Sulfonamides, Trimethoprim and Fluoroquinolones – Antimetabolites

by Pravin Shukle, MD

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    00:00 Let's talk about the sulfonamides.

    00:03 Now sulfonamides are weak acids.

    00:06 And they're congeners or structurally similar to a chemical called paraminobenzoic acid which is actually shown in an illustration right here.

    00:17 Now these are bacteriostatic inhibitors of folic acid synthesis.

    00:21 And they may also be involved in the production of faulty folic acid.

    00:25 So mammals obtain their folic acid from the diet, whereas bacteria have to manufacture it.

    00:33 Now most of this particular drug is going to be excreted in the urine.

    00:37 So trimethoprim is often added to the sulfonamides.

    00:41 These are selective inhibitors of dihydrofolate acid reductase.

    00:45 It inhibits the bacterial form and there isn't really a mammalian form to inhibit to speak of.

    00:51 It prevents formation of tetrahydrofolate.

    00:54 Now bacterial dihydrofolate reductase is five times more sensitive to trimethoprim then the human version of the same enzyme.

    01:04 So from a trimethoprim point of view, it's really a non-issue.

    01:09 We combine sulfomethoxazole with trimethoprim to create an agent called septra which is sold commercially are also called SMP/TMP.

    01:19 Now bacterial synergy is obtained because we're acting on two different levels of the folic acid production pathway.

    01:27 Now the sulfonamides work on these particular enzyme at the top of this structure.

    01:33 And trimethoprim works on dihydrofolate acid reductase at the middle of this structural pathway.

    01:41 These drugs are concentrated in the bladder so they're particularly effective in bladder infections.

    01:47 Now we also use this agent in pneumocystis carini infections and toxoplasmosis infections in HIV positive patients.

    01:58 So it's not just used in urinary tract infections alone.

    02:02 Now septra toxicity includes hypersensitivity reactions which are actually surprisingly common.

    02:11 A lot of patients are allergic to sulpha and they will have a cross allergy to this agent.

    02:16 There are also cross allergies with other agents as well.

    02:19 So an example for this is if patients are allergic to septra.

    02:23 For example, they may also be allergic to ace inhibitors.

    02:26 And even rare but seen is ARB's.

    02:30 Now another side effect with this medication is nausea, vomiting and diarrhea.

    02:36 And very rarely you may get episodes of granulocytopenia, thrombocytopenia.

    02:41 Hemolysis is often seen too in patients who have gluco 6 phosphate deficiency.

    02:46 So that's an important consideration in some patients.

    02:50 Let's move on to floroquinolones.

    02:54 Now we have several generations of floroquinolones out there.

    02:58 Let's talk at them one at a time.

    03:00 The first generation was norfloxacin.

    03:03 It's not really clinically used anymore because of the toxicity issues and lack of efficacy issues.

    03:08 So this was replace with a second generation floroquinolones.

    03:13 Ciprofloxacin being the prototypical one.

    03:15 And probably the best known of the floroquinolones.

    03:19 It has more gram negative activity specially against gonococcus.

    03:25 And it actually quite effective against atypical bacteria like mycoplasma pneumoniae and chlamydia pneumoniae.

    03:33 The third generation agents include levofloxacin.

    03:38 And these are less active against gram negative bacteria.

    03:42 But they have a much greater activity gram positive cocci and Methicillin-resistant Staphylococcus aureus anaerobes.

    03:51 Levofloxacin which is called Levaquin commercially, is often used in pneumonia.

    04:00 Now the floroquinolones in general have very good oral bioavailability.

    04:05 And they are eliminated through the kidney.

    04:07 So we have to be aware of renal function.

    04:10 The other issue that we have to be aware of that this drug is actually blocked probenecid, the excretion of it.

    04:16 So in patients who are also on probenecid you may have toxic levels.

    04:20 A new agent moxifloxacin has hepatic clearance and maybe used in renal failure.

    04:26 These agents have half lives with 3 to 9 hours.

    04:30 So they are most often given twice a day.

    04:32 Some formulations though are actually given once a day.

    04:35 And a good example is the formulation called Cipro XL which is ciprofloxacin in a special kind of pill that allows it to be given once a day.

