SULFONAMIDES AND OTHER ANTIMICROBIAL DRUGS. (Phthalazolum, Aethazolum, Sulfacylum-natrium, Sulfadimethoxinum, Sulfapyridazinum, Sulfalenum, Biseptolum (Bactrinum), Salazosulfopiridinum, Salazopiridazinum, Acidum nalidixicum, Nitroxolinum, Ofloxacinum, Cyprofloxacinum,, Furasolidonm, Furaginum)

SULFONAMIDES AND OTHER ANTIMICROBIAL DRUGS. ANTIMYCOBACTERIAL AGENTS

Sulfonamide

Sulfonamide functional group

Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based on the antibacterial sulfonamides.^[1]

Sulfa allergies are common,^[2] hence medications containing sulfonamides are prescribed carefully. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the same hypersensitivity reactions seen in the sulfonamides.

Because sulfonamides displace bilirubin from albumin, kernicterus (brain damage due to excess bilirubin) is an important potential side effect of sulfonamide use.

Function

Antimicrobial

Main article: Dihydropteroate synthetase inhibitor

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS), an enzyme involved in folate synthesis. Sulfonamides are therefore bacteriostatic and inhibit growth and multiplication of bacteria, but do not kill them. Humans, in contrast to bacteria, acquire folate (vitamin B₉) through the diet.^[3]

Structural similarity between sulfonamide (left) and PABA (center) is the basis for the inhibitory activity of sulfa drugs on dihydrofolate (right) biosynthesis

Other uses

The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among others), loop diuretics (including furosemide, bumetanide, and torsemide), sulfonylureas (including glipizide, glyburide, among others), and some COX-2 inhibitors (e.g., celecoxib), and acetazolamide.

Sulfasalazine, in addition to its use as an antibiotic, is also used in the treatment of inflammatory bowel disease.

History

Sulfonamide drugs were the first antimicrobial drugs, and paved the way for the antibiotic revolution in medicine. The first sulfonamide, trade-named Prontosil, was a prodrug. Experiments with Prontosil began in 1932 in the laboratories of Bayer AG, at that time a component of the huge German chemical trust IG Farben. The Bayer team believed that coal-tar dyes able to preferentially bind to bacteria and parasites might be used to target harmful organisms in the body. After years of fruitless trial-and-error work on hundreds of dyes, a team led by physician/researcher Gerhard Domagk (working under the general direction of Farben executive Heinrich Hörlein) finally found one that worked: a red dye synthesized by Bayer chemist Josef Klarer that had remarkable effects on stopping some bacterial infections in mice.^[4] The first official communication about the breakthrough discovery was not published until 1935, more than two years after the drug was patented by Klarer and his research partner Fritz Mietzsch.

Prontosil, as Bayer named the new drug, was the first medicine ever discovered that could effectively treat a range of bacterial infections inside the body. It had a strong protective action against infections caused by streptococci, including blood infections, childbed fever, and erysipelas, and a lesser effect on infections caused by other cocci. However, it had no effect at all in the test tube, exerting its antibacterial action only in live animals. Later, it was discovered by Bovet,^[5] Nitti and J. and Th. Tréfouël, a French research team led by Ernest Fourneau at the Pasteur Institute, that the drug was metabolized into two pieces inside the body, releasing from the inactive dye portion a smaller, colorless, active compound called sulfanilamide.^[6] The discovery helped establish the concept of “bioactivation” and dashed the German corporation’s dreams of enormous profit; the active molecule sulfanilamide (or sulfa) had first been synthesized in 1906 and was widely used in the dye-making industry; its patent had since expired and the drug was available to anyone.^[7]

The result was a sulfa craze.^[8] For several years in the late 1930s, hundreds of manufacturers produced tens of thousands of tons of myriad forms of sulfa. This and nonexistent testing requirements led to the elixir sulfanilamide disaster in the fall of 1937, during which at least 100 people were poisoned with diethylene glycol. This led to the passage of the Federal Food, Drug, and Cosmetic Act in 1938 in the United States. As the first and only effective antibiotic available in the years before penicillin, sulfa drugs continued to thrive through the early years of World War II.^[9] They are credited with saving the lives of tens of thousands of patients, including Franklin Delano Roosevelt, Jr. (son of US President Franklin Delano Roosevelt) (in 1936) and Winston Churchill. Sulfa had a central role in preventing wound infections during the war. American soldiers were issued a first-aid kit containing sulfa pills and powder, and were told to sprinkle it on any open wound.

The sulfanilamide compound is more active in the protonated form. The solubility of the drug is very low and sometimes can crystallize in the kidneys, due to its first pK_a of around 10. This is a very painful experience, so patients are told to take the medication with copious amounts of water. Newer analogous compounds prevent this complication because they have a lower pK_a, around 5–6,^{[citation needed]} making them more likely to remain in a soluble form.

Many thousands of molecules containing the sulfanilamide structure have been created since its discovery (by one account, over 5,400 permutations by 1945), yielding improved formulations with greater effectiveness and less toxicity. Sulfa drugs are still widely used for conditions such as acne and urinary tract infections, and are receiving renewed interest for the treatment of infections caused by bacteria resistant to other antibiotics.

Preparation

Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an amine. Certain sulfonamides (sulfadiazine or sulfamethoxazole) are sometimes mixed with the drug trimethoprim, which acts against dihydrofolate reductase. As of 2013, Republic of Ireland is the largest exporter worldwide of Sulfonamides, accounting for approximately 32% of total exports.^[10]

List of sulfonamides

Child antibacterial drugs

• Pediazole^[11]

Antibacterial Drugs

Short-acting

• Sulfamethoxazole

• Sulfisomidine (also known as sulfaisodimidine)

• Sulfadiazine

Intermediate-acting

• Sulfacetamide^[12]

• Sulfadoxine

Ophthalmologicals

• Dichlorphenamide (DCP)

Sulfonylureas (anti-diabetic agents)

• Carbutamide

• Acetohexamide

• Chlorpropamide

• Tolbutamide

• Tolazamide

• Glipizide

• Gliclazide

• Glibenclamide (glyburide)

• Glibornuride

• Gliquidone

• Glisoxepide

• Glyclopyramide

• Glimepiride

Diuretics

• Acetazolamide

• Bumetanide

• Chlorthalidone

• Clopamide

• Dorzolamide

• Furosemide

• Hydrochlorothiazide (HCT, HCTZ, HZT)

• Indapamide

• Mefruside

• Metolazone

• Xipamide

Anticonvulsants

• Acetazolamide

• Ethoxzolamide

• Sultiame

• Zonisamide

Dermatologicals

• Mafenide

Other

• Celecoxib (COX-2 inhibitor)

• Darunavir (Protease Inhibitor)

• Fosamprenavir (Protease Inhibitor)

• Tipranavir (Protease Inhibitor)

• Probenecid (PBN)

• Sotalol (Beta-blocker)

• Sulfasalazine (SSZ)

• Sumatriptan (SMT)

• Delavirdine (NNRTI)

• Tamsulosin (Flomax)

Side effects

Patient suffering from Stevens–Johnson syndrome

Sulfonamides have the potential to cause a variety of untoward reactions, including urinary tract disorders, haemopoietic disorders, porphyria, and hypersensitivity reactions. When used in large doses, they may cause a strong allergic reaction. Two of the most serious are Stevens–Johnson syndrome and toxic epidermal necrolysis (also known as Lyell syndrome).^[2]

Approximately 3% of the general population have adverse reactions when treated with sulfonamide antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about 60%.^[13]

Hypersensitivity reactions are less common ionantibiotic sulfonamides, and, though controversial, the available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the nonantibiotic agents.^[14] A key component to the allergic response to sulfonamide antibiotics is the arylamine group at N4, found in sulfamethoxazole, sulfasalazine, sulfadiazine, and the anti-retrovirals amprenavir and fosamprenavir. Other sulfonamide drugs do not contain this arylamine group; available evidence suggests that patients who are allergic to arylamine sulfonamides do not cross-react to sulfonamides that lack the arylamine group, and may therefore safely take non-arylamine sulfonamides. ^[15] It has therefore been argued that the terms ‘sulfonamide allergy’ or ‘sulfa allergy’ are misleading, and should be replaced by a reference to a specific drug (e.g. ‘cotrimoxazole allergy’). ^[16]

Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class.

