Antibiotics III

Question 1

What is the idea behind sulfonamides?

Answer 1

Selectivity: Bacteria synthesize folic acid; mammalian cells lack enzymes required to synthesize folate.

This guy is broad spectrum.

Question 2

Discuss the pathway of PABA to DNA (I’m not sure if this will come up, but knowing these assholes, this is the only concept they will test on the exams, so I’d learn it. Stop complaining Caitlin)

Answer 2

1. So you get this guy PABA, who meets this chick, Pteridine (sounds foreign…sexy), and with a little DS (Dihydropteroate synthase) you get Dihydropteric acid.
   - Sulfonamide stops this. What a dick.
2. Dihydropteric acid turns to dihyrofolic acid (DH2).
3. DH2 turns to DH4, Tetrahydrofolic acid, via dihydrofolate reductase.
   - Benzylpyrimidines stop this.
4. DH4 to Purines to DNA

Question 3

Where can sulfa drugs go?

Answer 3

Everywhere, dude, even the BB and placenta don’t stand a chance

Question 4

How do bacteria resist sulfonamides?

Answer 4

Decreased bacterial permeability/ influx

Active transport efflux

Increased production of PABA, decreased sensitivity of synthase

Question 5

Adverse effects of sulfonamides

Answer 5

Urinary tract: Crystalluria caused by precipitation of drug or metabolites; increased likelihood with high doses, acidic/neutral urine, dehydration Triple sulfa combination: decreases chance of precipitation of any one drug

Hematopoietic: hemolytic anemia, aplastic anemia, agranulocytosis

Hypersensitivity: rashes, fever, malaise, pruritus, photosensitivity, Stevens-Johnson syndrome

GI: Nausea, vomiting, diarrhea

Question 6

Drug interactions with sulfonamides?

Answer 6

Drug interactions: Potentiate effects of oral anticoagulants, sulfonylurea hypoglycemic agents& hydantoin antiseizure drugs

Question 7

Examples of benzylpyrimidines?

Answer 7

Trimethoprim and pyrimethamine

These guys are also broad spectrum antibiotics

Question 8

How do benzylpyrimidines work?

Answer 8

Selective inhibitor of bacterial isoform of dihydrofolate reductase; although there is a mammalian form of this enzyme, it is less sensitive to inhibition by these drugs.

Question 9

Where do benzylpyrimidines go?

Answer 9

• Oral is just fine
• They go everywhere, including BBB and placenta
• Interesting note, it is a weak base, so it gets trapped in prostatic and vaginal fluids

Question 10

How do bacteria become resistant to benzylpyrimidines?

Answer 10

Decreased bacterial permeability/ influx

Increased production of reductase, decreased sensitivity of reductase

Question 11

Adverse effects of benzylpyrimidines

Answer 11

Megaloblastic anemia, leukopenia, granulocytopenia (can be prevented by simultaneous administration of folinic acid)

Question 12

Talk about the coolness and not so coolness of combining trimethoprim and sulfamethoxazole

Answer 12

Synergism from sequential blockade of folate synthesis; also becomes bactericidal instead of bacteriostatic. Can be given orally or iv. Good tissue distribution including prostate and CSF.

Adverse effects:

• CNS disturbances
• Has been associated with birth defects—not safe during pregnancy
• AIDS patients have particularly high incidence of adverse effects

Simultaneous administration of folinic acid to AIDS patients not recommended (associated with increased treatment failures and morbidity)

Question 13

There are three drugs we consider together due to their similar resistance mechanisms and more importantly, how they work.

When you think direct inhibition of DNA replication or transciption, you think of:

Answer 13

Fluoroquinolones (cipro, levofloxacin, anything with -floxacin)
Nitroimidazoles (metronidazole)
Rifamycins (Rifampin)

Question 14

How do these DNA replcation/transcription inhibitors work?

Answer 14

Think DNA gyrase

Bacteria have DNA gyrase; mammalian cells lack DNA gyrase. Eukaryotic cells do have a type II DNA topoisomerase that can be inhibited by quinolones, but only at much higher concentrations (100-1000 ug/ml vs 0.1 to 10 ug/ml)

Question 15

What bacteria do these DNA drugs cover?

