Antibiotics that interfere with folate synthesis and nucleic acid processing Flashcards
Antifolate drugs
Disruption of the folate pathway is generally bacteriostatic in single agent therapy
Targets of bacterial folate antagonists- sulfonamides and trimethoprim
Sulfanomides- Prontosil
First commercial antibiotic from a red dye
Prodrug- no activity in cultures but protected mice and rabbits against lethal doses of staphylococci and streptococci.
Sulfandomides
Susceptible microorganisms require extracellular PBA to form dihydrofolic acid required for pruine synthesis.
Structural analogs of PABA and competitively inhibit the enzyme dihydropteroate synthase.
Bacteriostatic against gram (+) and gram (-) bacertia
Sulfanomide Resistance
Cross-resistance b/w agents
Mutations carried on plasma- additional production of PABA and changes in binding sites from sulfonamides.
Three major groups of Sulfanomides
Oral absorbable, oral nonabsorbable, and topical agents.
Sulfanomides- oral absorbables
Sulfadiazine (UTI, nocardiosis, rheumatic fever, prophylaxis, taxoplasmosis, uncomplicated malaria)
Sulfadoxine (+ pyrimethamine)
Sulfisoxazole (otitis media, UTI, chloroquine-resistant malaria, drug resistance malaria and toxoplasma gondii)
Sulfamethoxazole (+ trimethoprim) (URI, UTI, prophylaxis, and tx of P. carinii)
Sulfonamides- oral non-absorbable agents
Sulfasalazine- used for UC, enteritis, delayed release of tablets is used to treat RA.
Anti-inflammatory properties
Sulfonamides- topical agents
Sodium sulfacetamide (sulamyd)- use in opthalmic solution or ointment for tx of bacterial conjunctivitis. Also used to tx chlamydia trachoma infections SIlver sulfadiazine (Silvadene)- burn infection prophylaxis
Sulfonamide Pharmacokinetics
Well absorbed
Distributed throughout the body including CNS and fetus
Elimination is primarily renal
Sulfonamides Adverse Effects
NVD, HA, PHOTOSENSITIVITY
Up to 10% will have adverse rxn mixture of allergy and toxicity: rash, fever, blood dyscrasias (hemolytic anemia), many itis’s (nephritis, hepatitis, vasculitis), and crystalluria.
Sulfonamides- Special Populations
Silver Sulfadizine- Category B
Sulfacetamide- Category C
Sulfadiazine, sulfisoxazole- category B/D
Sulfamethoxazole/Trimethoprim- Category C/D
Neontal kernicterus- avoid in pregnancy near term and in the new born (causes grey baby)
Trimethopim
Competitive inhibitor of dihydrofolic acid reductase (Second step of folic acid synthesis)
Similar spectrum of sulfonamides but more potent
Similar pharmacokinetics with improved penetration into the prostate
Adverse effects- GI, megaloblastic anemai, leukopenia, granulocytopenia
Used for community aquired UTI or prophylaxis of UTI.
Sulfamethoxazole/Trimethoprim (Bactrim or Septra)
Produces sequential blocking in the metabolic sequence leading to marked synergism. Combination is bactericidal
Same spectrum as the individual agents
Only available IV sulfonamide antibiotic.
Sulfamethoxazole/Trimethoprim- Clinical uses
Alternative agent for CAP, UTI and prostatitis, acute otitis media
Tx o pneumocystitis carinii, bacterial diarrhea
Prophylaxis of UTI, PCP and taxoplasma gondii in AIDS pts, and peritonitis prevention in patients with cirrhosis.
Drugs that alter nucleic acid processing
Inhibit DNA processing
Quinolones, rafampin, and nirtrofurantoin
Qoinolones- MOA
Block bacterial DNA synthesis by inhibiting DNA topoisomerase IV and topoisomerase II.
Quinolones- Spectrum of Activity
Primary target differs according to organism-
Topo II primary, Topo IV secondary- E.coli
Topo IV primary, Topo II secondary- staphylococci and streptococci
Active against Gram (+) and gram (-) bacteria, Activity against topo IV accounts for gram (+) spectrum
Quinolone “classes”
Excellent gram negative coverage with only moderate gram (+) activity (Ciprofloxacin) Excellent gram (-) coverage with improved gram (+) coverage Continues gram (-) and (+) coverage with enhanced anaerobic coverage (Trovafloxacin)
Quinolone Spectrum of Activity 2
Atypical pneumonia organisms (Chlamydia pneumoniae and mycoplasma pneumoniae) Intracellular pathogens (Legionella, mycobacteria tuberculosis, and mycobacteria avium complex)
Quinolone Clinical Uses
UTI, sinusitis, mycobacterial infections, bacterial diarrhea, soft tissue, bone, and joint infections, gonoccocal and chlamydial infections, pneumonia, post exposure prophylaxis for anthrax, tx inhalation antrhax infection
Trovafloxacin FDA restricted to life-or limb threatening infections due to severe hepatic toxicity.