• The first is the N1 heterocyclic ring, which causes a type I hypersensitivity reaction.

• The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause either direct cytotoxicity or immunologic response.

The nonantibiotic sulfonamides lack both of these structures.^[17]

The most common manifestations of a hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, thrombocytopenia, and fulminant hepatic necrosis, among others.^[18]

Antimycobacterial Drugs: Introduction

Most antibiotics are more effective against rapidly growing organisms than against slowly growing ones. Because mycobacteria are very slowly growing organisms, they are relatively resistant to antibiotics. Mycobacterial cells can also be dormant and thus completely resistant to many drugs— or killed only very slowly by the few drugs that are active. The lipid-rich mycobacterial cell wall is impermeable to many agents. A substantial proportion of mycobacterial organisms are intracellular, residing within macrophages, and inaccessible to drugs that penetrate poorly. Finally, mycobacteria are notorious for their ability to develop resistance to any single drug. Combinations of drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years depending on which drugs are used. The various drugs used to treat tuberculosis, which is caused by Mycobacterium tuberculosis and the closely related M bovis, atypical mycobacterial infections, and leprosy, which is caused by M leprae, are described in thischapter.

Drugs Used in Tuberculosis

Tuberculosis in History

         Evidence of tubercular decay has been found in the spines of Egyptian mummies thousands of years old, and TB was common both in ancient Greece and Imperial Rome. Since that time, scientific advances, including the discovery of the tuberculosis mycobacterium and the development of new drugs and the Bacille Calmette-Guérin vaccine, caused TB to lessen its grip on mankind during some periods of history. However, TB never completely let go. Today, TB remains one of the leading infectious disease killers around the world. Emerging drug-resistant strains of the disease are presenting a new challenge in the ever-changing battle to control and prevent TB.

“I Must Die”

Tuberculosis, it seems, has always been with us. Evidence of tubercular decay has been found in the spines of Egyptian mummies thousands of years old, and the disease was common both in ancient Greece and Imperial Rome. While it may have lessened its grip on mankind during some periods of history, TB never completely let go.

Attempts at cures were varied, but uniformly ineffective. Roman physicians recommended bathing in human urine, eating wolf livers, and drinking elephant blood. Fresh milk—human, goat, or camel—figured in many treatment regimens. Depending upon the time and country in which they lived, patients were exhorted to rest or to exercise, to eat or to abstain from food, to travel to the mountains or to live underground.

And yet, TB continued to claim victims by the millions. When, in 1820, the poet John Keats (who had schooling in medicine) coughed a spot of bright red blood, he told a friend, “It is arterial blood. I cannot be deceived. That drop of blood is my death warrant. I must die.” Within a year, at just 25, he did.

German microbiologist Robert Koch

On the evening of March 24, 1882, before a skeptical audience of Germany’s most prominent men of medicine, Robert Koch announced a discovery that awed his listeners and brought him worldwide acclaim. New laboratory techniques had helped scientists discover microbial causes of other infectious diseases, but TB remained a stubborn exception. Koch succeeded by staining the organism with not one but two dyes, and at last was able to bring the elusive microbe into view. “Under the microscope the structures of the animal tissues, such as the nucleus and its breakdown products are brown, while the tubercle bacteria are a beautiful blue,” he wrote in the paper that followed his dramatic presentation that March evening.

Koch was the first to get colonies of TB bacteria to grow in the lab. The bacteria, he discovered, are extremely slow-growing, requiring 2 weeks before clumps of them could be seen with the naked eye. Further research by Koch revealed that TB was spread from person to person and, as such, potentially controllable. Also, the way TB spreads—carried on droplets expelled in an infected person’s cough—became clear. An optimistic Koch wrote, “When the conviction that tuberculosis is an exquisite infectious disease has become firmly established among physicians, the question of an adequate campaign against tuberculosis will certainly come under discussion and it will develop by itself.”

Resting the Lungs

         Magnified image of TB bacteriaCredit: ASM MicrobeLibrary, Electron micrograph by Delisle and Tomally

A key element in that campaign was a public health movement that isolated the sick—sometimes by force—from the well. This era of TB sanatoria actually began in 1849, well before the scientific proof of TB’s contagious nature. A consumptive German doctor traveled to the Himalayas and returned cured. The doctor, Hermann Brehmer, became convinced that life at high elevation, continuous exposure to fresh air, sun, and cold, along with copious amounts of food, could turn TB from a death sentence into a curable disease. In the United States, less emphasis was placed on high elevation, but the basic outlines of sanatorium care and philosophy remained the same.

A young doctor named Edward Livingston Trudeau established the most famous sanatorium in the United States at Saranac Lake, in New York’s Adirondack Mountains. Like Brehmer, Trudeau suffered from TB and was informed by his doctors that he would not live long. In 1882, Trudeau became aware of Koch’s experiments with TB bacteria and of Brehmer’s sanatorium. Although very weakened by his illness, Trudeau established a small laboratory in Saranac Lake and began an extraordinary series of experiments.

Five rabbits were inoculated with TB bacteria and set loose on a small island where they were provided with fresh vegetables in addition to the naturally occurring grasses. After 4 months, one rabbit died, but the others remained robustly healthy. Upon autopsy of the apparently healthy rabbits, no evidence could be found of the point of inoculation, reported Trudeau in an 1887 paper. Evidently, the rabbits’ healthy life permitted them to fend off infection.

Believing his findings gave a strong empirical basis to the European-style sanatorium treatment regimens, Trudeau instituted many of those regimens in the “cure cottages” he established at Saranac Lake. Patients were under strict and constant supervision; every aspect of their lives was detailed in rule books issued to each invalid. Typically, a newcomer spent a minimum of 3 months on complete bedrest. The resident was exposed to fresh air for most of the day and was required to consume enormous amounts of food, including many servings of milk, each day.

Public Health and a New Vaccine

A noticeable decline in the incidence of TB in the United States began around the turn of the century. Some of the decline was probably due to a natural waning of the epidemic, but some was also the product of quarantining the sick in sanatoria and of aggressive public health education campaigns. Publications aimed at children and adults admonished against spitting and recommended plenty of sleep, fresh air, and exercise for everyone.

In 1908, French scientists Albert Calmette and Camille Guérin developed a vaccine against TB. They began by isolating Mycobacterium bovis (which causes TB in cattle) from a dead cow. Every 3 weeks for the next 13 years, the scientists grew a new batch of bacteria in a solution of beef bile and potatoes. Each new generation of bacteria was weaker than the one before. Eventually the bacteria lost the power to cause disease, but could still provoke the immune system to protect a person from TB. The vaccine Bacille Calmette-Guérin (BCG) was first administered in 1921 to an infant whose mother had died of TB. Since then, more than a billion people have been inoculated with the cheap and safe BCG vaccine. The vaccine’s efficacy, however, is unclear. The consensus is that while BCG vaccine can prevent TB infection in the brain among children, it is nearly useless in preventing adult pulmonary TB.

During the 1940s, TB vaccines took a back seat to advances in drug therapy. Dogged effort by the American scientist Selman Waksman produced streptomycin, a relatively non-toxic antibiotic derived from a soil fungus. On November 20, 1944, a critically ill TB patient received streptomycin. Within days, he began a near-miraculous recovery. A host of drugs followed on the heels of streptomycin and, when used in combination, they could usually cure TB without engendering drug-resistant bacteria. Some of the most important drugs introduced during the 1940s and ’50s included isoniazid, rifampin, and ethambutol.

Effective drugs brought the sanatorium era to a close. Some research journals devoted to TB ceased publication, and organizations such as the American Lung Association (formerly known as The National Association for the Study and Prevention of Tuberculosis) redirected their efforts. Confidence arose that TB, like infectious diseases of previous centuries, could be completely conquered by drug therapy. Indeed, the United Nations predicted the worldwide elimination of TB by the year 2025. But this ancient enemy was not so easily routed.

A Killer Returns: The Face of the Epidemic

Tuberculosis continues to exact its terrible toll on humankind. Worldwide, a person is newly infected with TB every second, and overall nearly 2 billion people have been exposed to TB bacteria. During the 1990s, bright hopes that the disease would be vanquished by 2025 were extinguished as a variety of medical and social factors helped TB surge back to its familiar position among major causes of death.

