides) (bacteriostatic)
L: Linezolid (variable)
Describe the structure of aminoglycosides.
Explain their distribution.
How do aminoglycosides get into cells?
How does concentration effect bacterial killing? What is post antibiotic effec? How does this affect dosing?
Most of these agents have a six-membered ring with a glycosidic bond to two or more sugars. Removal of the amino or the hydroxyl groups results in the loss of antibacterial activity as well as the loss of toxicity.
These drugs are very water soluble, which limits their ability to cross the lipid membranes of the body (such as the blood-brain barrier).
There is an oxygen dependent active transport of the drug across the cell membrane. This process is inhibited by low pH and anaerobic conditions and is enhanced by cell wall active antibiotics such as penicillin (relationship to synergy).
Studies using time kill curves demonstrate that aminoglycosides have:
(1) concentration dependent killing (larger concentrations of drug kill a larger # of bacteria and do so faster),
(2) can act synergistically with other antibiotics, and
(3) have a post antibiotic effect (antibacterial effect lasts beyond the time measurable drug is present by several hours). 1 and 3 provide a rationale for once daily dosing.
State the following facts about aminoglycosides:
Drugs in this category
Mechanism of action
Clinical use
Toxicity (state reasons for toxicities and which drugs in this class cause which effects)
Mechanism of resistance
How is mechanism of resistance encoded?
Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin “Mean” (aminoglycoside) GNATS caNNOT kill anaerobes”
Mechanism of action: Bactericidal; irreversible inhibition of initiation complex through binding of the 30S subunit. Can cause misreading of mRNA. Also block translocation. Require O2 for uptake; therefore ineffective against anaerobes.
Clinical Use: Severe gram-negative rod infections. Synergistic with Beta lactam abx-B-lactams break down cell wall for aminoglycosides to more easily enter. Commonly used in treatment of nosocomial infections due to highly resistant organisms.
Excellent activity against many aerobic and facultative gram-negative Pseudomonas sp. (one of few drugs that kills Pseudomonas), and Haemophilus sp.
Aminoglycosides also have some activity against Staph and are used in combination with a penicillin agent or Vancomycin for the treatment of Enterococci. The aminoglycosides (particularly Streptomycin and Amikacin) are sometimes used in the treatment of mycobacterial infections.
Toxicity: Nephrotoxicity, Neuromuscular blockagde, Ototoxicity (esp when used with loop diuretics), Teratogen
Neuromuscular blockade–reduces the amount of acetylcholine released from motor nerve endings resulting in paralysis in susceptibleindividuals. These include patients receiving certain anesthetic agents and patients with Myasthenia gravis (and possibly Parkinsonism). This paralysis is reversed with calcium gluconate or neostigmine.
Ototoxicity–toxic to both hearing and balance. Streptomycin is particularly toxic to vestibular function, Amikacin to hearing, and Gentamicin and Tobramycin to both. Risk factors are preexisting renal failure and treatment for > than 10 days. The half-life in perilymph of the ear is 10-12 hours (5-6 times that of serum).
C. Nephrotoxicity–may cause an acute tubular necrosis (ATN) manifested by a loss of concentrating ability and a non-oliguric renal failure.
Mech of resistance: Bacterial transferase enzymes inactivate the drug by acetylation, phosphorylation, or adenylation. Many resistance genese coding for these enzymes are located on transposons (transposable genetic material).
How are aminoglycosides administered? What is the dosing?
Where is the drug distributed in the body? Does it bind to proteins?
Does it cross the placenta?
How is it eliminated? What is the half life? What is it dependent upon?
A. Poorly absorbed from the G.I. tract.
B. Volume of distribution equals the extracellular fluid volume.
C. Little protein binding.
D. Poor concentrations in the CSF and the eye (when used for these infections usually injected into the site); about 50% of serum concentrations in the pleural, pericardial, and ascitic fluids.
E. Crosses the placenta.
F. Excreted unmetabolized by glomerular filtration. The half life is 2-3 hours with normal renal function but increases to 100 hours or more with anuria.
G. Need to monitor serum levels and renal function.
Usually administered in 2-3 equal doses per day intravenously if renal function is normal. Once daily dosing has advantages of ease of administration (outpatient possible) and decreased cost – however, not proven in all settings.
Which of the aminoglycosides are most commonly used to treat gram - infections?
What bugs do Streptomycin and Amikacin have the greatest activity against?
How is Spectinomycin different from aminoglycosides? What is it primarily used for?
What is neomycin used for?
Which aminoglycosides are particularly synergistic with penicillin? Against what bugs?
The agents most commonly used to treat gram negative infections in this class are: Amikacin, Tobramycin, and Gentamicin. (Use GAT for gram negatives)
Streptomycin has the greatest activity against Mycobacterium tuberculosis and is the drug of choice for plague (Yersinia pestis).
Amikacin has excellent activity against Mycobacterium as well, including Mycobacterium avium-intracellulare.
