DNA/RA/FA Synthesis Inhibitors Flashcards
1
Q
Quinolones Examples
A
- Ciprofloxacin (Cipro)
- Levofloxacin (Levaquin)
- Moxifloxacin (Avelox)
2
Q
Quinolones
A
- DNA Topoisomerase inhibitors
- MoA: bind and trap DNA complex to stop transcription and replication and leads to cell death
- DNA gyrase (Topoisomerase II) and Topoisomerase IV are the targets in Gram “-“ and Gram “+” bacteria respectively
3
Q
Topoisomerases
A
- Enzymes that change DNA supercoiling to allow for replication and transcription into mRNA
- Essential in all bacteria
- Abx that target them tend to be bactericidal
- Selectivity for Abx is at least 3x higher for prokaryotic over eukaryotic enzymes
- Similarities between gyrase and Topo IV allow to target both enzymes with one drug
4
Q
Quinolone Resistance
A
- Mutations: bacterial DNA gyrase (gyrA) and topo IV (parC)
- Decreased porin permeability due to a decrease in the number of porins on outer membrane
- Energy-dependent efflux system in the cell membrane
- Production of target protection peptides (qnr)
5
Q
Quinolone Coverage
A
- Atypicals!
- Drug specific coverage also applies
6
Q
Cipro Coverage/Use
A
- Ciprofloxacin
- Systemic aerobic Gram “-“ infections (including P. aeruginosa)
- Drug of choice for prophylaxis and treatment of anthrax
- Poor staph./strept. coverage
- Good cell penetration, helps in infections where bacteria spend part of life in host cell (atypicals)
- Most used quinolone in USA
7
Q
Levaquin Coverage/Use
A
- Levofloxacin
- similar to Cipro but better S. pneumoniae activity
- Used for CAP and HAP
- PREFERRED in multi-drug resistant TB
8
Q
Avelox Coverage/Use
A
- Moxifloxacin
- Oral, broad spectrum single daily doses
- Used for CAP, CSSSIs, complicated intraabdominal infections
- Targets DNA gyrase instead of topo IV in Gram “+” organisms
- DON’T use for UTIs, doesn’t penetrate urine
9
Q
Quinolone PK
A
- Oral or IV
- Oral decreased by sucralfate, antacids, iron, zinc, and calcium (2 hours before or 6 hours after)
- High levels in bone, kidney, and prostate, low in CSF
- Dose adjust with renal impairment (exclusion: Moxifloxacin)
- CYP450 inhibition
- Efficacy: Concentration dependent
10
Q
Quinolone Boxed Warnings
A
- Tendinitis and tendon rupture
- Myasthenia gravis
- Peripheral neuropathy
- CNS effects
- QT prolongation
- GI effects
- Phototoxicity
11
Q
Quinolone CI
A
- Epilepsy
- QT prolongation
- CNS lesions/inflammation
- Stroke
12
Q
Bactrim
A
- Trimethoprim/Sulfamethoxazole (5:1 ratio)
- Antifolate drugs
- MoA: Trimethoprim targets dihydrofolate reductase and sulfonamides target dihydropteroate synthetase, combined is bactericidal
- Humans don’t synthesize folate, and TMP is 50,000-100,000X more active against the bacterial dihydrofolate reductase than our own
13
Q
Bactrim Resistance
A
- Decreased permeability and/or efflux pumps
- Increased production of PABA
- Increased expression of target enzymes -changes in gene promoter for DHFR
- Mutational changes in target enzymes (dhfr or dhps)
- Acquired resistance of drug-resistant target enzymes (altered dihydrofolate reductase lowers affinity for TMP)
14
Q
Bactrim Coverage
A
- Used to treat bronchitis (no longer drug of choice)
- Acute bacterial meningitis (good CSF penetration)
- Middle ear infection
- UTI
- Traveler’s diarrhea
- Effective against MRSA and Acinetobacter baumannii
- Severe infections like Pneumocystis pneumonia (fungal), shigellosis, systemic salmonella, typhoid fever, Gram “-“ bacterial sepsis
- Used as prophylaxis for Pneumocystis pneumonia and Toxoplasma gondii in AIDS patients and to prevent bacterial peritonitis in patients with cirrhosis
15
Q
Bactrim PK
A
- Oral or IV
- Hepatic metabolism by acetylation
- Inhibits CYP2C9 (anticoagulants, sulfonylureas, hydantoin anticonvulsants)
- Excreted in urine, dose adjust with renal impairment
- Widely distributed: enters CSF, crosses placenta
- Okay for 2nd trimesters pregnancy
- Time-dependent
16
Q
Bactrim Toxicity
A
- Hematopoietic disturbances (dyscrasias, agranulocytosis, aplastic anemia)
- Hyperkalemia
- Superinfection
- Toxic and allergic responses (5%)
- Dermatitis, rashes, photosensitivity, urinary tract complication from precipitation in urine
- Rare: Stevens-Johnson syndrome, hemolytic/aplastic anemia, other hematopoietic disturbances
17
Q
Rifadin
A
- Rifampin/rifampicin
- MoA: binds to beta-subunit of DNA-dependent RNA polymerase to inhibit RNA synthesis
- Human enzyme doesn’t bind
- Used for implant related S. aureus infections in combination with vanco (biofilms)
- Bactericidal to mycobacteria
- Active against Gram “+” and “-“ cocci and Chlamydia
18
Q
Rifadin Drug Interactions
A
- Induces CYP1A2, 2C9, 2C19, and 3A4
- Decreases the half-life for a number of compounds
19
Q
Flagyl
A
- Metronidazole
- MoA: Nitroimidazole - nitro group must be reduced for activity, then forms free radicals which lead to breaks in DNA
- Penetrates well into body tissues/fluids including vaginal and seminal secretions, saliva, breast milk, and CSF
- Activity: anaerobic bacteria
20
Q
Flagyl Toxicity
A
- Nausea, GI upset
- Metallic taste
- Headache, dizziness, peripheral neuropathy with chronic use
- Inhibits alcohol dehydrogenase - avoid alcohol (disulfiram-like reaction)
21
Q
Flagyl Box Warning
A
- Carcinogenic
- Unnecessary use should be avoided
- Reserve for conditions it is indicated for
22
Q
Macrobid
A
- Nitrofurantoin
- MoA: reduced by bacterial flavoproteins to reactive intermediates that inactive or alter bacterial ribosomal proteins, damage DNA, etc. which inhibits protein synthesis, aerobic energy metabolism, DNA/RNA/cell wall synthesis
- Only used for UTIs
- Bactericidal in urine at therapeutic doses
- Metabolized so rapidly that systemic activity is not observed
23
Q
Nitrofurantoin Toxicity
A
- N/V most common
- Neuropathies and hemolytic anemia occur in patients with G6P dehydrogenase deficiency
- Interstitial pulmonary fibrosis can occur in patients taking the drug chronically (mainly elderly)
- CI: severe renal insufficiency