Around 1985, cases of TB began to rise in the United States. Several interrelated forces drove the resurgence, including increases in prison populations, homelessness, injection drug use, crowded housing, and increases in populations in long-term care facilities. Along with increased immigration of people from countries where TB is endemic, these forces provided ideal conditions for TB transmission. Adding the most fuel to the fire, however, were the HIV/AIDS epidemic and increases in multidrug-resistant TB (MDR TB).

A Global Emergency

TB is a contagious disease. When people with active TB cough, spit, or even talk, bacteria that cause the disease are propelled into the air. A persoeeds to breathe in just a few TB bacteria to become infected. Without treatment, a person with an active case of TB will infect between 10 and 15 people a year. Infection with TB bacteria, however, does not necessarily lead to disease. In a person with a healthy immune system, TB germs take up residence in lung cells, but enter a kind of suspended animation and never cause widespread disease. Only between 5 and 10 percent of all healthy people infected with the germ will develop active TB at some point. In people with decreased immune function, whether due to HIV/AIDS, poor nutrition, or old age, the odds are much worse. When infected with both HIV and TB, for example, a person has a one in ten chance of developing active TB each year (compared with a one in ten chance over a lifetime for people without HIV).

TB kills between 2 and 3 million people each year, and is the leading cause of death among young adults and a major cause of death among women of childbearing age. So great was the concern about the worldwide epidemic of TB that in 1993, the World Health Organization (WHO) declared TB a global emergency, the first time a disease had ever achieved that dubious distinction.

Birth of a Superbug

Perhaps the most alarming aspect of the present epidemic is the rise in MDR TB. According to a survey conducted by WHO, up to 4 percent of all TB cases worldwide are resistant to more than one anti-tuberculosis drug. In parts of Eastern Europe, nearly half of all TB cases resist at least one first-line drug. Most of the burden of MDR TB falls on poor countries, but the United States has seen outbreaks of drug-resistant TB as well. In early 1990s, New York City had an epidemic of MDR TB that cost almost $1 billion to control.

With proper treatment, almost all cases of TB are curable. But proper treatment is not always easy to attain. Typically, a TB patient takes four different antibiotics for at least two months, then two drugs for four more months. Hitting TB germs with several drugs simultaneously lessens the chance that naturally occurring mutations in the bacteria will allow some to escape destruction. However, because the drugs often cause unpleasant side effects and because patients start feeling better after a month or so, not everyone completes the full course of treatment. In many less developed countries, where TB is most common, drug supplies may be inadequate and medical services spotty.

Unfortunately, partial treatment for TB is worse thao treatment at all. TB bacteria that linger following incomplete therapy are likely to resist anti-tuberculosis drugs in future flare-ups. Worse still, people with active cases of MDR TB can pass those superbugs on to new victims.

Isoniazid (INH), rifampin, pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis (Table 47–1). Isoniazid and rifampin are the two most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95–98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy (Table 47–2).

In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined. Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if either drug is used), but they do provide additional coverage should the isolate prove to be resistant to isoniazid, rifampin, or both. Unfortunately, such resistance occurs in up to 10% of cases in the United States. Most patients with tuberculosis can be treated entirely as outpatients, with hospitalization being required only for those who are seriously ill or who require diagnostic evaluation.

Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.

It is a small (MW 137), simple molecule freely soluble in water. The structural similarity to pyridoxine is shown below.

In vitro, isoniazid inhibits most tubercle bacilli in a concentration of 0.2 g/mL or less and is bactericidal for actively growing tubercle bacilli. Isoniazid is less effective against atypical mycobacterial species. Isoniazid is able to penetrate into phagocytic cells and thus is active against both extracellular and intracellular organisms.

Isoniazid (INH)

Mechanism of Action & Basis of Resistance

Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.

The activated form of isoniazid exerts its lethal effect by forming a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis. Resistance to isoniazid has been associated with mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl carrier protein reductase; mutation or deletion of katG; promoter mutations resulting in overexpression of ahpC, a putative virulence gene involved in protection of the cell from oxidative stress; and mutations in kasA.

Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide. KatG mutants express high-level isoniazid resistance and are usually not cross-resistant to ethionamide. Resistant mutants occur in susceptible mycobacterial populations with a frequency of about 1 bacillus in 106. Since tuberculous lesions often contain more than 108 tubercle bacilli, resistant mutants are readily selected out if isoniazid is given as the sole drug. However, addition of a second independently acting drug, to which resistance also emerges at a frequency of 1 in 106 to 1 in 108, is effective. The odds that a bacillus is resistant to both drugs are approximately 1 in 106 x 106, or 1 in 1012, which is several orders of magnitude more than the number of infecting organisms. Single- drug therapy with isoniazid and failure to use isoniazid plus at least one other drug to which the infecting strain is susceptible (which is tantamount to single-drug therapy) has led to the 10–20% prevalence of isoniazid resistance in clinical isolates from the Caribbean and Southeast Asia. Currently, about 8–10% of primary clinical isolates in the United States are isoniazid-resistant.

Pharmacokinetics

Isoniazid is readily absorbed from the gastrointestinal tract. The administration of a 300-mg oral dose (5 mg/kg in children) results in peak plasma concentrations of 3–5 g/mL within 1–2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations.

Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is genetically determined. The average concentration of isoniazid in the plasma of rapid acetylators is about one third to one half of that in slow acetylators and average half-lives are less than 1 hour and 3 hours, respectively. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this has not been proved. More rapid clearance of isoniazid by rapid acetylators is of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose.

Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine. The dose need not be adjusted in renal failure, but one third to one half of the normal dose is recommended in severe hepatic insufficiency.

Clinical Uses

The usual dosage of isoniazid is 5 mg/kg/d, with a typical adult dose being 300 mg given once daily. Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. A 15 mg/kg dose, or 900 mg, may be used in a twice-weekly dosing regimen in combination with a second antituberculous agent (eg, rifampin 600 mg). Pyridoxine, 25–50 mg/d is recommended for those with conditions predisposing to neuropathy, an adverse effect of isoniazid. Isoniazid is usually given by mouth but can be given parenterally in the same dosage.

Isoniazid as a single agent is also indicated for treatment of latent tuberculosis, which is usually determined by a positive tuberculin skin test.

Isoniazid is routinely recommended for individuals who are at greatest risk for developing active disease after being infected such as very young children, persons who test positive within 2 years after a documented negative skin test (ie, recent converters), and immunocompromised individuals, especially HIV-infected and AIDS patients.

Isoniazid is also indicated for prevention of tuberculosis in close contacts of active cases of pulmonary tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months.

Adverse Reactions

The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration.

Allergic Reactions

Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported.

Direct Toxicity

Isoniazid-induced hepatitis is the most frequent major toxic effect. This is distinct from the minor increases in liver aminotransferases (up to three or four times normal) seen in 10–20% of patients, who usually are asymptomatic. Such increases do not require cessation of the drug. Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly. There is histologic evidence of hepatocellular damage and necrosis. The risk of hepatitis depends on age. It occurs rarely under age 20, in 0.3% of those aged 21–35, 1.2% of those aged 36–50, and 2.3% for those aged 50 and above. The risk of hepatitis is greater in alcoholics and possibly during pregnancy and the postpartum period. Development of isoniazid hepatitis contraindicates further use of the drug. Peripheral neuropathy is observed in 10–20% of patients given dosages greater than 5 mg/kg/d but is infrequently seen with the standard 300 mg adult dose. It is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may also respond to pyridoxine.

Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort.

Isoniazid can reduce the metabolism of phenytoin, increasing its blood level and toxicity.

Rifampin

Rifampin is a large (MW 823), complex semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gramnegative cocci, some enteric bacteria, mycobacteria, and chlamydia.

Susceptible organisms are inhibited by less than 1 g/mL, but resistant mutants are present in all microbial populations at a frequency of approximately 1:106. Administration of rifampin as a single drug selects for these highly resistant organisms. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin.

Antimycobacterial Activity, Resistance, & Pharmacokinetics

Rifampin binds strongly to the subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.

Resistance results from one of several possible point mutations in rpoB, the gene for the beta subunit of RNA polymerase. These mutations prevent binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.

Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine. Dosage adjustment for renal insufficiency is not necessary.

Usual doses result in serum levels of 5–7 g/mL. Rifampin is distributed widely in body fluids and tissues. Rifampin is relatively highly protein-bound, but adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.