Answer 15

Fluoro - Mostly gram negative, some gram positive

Metronidazole - Anaerobes, but also Vanco resistant C Diff and a few aerobes

Rifampin - Often used for mycobacteria infections. Also great for Neisseria and mycobacteria infections, and prophylactic for meningitis from H. influenzae or menigococci

Question 16

Discuss the mechanism of action for Fluoroquinolones

Answer 16

Bactericidal

Primary for Gram-negative: inhibition of DNA gyrase (topoisomerase II); prevents relaxation of positively supercoiled DNA required for transcription & replication

Primary for Gram-positive: inhibition of topoisomerase IV

Probably interferes with separation of replicated DNA into daughter cells during cell division

Question 17

Discuss the pharmacokinetics of fluoroquinolones

Answer 17

Good oral absorption, impaired by dairy products, antacids and supplements containing divalent & trivalent cations

Broad distribution through the body; especially good for prostatitis

Drug clearance primarily renal

Question 18

Mechanism of resistance for fluoroquinolones?

Answer 18

Decreased bacterial permeability/ influx

Decreased affinity of DNA gyrase and / or topoisomerase IV

Question 19

Side effects of fluoroquinolones:

Answer 19

• Cartilage damage - Don’t give to nursing mothers or kids
• Psuedomembranous colitis - N/V/D (this is the most common)
• Sometimes: Headache, dizzy, skin rash (Stevens-Johnson syndrome), seizures, insomnia, hepatitis, tendonitis, photosensitivity
• Increased theophylline

Question 20

So how does metronidazole work?

Answer 20

Inhibits DNA replication

The nitro group of the nitrosohydroxyl amino moiety is reduced by an electron transport protein in anaerobic bacteria; the reduced drug causes strand breaks in the DNA.

Mammalian cells are unharmed because they lack enzymes to reduce the nitro group of these agents.

Question 21

Discuss the pharmacokinetics of metronidazole

Answer 21

Can be used iv; also good oral bioavailability approaches 100%

Penetrates the CNS

Metabolized in the liver by hydroxylation (CYP 3A4) as well as renal clearance

Question 22

Side effects of metro

Answer 22

• Leukopenia
• Seizures, peripheral neuropathy after prolonged treatment
• Interferes with alcohol metabolism

Question 23

Drug interactions with metro?

Answer 23

Drug interactions: Barbiturates induce liver enzymes which metabolize metronidazole, decreasing serum half-life.

Question 24

Where do rifamycins act?

Answer 24

Bactericidal

Inhibits bacterial RNA synthesis

Non-covalently binds to the beta subunit of the DNA-dependent RNA polymerase

Question 25

Resistance to rifamycins?

Answer 25

Resistance can be due to small amino acid mutations in the RNA polymerase beta subunit

Question 26

The two rifamycins, rifampin and rifamixin, are used differently. What do we use each for?

Answer 26

Rifampin - Neisseria and mycobacteria infections, also used prophylactically for meningitis from H. influenzae or menigococci

Rifamixin - Usually for non-invasive strains of E. coli (Travelers’ Diarrhea), also for Shigella, Salmonella, and other enteropathogens

Question 27

Are rifampin and rifamixin absorbed in the same ways?

Answer 27

Not really.

Rifampin

• Absorbed oral preparation
• Good CNS penetration
• Deacetylated in the liver (metabolite is also active)

Rifamixin

• Not absorbed from GI tract; only ~0.4%
• Mostly excreted unchanged in feces

Question 28

Adverse effects of our rifamycins?

Answer 28

Rifampin - Induces CYP3A4 and thus enhances metabolism of other drugs like contraceptives (rifamixin does this a little bit). Nausea, dermatitits, and one classic finding of red-orange discoloration of tears, sweat, urine feces.

Rifamixin with very few side effects

Question 29

What is an anti-biogram?

Answer 29

An antibiogram is derived from laboratory testing of antibiotic sensitivity of bacterial strains isolated from an individual hospital. By definition it tests in vitro sensitivity. Each hospital keeps a current antibiogram (often updated annually and available in the pharmacy), and antibiotics purchased by the pharmacy reflect sensitivity and resistance of bacterial strains of that hospital.