Antibiotic Interference with Folate/Nucleic Acid Flashcards
Which two enzymes in the folate synthesis pathway are targets for antibiotics? Is this disruption bacteriostatic or bactericidal?
Bacteriostatic (in general as single agent therapy)
2 enzyme targets:
- Dihydropteroate synthetase (Sulfonamides)
- Dihydrofolate reductase (Trimethoprim)
What is folate used for?
Folate is a cofactor for transferring 1-carbon groups and electrons
Reduced folates are used in pathways for biosynthesis of purine, DNA, and certain amino acids
Sulfonamides
Indications: Gram-positive and Gram-negative
Mechanism: Structural analog of PABA and competitively inhibit Dihydropteroate synthase (PABA is needed to form dihydrofolic acid, a folic acid precursor, that is needed for purine synthesis)
Metabolism: well-absorbed, distributed throughout body including CNS and fetus, primarily renal elimination so need to adjust for renal insufficiency
*Sulfamethoxazole highly albumin-bound
Due to protein binding can result in drug interactions with Warfarin, Phenytoin, Sulfonylureas
Resistance: Common cross-resistance between agents, resistance from plasmids carrying increased PABA production or binding site changes to prevent sulfonamide binding)
What are the 3 major groups of Sulfonamides? What are the drugs listed under each category?
ORAL ABSORBABLE:
- Sulfadiazine = UTI, nocardiosis, rheumatic fever, prophylaxis, toxoplasmosis, uncomplicated malaria
- Sulfadoxine (+pyrimethamine)
- Sulfisoxazole = otitis media, UTI, chloroquine-resistant/drug-resistant malaria, Toxoplasma gondii
- Sulfamethoxazole (+trimethoprim makes it become bactericidal) = URI, UTI, prophylaxis and tx of P. carinii
ORAL NONABSORBABLE
-Sulfasalazine = for non-infectious disease i.e. UC and enteritis, delayed-release tablets for RA (is anti-inflammatory since cleaved to sulfapyridine and 5-aminosalicyclate
TOPICAL
- Sodium sulfacetamide (Sulamyd) = bacterial conjunctivitis, also for chlamydia tracoma infection (most common cause of preventable blindness)
- Silver sulfadiazine (Silvadene) = burn infection prophylaxis
- Except for eyes and burn, there are better options
What are the ADRs of Sulfonamides?
ADR: N/V/D, HA, photosensitivity, 10% will have adverse reaction (allergy and toxicity response) = fever, mild to life-threatening skin rash, blood dyscrasia, nephritis/hepatitis/vasculitis, crystalluria… do not use in patients with Sulfa allergy
What are special populations to consider when using Sulfonamides?
Avoid using in patients with Sulfa allergy
Silver sulfadizine = Category B
Sulfacetamide = Category C
Sulfadiazine, Sulfisoxazole = Category B/D
Sulfamethoxazole/Trimethoprim = Category C/D
Avoid in pregnancy near-term and in newborn because can lead to kernicterus
What class does Trimethoprim belong to? How does it relate to sulfonamides?
Dihydrofolic reductase inhibitor (competitive)
This enzyme is needed in purine synthesis
Similar spectrum as sulfonamides but more potent, also similar pharmacokinetics as Sulfamethoxazole but penetrates better into prostate
Indication: usually not used alone except for community acquired UTI or prophylaxis of UTI
ADR: GI and megaloblastic anemia, leukopenia, granulocytopenia (which can be reversed with folinic acid)
Why is Sulfamethoxazole/Trimethoprim combo more effective?
Targets both the enzymes in the folate pathway, sequential blocking in synergism makes it bactericidal
Same spectrum as individual agents
Indications: an alternative tx for CAP, UTI and prostatitis, acute otitis media…also for pneumocystitis carinii, bacterial diarrhea, prophylaxis (UTI, PCP and Toxoplasma gondii in AIDS, peritonitis prevention in cirrhosis patients)
*Must consider local resistance patterns
Is the only available IV sulfonamide antibiotic
Name the drugs that alter nucleic acid processing
Inhibition of DNA topoisomerases i.e. Quinolones
Inhibition of DNA-dependent RNA polymerase i.e. Rifampin (directly) or Nitrofurantoin (indirectly)
How many generations of Quinolones are there?