Clinical Uses

Mycobacterial Infections

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, is administered together with isoniazid, ethambutol, or another antituberculous drug in order to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin is given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in some atypical mycobacterial infections and in leprosy when used together with a sulfone. Rifampin is an alternative to isoniazid prophylaxis for patients who are unable to take isoniazid or who have had close contact with a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.

Other Indications

Rifampin is used in a variety of other clinical situations. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is used to eradicate staphylococcal carriage. Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis. Rifampin has been recommended also for use in combination with ceftriaxone or vancomycin in treatment of meningitis caused by highly penicillin-resistant strains of pneumococci.

Adverse Reactions

Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may cause cholestatic jaundice and occasionally hepatitis.

Rifampin commonly causes light chain proteinuria. If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, thrombocytopenia, and sometimes is associated with acute tubular necrosis. Rifampin strongly induces most cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, some anticonvulsants, protease inhibitors, and contraceptives. Likewise, administration of rifampin with ketoconazole, cyclosporine, or chloramphenicol results in significantly lower serum levels of these drugs.

Ketoconazole in turn may reduce rifampin serum concentrations by interfering with absorption.

Ethambutol

Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro- isomer of the structure shown below, dispensed as the dihydrochloride salt.

Susceptible strains of M tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1–5 g/mL. Ethambutol is an inhibitor of mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene.

Ethambutol is well absorbed from the gut. Following ingestion of 25 mg/kg, a blood level peak of 2–5 g/mL is reached in 2–4 hours. About 20% of the drug is excreted in feces and 50% in urine in unchanged form. Ethambutol accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is less than 10 mL/min. Ethambutol crosses the blood-brain barrier only if the meninges are inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4% to 64% of serum levels in the setting of meningeal inflammation. As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs.

Clinical Use

Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a single daily dose in combination with isoniazid or rifampin. The higher dose is recommended for treatment of tuberculous meningitis. The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is used.

Adverse Reactions

Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis causing loss of visual acuity and red-green color blindness. This dose-related side effect is more likely to occur at a dosage of 25 mg/kg/d continued for several months. With dosages of 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used.

Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.

Pyrazinamide

Pyrazinamide (PZA) is a relative of nicotinamide, stable, slightly soluble in water, and quite inexpensive. At neutral pH, it is inactive in vitro, but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria at concentrations of approximately 20 g/mL. Drug is taken up by macrophages and exerts its activity against intracellular organisms residing within this acidic environment. Pyrazinamide is converted to pyrazinoic acid, the active form of the drug, by mycobacterial pyrazinamidase, which is encoded by pncA. The drug target and mechanism of action are unknown. Resistance is due to mutations in pncA that impair conversion of pyrazinamide to its active form. Impaired uptake of pyrazinamide may also contribute to resistance.

Clinical Use

Isoniazid inhibits cell wall formation and only kills dividing bacilli. Rifampicin inhibits transcription and therefore kills all metabolising cells including some that are not dividing. Pyrazinamide is converted to pyrazinoic acid, which in acid conditions, enters the cell by passive diffussion, where its acidity damages cell membranes but is excreted by an active proton pump. As a result, its bactericidal activity increases as metabolism winds down; it is the only drug to kill truly dormant bacilli.

Serum concentrations of 30–50 g/mL at 1–2 hours after oral administration are achieved with dosages of 25 mg/kg/d. Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges. The half-life is 8–11 hours. A 50–70 mg/kg dose is used for twice-weekly or thrice-weekly treatment regimens.

Pyrazinamide is an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie, 6- month) regimens as a “sterilizing” agent active against residual intracellular organisms that may cause relapse.

Tubercle bacilli develop resistance to pyrazinamide fairly readily, but there is no cross-resistance with isoniazid or other antimycobacterial drugs.

Adverse Reactions

Major adverse effects of pyrazinamide include hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy. Hyperuricemia may provoke acute gouty arthritis.

Streptomycin

Most tubercle bacilli are inhibited by streptomycin, 1–10 g/mL, in vitro. Nontuberculosis species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant. All large populations of tubercle bacilli contain some streptomycin-resistant mutants. On average, 1 in 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10–100 g/mL.

Resistance is due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein gene or rrs, encoding 16S ribosomal rRNA, that alters the ribosomal binding site.

Streptomycin penetrates into cells poorly, and consequently it is active mainly against extracellular tubercle bacilli.

Additional drugs are needed to eliminate intracellular organisms, which constitute a significant proportion of the total mycobacterial burden. Streptomycin crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges.

Clinical Use in Tuberculosis

Streptomycin sulfate remains an important drug in the treatment of tuberculosis. It is employed when an injectable drug is needed or desirable, principally in individuals with severe, possibly lifethreatening forms of tuberculosis, eg, meningitis and disseminated disease, and in treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20–40 mg/kg/d, not to exceed 1–1.5 g, for children) for several weeks, followed by 1–1.5 g two or three times weekly for several months.

Serum concentrations of approximately 40 g/mL are achieved 30–60 minutes after intramuscular injection of a 15 mg/kg dose. Other drugs are always given simultaneously to prevent emergence of resistance.

Adverse Reactions

Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common side effects and may be permanent.

Toxicity is dose-related, and the risk is increased in the elderly. Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible.

Alternative Second-Line Drugs for Tuberculosis

The alternative drugs listed below are usually considered only (1) in the case of resistance to the drugs of first choice (which occurs with increasing frequency); (2) in case of failure of clinical response to conventional therapy; and (3) when expert guidance is available to deal with the toxic effects.

For many of the second-line drugs listed below, the dosage, emergence of resistance, and long-term toxicity have not been fully established.

Ethionamide

Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids.

It is poorly water soluble and available only in oral form. It is metabolized by the liver.

Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 g/mL, or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 g/mL. Serum concentrations in plasma and tissues of approximately 20 g/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum. A 1 g/d dosage, although effective in the treatment of tuberculosis, is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur.

Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine.

Ethionamide is administered at an initial dosage of 250 mg once daily, which is increased in 250 mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d) if possible. The 1 g/d dosage, although theoretically desirable, is seldom tolerated, and one often must settle for a total daily dose of 500–750 mg.

Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be lowlevel cross-resistance between isoniazid and ethionamide.

Capreomycin

Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 g/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis.

Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis.

Strains of M tuberculosis that are resistant to streptomycin or amikacin (eg, the multidrug-resistant W strain) usually are susceptible to capreomycin. Resistance to capreomycin, when it occurs, may be due to an rrs mutation.

Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may occur. Dosing of capreomycin is the same as streptomycin.

Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule.

Antibiotics & Other Inhibitors of Cell Wall Synthesis.

Concentrations of 15–20 g/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided doses.

Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions.

Pyridoxine 150 mg/d should be given with cycloserine as this ameliorates neurologic toxicity. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses.

Side effects can be minimized by monitoring peak serum concentrations. The peak concentration is reached 2–4 hours after dosing. The recommended range of peak concentrations is 20–40 g/mL.

Aminosalicylic Acid (PAS)

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis..

Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 g/mL. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Serum levels are 50 g/mL or more after a 4

g oral dose. The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid.

Aminosalicylic acid is rapidly excreted in the urine, in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.

Aminosalicylic acid, formerly a first-line agent for treatment of tuberculosis, is used infrequently now because other oral drugs are better-tolerated. Gastrointestinal symptoms often accompany full doses of aminosalicylic acid.

Anorexia, nausea, diarrhea, and epigastric pain and burning may be diminished by giving aminosalicylic acid with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia, often occur after 3–8 weeks of aminosalicylic acid therapy, making it necessary to stop aminosalicylic acid administration temporarily or permanently.

Kanamycin & Amikacin

Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) have rendered it obsolete.

The role of amikacin in treatment of tuberculosis has increased with the increasing incidence and prevalence of multidrug-resistant tuberculosis.

Prevalence of amikacin-resistant strains is low (less than 5%), and most multidrug-resistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 g/mL or less.

Amikacin is also active against atypical mycobacteria.

There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Serum concentrations of 30–50 g/mL are achieved 30–60 minutes after a 15 mg/kg intravenous infusion. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. Amikacin must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases.

The recommended dosage is 15 mg/kg/d intramuscularly or intravenously daily for 5 days a week for the first 2 months of therapy and then 1–1.5 g two or three times weekly to complete a 6-month course.

