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Antimetabolites: Sulfonamides and trimethoprim

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Antimetabolites: Sulfonamides and trimethoprim

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Antimetabolites: Sulfonamides and trimethoprim

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USMLE® Step 1 style questions USMLE

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A 28-year-old man comes to his primary care physician's office for a follow-up visit. The patient was given clindamycin 2 weeks before to treat a severe case of otitis media. The patient states that he is doing better, however he noticed multiple purulent lesions on his forearms that started shortly after he began taking the antibiotics and continued to spread. The patient states this never happened to him before. The patient's lesions are drained and a sample was sent to the lab for analysis. When the results arrive, the patient is given a different course of oral antibiotics. On day 6 of outpatient therapy, the patient calls the office concerned that the skin on his chest is peeling. Which of the following is a bacterial target of the antibiotic he was most likely given?


Transcript

Antimetabolites are medications that interfere with the synthesis of DNA.

Some antimetabolites are used in chemotherapy to kill cancer cells, while others are used as antibiotics since they inhibit bacterial folate synthesis.

Folate, or folic acid, also known as vitamin B9, is necessary for the synthesis of nucleic acids, which are the building blocks of DNA and RNA.

Simply put, a lack of folate results in a lack of nucleic acids, which then results in decreased DNA and RNA synthesis, leading to hindered cell division and function.

Now, a key difference between our cells and bacterial cells is that we get all of our folate through our diet, while bacteria can make their own folate from scratch.

Because of this, we can target the bacterial folate synthesis pathway to minimize the damage done to our cells.

So in order to synthesize folate, the bacteria will first use the host’s para-aminobenzoic acid, or pABA, and convert it to dihydropteroic acid via the enzyme dihydropteroate synthetase, or DHPS.

In the second step, dihydropteroic acid is converted into dihydrofolic acid by dihydrofolate synthetase.

The third step is the conversion of dihydrofolic acid into tetrahydrofolic acid via dihydrofolate reductase.

Tetrahydrofolic acid is a folic acid derivative and can be used to synthesize purines like adenine and guanine, which are used to build DNA and RNA, as well as thymidine, which is only used in DNA.

Now, the first group of antimetabolite antibiotics are the sulfonamides, which include sulfamethoxazole, or SMX, sulfisoxazole, and sulfadiazine.

These medications bind to dihydropteroate synthetase, or DHPS, in the first step of folate synthesis and prevents the bacteria from making dihydropteroic acid.

These medications can be given peroral or injected into a vein, but they need to be metabolized by the liver in order to work.

Now, they are broad spectrum and can treat a variety of gram positive and gram negative bacteria, as well as chlamydia and nocardia species.

Next we have trimethoprim, which inhibits the 3rd step of folate synthesis by inhibiting dihydrofolate reductase, or DHFR, preventing the formation of tetrahydrofolic acid.

Now humans also have dihydrofolate reductase, but the bacterial version of this enzyme is 4-5 times more sensitive to this medication.

Trimethoprim is also broad spectrum and is effective against both gram positive and gram negative bacteria.

Now, it’s mainly used in combination with sulfamethoxazole. The combination of these medications is called TMP/SMX.

These medications are used together because they are synergistic and can block folate synthesis at two key steps.

When used alone, both medications are bacteriostatic, meaning they can stop the bacteria from reproducing.

But when combined, they are bactericidal, meaning they will kill off the bacteria.

TMP/SMX is most commonly used to treat traveler's diarrhea and simple urinary tract infections, but it’s also effective in treating pneumonia and sinus infections caused by haemophilus influenzae and moraxella catarrhalis.

It’s the first line therapy for the treatment and prevention of pneumocystis jirovecii infections, which are caused by a yeast-like fungus that can affect immunocompromised people.

Finally, it’s effective against Methicillin Resistant Staph. Aureus, or MRSA.

A few bacteria exist that are notably not susceptible to antimetabolites, and those are Pseudomonas aeruginosa and bacteria from the Mycoplasma family.

Okay for side effects, some people are allergic to sulfonamide and can develop a hypersensitivity reaction to these antibiotics.

They can also develop a cross reaction with other drugs that contain the sulfonamide functional group such as glyburide, a diabetic medication, and thiazide diuretics.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Methotrexate, and trimethoprim-sulfamethoxazole: toxicity from this combination continues to occur" Can Fam Physician (2014)
  5. "Prophylactic Trimethoprim-Sulfamethoxazole Does Not Affect Pharmacokinetics or Pharmacodynamics of Methotrexate" Journal of Pediatric Hematology/Oncology (2016)
  6. "Medication Use and the Risk of Stevens–Johnson Syndrome or Toxic Epidermal Necrolysis" New England Journal of Medicine (1995)