topic 11 Flashcards
What is the spectrum of sulfonamides? static or cidal? Used today?
Aerobic gram positives and negatives. static. only used in specific situations today b/c resistance quickly developed and newer drugs are less toxic.
What is the absorption of sulfonamides
absorbed well in small intest
what is the distribution of sulfonamides
well distributed to all tissues. Found in ocular, peritoneal and lung fluids. Crosses placenta and breast milk (avoid during pregnancy). Enters CSF but no longer used for mening. Significant protein binding.
What is the elimination of sulfonamides?
N4 acetylated and made inactive in the liver.
Acetylated form is not antibacterial but still shows side effects
Both acetylated and parent form are excreted in urine. Adjust doses based on renal function.
What is the mechanism of action of sulfonamides? Why are their effects a little delayed?
They are compepitive inhibitors of dihydropteroate synthetase and analogs of PABA. In this way, they prevent production of folate which is necessary for production of NTs. Their effects are delayed due to the fact that initially, bacteria still have built up stores of folic acid.
How do bacteria gain resistance to sulfonamides?
Altered structure of dihydropteroate synthetase
decreased transport into cell of sulfonamide
increased production of PABA
Resistance to one sulfonamide usually means resistance to all sulfonamides.
In general, what 2 systems of the body are adversely affected by sulfonamides? In what patients are these affects worse? What are 6 adverse effects of sulfonamides?
GI and Skin. In HIV and elderly patients.
- GI (Vomiting, diarrhea)
- Allergic response (rash/fever, insterstitial nephritis, stephens johnsons-skin sloughs off)
- Renal crystalluria-crystallizes in urine–>kidney damage/failure
- hematapoetic systemic disorders (granulcytopenia, thrombocytopenia, hemolytic anemia in G6PD patients)
- Interactions with other drugs due to protein binding.
- Don’t used in pregnant women/infants under 2 months (kernicterus-bilirubin in brain–>brain damage).
What is sulfadiazine used to treat?
- Used alone, primarily to treat UTI
- Not as soluble as sulfisoxazole, thereby more potential for crystalluria
- Used with pyrimethamine, treat Toxoplasmosis in
immunocompromised
- Silver sulfadiazine (topical)
- Widely-used, broad-spectrum antibiotic ointment to prevent and treat infections of burns and other skin wounds.
- Effective against a broad range of bacteria, fungi, and some yeasts
What are sulfisoxazole and sulfamethoxasole used for? What is sulfamethoxasole commonly used with?
- Good solubility (less chance of crystalluria)
- For treatment of UTI, ear infections, and alternate amoxicillin therapy for children
Sulfamethoxasole is commonly used in combination with trimethoprim
What is sulfacetamide used to treat?
- Gram (-) or gram (+)
- Eye drops against common eye infection (bacterial conjunctivitis)
- Topical ointment for Rosaceae
What is the mechanism of action of trimethoprim?
It competitively inhibits dihydrofolate reductase which converts which converts dihydrofolate into tetrahydrofolate, thus blocking the synth of NTs. It is an analog of dihydrofolate
It blocks the bacterial enzyme much more strongly than the human one.
What is trimethoprim often prescribed with? Why?
- Trimethoprim often prescribed with sulfamethoxazole to block two separate steps in a common pathway
- Synergistic effect reduces minimum inhibitory concentration (MIC) by 4 fold
What is the administration, distribution, and elimination of trimethoprim?
- Administration: Oral/IV
- Elimination: excretion in urine
- Distribution: throughout all tissues (Effective CNS distribution)
What is the combination sulfamethoxazole and trimethoprim (cotrimoxazole, TMP/SMX) used for? cidal or static?
Cidal
- Effective in the treatment of Uncomplicated infections of the urinary tract (In some areas resistance to cotrimoxasole is high and other antibiotics may be recommended (e.g. ciprofloxacin)).
- Prostatitis, again guided by local recommendations (TMP/SMX concentrates in prostate)
- Drug of choice for Nocardia and Stenotrophomonas maltophilia.