Ciprofloxacin & Levofloxacin

In addition to their activity against many gram-positive and gram-negative bacteria, ciprofloxacin and levofloxacin inhibit strains of M tuberculosis at concentrations less than 2 g/mL. They are also active against atypical mycobacteria.

Ofloxacin was used in the past, but levofloxacin is preferred because it is the L-isomer of ofloxacin (a racemic mixture of D- and L-stereoisomers), the active antibacterial component of ofloxacin, and it can be administered once daily.

Levofloxacin tends to be slightly more active in vitro than ciprofloxacin against M tuberculosis; ciprofloxacin is slightly more active against atypical mycobacteria. Serum concentrations of 2–4 g/mL and 4–8 g/mL are achieved with standard oral doses of ciprofloxacin and levofloxacin, respectively.

Fluoroquinolones are an important recent addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from any one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents.

The standard dosage of ciprofloxacin is 750 mg orally twice a day. That of levofloxacin is 500–750 mg as a single daily dose.

Rifabutin (Ansamycin)

This antibiotic is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs which also are cytochrome P450 substrates. The usual dose of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dose should be reduced to 150 mg/d. If efavirenz (also a P450 inducer) is used, the recommended dose of rifabutin is 450 mg/d. (See Havlir 1999, and Centers 1998, for details.)

Rifabutin is effective in prevention and treatment of disseminated atypical mycobacterial infection in AIDS patients with CD4 counts below 50/ L. It is also effective for preventive therapy of tuberculosis, either alone in a 6-month regimen or with pyrazinamide in a 2-month regimen.

Rifapentine

Rifapentine is an analog of rifampin. It is active against both M tuberculosis and M avium. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine is indicated for treatment of tuberculosis caused by rifampin-susceptible strains. The dose is 600 mg once or twice weekly. Whether rifapentine is as effective as rifampin has not been established, and rifampin therefore remains the rifamycin of choice for treatment of tuberculosis.

Drugs Active Against Atypical Mycobacteria

About 10% of mycobacterial infections seen in clinical practice in the USA are caused not by M tuberculosis or M leprae but by nontuberculous or so-called “atypical” mycobacteria. These organisms have distinctive laboratory characteristics, occur in the environment, and are not communicable from person to person. Disease caused by these organisms is often less severe than tuberculosis. As a general rule, these mycobacterial species are less susceptible than M tuberculosis to antituberculous drugs. On the other hand, agents such as erythromycin, sulfonamides, or tetracycline, which are not effective against M tuberculosis, may be effective against atypical strains. Emergence of resistance during therapy is also a problem with these mycobacterial species, and active infection should be treated with combinations of drugs. M kansasii is susceptible to rifampin and ethambutol but relatively resistant to isoniazid and completely resistant to pyrazinamide. A three-drug combination of isoniazid, rifampin, and ethambutol is the conventional treatment for M kansasii infection. A few representative pathogens, with the clinical presentation and the drugs to which they are often susceptible, are given in Table 47–3.

M avium complex (MAC), which includes both M avium and M intracellulare, is an important and common cause of disseminated disease in late stages of AIDS (CD4 counts < 50/ L).

Mycobacterium avium complex is much less susceptible than M tuberculosis to most antituberculous drugs. Combinations of agents are required to suppress the disease. Disseminated MAC is incurable and therapy is life-long if CD4 counts are below 200/ L. The need for multidrug therapy frequently leads to side effects that can be difficult to manage. Azithromycin, 500 mg once daily, or clarithromycin, 500 mg twice daily, plus ethambutol, 15 mg/kg/d, is an effective and welltolerated regimen for treatment of disseminated disease. Some authorities recommend use of a third agent, such as ciprofloxacin 750 mg twice daily or rifabutin, 300 mg once daily. Other agents that may be useful are listed in Table 47–3. Rifabutin in a single daily dose of 300 mg has been shown to reduce the incidence of M avium complex bacteremia in AIDS patients with CD4 < 200/ L but may not offer a survival advantage. Clarithromycin also effectively prevents MAC bacteremia in AIDS patients, but if breakthrough bacteremia occurs, the isolate often is resistant to both clarithromycin and azithromycin, precluding the use of the most effective drugs for treatment.

Rifampin

This drug (see Rifapentine) in a dosage of 600 mg daily can be strikingly effective in lepromatous leprosy. Because of the probable risk of emergence of rifampin-resistant M leprae, the drug is given in combination with dapsone or another antileprosy drug. A single monthly dose of 600 mg may be beneficial in combination therapy.

Clofazimine

Clofazimine is a phenazine dye that can be used as an alternative to dapsone. Its mechanism of action is unknown but may involve DNA binding.

Absorption of clofazimine from the gut is variable, and a major portion of the drug is excreted in feces. Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen inside phagocytic reticuloendothelial cells. It is slowly released, so that the serum half-life may be 2 months.

Clofazimine is given for sulfone-resistant leprosy or when patients are intolerant to sulfone. A common dosage is 100 mg/d orally. The most prominent untoward effect is skin discoloration

ranging from red-brown to nearly black. Gastrointestinal intolerance occurs occasionally.

Antimycobacterial Drugs >

Preparations Available

Drugs Used in Tuberculosis

Aminosalicylate sodium (Paser)

Oral: 4 g delayed release granules

Capreomycin(Capastat Sulfate)

Parenteral: 1 g powder to reconstitute for injection

Cycloserine(Seromycin Pulvules)

Oral: 250 mg capsules

Ethambutol(Myambutol)

Oral: 100, 400 mg tablets

Ethionamide(Trecator-SC)

Oral: 250 mg tablets

Isoniazid (generic)

Oral: 50, 100, 300 mg tablets; syrup, 50 mg/5 mL

Parenteral: 100 mg/mL for injection

Pyrazinamide (generic)

Oral: 500 mg tablets

Rifabutin(Mycobutin)

Oral: 150 mg capsules

Rifampin(generic, Rifadin, Rimactane)

Oral: 150, 300 mg capsules

Parenteral: 600 mg powder for IV injection

Rifapentine (Priftin)

Oral: 150 mg tablets

Streptomycin (generic)

Parenteral: 1 g lyophilized for IM injection

Drugs Used in Leprosy

Clofazimine(Lamprene)

Oral: 50 mg capsules

Dapsone(generic)

Oral: 25, 100 mg tablets

 Sulfonamides, Trimethoprim, Quinolones

Sulfonamides

Chemistry

Sulfonamides with varying physical, chemical, pharmacologic, and antibacterial properties are produced by attaching substituents to the amido group (–SO2–NH– R) or the amino group (–NH2) of the sulfanilamide nucleus. Sulfonamides tend to be much more soluble at alkaline than at acid pH. Most can be prepared as sodium salts, which are used for intravenous administration.

Antimicrobial Activity

Susceptible microorganisms require extracellular PABA in order to form dihydrofolic acid, an essential step in the production of purines and the synthesis of nucleic acids.

Sulfonamides are structural analogs of PABA that competitively inhibit dihydropteroate synthase. They inhibit growth by reversibly blocking folic acid synthesis. Sulfonamides inhibit both grampositive and gram-negative bacteria, nocardia, Chlamydia trachomatis, and some protozoa. Some enteric bacteria, such as E coli, klebsiella, salmonella, shigella, and enterobacter, are inhibited.

Interestingly, rickettsiae are not inhibited by sulfonamides but are actually stimulated in their growth.

Resistance

Mammalian cells (and some bacteria) lack the enzymes required for folate synthesis and depend upon exogenous sources of folate; therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may occur as a result of mutations that cause overproduction of PABA, cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or cause a loss of permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely.

Sulfonamideresistant cells may be present in susceptible bacterial populations and can emerge under selective pressure.

Pharmacokinetics

Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable; and (3) topical.

Sodium salts of sulfonamides in 5% dextrose in water can be given intravenously, but except for sulfamethoxazole-trimethoprim combinations, these are rarely used. The oral, absorbable sulfonamides can be classified as short-, medium-, or long-acting on the basis of their half-lives. They are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous system and cerebrospinal fluid), placenta, and fetus. Absorbed sulfonamides become bound to serum proteins to an extent varying from 20% to over 90%. Therapeutic concentrations are in the range of 40–100 g/mL of blood. Peak blood levels generally occur 2–6 hours after oral administration.

A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides and inactivated metabolites are then excreted into the urine, mainly by glomerular filtration. In significant renal failure, the dosage of sulfonamide must be reduced.

