Unit 8: Sulfonamides, Fluoroquinolones, Macrolides, Chloramphenicol

Question 1

what is elixir sulfanilamide

Answer 1

• contained diethylene glycol, unknown by the chemist at the time to be poisonous.

This concoction resulted in hundreds of fatalities, thus regulations on drug manufacturing were born.

Question 2

what are sulfonamides and how do they work?

Answer 2

aka sulfa drugs, antimicobial agents that contain a sulfonamide group

• inhibit the metabolic pathway required for folic acid synthesis
• sulfonamides are competitive inhbitors of dihydropteroate synthetase - key enzyme in folate synthesis

*alone sulfonammides are bacteriostatic

Question 3

what is folic acid? What is the structure?

Answer 3

0 vitamin that is invovled in enzyme reactions in transfer of one carbon units

• reactions used in biosynthesis of RNA and RNA precursors
• Structure contains 3 chemical moieties: pteridine ring system, para-aminobenzoic acid (PABA) and the amino acid glutamate
• folate is formed by condensation of pteridine, para-aminobenzoic acid (PABA), and glutamate - its the deprotonated form of folic acid

* folate is essential vitamin for humans but in lower organisms its synthesized from precurcors

Question 5

describe folate synthesis

Answer 5

1. formation of dihydropteroic acid from pteridine and para-aminobenzoic acid (PABA) - Rxn catalyzed by dihydropteroate synthase this is where fulonamides inhibit
2. Glutamate and dihydropteroic acid condense to form dihydrofolate (DHF).
3. DHF is reduced to tetrahydrofolate (THF) by dihydrofolate reductase (DHFR).
4. THF and its congeners (not shown) serve as one-carbon donors in numerous reactions necessary for the formation of DNA, RNA, and proteins.

Question 6

what are the pharmacokinetics of sulfonamides

Answer 6

Distribtuion

• widely distributed throughout all tissues, broad spectum activity against most bacteria and some protozoa
• clinically used for gram neg bacteria and some atypical bacteria and protozoa

Excretion:

• active drug and inactive metbaolites are excreted in urine and accumulation can occur in renal tubule
• renal damage may occur if patient is dehydrated

Question 7

sulfonamides when used alone

Answer 7

highly ineffective

• effectiveness restored when combined with inhibitiors like trimethoprim
• combination of sulfonamides (S) and trimethoprim (TM) is referred to as potentiated sulfonamide (TM + S) and this effect is often bactericidal

*may see written as TMS or co-trimoxazole

Question 8

adverse effects of sulfonamides

Answer 8

May be mild or erious

Fiver and skin problems, esp if drug is aplpied topically

Allergies common to oral preps

Precipitation of drug and metabolites in renal tubules of dehydrates patietns may occur and cause renal damage

Kernicterus: rare, displcaemnt of bilirubin from albumin in infants which then crosses the BB. Regions most commonly affected are basal gnaglia, hippocampus and geniculate bodies which cause various signs of brain damage

Question 9

sulfonamides and resistance

Answer 9

• common

can develop rapdily via acquisiton of an altered dihydropteroate synthetase enzyme which is encoded by plasmids.

• new enzyme bidns PABA but not sulfonamide - can occur during treatment
• result = increase PABA uptake in presence of pus and debris which reduces uptake of the drug

Question 10

resistance to Trimthoprim

Answer 10

Resistance to TM is usually due to acquisition of an altered form of dihydrofolate reductase that can no longer bind TM.

Question 11

when are sulfonamides used

Answer 11

• lower URI’s (use a high conc)
• toxoplasmosis (TMS is drug of choice)

certain other infections that are resistant to newer antimmicrobials like pneumonia in AIDS patients

Question 12

what are PABAs

Answer 12

para-aminobenzoic acid (PABA)

• invovled in formation of folic acid

* sulfonamides are PABA analogues and inhibit dihydropteroate synthase, the enzyme that catalyzes the formation of dihydropteroic acid from PABA and pteridine.

Question 13

what are fluoroquinolones

Answer 13

• newer class
• most promosing new antibacterial group bc unique MOA
• inhibit bacterial type II topoisomerases, damaging DNA by binging to abcteria DNA gyrase and topoisomerase which inhibits supercoiling and resealing of cleaved DNA ends

*widespread voeruse has lead to resistance

Question 14

what is the standard fluoroquinolone drug of choice?

Answer 14

Ciprofloxacin

• levofloxacin and moxifloxacin also used

Question 15

activity spectrum of ciprofloxacin and what is ti used to treat

Answer 15

• similar to gentamycin
• can target many Gram negative aerobes but Staphylococcus are essentially the only Gram positive that it will have activity against
• used to treat mycoplasma and chlamydia but ciprofloxacin is ineffective against all anaerobes.

*fuoroquinolones are a newer class of drugs - spectrum somewhat inconsistent: Tsome drugs are effective against some Gram +ve bacteria while others are effective against certain anaerobes.

