Rifamycins

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The rifamycins are a group of chemically related antibiotics obtained by fermentation from cultures of Streptomyces mediterranei. They belong to a class of antibiotics called the ansamycins that contain a macrocyclic ring bridged across two nonadjacent positions of an aromatic nucleus. The term ansa means "handle," describing well the topography of the structure. The rifamycins and many of their semisynthetic derivatives have a broad spectrum of antimicrobial activity. They are most notably active against Gram-positive bacteria and m. tuberculosis. However, they are also active against some Gram-negative bacteria and many viruses. Rifampin, a semisynthetic derivative of rifamycin B, was released as an antitubercular agent in the United States in 1971. A second semisynthetic derivative, rifabutin, was approved in 1992 for the treatment of atypical mycobacterial infections.

The chemistry of rifamycins and other ansamycins has been reviewed.75 All of the rifamycins (A, B, C, D, and E) are biologically active. Some of the semisynthetic derivatives of rifamycin B are the most potent known inhibitors of DNA-directed RNA polymerase in bacteria,76 and their action is bactericidal. They have no activity against the mammalian enzyme. The mechanism of action of rifamycins as inhibitors of viral replication appears to differ from that for their bactericidal action. Their net effect is to inhibit the formation of the virus particle, apparently by preventing a specific polypeptide conversion.77 Rifamycins bind to the [ subunit of bacterial DNA-dependent RNA polymerases to prevent chain initia-tion.78 Bacterial resistance to rifampin has been associated with mutations leading to amino acid substitution in the [ subunit.78 A high level of cross-resistance between various rifamycins has been observed.

Rifampin

Rifampin (Rifadin, Rimactane, Rifampicin) is the most active agent in clinical use for the treatment of tuberculosis. A dosage of as little as 5 ^g/mL is effective against sensitive strains of m. tuberculosis. Rifampin is also highly active against staphylococci and Neisseria, Haemophilus, Legionella, and Chlamydia spp. Gram-negative bacilli are much less sensitive to rifampin. However, resistance to rifampin develops rapidly in most species of bacteria, including the tubercle bacillus. Consequently, rifampin is used only in combination with other antitubercular drugs, and it is ordinarily not recommended for the treatment of other bacterial infections when alternative antibacterial agents are available.

Toxic effects associated with rifampin are relatively infrequent. It may, however, interfere with liver function in some patients and should neither be combined with other potentially hepatotoxic drugs nor used in patients with impaired hepatic function (e.g., chronic alcoholics). The incidence of hepatotoxicity was significantly higher when rifampin was combined with isoniazid than when either agent was combined with ethambutol. Allergic and sensitivity reactions to rifampin have been reported, but they are infrequent and usually not serious. Rifampin is a powerful inducer of hepatic cytochrome P450 oxygenases. It can markedly potentiate the actions of drugs that are inactivated by these enzymes. Examples include oral anticoagulants, barbiturates, benzodiazepines, oral hypoglycemic agents, phenytoin, and theophylline.

Rifampin is also used to eradicate the carrier state in asymptomatic carriers of Neisseria meningitidis to prevent outbreaks of meningitis in high-risk areas such as military facilities. Serotyping and sensitivity tests should be performed before its use because resistance develops rapidly. However, a daily dose of 600 mg of rifampin for 4 days suffices to eradicate sensitive strains of n. meningitidis. Rifampin has also been very effective against m. leprae in experimental animals and in humans. When it is used in the treatment of leprosy, rifampin should be combined with dapsone or some other lep-rostatic agent to minimize the emergence of resistant strains of m. leprae.

Other, nonlabeled uses of rifampin include the treatment of serious infections such as endocarditis and osteomyelitis caused by methicillin-resistant s. aureus or s. epidermidis, Legionnaires disease when resistant to erythromycin, and prophylaxis of H. influenzae-induced meningitis.