- Used in immunocompromised patients for prophylaxis and treatment of Pneumocystis jiroveci pneumonia.
What are the adverse effects of cotrimoxazole?
- Same as those for sulfonamides
- The trimethoprim part can also cause
–Pancytopenia in patients at risk for folate deficiency due to the trimethoprim component
–Hyperkalemia and polyuria. Trimethoprim is structurally similar to amiloride, and can act as a potassium sparing diuretic
• There is more frequent occurrences of rash, drug-induced fever, pancytopenia, diarrhea in immunocompromised patients (e.g. AIDS patients) on this combination
Contraindications
• Should not be taken during pregnancy
What are some general properties of quinolones?
- Bactericidal, broad spectrum antibiotics
- Relatively safe profile
- Available in oral and IV
- Relatively good pharmacokinetics/dosing interval
What is the administration/absorption of quinolones?
Oral/IV admin.
Absorbed quickly and almost entirely in Small intest (similar conc. to IV)
• Absorption decreased if taken with metals (antacids with magnesium or aluminum, iron or zinc supplements) or with divalent cations (calcium), and these should be avoided.
What is the elimination of quinolones?
- Elimination:
- Renal excretion is the major route of elimination for the quinolones except for moxifloxacin.
- Hepatic metabolism and biliary excretion is the major route of excretion for moxifloxacin.
- Dosing should be adjusted based on renal function except for moxifloxacin.
- Half-life for the fluoroquinolones is relatively long, allowing twice or even once-a-day dosing
What is the distribution of quinolones?
- Broad tissue distribution, some penetration into CSF
- Moxifloxacin not excreted in urine, should not be used for UTI
- Can cross placenta
What is the mechanism of action of quinolones?
- Bacteria have DNA gyrase and/or topoisomerase IV that can “unwind” the downstream DNA by cutting the DNA, unwinding the DNA, then religating the ends.
- Quinolones interefere with the function of DNA gyrase and topoisomerase IV.
- DNA gyrase and topoisomerase IV are found in bacteria and not in humans
How do bacterial cells develop resistance to quinolones? Does cross resistance occur?
- Alterations in the quinolone enzymatic targets
- Mutations in bacterial DNA gyrase
- Mutations in bacterial topoisomerase IV
- Decreased outer membrane permeability to fluroquinolones through decreased number of porins
- Development of pumps that increase efflux of
fluoroquinolones
Cross-resistance amongst the quinolones is expected, but the extent to which the minimum inhibitory concentration is affected varies from agent to agent.
What are the untoward effects of quinolones?
- GI effects (most common adverse effects – 3-6%): Nausea, Vomiting, Diarrhea. As with all antibiotics,C. Difficile colitis
- CNS effects: Headache, Dizziness, Mood changes, Delerium, Siezures (use with caution in patients with epilepsy)
- Dermatologic: Rash, Phototoxicity after exposure to UVA. (avoid sunlight, sunblockers often block only UVB)
- Arthralgias, reversible
- Tendonitis/tendon rupture avoid use in patients on steroids or with renal failure
•Drug interactions: Potentiation of warfarin effect,
Increase levels of theophylline
Dysglycemias, mostly in diabetics.
What are some contraindications on quinolones?
- QT interval: should not be given to patients with or at risk for QT prolongation
• Do not give with other drugs known to prolong the QT interval, e.g. amiodarone
- Age: not FDA approved for patients younger than 18 in the US
- Potential cartilage toxicity– animal models show cartilage toxicity in young animals, avoid in children <18 y/o and pregnant women and nursing mothers
- However, no clear data on the incidence of quinolone-induced arthropathy
- Has been used in children with cystic fibrosis (pseudomonal infections)
Which drug is in the 1st generation of quinolones? What is it used for?
Nalidixix acid
- Narrow spectrum, only gram negative
- The oldest quinolone
- Rarely used
- Restricted to treatment of UTI
