Chapter 86 - Antimycobacterial Agents- Drugs For Tb, Leprosy

CHAPTER 86 ANTIMYCOBACTERIAL AGENTS: DRUGS FOR TUBERCULOSIS, LEPROSY, AND MYCOBACTERIUM AVIUM COMPLEX INFECTION Infections caused by three mycobacteria which are slow growing microbes, and the infections they cause require prolonged treatment - because treatment is prolonged, drug toxicity and poor patient compliance are significant clinical problems - prolonged treatment promotes the emergence of drug-resistant microbes

I.

TUBERCULOSIS I: CLINICAL CONSIDERATIONS

- a global epidemic - transmitted from person to person by inhaling infected sputum that has been aerosolized, usually by coughing or sneezing - initial infection is in the lung - taken up by phagocytic cells - can spread from the lungs to other organs via the lymphatic and circulatory systems - in the absence of treatment, there is always some risk that latent infection may become active A.

DIAGNOSIS AND TREATMENT OF ACTIVE TUBERCULOSIS - goal of treatment is to eliminate symptoms and prevent relapse - treatment must kill tubercle bacilli that are actively dividing as well as those that are “resting” - success is indicated by an absence of observable mycobacteria in sputum and by the failure of sputum cultures to yield colonies - diagnosis testing is indicated for: • individuals with clinical manifestations that suggest tuberculosis • individuals with a positive tuberculin skin test - definitive diagnosis is made with a chest radiograph and microbiologic evaluation of sputum - sputum evaluations: microscopic examination of sputum smears culturing sputum samples - microscopic exam cannot provide a definitive diagnosis because direct observation cannot distinguish between M. Tuberculosis and other mycobacteria - less sensitive than culturing - sputum cultures are often delayed by as long as 3 – 6 weeks - with newer culturing techniques, results can be obtained in less than 1 week - cultures are necessary to determine drug sensitivity 1. Drugs

Prime Directive: Always Treat Tuberculosis with Two or More

- antituberculosis regimens must always contain two or more drugs to which the infecting

organism is sensitive - resistance occurs because of spontaneous mutations - each mutational event confers resistance to only one drug - mutations conferring resistance to a single drug occur in about 1 in every 100 million bacteria - bacterial burden in active tuberculosis is well above 100 million organisms but far below 1016 - tuberculosis grows slowly, hence treatment is prolonged - not only do drug combinations decrease the risk of resistance, combination therapy can reduce the incidence of relapse - because treatment is prolonged, there is a high risk that drug-resistant bacilli will emerge if only one antituberculosis agent is employed - minimizes the risk of drug resistance 2. Drug-Sensitive Tubercle Bacilli and Duration of Treatment - induction phase lasts 2 months, consists of daily therapy with four drugs: • isoniazid • rifampin • pyrazinamide • ethambutol - continuation phase lasts 4 months, consists of daily therapy or biweekly therapy with just two drugs: • isoniazid • rifampin - treatment requires at least three drugs to which the organism is sensitive and should continue for 12 – 24 months after sputum conversion - ideal duration of treatment has not been established - minimal duration is 6 months - hopefully, with treatment, the patient will have an improved recovery in about 3 months B.

DIAGNOSIS AND TREATMENT OF LATENT TUBERCULOSIS 1. How Do We Test for Latent Tuberculosis? - tuberculosis skin test is the primary tool used to identify individuals with latent tuberculosis - performed by giving an intradermal injection of preparation known as purified protein derivative (PPD), an antigen derived from M. Tuberculosis - if individual has an intact immune system and has been exposed to M. Tuberculosis in the past, the PPD will elicit a local immune response - the test is read 48 – 72 hours after the injection - positive reaction is indicated by a region of induration (hardness) around the

injection site 2.

Who Should be Tested? - those having acquired the infection recently - progression from latent tuberculosis to active tuberculosis - these include people with HIV infection, people receiving immunosuppressive drugs, recent contacts of tuberculosis patients, and people with high-risk medical conditions, such as diabetes mellitus, silicosis, or chronic renal failure 3.

Interpreting the Results: Who Should be Treated? - those at high risk, treatment is recommended if the region of induration is relatively small (5 mm or larger) - those at moderate risk, treatment is indicated when the region of induration is larger (10 mm or more) - those at low risk (who should not be routinely tested), the region must be larger still (15 mm or more) to justify treatment 4. Isoniazid – preferred treatment for latent tuberculosis in all patients, including those who are HIV positive - hepatotoxic - to reduce the risk of liver injury, liver function should be evaluated at the beginning of therapy and every 4 weeks thereafter 5. Rifampin – two months of daily therapy with rifampin plus pyrazinamide is as effective as 9 months daily isoniazid - more expensive the isoniazid - greater risk of liver injury than isoniazid

II.