Question 16

what are pharmacokinetics of fluoroquinolones

Answer 16

oral bioavailability approaches 100%

long half lives (for example, ciprofloxacin ~4 hr; moxifloxacin ~10 hr).

excreted by the renal system, with the exception of moxifloxacin which goes through the hepatic system.

Question 17

adverse effects of fluoroquinolones

Answer 17

• several
• affects on CNA like headache, dizziness a

lower the seizure threshold which can be dangerous for those who are susceptible to episodes

• phototoxicity can result: those taking should avodi excessive sunlnight exposure during treatment
• some like levofloxacin cna cause heart problems that prolong QT interval time * avoid in pt with long PT syndrome
• cartial damage may occur but more for animals not huamns
• in adults endonitis and achilles tendon rupture may occur.

*avoid is under 18, pregnant or nuraing as a precaution

Question 18

resistance to flyiriquinolones

Answer 18

• can occur by multi drug efflux pump (AcrAB)
• Mutations permit increased expression of a pump thats normally in low numbers
• almso plamsid borne mechanisms

Question 19

describe the plasmid borne mechanisms of resistance for fluoroquinones

Answer 19

QnrA, qnrB, and qnrS genes encode peptides that inhibit fluoroquinolones from binding to DNA gyrase and topoisomerase

*called hyrase protection proteins

• plasmid, encoding Aac(6’)-Ib-cr, is a variant of an aminoglycoside modifying enzyme modifies ciprofloxacin and reduces its activity, making it a fluoroquinolone modifying enzyme

*genes often contained on some plasmids that carry extended spectrum of beta lactamases and soemtimes other resistance genes making bacteria resistance to several common drugs

Question 20

when to use fluoroquinolones

Answer 20

esting shows high susceptibility, either individually or on a population basis (such as testing of a subset of isolates in hospital situations).

This is often not the case in practice.

Question 21

what is ciprofloxacin

Answer 21

Type of fluoroquinolone

Activity spec is similar to gentamycin

can target many Gram negative aerobes but Staphylococcus are essentially the only Gram positive that it will have activity against

used to treat mycoplasma and chlamydia but ciprofloxacin is ineffective against all anaerobes.

Question 22

what are macrolides

Answer 22

Target the 50S ribosomal subunit

Have large lactone ring attached to one or more deoxy sugars

Activity on some atypical bacteria

Mainly bacteriostatic

One of safest antibacterials

Question 23

pharmacokinetics of macrolides

Answer 23

Metabolized and excreted in bile, but erythromycin shown to inhibit P450 metabolism of other drugs - consider before prescribing other meds

Widely distribute except the CNS, one of few antimicrobials that enters prostate relatively well

Also dsitributes well to lungs and concnetrate in lung (can be 100x higher than in plasma)

Question 24

adverse effects of macrolides

Answer 24

Tissue irritation (severe pain with IM admin and vomiting

Vomiting esp problematic with erythromycin

Question 25

MOA of macrolides

Answer 25

Inhibiiton of proien synthesis by binding reversibly to bacterial ribosmoes 50S subunit

causing dissociation of peptide carrying tRNA from ribosome during translocation

Question 26

what is Erythromycin

Answer 26

Most common macrolide similar spectru to amoxicillin

shown to inhibit P450 metabolism of other drugs - consider before prescribing other meds

Major vomiting side effect bc stimulates motilin receptors in GI tract causing nausea (highly variable between aptients)

Question 27

Azithromycin

Answer 27

Newer macrolide that’s more effectie than erythromycin against gram neg aerobes

Logner half life and can be administered once daily rather than 4 times a day

Commonly used for resp tract infections and one of worlds best selling drugs

Question 28

clarithromycin

Answer 28

Newer macrolie

More effective than erythromycin and azithromycin against gram positive apthogens

Logne rhalf life than erythromycin and therefore needs to be admin twice a day

Common to treat community acquired respiratory tract infections

More acid stable than erythromycin so has fewer GI adverse effects

Question 29

what is telithromycin?

Answer 29

Treatment of certant resistant respiratory pathogens

Resistance that develops following administration of macrolides is mainly due to target modification and efflux pumps

macrolides are predominantly prescribed as antimicrobial agents, they also have anti-inflammatory effects that inhibit neutrophil migration and leukotriene synthesis.

Question 30

what is Chloramphenicol

Answer 30

Also targets 50S subunit

Isolated from Streptomyces venezuelae

bacteriostati active against both aerobic and anaerobic Gram positive and Gram negative organisms.

Penetrates the cornea really well

Available on oral, topical and injectible forms

Currently banned in good producing animals due to documented fatailied

Only use in those with serious infections when less potentially dangerous drugs are ineeffective or contraindicted

Question 31

adverse effects of chloramphenicol

Answer 31

Usually very safe but fatal aplastic anemia can occur in humans

Only in 1/30,000 and due to genetic defect that is simialr to malignan hyperthermia

Effect not dose related or irreversible and may occur weeks ro months after therapy is stopped