Rifampin occurs as an orange to reddish brown crystalline powder that is soluble in alcohol but only sparingly soluble in water. It is unstable to moisture, and a desiccant (silica gel) should be included with rifampin capsule containers. The expiration date for capsules stored in this way is 2 years. Rifampin is well absorbed after oral administration to provide effective blood levels for about 8 hours. Food, however, markedly reduces its oral absorption, and rifampin should be administered on an empty stomach. The drug is distributed in effective concentrations to all body fluids and tissues except the brain, despite the fact that it is 70% to 80% protein bound in the plasma. The principal excretory route is through the bile and feces, and high concentrations of rifampin and its primary metabolite, deacetylrifampin, are found in the liver and biliary system. Deacetylrifampin is also biologically active. Equally high concentrations of rifampin are found in the kidneys, and although substantial amounts of the drug are passively reabsorbed in the renal tubules, its urinary excretion is significant. Patients should be made aware that rifampin causes a reddish orange discoloration of the urine, stool, saliva, tears, and skin. It can also permanently discolor soft contact lenses.

Rifampin is also available in a parenteral dosage form consisting of a lyophilized sterile powder that, when reconstituted in 5% dextrose or normal saline, provides 600 mg of active drug in 10 mL for slow intravenous infusion. The par-enteral form may be used for initial treatment of serious cases and for retreatment of patients who cannot take the drug by the oral route. Parenteral solutions of rifampin are stable for 24 hours at room temperature. Although rifampin is stable in the solid state, in solution it undergoes various chemical changes whose rates and nature are pH and temperature dependent.79 At alkaline pH, it oxidizes to a quinone in the presence of oxygen; in acidic solutions, it hy-drolyzes to 3-formyl rifamycin SV. Slow hydrolysis of the ester functions also occurs, even at neutral pH.

Rifabutin

Rifabutin, the spiroimidazopiperidyl derivative of rifamycin B was approved in the United States for the prophylaxis of disseminated MAC in AIDS patients on the strength of clinical trials establishing its effectiveness. The activity of rifabutin against MAC organisms greatly exceeds that of rifamycin. This rifamycin derivative is not effective, however, as monotherapy for existing disseminated MAC disease.

Formyl Rifamycin

Rifabutin is a very lipophilic compound with a high affinity for tissues. Its elimination is distribution limited, with a half-life averaging 45 hours (range, 16-69 hours). Approximately 50% of an orally administered dose of rifabutin is absorbed, but the absolute oral bioavailability is only about 20%. Extensive first-pass metabolism and significant biliary excretion of the drug occur, with about 35% and 53% of the orally administered dose excreted, largely as metabolites, in the feces and urine, respectively. The 25-O-desacetyl and 31-hydroxy metabolites of rifabutin have been identified. The parent drug is 85% bound to plasma proteins in a concentration-independent manner. Despite its greater potency against M. tuberculosis in vitro, rifabutin is considered inferior to rifampin for the short-term therapy of tuberculosis because of its significantly lower plasma concentrations.

Although rifabutin is believed to cause less hepatotoxicity and induction of cytochrome P450 enzymes than rifampin, these properties should be borne in mind when the drug is used prophylactically. Rifabutin and its metabolites are highly colored compounds that can discolor skin, urine, tears, feces, etc.

Cycloserine d-(+)-4-Amino-3-isoxazolidinone (Seromycin) is an antibiotic that has been isolated from the fermentation beer of three different Streptomyces species: S. orchidaceus, S. garyphalus, and S. lavendulus. It occurs as a white to pale yellow crystalline material that is very soluble in water. It is stable in alkaline, but unstable in acidic, solutions. The compound slowly dimerizes to 2,5-bis(aminoxymethyl)-3,6-diketopiper-azine in solution or standing.

The structure of cycloserine was reported simultaneously by Kuehl et al.80 and Hidy et al.81 to be d-(+)-4-amino-3-isoxazolidinone. It has been synthesized by Stammer et al.82 and by Smart et al.83 Cycloserine is stereochemical^ related to d-serine. However, the l-form has similar antibiotic activity.