Spectinomycin is primarily used to treat penicillin resistant Neisseria gonorrhoeae.
Neomycin is mainly given orally as part of a “bowel prep” prior to G.I. surgery or to decrease gut organisms and their products for the treatment of hepatic coma. It is also used topically on burns, etc.
Explain the resistance of Enterococci to aminoglycosides.
Aminoglycoside-Resistant Enterococci
- Enterococci have intrinsic resistance (low level) to aminoglycosides. This may be due to the fact that these organisms have an anaerobic metabolism and oxidative metabolism enhances uptake. Aminoglycosides are still active synergistically with cell wall active agents against these Enterococci.
- High level aminoglycoside resistance has increasingly common (MIC>2,000 ug/ml). This may arise by chromosomally induced changes in the target site or permeability or plasmid induced drug inactivation. When high level resistance occurs, aminoglycosides are not useful alone or synergistically.
State the following facts about macrolides:
Drugs in this category
Mechanism of action
Clinical use
Toxicity
Mechanism of resistance
Can they cross the BBB? What is the normal half-life?
Azithromycin, clarithromycin, erythromycin.
Mech of action: Inhibit protein synthesis by blocking translocation (“macroslides”); bind to the 23S rRNA of the 50S ribosomal subunit. Bacteriostatic.
Clinical Use: Atypical pneumonias (Mycoplasma, Chlamydia, Legionella), STIs (Chlamydia), gram-positive cocci (streptococcal infections in patients allergic to penicillin), and B. pertussis. Also Campylobacter jejuni, Corynebacterium diphtheria, syphilis and many anaerobes.
Toxicity MACRO: Gastrointestinal Motility issues, Arrhythmia caused by prolonged QT interval, acute Cholestatic hepatitis, Rash, eOsinophilia. Increases serum concentration of theophyllines, oral anticoagulants. Clarithromycin and erythromycin inhibit CYP450. IV form associated with phlebitis. Transient hearing loss.
Mech of resistance: methylation of 23S rRNA binding site prevents macrolide binding
Crosses BBB. Normal half life is 1.5 hours.
How is erythromycin affected by the stomach? What is given to decrease this effect?
Explain the difference in activity of Clarithomycin as compared to erythromycin. Explain the dosing and form of administration.
Explain the difference in activity of azithromycin as compared to erythromycin. What is the dosing?
Erythromycin may be destroyed by gastric acid. Sterate and ethylsuccinate preparations are more acid stable. Decreased absorbtion with food (except estolate).
Clarithromycin: Two to four times more active against susceptible strep and Staph. Active against Moraxella cattarhalis, Legionella, M. pneumoniae, Borrelia. Possible decreased GI toxicity. Well absorbed. BID dose.
Azithromycin: Two to fourfold less active than erythro against Staph and Strep. Otherwise, similar spectrum but increased activity against H. flu and Salmonella/Campylobacter. Decreased absorption with food. Long half-life with an elimination half life of ~3 days which can allow for shorter courses of treatment. Once per day dose. Active against Chlamydia STDs.
State the following facts about tetracyclines:
Drugs in this category
Mechanism of action
Clinical use
Toxicity
Mechanism of resistance
Half life, Route of administration
What can’t you consume while taking these drugs? Which of the tetracyclines is eliminated fecally? What is the significance of this?
What interactions may occur with this drug?
Tetracycline, doxycycline, minocycline.
Mechanism Bacteriostatic; bind to 30S and prevents attachment of aminoacyl-tRNA; limited CNS penetration. Doxycycline is fecally eliminated and can be used in patients with renal failure. Tetra- and minocycline are renally excreted.
More lipophilic agents-Doxy and minocycline have somewhat increased activity against gram + organisms.
Clinical Use: Broad specturm: Borrelia burgdorferi, M. pneumoniae. Drugs’ ability to accumulate intracellularly makes them very effective against Rickettsia and Chlamydia. Cholera, Brucella, H. pylori, meningococcal carrier state (minocyclin). Also used to treat acne.
Toxicity: GI distress, Hypoplasia of tooth enamel and discoloration of teeth, inhibition of bone growth in children (not given to children under age 8), photosensitivity. Contraindicated in pregnancy-crosses BBB and may accumulate in bones and teeth. Hepatotoxicity, esp in pregnant women. Vertigo is associated with minocycline. Renal disease: increased azotemia (elevated BUN) in renal failure pts, Fanconi syndrome (PCT disease where nutrients/minerals normally reabsorbed secreted)
Mech of resistance: Decrease uptake or increase efflux out of bacterial cells by plasmid encoded transport pumps.
All are absorbed well from the GI tract. Tetracycline is short active with a half life of ~8 hours. Doxy: 18 hours. minocycline: 16 hours
Do not take tetracyclines with milk (Ca2+), antacids (Ca2+ or Mg2+), or iron-containing preparations because divalent cations inhibit drugs’ absorption in the gut.
