Sulfa, Quinolones Etc Flashcards

1
Q

Sulfonamides MOA

A

block various steps in the purine metabolism pathway, thus inhibiting the production of nucleic acids and DNA

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2
Q

Significance for PABA in bacteria

A

Many bacteria, unlike mammals, cannot use folate from their environment but must synthesize it from PABA

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3
Q

Relationship between PABA and sulfonamides

A

As structural analogs of PABA, sulfonamides inhibit dihydropteroate synthase and folate production via competitive inhibition.

Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis.

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4
Q

Mechanism of resistance against sulfonamides

A

Lack of target: some species of bacteria use exogenous folate and do not have this pathway

Mutated enzyme that drug can’t bind

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5
Q

Toxicities of sulfa drugs

A

These drugs are all contraindicated in newborns and nursing mothers as they displace unconjugated bilirubin from albumin, increasing the risk of kernicterus.

They can all cause bone marrow suppression that may or may not be due to folate underproduction: nutritional vs. immune-mediated BM suppression, megaloblastic anemia

Sulfonamides increase oxidative stress and thus can precipitate hemolytic anemia in G6PD-deficient patients. This will look like a typical hemolytic crisis you should be familiar with from last year: sudden jaundice, dark urine, normocytic anemia, elevated reticulocyte count.

Solubility of the drugs is a major problem, which can result in crystallization in urinary tract when patients become dehydrated and their urine is more concentrated; treatment is to hydrate and give IV bicarbonate as they are more soluble in alkaline fluids

Rashes are tremendously common with sulfa drugs and can range from photosensitivity, annoying-to-fatal skin rashes like Stevens-Johnson syndrome

Sulfa drugs are very allergenic and can cause hypersensitivity reactions that look like autoimmune disorders: arthritis, conjunctivitis, stomatitis, polyarteritis nodosa, psychosis

Since these hypersensitivity drug reactions are not unique to sulfa drugs, the way they will usually be asked about on exams is to have the patient on a sulfa drug, and then a specific question will be asked about diagnosing the reaction rather than the drug itself.

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6
Q

Examples of dihydrofolate reductase inhibitors

A

Trimethoprim (TMP) and pyrimethamine

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7
Q

Use of dihydrofolate inhibitors

A

Commonly be complexed to sulfonamides for synergistic and sequential inhibition of the pathway. TMP is used in bacterial disease complexed as TMP/SMZ, and pyrimethamine for protozoal (parasitic) diseases.

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8
Q

Toxicities of dihydrofolate inhibitors and population most susceptible to them

A

Toxicity for these drugs is similar to the sulfonamides and increased in AIDS patients, who commonly take these drugs daily for prophylaxis or treatment of opportunistic infections.

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9
Q

Folate DNA pathway

A
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10
Q

MOA of fluroquinolones

A

Fluoroquinolones inhibit the DNA gyrase enzyme complex.

This complex has multiple subunit enzymes, and the drugs specifically inhibit:

Topoisomerase II, preventing uncoiling of DNA for transcription and replication, and

Topoisomerase IV, preventing separation of duplicated chromosomes into daughter cells.

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11
Q

First line use of fluroquinolones

A

Earlier generations of FQs have gram - coverage only, later generations add gram + coverage.

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12
Q

Examples and uses of gen 2-4 of fluroquinolones

A
  1. Ciprofloxacin–“urinary FQ”, includes Pseudomonas aeruginosa coverage
  2. Levofloxacin–“respiratory FQ”
  3. Moxifloxacin–very broad coverage for resistant pathogens in hospitalized patients
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13
Q

How is fluroquinolones resistance achieved

A

Low-level plasmid-mediated: Qnr chaperone proteins that protect DNA gyrase. These give a permissive effect so that the bacteria can develop higher-level resistance using:

Efflux pumps

Porin size change

Enzyme point mutations to decrease binding affinity: for example, the gyrA gene in gonococcus

Usually class-wide

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14
Q

Pharmacokinetics/dynamics or FQs

A

Good bioavailability so useful orally

Mineral or cationic medications will block absorption (remember this problem with the tetracyclines?)