Cycloserine is presumed to exert its antibacterial action by preventing the synthesis of cross-linking peptide in the formation of bacterial cell walls.84 Rando85 has recently suggested that it is an antimetabolite for alanine, which acts as a suicide substrate for the pyridoxal phosphate-requiring enzyme alanine racemase. Irreversible inactivation of the enzyme thereby deprives the cell of the d-alanine required for the synthesis of the cross-linking peptide.

Although cycloserine exhibits antibiotic activity in vitro against a wide spectrum of both Gram-negative and Gram-positive organisms, its relatively weak potency and frequent toxic reactions limit its use to the treatment of tuberculosis. It is recommended for patients who fail to respond to other tuberculostatic drugs or who are known to be infected with organisms resistant to other agents. It is usually administered orally in combination with other drugs, commonly isoniazid.

Sterile Capreomycin Sulfate

Capastat sulfate, or capreomycin, is a strongly basic cyclic peptide isolated from Streptomyces capreolus in 1960 by Herr et al.86 It was released in the United States in 1971 exclusively as a tuberculostatic drug. Capreomycin, which resembles viomycin (no longer marketed in the United States) chemically and pharmacologically, is a second-line agent used in combination with other antitubercular drugs. In particular, it may be used in place of streptomycin when either the patient is sensitive to, or the strain of M. tuberculosis is resistant to, streptomycin. Similar to viomycin, capreomycin is a potentially toxic drug. Damage to the eighth cranial nerve and renal damage, as with viomycin, are the more serious toxic effects associated with capreomycin therapy. There are, as yet, insufficient clinical data for a reliable comparison of the relative toxic potentials of capreomycin and streptomycin. Cross-resistance among strains of tubercle bacilli is rare between capreomycin and streptomycin.

NH2 O

NH2 O

Synthesis Capreomycine
Capreomycin IA

Four capreomycins, designated IA, IB, IIA, and IIB, have been isolated from cultures of S. capreolus. The clinical agent contains primarily IA and IB. The close chemical relationship between capreomycins IA and IB and viomycin was established,87 and the total synthesis and proof of structure of the capreomycins were later accomplished.88 The structures of capreomycins IIA and IIB correspond to those of IA and IB but lack the jS-lysyl residue. The sulfate salts are freely soluble in water.

o ANTIPROTOZOAL AGENTS

In the United States and other countries of the temperate zone, protozoal diseases are of minor importance, whereas bacterial and viral diseases are widespread and are the cause of considerable concern. On the other hand, protozoal diseases are highly prevalent in tropical Third World countries, where they infect both human and animal populations, causing suffering, death, and enormous economic hardship. Protozoal diseases that are found in the United States are malaria, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and, as a direct consequence of the AIDS epidemic, P. carinii pneumonia (PCP).

Although amebiasis is generally thought of as a tropical disease, it actually has a worldwide distribution. In some areas with temperate climates in which sanitation is poor, the prevalence of amebiasis has been estimated to be as high as 20% of the population. The causative organism, Entamoeba histolytica, can invade the wall of the colon or other parts of the body (e.g., liver, lungs, skin). An ideal chemotherapeutic agent would be effective against both the intestinal and extraintestinal forms of the parasite.

Amebicides that are effective against both intestinal and extraintestinal forms of the disease are limited to the somewhat toxic alkaloids emetine and dehydroemetine, the ni-troimidazole derivative metronidazole, and the antimalarial agent chloroquine (Chapter 7). A second group of amebi-cides that are effective only against intestinal forms of the disease includes the aminoglycoside antibiotic paro-momycin, the 8-hydroxyquinoline derivative iodoquinol, the arsenical compound carbarsone, and diloxanide.