    04:43 And that's used most commonly in epididymitis, for example.

    04:50 So how do these agents work? The mechanism of action of floroquinolones is actually quite interesting.

    04:57 They interfere with DNA topoisomerase II.

    05:02 So DNA topoisomerase is the enzyme that's responsible for taking that helical twisted 3 dimensional structure and untwisting it so that we can get access to the genetic information inside it.

    05:15 So by interfering with it, you actually interfere with the first step of DNA transcription.

    05:22 Topoisomerase II is inhibited in the gram negative organisms and type IV is inhibited in gram positive organisms.

    05:33 Now I want to make sure that you know this, because this is a great exam question.

    05:38 One of those useless pieces of information that we left to put on exams for you.

    05:42 So make sure you remember this and then once you pass your exams, you can forget it.

    05:46 Now these agents are bactericidal.

    05:49 These agents also have a post antibiotic effect which is quite nice when you give them short term, you know that there is going to be a long term beneficial effect with these agents.

    06:01 In terms of how bacteria develop resistance to floroquinolones it's kind of an interesting phenomenon.

    06:08 What they do is they change their porins, so that they actually reduce the intercellular concentration or accumulation of this drug.

    06:17 The efflux mechanisms in microbacterium tuberculosis, staphylococcus aureus and streptococcus pneumoniae are also in play here.

    06:26 The other thing that will happen too that they will see changes in the sensitivity of the target enzymes.

    06:32 So sometimes that DNA topoisomerase will have a point mutation that prevents the floroquinolone from doing it's job.

    06:40 Now these are interesting in the sense that they are actually drug and bug specific.

    06:45 So gyrA is actually a gene that codes for the resistance to certain floroquinolones in the gonococcus bacteria.

    06:56 So it's really quite an interesting thing to, you know, to behold looking at the way that these agents are able to be resistant to the floroquinolones.

    07:08 In terms of toxicity, gastrointestinal distress, skin rash, headache and insomnia are quite commonly seen.

    07:16 More rarely you will see phototoxicity.

    07:19 Now tendinitis and tendon rupture has been reported in terms of floroquinolone toxicity.

    07:26 It's important to note that we do not recommend these agents in pregnant women or in children who are growing.

    07:32 And the reason is, because it may damage their cartilage and they may develop arthropathy.

    07:38 Specially in patients who are in their teenage years, I find that a lot of physicians forget this and they prescribe it to their teens and kids who haven't finished growing.

    07:47 So do not do that.

    07:48 Only in fully grown mature adults.

    07:51 Now the newer agents in this drug class may also prolong the QT interval.

    07:57 So we have to be aware of that potential problem as well.

    About the Lecture

    The lecture Sulfonamides, Trimethoprim and Fluoroquinolones – Antimetabolites by Pravin Shukle, MD is from the course Antimicrobial Pharmacology. It contains the following chapters:

    • Sulfonamides
    • Trimethoprim
    • Sulfamethoxazole/Trimethoprim
    • Flouroquinolones

    Included Quiz Questions

    1. It concentrates in the bladder before being excreted in the urine.
    2. It requires a low pH environment to become activated.
    3. They are also effective against certain fungal infections which are commonly diagnosed in bladder infections.
    4. They are weak acids that must be deprotonated to exert their effect.
    5. Cells of the bladder do not require folate, so there is less organ damage compared to other drugs.
    1. ACE inhibitors
    2. Fluoroquinolones
    3. Tetracyclines
    4. Probenicid
    5. Warfarin
    1. Atypical bacteria
    2. Gram positive cocci
    3. VRSA
    4. MRSA
    5. Anaerobes
    1. Moxifloxacin
    2. Ciprofloxacin
    3. Levofloxacin
    4. Norfloxacin
    5. Oflaxacin
    1. These agents are bacteriostatic.
    2. They have good oral bioavailability.
    3. They work by interfering with DNA topoisomerase II in gram negative organisms.
    4. They are usually administered twice daily.
    5. Kidney excretion of fluroquinolones is blocked by probenecid which may lead to toxic accumulation.

    Author of lecture Sulfonamides, Trimethoprim and Fluoroquinolones – Antimetabolites

     Pravin Shukle, MD

    Pravin Shukle, MD

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