Living Textbook MC610

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Nitrofurans

Mechanism of Action:

These agents have a dual mechanism of action, depending on the site of reduction of their nitro group:

The nitro group can be reduced by the bacterial or host enzymes, leading to various enzymatic inhibitions, specifically these enzymes important for energy production. These enzymes are protected in mammalian cells in the mitochondria, while they are in the cytoplasm of the bacterial cells.

In addition, the nitroreductase systems in bacteria and protozoa can act on the nitro group, leading to its reduction. These nitroreductase systems are however coupled with the formation of free radicals, such as the hydroxyl radical OH• causing unknown DNA damage.

Resistance is not a significant problem in these agents.

These agents may inhibit Cytochrome P450 enzymes.

Nitrofurazone is used topically for burns and shows broad spectrum. It is useful for patients with second or third degree burns.

Furazolidene can be used orally for diarrhea against bacterial and protozoal agents, since only a very small amount is absorbed.

Nitofurantoin is used orally in acute UTI, its systemic tissue distribution is very low. Nausea and vomiting was a problem experienced by some patients, and has been overcome by the use of a wax-coated macrocrystalline form of the drug that slows down absorption. Adverse effects include nausea, vomiting and headache. Rare but serious effects include jaundice, pulmonary toxicity and peripheral neuropathy. Patients with G6PD deficiency may develop hemolytic anemia.

A related group, Nitroimidazoles include Metronidazole was originally introduced for treatment of vaginal infections by amoeba, but has found use against a wide variety of organisms, especially anaerobes, but including protozoa and bacteria. It is especially useful in treatment of pseudomembranous enterocolitis caused by Clostridium difficile an opportunistic pathogen that flourishes after the use of some wide spectrum antibiotics and can be life threatening. It is also part of a cocktail for Helicobacter pylori. It may cause QT prolongation and may color body fluids brown red.

Metronidazole is an inhibitor of CYP450, especially CYP2C9, and could lead to higher levels of warfarin, some anticonvulsants and agents used in AIDS.

Methenamine

Methenamine acts by releasing Formaldehyde in urine, and thus can be used in recurrent UTI. It acts on cell membranes similar to antiseptics. Formaldehyde will only be released under acidic conditions, and so administer with an acidic salt such as ammonium chloride or sodium biphosphate or as a Mandolate or hippurate salt.

Bacterial resistance can occur by producing urease that breaks down urea to ammonia, causing alkalization of the urea. This can be overcome by the use of Lethostat, a urease inhibitor.

Clinical Application:

General: Bactericidal with a broad spectrum.

Nitrofurazone:

Indications and Uses: Topically for second or third-degree burns

Nitrofurantoin:

Coverage include Gram positive agents such as S. aureus, saprophyticus and Enterococci spp. (including VRE), Gram negative agents such as E. coli (resistance is common), Citrobacter,Enterobacter and Klebsiella spp.

Non-susceptible organisms include some Gram negative bacteria such as most Proteus species, Serratia marcescens, and Pseudomonas aeruginosa.

Indications and Uses: Acute uncomplicated and catheter-associated UTI caused by susceptible organisms.

Methenamine:

Indications and Uses: UTIs prophylaxis and suppression

Metronidazole:

Coverage includes anaerobes such as Clostridium difficile, Bacteroides fragilis and Helicobacter pylori and protozoa such as amoeba

Indications and Uses: It is particularly useful in infections caused by anaerobic bacteria, including pseudomembranous colitis, septicemia, bone and joint infections, SSSI and lower RTI infections. It is also indicated for gynecological infections, meningitis and other CNS infections caused by anaerobes. It is part of drug cocktails used in H. pylori infections. It is used in some protozoal infections such as amebiasis.