Antibiotics that interfere with folate synthesis and nucleic acid processing

Question 1

Antifolate drugs

Answer 1

Disruption of the folate pathway is generally bacteriostatic in single agent therapy
Targets of bacterial folate antagonists- sulfonamides and trimethoprim

Question 2

Sulfanomides- Prontosil

Answer 2

First commercial antibiotic from a red dye

Prodrug- no activity in cultures but protected mice and rabbits against lethal doses of staphylococci and streptococci.

Question 3

Sulfandomides

Answer 3

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

Question 4

Sulfanomide Resistance

Answer 4

Cross-resistance b/w agents

Mutations carried on plasma- additional production of PABA and changes in binding sites from sulfonamides.

Question 5

Three major groups of Sulfanomides

Answer 5

Oral absorbable, oral nonabsorbable, and topical agents.

Question 6

Sulfanomides- oral absorbables

Answer 6

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)

Question 7

Sulfonamides- oral non-absorbable agents

Answer 7

Sulfasalazine- used for UC, enteritis, delayed release of tablets is used to treat RA.
Anti-inflammatory properties

Question 8

Sulfonamides- topical agents

Answer 8

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

Question 9

Sulfonamide Pharmacokinetics

Answer 9

Well absorbed
Distributed throughout the body including CNS and fetus
Elimination is primarily renal

Question 10

Sulfonamides Adverse Effects

Answer 10

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.

Question 11

Sulfonamides- Special Populations

Answer 11

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)

Question 12

Trimethopim

Answer 12

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.

Question 13

Sulfamethoxazole/Trimethoprim (Bactrim or Septra)

Answer 13

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.

Question 14

Sulfamethoxazole/Trimethoprim- Clinical uses

Answer 14

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.

Question 15

Drugs that alter nucleic acid processing

Answer 15

Inhibit DNA processing

Quinolones, rafampin, and nirtrofurantoin

Question 16

Qoinolones- MOA

Answer 16

Block bacterial DNA synthesis by inhibiting DNA topoisomerase IV and topoisomerase II.

Question 17

Quinolones- Spectrum of Activity

Answer 17

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

Question 18

Quinolone “classes”

Answer 18

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)

Question 19

Quinolone Spectrum of Activity 2

Answer 19

Atypical pneumonia organisms (Chlamydia pneumoniae and mycoplasma pneumoniae)
Intracellular pathogens (Legionella, mycobacteria tuberculosis, and mycobacteria avium complex)

Question 20

Quinolone Clinical Uses

Answer 20

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.

Question 21

Fluoroquinolone resistance

Answer 21

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

Question 22

Quinolones pharmacokinetics

Answer 22

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

Question 23

Quinolone Adverse Effects

Answer 23

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

Question 24

Quinolone Drug interactions

Answer 24

Interactions if taken at the same time as antacids, sucralfate, iron, and multivitamins
CYP interactions most common with ciprofloxacin

Question 25

Quinolone- Moxifloxacin (avelox)

Answer 25

Oral or IV
Broad spectrum single dose daily
Targets DNA gyrase instead of topo IV in gram (+)

Question 26

Quinolone- Gemifloxacin (factive)

Answer 26

Approved to treat mild-moderate CAP due to multi-drug resistant Streptococcus pneumoniae.

Question 27

Miscellaneous Antibacterial Drugs

Answer 27

Metronidazole
Notrofurantoin
Polymyxins
Daptomycin

Question 28

Metronidazole (Flagyl) MOA

Answer 28

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

Question 29

Metronidazole (Flagyl)- spectrum of activity and pharmacokinetics

Answer 29

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

Question 30

Metronidazole (flagyl)- contracindications/cautions and drug interactiosn

Answer 30

Hx of blood dyscrasias, alcoholism, hepatic dz, CNS disorders, visual changes, 1st trimester of pregnancy
Drug interactions- warfarin, cimetidine, lithium toxicity, ETOH

Question 31

Metronidazole (flagyl)- ADRs

Answer 31

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

Question 32

Nitrofurantoin (Macrodantin, Macrobid)- MOA, spectrum of activity, and ROA

Answer 32

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

Question 33

Nitrofurantoin (marcodantin, macrobid)- ADRs

Answer 33

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.

Question 34

Polymyxin B- MOA

Answer 34

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

Question 35

Polymyxin B- spectrum and ROA

Answer 35

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.

Question 36

Daptomycin (Cubicin)

Answer 36

Used for multi-drug resistant gram (+) bacteria
Bactericidal disruption of plasma membrane
Once daily dosing
ADRs- reversible myopathy, GI