Antimicrobials 3 Flashcards
What are the different categories of drugs that affect nucleic acid synthesis?
- Fluoroquinolones
- Sulfonamides
- Trimethoprim
What specific drugs fall into the 1st through 4th generation of Fluoroquinolones?
1st gen - Nalidixic Acid (quinolone) - gram negative activity, used for Uncomplicated UTIs
2nd gen - Ciprofloxacin - expanded gram neg activity with some gram pos (synergistic with B-lactams), used for travelers diarrhea, pseudomonas in CF pts, prophylaxis against meningitis
3rd gen - Levofloxacin - expanded gram neg activity, improved gram positive activity (excellent activity agaisnt S. pneumoniae), used to tx prostatitis, STDs (except syphilis), skin infections, community acquired pneumonia
4th gen - Gemifloxacin, Moxifloxacin - gram positive activity and anaerobic activity, used to tx community acquired pneumonia
Fluoroquinolones?
Broad spectrum, Bactericidal
Enters the bacterium via porins and then interferes with topoisomerase II (DNA gyrase) and IV thereby inhibiting bacterial DNA replication.
There is good oral bioavailability and is well distributed into all tissues. Divalent cations interfere with absorption so do not administer simultaneously.
Renal dysfunction may require dosage adjustment - except Moxifloxacin.
Esp with 2nd gen - resistance emerged rapidly due to chromosomal mutations that encoded DNA gyrase and topo IV. There was also increased regulation of expression of efflux pumps. Cross- resistance b/t drugs does occur.
AE - Connective tissue problems leading to tendon ruptures (avoid in pregnancy, nursing mothers and children under 18 yo), QT prolongation (Moxifloxacin, Gemifloxacin, Levofloxacin), GI Distress, Photosensitivity, Rash, Superinfections (esp with C. diffe, C. albicans, streptococci)
What are the respiratory fluoroquinolones?
Levofloxacin, Moxifloxacin, Gemifloxacin
**These have excellent activity against S. pneumonia, H. flu and M. catarrhalis
Used in tx of pneumonia when.. 1. 1st line agents have failed 2. in presence of comorbidities 3. pt is in an inpatients [this is a more aggressive Abx used primarily in inpatient settings]
What interactions with Fluoroquinolones need to be watched?
Theophylline, NSAIDs, corticosteroinds = enhance toxicity of fluoroquinolones
3rd and 4th generation = raise serum levels of warfarin, caffeine, cyclosporine
Sulfonamides?
Sulfamethoxazole, Sulfadiazine, Sulfasalazine
structural analogs of PABA, Bacteriostatic against Gram positive AND gram negative organisms
MOA - synthetic analog of PABA that competitively inhibits dihydropteroate synthase thereby inhibiting bacterial folic acid synthesis
Resistance - via plasmid transfer or random mutation [synthase altered, decreased permeability, enhanced PABA outcompetes drug, decreased intracellular accumulation]
Application - topical agents (ocular, burn infections), oral agents (simple UTIs), Sulfasalazine (oral) for UC Crohns enteritis and IBD
Drug is acetylated in the liver then precipitates at neutral or acid pH thereby accumulating in the kidney and causing renal failure.
AE - GI distress, fever, rashes, phosphosensitivity, Crystalluria (nephrotoxicity), HSN rxn, Hematopoietic disturbance (esp in pts with G6PD def), Kernicterus (in newborns and infants by displacing bilirubin from albumin binding)
Drug interactions - warfarin, phenytoin, methotrexate can all lead to increased plasma levels
Trimethoprim?
Structurally similar to folic acid, Bacteriostatic against gram positive AND gram negative organisms
MOA - potent inhibitor of bacterial dihydrofolate reductase thereby inhibiting purine, pyrimidine and AA synthesis
Clinical applications - uncomplicated UTIs, bacterial prostatitis and vaginitis [reaches high concentrations in prostatic and vaginal fluids]
Excretion via the kidneys unchanged.
AE - Antifolate effects eg, megaloblastic anemias, leukopenia, granulocytopenia therefore is contraindicated in pregnancy, may also cause skin rash and pruritis
Cotrimoxazole?
Broad spectrum Abx, that is a combination of trimethoprim and sulfamethoxazole, bactericidal
MOA - Sulfonamide + DHFR Inhibitor [Dihydropteroate Synthase & dihydrofolate reductase inhibitors]
Tx - Uncomplicated UTI’s (DOC), mild-moderate infections eg, respiratory, ear, sinus, PCP (DOC), Nocardiosis (DOC), Toxoplasmosis (alt. drug)
Oral or IV admin, well distributed in the CSF
AE - Dermatologic, Hemolytic Anemia, GI, contraindicated in pregnancy
Metronidazole?