Other protozoal species that colonize the intestinal tract and cause enteritis and diarrhea are Balantidium coli and the flagellates, g. lamblia and Cryptosporidium spp. Balantidiasis responds best to tetracycline. Metronidazole and iodoquinol may also be effective. Giardiasis may be treated effectively with furazolidone, metronidazole, or the antimalarial drug quinacrine (Chapter 7). Cryptosporidiosis is normally self-limiting in immunocompetent patients and is not normally treated. The illness can be a serious problem in AIDS patients because no effective therapy is currently available.

Trichomoniasis, a venereal disease caused by the flagellated protozoan T. vaginalis, is common in the United States and throughout the world. Although it is not generally considered serious, this affliction can cause serious physical discomfort. Oral metronidazole provides effective treatment against all forms of the disease. It is also used to eradicate the organism from asymptomatic male carriers.

p. carinii is an opportunistic pathogen that may colonize the lungs of humans and other animals and, under the right conditions, can cause pneumonia. The organism has long been classified as a protozoan, but recent RNA evidence suggests that it may be more closely related to fungi. At one time, occasional cases of PCP were known to occur in premature, undernourished infants and in patients receiving immunosuppressant therapy. The situation changed with the onset of the AIDS epidemic. It is estimated that at least 60% and possibly as high as 85% of patients infected with HIV develop PCP during their lifetimes.

The combination of the antifolate trimethoprim and the sulfonamide sulfamethoxazole constitutes the treatment of choice for PCP. Other effective drugs include pentamidine, atovaquone, and a new antifolate, trimetrexate.

Toxoplasma gondii is an obligate intracellular protozoan that is best known for causing blindness in neonates. Toxoplasmosis, the disseminated form of the disease in which the lymphatic system, skeletal muscles, heart, brain, eye, and placenta may be affected, has become increasingly prevalent in association with HIV infection. A combination of the antifolate pyrimethamine and the sulfa drug sulfadiazine constitutes the most effective therapy for toxoplasmosis.

Various forms of trypanosomiasis, chronic tropical diseases caused by pathogenic members of the family Trypanosomidae, occur both in humans and in livestock. The principal disease in humans, sleeping sickness, can be broadly classified into two main geographic and etiological groups: African sleeping sickness caused by Trypanosoma gambiense (West African), Trypanosoma rhodesiense (East African), or Trypanosoma congolense; and South American sleeping sickness (Chagas disease) caused by Trypanosoma cruzi. Of the various forms of trypanosomiasis, Chagas disease is the most serious and generally the most resistant to chemotherapy. Leishmaniasis is a chronic tropical disease caused by various flagellate protozoa of the genus Leishmania. The more common visceral form caused by Leishmania donovani, called kala-azar, is similar to Chagas disease. Although these diseases are widespread in tropical areas of Africa and South and Central America, they are of minor importance in the United States, Europe, and Asia.

Chemotherapy of trypanosomiasis and leishmaniasis remains somewhat primitive and is often less than effective. In fact, it is doubtful that these diseases can be controlled by chemotherapeutic measures alone, without successful control of the intermediate hosts and vectors that transmit them. Heavy metal compounds, such as the arsenicals and antimo-nials, are sometimes effective but frequently toxic. The old standby suramin appears to be of some value in long- and short-term prophylaxis. The nitrofuran derivative nifurtimox may be a major asset in the control of these diseases, but its potential toxicity remains to be fully determined.

Metronidazole

2-Methyl-5-nitroimidazole-1-ethanol (Flagyl, Protostat, Metro IV) is the most useful of a group of antiprotozoal ni-troimidazole derivatives that have been synthesized in various laboratories throughout the world. Metronidazole was first marketed for the topical treatment of T. vaginalis vaginitis. It has since been shown to be effective orally against both the acute and carrier states of the disease. The drug also possesses useful amebicidal activity and is, in fact, effective against both intestinal and hepatic amebiasis. It has also been found of use in the treatment of such other protozoal diseases as giardiasis and balantidiasis.

