Chapter: Modern Pharmacology with Clinical Applications: Synthetic Organic Antimicrobials: Sulfonamides, Trimethoprim, Nitrofurans, Quinolones, Methenamine

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Urinary Antiseptics

Urinary antiseptics are drugs that exert their antimicro-bial effect in the urine and are devoid of virtually any significant systemic effect.

URINARY ANTISEPTICS

 

Urinary antiseptics are drugs that exert their antimicro-bial effect in the urine and are devoid of virtually any significant systemic effect. Prolonged use for prophylaxis and/or suppression is common in recurrent or chronic UTIs where other antimicrobials can be used only for short durations because they do not sustain sterility.

Nitrofurans (Nitrofurantoin)

Chemistry and Mechanism of Action

 

A number of 5-nitro-2-furaldehyde derivatives, called nitrofurans, are used in the treatment and/or prophy-laxis of microbial infections, primarily in the urinary tract. Recent evidence suggests that the reduction of the 5-nitro group to the nitro anion results in bacterial tox-icity. Intermediate metabolites modify various bacterial macromolecules that affect a variety of biochemical processes (e.g., DNA and RNA synthesis, protein syn-thesis); this observation may explain the lack of resist-ance development to these drugs. Evidence also indi-cates that the nitro anion undergoes recycling with the production of superoxide and other toxic oxygen com-pounds. It is presumed that the nitrofurans are selec-tively toxic to microbial cells because in humans, the slower reduction by mammalian cells prevents high serum concentrations.

 

 

Antibacterial Spectrum and Resistance

 

Nitrofurantoin (Furadantin, Macrodantin) is primarily active against gram-negative bacteria (E. coli, P. mir-abilis is variable) and some susceptible gram-positive organisms, such as S. aureus and Enterococcus faecalis. In vitro activity is demonstrated against Staphylococcus saprophyticus and Staphylococcus epidermidis, but it may not be helpful in predicting patient response; the same applies for certain species of Klebsiella and Citrobacter. Most Proteus (indole positive), Serratia, and Pseudomonas spp. are resistant. Development of resistant strains is virtually unknown, and cross-resistance with other antimicrobials has not been re-ported.

 

 

Absorption, Metabolism, and Excretion

 

Nitrofurantoin is administered orally and is rapidly and almost completely absorbed from the small intestine; only low levels of activity are achieved in serum be-cause the drug is rapidly metabolized. Relatively high protein binding (about 70%) also affects serum levels, reducing potential for systemic toxicity and alteration of intestinal flora. Relative tissue penetration is much lower than other antimicrobials for UTIs, and therefore, nitrofurantoin is not indicated in the therapy of infec-tions such as pyelonephritis and renal cortical or per-inephric abscesses. Nitrofurantoin is rapidly excreted by glomerular filtration and tubular secretion to yield ef-fective urinary levels. In moderate to severe renal dys-function, toxic blood levels may occur while urinary lev-els may be inadequate. The drug is inactivated in the liver.

 

Nitrofurazone (Furacin) is used topically and is not readily absorbed from the skin.

blood levels may occur while urinary lev-els may be inadequate. The drug is inactivated in the liver.

 

Nitrofurazone (Furacin) is used topically and is not readily absorbed from the skin.

 

Clinical Use

 

The singular indication for nitrofurantoin is the treat-ment and long-term prophylaxis of lower UTIs caused by susceptible bacteria; it is not used as a bacterial sup-pressant. It is often used prophylactically post inter-course in women with chronic UTIs. Although serum drug concentrations are low, concentrations (100–200  μg/mL) are found in urine that are well above the mini-mum inhibitory concentration for susceptible bacteria. The bacteriostatic or bactericidal activity of nitrofuran-toin is concentration dependent; a urinary concentration greater than 100  μg/mL ensures bactericidal activity. Because nitrofurantoin lacks the broad tissue distribu-tion of other antimicrobial agents, urine cultures should be obtained before and after therapy. Alkalinization of the urine increases urinary concentrations of the drug but decreases its antibacterial efficacy; acidifying agents, including cranberry juice, can be useful.

 

Nitrofurazone, a topical antibiotic, is occasionally used in the treatment of burns or skin grafts in which bacterial contamination may cause tissue rejection.

 

Adverse Effects and Drug Interactions

 

Nausea and vomiting are the most commonly observed adverse effects. Pulmonary hypersensitivity reactions can result in chronic morbidity, usually after therapy lasting at least 6 months. Findings can include chronic desquamative interstitial pneumonia with fibrosis. Reso-lution may not occur with discontinuation of therapy; fever is absent. Reactions may also be acute or suba-cute. Patients may present acutely with findings resem-bling acute respiratory distress syndrome. Infiltrates (especially at the base of the lung) and/or effusions may develop but are usually reversible when the drug is stopped; fever is a common finding. In contrast, resolu-tion of pulmonary disease may require several months, especially in subacute reactions, with which fever is not frequent. These reaction types have all been reported as contributing factors in mortality. When a patient taking nitrofurantoin develops pulmonary symptoms, a suspi-cion of drug-associated toxicity must be entertained.

 

Intrahepatic cholestasis and hepatitis similar to that seen in chronic active hepatitis can rarely occur; fatali-ties have been reported. Nitrofurantoin can interfere with immature red blood cell enzyme systems found in babies less than 1 month of age and in nursing infants. This leads to cellular damage and anemia. Nitro-furantoin use is also contraindicated in pregnant women near term.

 

In vitro antagonism between nitrofurantoin and the quinolones has been shown, but a demonstration of clinical relevance warrants further study. Certain drugs used in treating gout, which inhibit tubular secretion, can affect UTI therapy by raising serum levels of nitro-furantoin with concomitant diminished urinary levels.

 

Nitrofurazone is a relatively safe topical agent. Skin sensitization has been reported.

 

Methenamine

 

Methenamine (hexamethylenetetramine) is an aromatic acid that is hydrolyzed at an acid pH ( 6) to liberate am-monia and the active alkylating agent formaldehyde, which denatures protein and is bactericidal. Meth-enamine is usually administered as a salt of either man-delic (Mandelamine) or hippuric (Hiprex, Urex) acid. Not only do these acids acidify the urine, which is necessary to generate formaldehyde, but also, the resulting low urine pH is by itself bacteriostatic for some organisms.

 

Methenamine is administered orally and is well ab-sorbed from the intestinal tract. However, 10 to 30% decomposes in the stomach unless the tablets are protected by an enteric coating. The inactive form (methenamine) is distributed to virtually every body fluid. Almost all of the methenamine moiety is excreted into the urine by 24 hours, having reached the urine by both glomerular filtration and tubular secretion.

 

Methenamine is primarily used for the long-term prophylactic or suppressive therapy of recurring UTIs. It is not a primary drug for therapy of acute infections. It should be used to maintain sterile urine after appropri-ate antimicrobial agents have been employed to eradi-cate the infection.

 

Gastric distress (nausea and vomiting) is one of the most frequently reported adverse reactions. Bladder ir-ritation (e.g., dysuria, polyuria, hematuria, and urgency) may occur. The mandelic salt can crystallize in urine if there is inadequate urine flow and should not be given to patients with renal failure. Patients with preexisting hepatic insufficiency may develop acute hepatic failure due to the small quantities of ammonia formed during methenamine hydrolysis.

 

The coadministration of methenamine with certain sulfonamides (sulfamethizole or sulfathiazole) can form a urine precipitate resulting in drug antagonism.

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