Dilantin (phenytoin) and barbituates decrease the half-life of tetracyclines (are P450 inducers)
Methoxyfluorine anestheisa may cause nephrotoxicity if given with tetracyclines
State the following facts about Chloramphenicol:
Mechanism of action
Clinical use
Toxicity
Mechanism of resistance
Explain the absorbtion of Chloramphenicol. How is it elinated? What is its distribution?
Chloramphenicol
Mechanism of action: Blocks peptidyltransferase at 50S ribosomal subunit. Bacteriostatic.
Clinical Use: Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae) and Rocky Mountain spotted fever (Rickettsia rickettsii). One of few drugs (like imipenem) that kills most clinically important bacteria. Is like pouring chlorine on organisms. Limited use owing to toxicities but often still used in developing countries because of low cost.
Toxicity: Anemia (dose dependent), aplastic anemia (dose independent), gray baby syndrome (in premature infants bc they lack liver UDP-glucuronyl transferase). Optic neuritis. Mitochondria may be affected, explaining some of toxicity seen.
Imagine pouring chlorine into a bone. Anemia is reversible. Aplastic anemia is idiosyncratic and irreversible, usually fatal. Occurs in small number of pts who get the drug.
Imagine baby leaps into freshly chlorinated pool and crawls out gray. Gray baby syndrome: neonate with abdominal distension, flaccidity, ashen gray cyanosis of lips, skin, nailbeds. can lead to death.
Mech of resistance: Plasmid encoded acetyltransferase inactivates chloramphenicol.
Well absorbed from GI tract. Increased levels after PO dosing vs IV (IV drug must be hydrolyzed to active form).
Metabolized by liver (conjugated with glucoronic acid) and excreted by kidneys
- Wide distribution - CSF, tears, crosses placenta. Drug of choice in kids and pregnant women with Rickettsia rickettsii due to Doxycycline toxicity.
- Reduce dose in liver failure
State the following facts about Clindamycin:
Mechanism of action
Clinical use
Toxicity
Explain the oral absorption of Clindamycin. Describe its distribution. How is it metabolized?
Clindamycin
Mechanism of action: Blocks peptide transfer (translocation) at 50S ribosomal subunit (like the macro”slides”). Bacteriostatic.
Clinical Use: Anaerobic infections (e.g., Bacteroides spp., Clostridium perfringens) in aspiration pneumonia, lung abscesses, and oral infections. Also effective against invasive group A streptococcal infection. Toxoplasmosis. Sum: most anaerobic bacteria and gram + cocci.
Treats anaerobic infections above the diaphragm vs. metronidazole (anaerobic infections below diaphragm).
Toxicity: Pseudomembranous colitis (C. difficile overgrowth), fever, diarrhea.
90% GI absorption, not decreased by food.
Penetration into most tissues, poor CSF but does penetrate brain tissue.
Metabolized by the liver.
State the following facts about Oxazolidinones:
Drugs in this class
Mechanism of action
Clinical use
Toxicity
Mech of resistance
Explain the oral absorption and elimination of Oxazolidinones.
Oxazolidinones: Linezolid
Mechanism of action: Inhibit protein synthesis by binding to 50S subunit and preventing formation of the initiation complex.
Clinical Use: Gram-positive species including MRSA and VRE. Active against gram positive organisms, particularly staphylococci, streptococci, enterococci, gram positive anaerobic cocci (peptostreptococci), and gram positive rods such as Corynebacterium and Listeria. No cross resistance with other drug classes. Bacteriostatic for Staph and Enterococci and cidal for Streptococci.
Toxicity: Bone marrow suppression (especially thrombocytopenia), peripheral neuropathy, serotonin syndrome.
Does not effect cytochrome P 450 system. Decreased platelets have been seen in 2-4% of cases. A weak monoamine oxidase inhibitor so patients on an adrenergic or serotonergic agent or those taking greater than 100 mg of tyramine/day may have an enhanced drug effect.
Mech of resistance: Point mutation of ribosomal RNA
Well absorbed from GI tract regardless of timing from meal. Dosing from oral site the same as IV, since bioavailability after oral administration is nearly 100%. Eighty percent of agent appears in urine; 30% as active compound. 10% of metabolized drug is in feces. Parent drug concentrations not altered by renal failure, but metabolites accumulate (unclear significance). Eliminated by dialysis.
State the following facts about Trimethoprim:
Mechanism of action
Clinical use
Toxicity
Trimethoprim
Mechanism of action: Inhibits bacterial dihydrofolate reductase. Bacteriostatic.
Clinical Use: Used in combination with sulfonamides (trimethoprim-sulfamethoxazole [TMPSMX]), causing sequential block of folate synthesis. Combination used for UTIs, Shigella, Salmonella, Pneumocystis jirovecii pneumonia treatment and prophylaxis, toxoplasmosis prophylaxis.
Toxicity: Megaloblastic anemia, leukopenia, granulocytopenia. (May alleviate with supplemental folinic acid). TMP Treats Marrow Poorly