Moxifloxacin is excreted in the bile, which makes it a) not a good choice for urinary tract infections and b) useful in patients with renal failure

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15
Q

Black box warning of FQs

A

musculoskeletal toxicity most established in the medical literature is tendon rupture

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16
Q

Non-black box toxicities of FQs

A

Qtc interval prolongation with risk of arrhythmia and sudden death is seen also (remember this is a toxicity for the macrolides as well!).

All fluoroquinolones are considered teratogens due to potential effects on growing cartilage.

17
Q

Metronidazole MOA

A

Metronidazole is a prodrug that is selectively absorbed by anaerobic bacteria and protozoa.

Once inside the prokaryotic cell, it undergoes a reduction reaction with reduced ferredoxin, creating active drug metabolites that are toxic and cause oxidative damage to pathogen DNA, proteins, etc

18
Q

Pharmacokinetics/dynamics of metronidazole

A

Metronidazole can be given many ways and has good bioavailability when taken orally. It undergoes hepatic metabolism and accumulates in liver failure. It also causes a disulfuram-like reaction (puking, wanting to die) when alcohol is ingested while on the drug due to inhibition of the hepatic enzyme acetaldehyde dehydrogenase that is needed to metabolize alcohol

19
Q

Metronidazole toxicities

A

Cumulative neurotoxicity can occur with prolonged courses or with repeated dosing for c. difficile colitis; this can manifest as seizures and peripheral neuropathy.

Metronidazole also has an important interaction with warfarin (coumadin) by altering vitamin K-producing flora in gut; this creates a relative vitamin K deficiency over time and can cause Coumadin toxicity with GI or other bleeding and very high INR/PT.

Phenytoin and Phenobarbital cause accumulation of the drug due to inhibition of the metabolic pathway for the drug in the liver.

Metronidazole also causes lithium toxicity in some patients.

20
Q

MOA of mupirocin

A

Mupirocin (pseudomonic acid) is an antistaphylococcal topical agent that is actually a product of a pseudomonas bacteria, P. fluorescens. It is classified as topical only because although it is absorbed, it is too rapidly inactivated to have systemic or tissue effect. The drug has a very specific mechanism of action via inactivation of staphylococcal isoleucyl tRNA sythetase.

21
Q

Use of mupirocin

A

It has been the initial drug of choice for topical decolonization of MRSA for many years, but high-level resistance via plasmid-encoded new isoleucyl tRNA sythetase has evolved causing complete loss of activity of the drug.

22
Q

Polymyxcin B and E MOA

A

These topical agents are cationic detergents that dissolve/disrupt the lipophilic cell membrane as well as bind and inactivate endotoxin

23
Q

Use of Polymyxcin B and E

A

gram - activity only.

Systemic use of these agents is toxic, so it is used clinically in antibiotic ointments (including Neosporin) and in eye and ear drops for those infections.

24
Q

Fidaxomicin MOA and use

A

Fidaxomicin is a macrolide that is non-absorbed, used exclusively to treat infections inside the gut lumen. It is a fermentation product of a fungus and binds to the sigma factor required for RNA polymerase binding to gene promoter regions.

25
Q

nitrofurantoin MOA and use

A

generation of intracellular highly reactive intermediates,

The use of these drugs is limited to UTI’s affecting the bladder or urethra only.

They are absorbed from the GI tract and immediately excreted into the urine and have no systemic effect.

26
Q

Can nitrofurantoin be used for kidney infection

A

NO, nitrofurantoin is not systemic and kidney nfections are serious, deep-seated tissue infections of an organ that has a rich arterial and venous blood supply and bacteremia is common with this type of infection.

27
Q

Nitrofurantoin toxicities and contraindications

A

The drug is contraindicated in renal failure, as it would be unable to be excreted.

It can cause hemolytic anemia crisis and neuropathy in G6PD deficiency patients due to its mechanism of oxidative injury.

A major toxicity you will see asked about on exams is the development of irreversible pulmonary fibrosis. This is a cumulative risk and most important for patients with recurrent UTIs that take the drug daily over a long time to prevent UTIs. Patients taking this drug chronically should have regularly scheduled pulmonary function tests (PFT’s) to look for this toxicity and the drug should be discontinued if a restrictive pattern on PFT’s develops. Below is a chest x-ray of a patient with nitrofurantoin pulmonary fibrosis with all kinds of nodules and scarring.