TUBERCULOSIS II: PHARMACOLOGY

OF

INDIVIDUAL ANTITUBERCULOSIS DRUGS

- first-line drugs are isoniazid, rifampin, rifapentine, rifabutin, pyrazinamide, ethambutol - isoniazid and rifampin are the most important - second-line drugs are para-aminosalicylic acid, kanamycin, amikacin, capremycin, ethionamide, cycloserine, ciprofloxacin, and ofloxacin - generally less effective and more toxic than the primary drugs A.

ISONIAZID - primary agent for treatment and prophylaxis of tuberculosis - administered orally (tablets and syrup) and IM - parenteral therapy is administered in critical situations when oral treatment is not possible - widely distributed to tissues and body fluids - inactivated in the liver, primarily by acetylation

- excreted in the urine 1. Therapeutic Uses – indicated only for treating active and latent tuberculosis - when used for active tuberculosis, must be given in combination with at least one other antituberculosis agent (rifampin) 2.

Adverse Effects - peripheral neuropathy = most common adverse effect - symptoms are symmetric paresthesias (tingling, numbness, burning, pain) of the hands and feet - clumsiness, unsteadiness, and muscle aches may also develop - hepatotoxicity = can cause hepatocellular injury and multilobular necrosis - deaths have occurred - greatest risk factor for liver damage is advancing age - should inform patients about signs of hepatitis (anorexia, malaise, fatigue, nausea, yellowing of the skin or eyes) - patients should undergo monthly evaluation for these signs - variety of central nervous system (CNS) effects can occur - include optic neuritis, seizures, dizziness, ataxia, and psychologic disturbances (depression, agitation, impairment of memory, hallucinations, toxic psychosis) - anemia - GI distress, dry mouth and urinary retention - allergy with fever, rashes, and a syndrome resembling lupus erythematosus 3.

Drug Interactions a. Phenytoin - can interfere with the metabolism causing the anticonvulsant to accumulate to toxic levels - signs of excess include ataxia and incoordination b.

Alcohol, Rifampin, and Pyrazinamide – increases the risk of

hepatotoxicity B.

RIFAMPIN (RIFADIN, RIMACTANE) - broad spectrum antibiotic - well absorbed if taken on an empty stomach - both the rate and extent of absorption can be significantly reduced - widely distributed to tissues and body fluids, including CSF - eliminated primarily by hepatic metabolism 1.

Therapeutic Use – one of the most effective antituberculosis drugs

- drug of choice for treating pulmonary tuberculosis and disseminated disease - always employed in combination with at least one other antituberculosis agent - has become an important agent for the treatment of leprosy 2.

Adverse Effects – generally well tolerated - rarely causes significant toxicity - hepatotoxicity = toxic to the liver and may cause jaundice and even hepatitis - patients should be monitored closely for signs of liver dysfunction - tests of liver function (serum transaminase levels) should be made prior to treatment and every 2 – 4 weeks thereafter - patients should be informed about signs of hepatitis (jaundice, anorexia, malaise, fatigue, nausea) - frequently imparts a red-orange color to urine, sweat, saliva, and tears - patients should be forewarned of this harmless effect - permanent staining of soft contact lenses has occurred - gastrointestinal disturbances (anorexia, nausea, abdominal discomfort) - cutaneous reactions (flushing, itching, rash) - rarely, flu-like syndrome characterized by fever, chills, muscle aches, headache, and dizziness - appears to have an immunologic basis - shortness of breath, hemolytic anemia, shock, and acute renal failure 3. Drug Interactions – can hasten the metabolism of many drugs, reducing their effects - special concern with oral contraceptives (women should consider a nonhormonal form of birth control) - affects warfarin (an anticoagulant) and certain drugs for HIV

III.

DRUGS

FOR

LEPROSY (HANSEN’S DISEASE)

- leprosy is a chronic infectious disease - if left untreated, can cause grotesque disfiguration - with the drugs available today, most patients can be cured - affects the skin, peripheral nerves, and mucous membranes of the upper respiratory tract - characteristic features are skin lesions with local loss of sensation, thickening of peripheral nerves, and acid-fast bacilli in smears from skin lesions - cornerstone of treatment is multi-drug therapy - most regimens include rifampin - can take these drugs for up to 12 months

1.

Pharmacology of Individual Antileprosy Drugs a. Rifampin – most effective agent for treating leprosy - most effective than any combination of other agents - monthly administration is just as effective as daily administration - less expressive - minimizes adverse effects, including hepatoxicity b.

Dapsone – absorbed rapidly and nearly completely from the GI

tract - widely distributed to tissues and body fluids - undergoes hepatic metabolism followed by excretion in the urine - generally well tolerated - most common adverse effects are GI disturbances, headache, rash, and a syndrome that resembles mononucleosis - hemolytic anemia occurs occasionally c.

Clofazimine – trade name Lamprene - administered orally and undergoes partial absorption - retained in fatty tissue and the skin - very safe and dangerous reactions are rare - GI symptoms (nausea, vomiting, cramping,

diarrhea) are common - imparts a harmless red color to feces, urine, sweat, tears, and saliva - deposition in the small intestine produces the most serious effects: intestinal obstruction, pain and bleeding - causes reversible reddish-black discoloration of the skin in most patients