4 generations (currently using mostly 2nd and 3rd generation drugs)
First generation was nalidixic acid, the important quinalones are synthetic fluorinated analogs of it
2nd = interferes with normal transcription/replication by preventing relaxation of supercoiled DNA
3rd = interferes with replicated chromosomal DNA separation into respective daughter cells
Quinalones
Indication: Gram-positive and Gram-negative (activity against topoisomerase 4 accounts for the gram-positive spectrum covered)… achieve bactericidal concentrations in all tissues
- Primary target differs according to organism but can cover i.e. E.coli, Staphylococci, Streptococci
- Originally made for enhanced gram-negative coverage i.e. Enterobacter, E. coli, H. influenzae, Klebsiella etc.
Mechanism: inhibits topoisomerase 3 and topoisomerase 2 (DNA gyrase)
Quinalones were originally made for enhanced gram-negative coverage, it is useful to further classify them based on what gram-positive organisms can be covered. What are these “classes”?
*In general, these are pretty broad spectrum
Excellent Gram-negative, moderate Gram-positive = Ciprofloxacin (Cipro)
Excellent Gram-negative, improved Gram-positive = Levofloxacin (Levaquin) and Moxifloxacin (Avelox)
Gram-negative, Gram-positive, with enhanced Anaerobc Coverage (B. Fragilis) = Trovafloxacin (Trovan)
…Other targets:
- Atypical pneumonia organisms i.e. Chlamydia pneumoniae and Mycoplasma pneumoniae
- Intracellular pathogens i.e. Legionella, Mycobacteria tuberculosis, Mycobacteria avium complex
What are the clincal uses for Quinalones
UTI, sinusitis, mycobacterial infections, CAP and HAP
Bacterial diarrhea (salmonella, shigella, vibrio, campylobacter, traveler’s diarrhea…but C.diff is not covered)
Soft tissue/bone/joint infection (decubitis, prosthetics, osteomyelitis)
Gonoccocal and Chlamydial infections
Post-exposure prophylaxis anthrax (use Ciprofloxacin)
Vs. Inhalation anthrax tx (use Levofloxacin)
Trovafloxacin has expanded anerobic coverage, but reserved for limb-threatening infections due to severe hepatic toxicity
How do bacteria gain resistance to Quinalones/Fluoroquinalones?
1+ point mutations on bacterial chromosome leading to binding site change or decreased permeability
If resistance is aggresive, means can’t use any of the quinalones; therefore should not use quinalones for routine upper or lower respiratory infections or skin/soft tissue infection where there are better first-choices to treat the predominant organisms involved (Strep and pneumococci)…better to reserve for treating serious infections i.e. pseudomonas, serratia and MRSA (great activity and oral bioavailability)
What are the pharmacokinetics and ADRs of Quinalones?
Metabolism: well-absorbed but possibly diminished by divalent or trivalent cations, distributes widely including prostate, excretion varies depending on specific drug =
- Eye drop ones mostly by renal (so adjust for insufficiency) i.e. Gatifloxacin, Levofloxacin, Lomefloxacin and Ofloxacin
- Trovafloxacin and Moxifloxacin through bile
- Ciprofloxacin is 50% renal and 40% bile
- Gemifloxacin 60% bile and 40% urine
ADR: N/V/D most common, then comes HA/dizziness/insomnia, rarely is it seizures (increased risk if using NSAIDs too) or blood dyscrasia or irreversible peripheral neuropathy…renal failure if using glucocorticoid…tendinitis and tendon rupture in elderly
Drug interactions: antacids, sucralfate, iron, multivitamins… CYP interaction most common with Ciprofloxacin (would increase Methodone and Theophylline levels… fatal hypoglycemia if used with Glyburide)