Fluoroquinolone resistance
Due to one or more point mutations in bacterial chromonsomes, high levels usually confers resistance to all quinolones.
SHould not be used for routine URI or LRI or skin/soft tissue infections
Quinolones pharmacokinetics
Well absorbed (oral is decreased by divalent and trivalent cations)
Widley distributed including prostate
Excretion is renal, non renal, bile, and urine depending on the drug
Quinolone Adverse Effects
Mostly- N/V/D
Secondary- HA, dizziness, insomnia
Rarely- seizures, blood dyscrasias, and peripheral neuropathy that is irriversible.
May damage growing cartilage, tendinitis and rupture in elderly, renal failure with glucocorticoid use
Quinolone Drug interactions
Interactions if taken at the same time as antacids, sucralfate, iron, and multivitamins
CYP interactions most common with ciprofloxacin
Quinolone- Moxifloxacin (avelox)
Oral or IV
Broad spectrum single dose daily
Targets DNA gyrase instead of topo IV in gram (+)
Quinolone- Gemifloxacin (factive)
Approved to treat mild-moderate CAP due to multi-drug resistant Streptococcus pneumoniae.
Miscellaneous Antibacterial Drugs
Metronidazole
Notrofurantoin
Polymyxins
Daptomycin
Metronidazole (Flagyl) MOA
Bacteriacidal
Metabolized to an intermediate that inhibits bacterial DNA synthesis and decreases existing DNA
Selectivity due to its toxic metabolite that is not produced in mammalian cells
ROA- oral, IV, topical
Metronidazole (Flagyl)- spectrum of activity and pharmacokinetics
Anaerobic and protozoan infections- amebiasis, trichomoniasis, skin infections, CNS infections, inra-abdominal infections, systematic anaerobic infections, tx C. diff, bacterial vaginosis, H. pylori and acne rosacea
Pharmacokinetics- absorption- 80% food delays and excreted in urine
Metronidazole (flagyl)- contracindications/cautions and drug interactiosn
Hx of blood dyscrasias, alcoholism, hepatic dz, CNS disorders, visual changes, 1st trimester of pregnancy
Drug interactions- warfarin, cimetidine, lithium toxicity, ETOH
Metronidazole (flagyl)- ADRs
Vertigo, HA, confusion, seizures (w/ previous condition) Edema N/V/D, abd cramping, constipation Darkened urine, polyuria, dysuria Transient leukopenia, neutropenia Extreme reaction when combines with ETOH
Nitrofurantoin (Macrodantin, Macrobid)- MOA, spectrum of activity, and ROA
MOA- poorly defined reactive form damages DNA nd interferes with RNA synthesis and DNA replication
Spectrum- Gram (+) and (-)
ROA- oral and reaches highest [] in the urine
TX UTI
Nitrofurantoin (marcodantin, macrobid)- ADRs
Gi- N/V Interstitial pulmnary fibrosis with chronic use Hemolysis in pt with G6PD deficiency Aggranulocytosis, thrombocytopenia Peripheral neuropathies, HA, Dizziness, Significant skin reactions w/ allergies.
Polymyxin B- MOA
Bactericidal
Interact w/ phospholipis on the outer plasma cell membrane of gram (-) bacteria disrupting their structure
Disruption destroys bacteria’s osmotic battier leading to lysis
Resistance is low
Polymyxin B- spectrum and ROA
Gram (-) bacteria (pseudomonas aeruginosa)
ROA- high nephro- and neuro- toxicity limits to topical application
IV, IM, intrathecal admin in hospitalized pts w/ serious infections
Topical= gut sterilization, bladder, irrigation, and ophthalmic.
Daptomycin (Cubicin)
Used for multi-drug resistant gram (+) bacteria
Bactericidal disruption of plasma membrane
Once daily dosing
ADRs- reversible myopathy, GI