Clinical Uses

Sulfonamides are infrequently used as single agents. Formerly drugs of choice for infections such as

Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections, they have been largely supplanted by the fixed drug combination of trimethoprim-sulfamethoxazole.

Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant.

Nevertheless, sulfonamides can be useful for treatment of urinary tract infections due to susceptible organisms and in other special clinical situations discussed below.

Oral Absorbable Agents

Sulfisoxazole and sulfamethoxazole are short- to medium-acting agents that are used almost exclusively to treat urinary tract infections. The usual adult dosage is 1 g of sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily.

Sulfadiazine achieves therapeutic concentrations in cerebrospinal fluid and in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Pyrimethamine, an antiprotozoal agent, is a potent inhibitor of dihydrofolate reductase. The combination of sulfadiazine and pyrimethamine is synergistic because these drugs block sequential steps in the folate synthetic pathway blockade. The dosage of sulfadiazine is 1 g four times daily, with pyrimethamine given as a 75 mg loading dose followed by a 25 mg once-daily dose.

Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression.

Sulfadoxine is the only long-acting sulfonamide currently available in the United States. Urinary excretion—especially of the free form—is very slow, resulting in prolonged drug levels in serum.

Sulfadoxine is available only as Fansidar, a combination formulation with pyrimethamine, which is used as a second-line agent in treatment for malaria.

Oral Nonabsorbable Agents

Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease.

Topical Agents

Sodium sulfacetamide ophthalmic solution or ointment is effective treatment for bacterial conjunctivitis and as adjunctive therapy for trachoma. Mafenide acetate is used topically to prevent bacterial colonization and infection of burn wounds.

Mafenide is absorbed from burn sites, and systemic levels are produced. The drug and its primary metabolite also inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds.

Adverse Reactions

All sulfonamides and their derivatives, including carbonic anhydrase inhibitors, thiazides, furosemide, bumetanide, torsemide, diazoxide, and the sulfonylurea hypoglycemic agents, are cross-allergenic. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below).

Stevens-Johnson syndrome, although relatively uncommon (ie, less than 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see Urinary Tract Disturbances), hepatitis, and, rarely, polyarteritis nodosa and psychosis.

Urinary Tract Disturbances

Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine when given in large doses, particularly if fluid intake is poor, can cause crystalluria. Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to maintain adequate hydration. Sulfonamides have also been implicated in various types of nephrosis and in allergic nephritis.

Hematopoietic Disturbances

Sulfonamides can cause hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid reactions. Sulfonamides may provoke hemolytic reactions in patients whose red cells are deficient in glucose-6-phosphate dehydrogenase. Sulfonamides takeear the end of pregnancy increase the risk of kernicterus iewborns.

Trimethoprim & Trimethoprim-Sulfamethoxazole Mixtures

 Trimethoprim, a trimethoxybenzylpyrimidine, inhibits bacterial dihydrofolic acid reductase about 50,000 times more efficiently than the same enzyme of mammalian cells. Pyrimethamine, another benzylpyrimidine, inhibits the activity of dihydrofolic acid reductase of protozoa more than that of mammalian cells. Dihydrofolic acid reductases convert dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA. Trimethoprim or pyrimethamine, given together with sulfonamides, produces sequential blocking in this metabolic sequence, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared to the bacteriostatic activity of a sulfonamide alone.

Resistance to trimethoprim can result from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding. Resistance can emerge by mutation, though more commonly it is due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases. These resistant enzymes may be located within transposons on conjugative plasmids that exhibit a broad host range, accounting for rapid and widespread dissemination of trimethoprim resistance among numerous bacterial species.

Pharmacokinetics

Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, the latter chosen because it has a similar half-life. Trimethoprim-sulfamethoxazole can also be given intravenously. Trimethoprim is absorbed efficiently from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid. Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the ratio in the formulation), the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in vitro. About 65–70% of each participant drug is protein-bound, and 30–50% of the sulfonamide and 50–60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours. The dose should be reduced by half for patients with creatinine clearances of 15 to 30 mL/min.

Trimethoprim (a weak base of pKa 7.2) concentrates in prostatic fluid and in vaginal fluid, which are more acid than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs.

Clinical Uses

Oral Trimethoprim

Trimethoprim can be given alone (100 mg twice daily) in acute urinary tract infections.

Most community-acquired organisms tend to be susceptible to the high concentrations that are found in the urine (200–600 g/mL).

Oral Trimethoprim-Sulfamethoxazole

A combination of trimethoprim-sulfamethoxazole is effective treatment for P jiroveci pneumonia, shigellosis, systemic salmonella infections (caused by ampicillin- or chloramphenicol-resistant organisms), complicated urinary tract infections, prostatitis, some nontuberculous mycobacterial infections, and many others. It is active against many respiratory tract pathogens, including the pneumococcus, haemophilus species, Moraxella catarrhalis, and Klebsiella pneumoniae (but not Mycoplasma pneumoniae), making it a potentially useful alternative to -lactam drugs for treatment of upper respiratory tract infections and community-acquired bacterial pneumonia.

However, the increasing prevalence of strains of E coli (up to 30% or more) and pneumococci (particularly penicillin-resistant strains, but also some penicillin-susceptible strains) that are resistant to trimethoprim-sulfamethoxazole must be considered before using this combination for empirical therapy of upper urinary tract infections or pneumonia.

Two double-strength tablets (trimethoprim 160 mg plus sulfamethoxazole 800 mg) given every 12 hours is effective treatment for urinary tract infections and prostatitis. One half of the regular size (single-strength) tablet given three times weekly for many months may serve as prophylaxis in recurrent urinary tract infections of some women. Two double-strength tablets every 12 hours is effective treatment for infections caused by susceptible strains of shigella and salmonella. The dosage for children treated for shigellosis, urinary tract infection, or otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole every 12 hours.

Infections with P jiroveci and some other pathogens can be treated orally with high doses of the combination (dosed on the basis of the trimethoprim component at 15–20 mg/kg) or can be prevented in immunosuppressed patients by one double-strength tablet daily or three times weekly.

Intravenous Trimethoprim-Sulfamethoxazole

A solution of the mixture containing 80 mg trimethoprim plus 400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5% dextrose in water can be administered by intravenous infusion over 60–90 minutes. It is the agent of choice for moderately severe to severe pneumocystis pneumonia. It may be used for gram-negative bacterial sepsis, including that caused by some multidrug-resistant species such as enterobacter and serratia; shigellosis; typhoid fever; or urinary tract infection caused by a susceptible organism when the patient is unable to take the drug by mouth. The dosage is 10– 20 mg/kg/d of the trimethoprim component.

Oral Pyrimethamine with Sulfonamide

Pyrimethamine and sulfadiazine have been used for treatment of leishmaniasis and toxoplasmosis. In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been employed.

Adverse Effects

Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia.

This can be prevented by the simultaneous administration of folinic acid, 6–8 mg/d.

Use of folinic acid to prevent hematologic toxicity resulting from trimethoprim-sulfamethoxazole during treatment of pneumocystis pneumonia in AIDS patients is associated with increased morbidity and treatment failures and is not recommended. In addition, the combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur also.

Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of untoward reactions to trimethoprimsulfamethoxazole, especially fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia.

Fluoroquinolones

The important quinolones are synthetic fluorinated analogs of nalidixic acid.

They are active against a variety of gram-positive and gram-negative bacteria.

Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.

Earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) did not achieve systemic antibacterial levels. These agents were useful only for treatment of lower urinary tract infections; nalidixic acid and cinoxacin are still available. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.

Antibacterial Activity

Fluoroquinolones were originally developed because of their excellent activity against gramnegative aerobic bacteria; they had limited activity against gram-positive organisms. Several newer agents have improved activity against gram-positive cocci.

This relative activity against gramnegative versus gram-positive species is useful for classification of these agents. Norfloxacin is the least active of the fluoroquinolones against both gram-negative and gram-positive organisms, with MICs fourfold to eightfold higher than those of ciprofloxacin, the prototype drug.

Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, and pefloxacin comprise a second group of similar agents possessing excellent gram-negative activity and moderate to good activity against grampositive bacteria. Minimum inhibitory concentrations (MICs) for gram-negative cocci and bacilli, including Enterobacteriaceae, pseudomonas, neisseria, haemophilus, and campylobacter, are 1–2 g/mL and often less. Methicillin-susceptible strains of S aureus are generally susceptible to these fluoroquinolones, but methicillin-resistant strains of staphylococci are often resistant. Streptococci and enterococci tend to be less susceptible than staphylococci, and efficacy in infections caused by these organisms is limited.