Antimicrobial (esp. anaerobic bacteria), amebicide, antiprotozoal – Bactericidal
Anaerobic conditions are vital for optimal activity
Metronidazole undergoes reductive bioactivation of its nitro groups by ferredoxin forming cytotoxic products that interfere with nucleic acid synthesis.
Tx - C. diffe infection (DOC), Anaerobic or mixed intra-abdominal infection, Vaginitis (trichomonas, bacterial vaginosis, G. vaginalis), brain abscesses, H. pylori eradication (in combination)
Oral, IV, rectal and topical admin
Wide distribution esp in the CSP
Elimination - hepatic metabolism
AE - Disulfiram-like reactions, Headache, Metallic taste, not used in the 1st trimester
Nitrofurantoin?
Bacteriostatic, Bacteriocidal
Active against gram positive and gram negative bacteria
MOA - reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA. There is slow emergence of resistance and no cross-resistance
AE - GI Distress, Hemolytic Anemia (G6PD deficient patients), neuropathies, don’t use in pregnancy post 38 weeks or in infants less than 1 months as they are at risk for hemolytic anemia
1st and 2nd line drugs for TB?
1st line
• Isoniazid - associated with slow vs fast acetylators
• Rifampin
• Rifabutin (1st line in HIV +ve patients)
• Ethambutol
• Pyrazinamide
2nd line [used to be 1st line btu b/c of resistance they have been downgraded to 2nd line- used when 1st line resistance occurs] • Streptomycin • Ethionamide • Levofloxacin • Amikacin
What is directly observed therapy (DOT)?
Regimes recommended in non-compliant patients or resistant strains - you have to watch the pt swallow each individual tablet. Sounds extreme, but the spread of infection in the community is a risk so it is better for the pt and the community as a whole.
Isoniazid?
- Synthetic analog of pyridoxine
- First-line agent [narrow spectrum that ONLY covers TB]
- Most potent antitubercular drug
- PART OF COMBINATION THERAPY - using it alone causes resistance to rapidly emerge
- Sole drug in treatment of latent infection [close contact or you are immunocompromised]
Prodrug activated by mycobacterial catalase-peroxidase-KatG (produced by mycobacteria) – requires activation by the bacteria so if the bacteria downregulates the enzyme then Isoniazid has no effect and resistance has developed fairly quickly. Once activated Isoniazid targets enzymes involved in mycolic acid synthesis [enoyl acyl carrier protein reductase (InhA) and B-ketoacyl-ACP synthase (KasA)]. – selectively toxic as it is targeting enzymes that only the bacteria has. [mycolic acids are the first to get through to get in to the cell – Isoniazid is targeting that formation]
Bacteriostatic - against bacilli in stationary phase (mycolic acids only being produced when necessary – not extreme production as what occurs in actively dividing cells)
Bacteriocidal - against rapidly dividing bacilli (cell auto-destructs)
Resistance occurs via chromosomal mutations…
1. mutation of deletion of KatG
2. mutation of acyl carrier proteins
3. overexpression of inhA
[cross-resistance b/t other anti-mycobacterial Abx doesn’t occur due to specific mechanisms]
Administration: oral, IV, IM [all modes diffuse into all body fluids, cells and caseous material]
AE - peripheral neuritis (caused by deficiency in B6 and is the 1st AE that appears), hepatotoxicity, potent CYP450 inhibitor, lupus-like syndrome (due to acetylation that metabolizes the drug - this reaction is rare)
**safe in pregnancy
How is peripheral neuritis by Isoniazid corrected?
Pyridoxine supplementation – you should also give this to pregnant women taking Isoniazid to decrease risk of hepatitis so give the pyridoxine at the beginning
Rifampin?
• First-line drugs for treatment of all susceptible forms of
TB
• PART OF COMBINATION THERAPY
MOA - blocks transcription by binding to B subunit of bacterial DNA-dependent RNA polymerase leading to inhibition of RNA synthesis [bactericidal for intracellular AND extracellular mycobacteria, gram positive and negative organisms, including MRSA tx in combination to other drugs as well] – similar to daptomycin??
Resistance via point mutation in rpoB, the gene for the B subunit of RNA polymerase, decreasing affinity of bacterial DNA-dependent RNA polymerase for drug. Resistance can also be achieved through decreased permeability so it can’t get to its site of action.
Clinical application - TB, latent TB in Izoniazid (INH) tolerant pts - ex. can’t take it due to peripheral neuritis, Leprosy, MRSA (with vancomycin) and prophylaxis for individuals exposed to meningitis (therefore can cross in to the CSF easily)
Oral + parenteral (in serious situations and for peolple who cannot take the medication orally) administration, well distributed (esp in to CSF), excreted in the feces
**STRONGEST CYP450 inducer - induces just about every cytochrome
AE - light chain proteinuria, GI distress, thrombocytopenia, rashes, nephritis, liver dysfunction, turns bodily fluids orange/red
**safe in pregnancy