More recently, metronidazole has been found to possess efficacy against obligate anaerobic bacteria, but it is ineffective against facultative anaerobes or obligate aerobes. It is particularly active against Gram-negative anaerobes, such as Bacteroides and Fusobacterium spp. It is also effective against Gram-positive anaerobic bacilli (e.g., Clostridium spp.) and cocci (e.g., Peptococcus, Peptidostreptococcus spp.). Because of its bactericidal action, metronidazole has become an important agent for the treatment of serious infections (e.g., septicemia, pneumonia, peritonitis, pelvic infections, abscesses, meningitis) caused by anaerobic bacteria.

The common characteristic of microorganisms (bacteria and protozoa) sensitive to metronidazole is that they are anaerobic. It has been speculated that a reactive intermediate formed in the microbial reduction of the 5-nitro group of metronidazole covalently binds to the DNA of the microorganism, triggering the lethal effect.89 Potential reactive intermediates include the nitroxide, nitroso, hydroxylamine, and amine. The ability of metronidazole to act as a radiosensitiz-ing agent is also related to its reduction potential.

Metronidazole is a pale yellow crystalline substance that is sparingly soluble in water. It is stable in air but is light sensitive. Despite its low water solubility, metronidazole is well absorbed following oral administration. It has a large apparent volume of distribution and achieves effective concentrations in all body fluids and tissues. Approximately 20% of an oral dose is metabolized to oxidized or conjugated forms. The 2-hydroxy metabolite is active; other metabolites are inactive.

Metronidazole is a weak base that possesses a pKa of 2.5. Although it is administered parenterally only as the free base by slow intravenous infusion, metronidazole for injection is supplied in two forms: a ready-to-inject 100-mL solution containing 5 mg of base per mL; and a hydrochloride salt as 500 mg of a sterile lyophilized powder. Metronidazole hy-drochloride for injection must first be reconstituted with sterile water to yield 5 mL of a solution having a concentration of 100 mg/mL and a pH ranging from 0.5 to 2.0. The resulting solution must then be diluted with either 100 mL of normal saline or 5% dextrose and neutralized with 5 mEq of sodium bicarbonate to provide a final solution of metronidazole base with an approximate concentration of 5 mg/mL and a pH of 6 to 7. Solutions of metronidazole hydrochloride are unsuitable for intravenous administration because of their extreme acidity. Reconstituted metronidazole hydrochloride solutions are stable for 96 hours at 30°C, whereas ready-to-use solutions of metronidazole base are stable for 24 hours at 30°C. Both solutions should be protected from light.

Diloxanide

Furamide, or eutamide, is the 2-furoate ester of 2,2-dichloro-4'-hydroxy-N-methylacetanilide. It was developed as a result of the discovery that various a,a-dichloroacetamides possessed amebicidal activity in vitro. Diloxanide itself and many of its esters are also active, and drug metabolism studies indicate that hydrolysis of the amide is required for the amebicidal effect. Nonpolar esters of diloxanide are more potent than polar ones. Diloxanide furoate has been used in the treatment of asymptomatic carriers of E. histolytica. Its effectiveness against acute intestinal amebiasis or hepatic abscesses, however, has not been established. Diloxanide furoate is a white crystalline powder. It is administered orally only as 500-mg tablets and may be obtained in the United States from the CDC in Atlanta, Georgia.

8-Hydroxyquinoline

Oxine, quinophenol, or oxyquinoline is the parent compound from which the antiprotozoal oxyquinolines have been derived. The antibacterial and antifungal properties of oxine and its derivatives, which are believed to result from the ability to chelate metal ions, are well known. Aqueous solutions of acid salts of oxine, particularly the sulfate (Chinosol, Quinosol), in concentrations of 1:3,000 to 1:1,000, have been used as topical antiseptics. The substitution of an iodine atom at the 7-position of 8-hydroxyquino-lines yields compounds with broad-spectrum amebicidal properties.

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