Ciprofloxacin is the most active agent of this group against gramnegatives, P aeruginosa in particular. Levofloxacin, the L-isomer of ofloxacin and twice as potent, has superior activity against gram-positive organisms, including S pneumoniae.

Gatifloxacin, moxifloxacin, sparfloxacin, and trovafloxacin comprise a third group of fluoroquinolones with improved activity against gram-positive organisms, particularly S pneumoniae and to some extent staphylococci. Although MICs of these agents for staphylococci are lower than those of ciprofloxacin (and the other compounds mentioned in the paragraph above) and may fall within the susceptible range, it is not known whether the enhanced activity is sufficient to permit use of these agents for treatment of infections caused by ciprofloxacin-resistant strains. None of these agents are as active as ciprofloxacin against gram-negative organisms.

Fluoroquinolones also are active against agents of atypical pneumonia (eg, mycoplasmas and chlamydiae) and against intracellular pathogens such as legionella species and some mycobacteria, including Mycobacterium tuberculosis and M avium complex. Moxifloxacin and trovafloxacin, in addition to enhanced grampositive activity, also have good activity—which other fluoroquinolones lack—against anaerobic bacteria.

Resistance

During fluoroquinolone therapy, resistant organisms emerge with a frequency of about especially among staphylococci, pseudomonas, and serratia. Resistance is due to one or more point mutations in the quinolone binding region of the target enzyme or to a change in the permeability of the organism. DNA gyrase is the primary target in E coli, with single-step mutants exhibiting amino acid substitution in the A subunit of gyrase. Topoisomerase IV is a secondary target in E coli that is altered in mutants expressing higher levels of resistance. In staphylococci and streptococci, the situation is reversed: topoisomerase IV is usually the primary target, and gyrase is the secondary target. Resistance to one fluoroquinolone, particularly if of high level, generally confers cross-resistance to all other members of this class. With the increasing use of fluoroquinolones for a variety of infections, including respiratory tract infections, fluoroquinolone resistance has emerged among strains of Streptococcus pneumoniae.

Pharmacokinetics

After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80–95%) and distributed widely in body fluids and tissues. Serum half-lives range from 3 hours (norfloxacin and ciprofloxacin) up to 10 (pefloxacin and fleroxacin) or longer (sparfloxacin). The relatively long half-lives of levofloxacin, moxifloxacin, sparfloxacin, and trovafloxacin permit once-daily dosing. The pharmacokinetics of ofloxacin and levofloxacin are identical. Oral absorption is impaired by divalent cations, including those in antacids. Serum concentrations of intravenously administered drug are similar to those of orally administered drug.

Alatrovafloxacin is the inactive, prodrug form of trovafloxacin for parenteral administration. It is rapidly converted to the active compound. Concentrations in prostate, kidney, neutrophils, and macrophages exceed serum concentrations. Most fluoroquinolones are eliminated by renal mechanisms, either tubular secretion or glomerular filtration. Dose adjustment is required for patients with creatinine clearances less than 50 mL/min, the exact adjustment depending upon the degree of renal impairment and the specific fluoroquinolone being used. Dose adjustment for renal failure is not necessary for trovafloxacin or moxifloxacin. Nonrenally cleared fluoroquinolones are contraindicated in patients with hepatic failure.

Clinical Uses

Fluoroquinolones are effective in urinary tract infections even when caused by multidrug-resistant bacteria, eg, pseudomonas. Norfloxacin 400 mg, ciprofloxacin 500 mg, and ofloxacin 400 mg given orally twice daily are all effective. These agents are also effective for bacterial diarrhea caused by shigella, salmonella, toxigenic E coli, or campylobacter. Fluoroquinolones (except norfloxacin, which does not achieve adequate systemic concentrations) have been employed in infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections, including those caused by multidrug-resistant organisms such as pseudomonas and enterobacter.

Ciprofloxacin and ofloxacin are effective for gonococcal infection, including disseminated disease, and ofloxacin is effective for chlamydial urethritis or cervicitis.

Ciprofloxacin is a second-line agent for legionellosis. Ciprofloxacin or levofloxacin is occasionally used for treatment of tuberculosis and atypical mycobacterial infections. They may be suitable for eradication of meningococci from

carriers or for prophylaxis of infection ieutropenic patients. Owing to their marginal activity against the pneumococcus, fluoroquinolones have not been routinely recommended for empirical treatment of pneumonia and other upper respiratory tract infections.

However, levofloxacin, gatifloxacin, and moxifloxacin, with their enhanced grampositive activity and activity against atypical pneumonia agents (eg, chlamydia, mycoplasma, and legionella), are likely to be effective and used increasingly for treatment of upper and lower respiratory tract infections.

Adverse Effects

Fluoroquinolones are extremely well tolerated. The most common effects are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests develop. Trovafloxacin has been associated with acute hepatitis and hepatic failure, which has led to its restricted indications. Photosensitivity has been reported with lomefloxacin and pefloxacin.

Grepafloxacin was withdrawn by the manufacturer shortly after approval because of QTc interval prolongation and its tendency to cause cardiac arrhythmias. QTc prolongation may also occur with other fluoroquinolones—particularly sparfloxacin but also gatifloxacin, levofloxacin, and moxifloxacin.

Ideally, these agents should be avoided or used with caution in patients with known QTc interval prolongation or uncorrected hypokalemia; in those receiving class IA (eg, quinidine or procainamide) or class III antiarrhythmic agents (sotalol, ibutilide, amiodarone); and in patients who are receiving other agents known to increase the QTc interval (eg, erythromycin, tricyclic antidepressants). Gatifloxacin has been associated with hyperglycemia in diabetic patients and with hypoglycemia in patients also receiving oral hypoglycemic agents.

Fluoroquinolones may damage growing cartilage and cause an arthropathy.

Thus, they are not routinely recommended for use in patients under 18 years of age. However, the arthropathy is reversible, and there is a growing consensus that fluoroquinolones may be used in children in some cases (eg, for treatment of pseudomonal infections in patients with cystic fibrosis).

Tendinitis, a rare complication that has been reported in adults, is potentially more serious because of the risk of tendon rupture. They should be avoided during pregnancy in the absence of specific data documenting their safety.

Nalidixic Acid & Cinoxacin

Nalidixic acid, the first antibacterial quinolone, was introduced in 1963. It is not fluorinated and is excreted too rapidly to be useful for systemic infections. Oxolinic acid and cinoxacin are similar in structure and function to nalidixic acid. Their mechanism of action is the same as that of the fluoroquinolones.

These agents were useful only for the treatment of urinary tract infections and are rarely used now, having been made obsolete by the more efficacious fluorinated quinolones.

 Alternative Second-Line Drugs for Tuberculosis

The alternative drugs listed below are usually considered only (1) in the case of resistance to the drugs of first choice (which occurs with increasing frequency); (2) in case of failure of clinical response to conventional therapy; and (3) when expert guidance is available to deal with the toxic effects.

For many of the second-line drugs listed below, the dosage, emergence of resistance, and long-term toxicity have not been fully established.

Ethionamide

Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids.

It is poorly water soluble and available only in oral form. It is metabolized by the liver.

 Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 g/mL, or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 g/mL. Serum concentrations in plasma and tissues of approximately 20 g/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum. A 1 g/d dosage, although effective in the treatment of tuberculosis, is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur.

Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine.

Ethionamide is administered at an initial dosage of 250 mg once daily, which is increased in 250 mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d) if possible. The 1 g/d dosage, although theoretically desirable, is seldom tolerated, and one often must settle for a total daily dose of 500–750 mg.

Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be lowlevel cross-resistance between isoniazid and ethionamide.

Capreomycin

Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 g/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis.

Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis.

Strains of M tuberculosis that are resistant to streptomycin or amikacin (eg, the multidrug-resistant W strain) usually are susceptible to capreomycin. Resistance to capreomycin, when it occurs, may be due to an rrs mutation.

Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may occur. Dosing of capreomycin is the same as streptomycin.

Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule.

Antibiotics & Other Inhibitors of Cell Wall Synthesis.

Concentrations of 15–20 g/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided doses.

Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions.

Pyridoxine 150 mg/d should be given with cycloserine as this ameliorates neurologic toxicity. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses.

Side effects can be minimized by monitoring peak serum concentrations. The peak concentration is reached 2–4 hours after dosing. The recommended range of peak concentrations is 20–40 g/mL.

Aminosalicylic Acid (PAS)

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis..

Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 g/mL. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Serum levels are 50 g/mL or more after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid

Aminosalicylic acid is rapidly excreted in the urine, in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.

Aminosalicylic acid, formerly a first-line agent for treatment of tuberculosis, is used infrequently now because other oral drugs are better-tolerated. Gastrointestinal symptoms often accompany full doses of aminosalicylic acid.

Anorexia, nausea, diarrhea, and epigastric pain and burning may be diminished by giving aminosalicylic acid with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia, often occur after 3–8 weeks of aminosalicylic acid therapy, making it necessary to stop aminosalicylic acid administration temporarily or permanently.

Kanamycin & Amikacin

Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) have rendered it obsolete.

The role of amikacin in treatment of tuberculosis has increased with the increasing incidence and prevalence of multidrug-resistant tuberculosis.

Prevalence of amikacin-resistant strains is low (less than 5%), and most multidrug-resistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 g/mL or less.

Amikacin is also active against atypical mycobacteria.

There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Serum concentrations of 30–50 g/mL are achieved 30–60 minutes after a 15 mg/kg intravenous infusion. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. Amikacin must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases.

The recommended dosage is 15 mg/kg/d intramuscularly or intravenously daily for 5 days a week for the first 2 months of therapy and then 1–1.5 g two or three times weekly to complete a 6-month course.

Ciprofloxacin & Levofloxacin

In addition to their activity against many gram-positive and gram-negative bacteria, ciprofloxacin and levofloxacin inhibit strains of M tuberculosis at concentrations less than 2 g/mL. They are also active against atypical mycobacteria.

Ofloxacin was used in the past, but levofloxacin is preferred because it is the L-isomer of ofloxacin (a racemic mixture of D- and L-stereoisomers), the active antibacterial component of ofloxacin, and it can be administered once daily.

Levofloxacin tends to be slightly more active in vitro than ciprofloxacin against M tuberculosis; ciprofloxacin is slightly more active against atypical mycobacteria. Serum concentrations of 2–4 g/mL and 4–8 g/mL are achieved with standard oral doses of ciprofloxacin and levofloxacin, respectively.

Fluoroquinolones are an important recent addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from any one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents.

The standard dosage of ciprofloxacin is 750 mg orally twice a day. That of levofloxacin is 500–750 mg as a single daily dose.

Rifabutin (Ansamycin)

This antibiotic is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs which also are cytochrome P450 substrates. The usual dose of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dose should be reduced to 150 mg/d. If efavirenz (also a P450 inducer) is used, the recommended dose of rifabutin is 450 mg/d. (See Havlir 1999, and Centers 1998, for details.)

Rifabutin is effective in prevention and treatment of disseminated atypical mycobacterial infection in AIDS patients with CD4 counts below 50/ L. It is also effective for preventive therapy of tuberculosis, either alone in a 6-month regimen or with pyrazinamide in a 2-month regimen.

Rifapentine

Rifapentine is an analog of rifampin. It is active against both M tuberculosis and M avium. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine is indicated for treatment of tuberculosis caused by rifampin-susceptible strains. The dose is 600 mg once or twice weekly. Whether rifapentine is as effective as rifampin has not been established, and rifampin therefore remains the rifamycin of choice for treatment of tuberculosis.

New Tuberculosis (TB) Drugs under Development

Several new types of TB drugs currently under development are shown here with their mechanisms of action. NIAID has supported the development of two of these compounds, SQ-109 and PA-824, which are denoted by asterisks (*) above.

 Drugs Active Against Atypical Mycobacteria

About 10% of mycobacterial infections seen in clinical practice in the USA are caused not by M tuberculosis or M leprae but by nontuberculous or so-called “atypical” mycobacteria. These organisms have distinctive laboratory characteristics, occur in the environment, and are not communicable from person to person. Disease caused by these organisms is often less severe than tuberculosis. As a general rule, these mycobacterial species are less susceptible than M tuberculosis to antituberculous drugs. On the other hand, agents such as erythromycin, sulfonamides, or tetracycline, which are not effective against M tuberculosis, may be effective against atypical strains. Emergence of resistance during therapy is also a problem with these mycobacterial species, and active infection should be treated with combinations of drugs. M kansasii is susceptible to rifampin and ethambutol but relatively resistant to isoniazid and completely resistant to pyrazinamide. A three-drug combination of isoniazid, rifampin, and ethambutol is the conventional treatment for M kansasii infection. A few representative pathogens, with the clinical presentation and the drugs to which they are often susceptible.

M avium complex (MAC), which includes both M avium and M intracellulare, is an important and common cause of disseminated disease in late stages of AIDS (CD4 counts < 50/ L).

Mycobacterium avium complex is much less susceptible than M tuberculosis to most antituberculous drugs. Combinations of agents are required to suppress the disease. Disseminated MAC is incurable and therapy is life-long if CD4 counts are below 200/ L. The need for multidrug therapy frequently leads to side effects that can be difficult to manage. Azithromycin, 500 mg once daily, or clarithromycin, 500 mg twice daily, plus ethambutol, 15 mg/kg/d, is an effective and welltolerated regimen for treatment of disseminated disease. Some authorities recommend use of a third agent, such as ciprofloxacin 750 mg twice daily or rifabutin, 300 mg once daily. Rifabutin in a single daily dose of 300 mg has been shown to reduce the incidence of M avium complex bacteremia in AIDS patients with CD4 < 200/ L but may not offer a survival advantage. Clarithromycin also effectively prevents MAC bacteremia in AIDS patients, but if breakthrough bacteremia occurs, the isolate often is resistant to both clarithromycin and azithromycin, precluding the use of the most effective drugs for treatment.

Rifampin

This drug (see Rifapentine) in a dosage of 600 mg daily can be strikingly effective in lepromatous leprosy. Because of the probable risk of emergence of rifampin-resistant M leprae, the drug is given in combination with dapsone or another antileprosy drug. A single monthly dose of 600 mg may be beneficial in combination therapy.

Clofazimine

Clofazimine is a phenazine dye that can be used as an alternative to dapsone. Its mechanism of action is unknown but may involve DNA binding.

Absorption of clofazimine from the gut is variable, and a major portion of the drug is excreted in feces. Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen inside phagocytic reticuloendothelial cells. It is slowly released, so that the serum half-life may be 2 months.

Clofazimine is given for sulfone-resistant leprosy or when patients are intolerant to sulfone. A common dosage is 100 mg/d orally. The most prominent untoward effect is skin discoloration ranging from red-brown to nearly black. Gastrointestinal intolerance occurs occasionally.

 TB and HIV Infection

 The World Health Organization (WHO) estimates 11.4 million people worldwide are infected with both Mycobacterium tuberculosis (Mtb) and HIV. The primary cause of death in those infected with both microbes is from TB, not AIDS. In the United States, healths experts estimate about two out of ten people who have TB are also infected with HIV.

One of the first signs that a person is infected with HIV may be that he or she suddenly develops TB. This form of TB often occurs in areas outside the lungs, particularly when the person is in the later stages of AIDS.

It is much more likely for people infected with Mtb and HIV to develop active TB than it is for someone that is infected only with Mtb. Fortunately, TB disease can be prevented and cured, even in people with HIV infection.

People infected with both multidrug-resistant TB (MDR TB) and HIV appear to have a more rapid and deadly disease course than do those with MDR TB only. If no medicines are available, as many as eight out of ten people with both infections may die, often within months of diagnosis.

Diagnosing TB in people with HIV infection is often difficult. They frequently have disease symptoms similar to those of TB and may not react to the standard TB skin test because their immune systems do not work properly. X-rays, sputum tests, and physical exams also may fail to show evidence of Mtb infection in people infected with HIV.

1.     http://www.apchute.com/moa.htm

2.     http://www.youtube.com/watch?v=xFrqHmuF3cA

3.     http://www.youtube.com/watch?v=TwdjMhVKbDU

4.     http://www.youtube.com/watch?v=hvjyVhX9zFA&feature=related

5.     http://www.youtube.com/watch?v=lDrG7g96Wcw&feature=related