Chapter 18: Drugs and Drug Interactions
by Pedro Almeida da Silva and José A. Aínsa
The history of tuberculosis (TB) changed dramatically after the introduction of anti-mycobacterial agents. Drug treatment is fundamental for controlling TB, promoting the cure of the patients and breaking the chain of transmission when the antituberculosis drug regimen is completely and correctly followed.
Antituberculosis drug treatment started in 1944, when streptomycin (SM) and para-aminosalicylic acid (PAS) were discovered. In 1950, the first trial was performed comparing the efficacy of SM and PAS both as monotherapy or combined. The study demonstrated that combined therapy was more effective and resulted in the first multidrug antituberculosis treatment that consisted of a long course of both drugs. In 1952, a third drug, isoniazid (INH), was added to the previous combination, greatly improving the efficacy of treatment, but which still had to be administered for 18-24 months. In 1960, ethambutol (EMB) substituted PAS, and the treatment course was reduced to 18 months. In the ’70s, with the introduction of rifampicin (RIF) into the combination, treatment was shortened to just nine months. Finally, in 1980, pyrazinamide (PZA) was introduced into the antituberculosis treatment, which could be reduced further to only six months.
Two biological features explain why combined drug therapy is more effective at curing TB than monotherapy. One is that treatment of active TB with a single drug results in the selection of drug resistant bacilli and failure to eliminate the disease. The other is that different populations of tubercle bacilli – each of them showing a distinct pattern of susceptibility for antituberculosis drugs – may co-exist in a TB patient (Shamputa 2006).
Soon after the introduction of the first anti-mycobacterial drugs, drug resistant bacilli started to emerge, but the launch of both combination therapy and new and more effective drugs seemed to be enough to control the disease. In fact, it was thought that TB could be eradicated by the end of 20th century. However, TB unexpectedly re-emerged in the ’80s, and in the following years there was an important increase in the incidence of poly-, multiple-, and extensively drug resistant strains. Since 1970, no new drug has been discovered for antituberculosis treatment, which today seems insufficient to confront the disease. Fortunately, research efforts have been accomplished and today there is a wide range of new molecules with promising antituberculosis activity.
In our days, due to the worldwide re-emergence of TB and the increased incidence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis (Centers for Disease Control and Prevention 2006, see also Chapter 19), new anti-mycobacterial agents (see section 18.6 below), new drug delivery systems (Gelperina 2005), and new treatment regimens are being investigated.
In this chapter, we describe the basic guidelines on TB treatment along with a description of the major antituberculosis drugs (the classical drugs) and their pharmacokinetic properties, toxicity, and interactions with other drugs. Mechanisms of drug resistance in the tuberculous bacillus are also described. In the final part of this chapter we review the main new antimycobacterial drugs that are being developed as candidates to be incorporated in the arsenal of anti-tuberculosis drugs.
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18.2. Overview of existing treatment schemes 18.2.1. Rationale Antituberculosis treatment has two main objectives (Onyebujoh 2005). First, there is a need to rapidly kill those bacilli living extracellularly in lung cavities, which are metabolically active and are dividing continuously; this is required in order to attain the negativization of sputum and therefore to prevent further transmission of the disease. Second, it is necessary to achieve complete sterilization and elimination of those bacilli replicating less actively in acidic and anoxic closed lesions, and to kill semi-dormant bacilli living intracellularly in other host tissues, otherwise these bacilli may persist and will be responsible for subsequent TB relapses. INH is the drug with the highest activity against rapidly dividing bacilli, whereas RIF and PZA have the greatest sterilizing activity against bacteria that are not dividing. These reasons, along with the prevention of drug resistance, support the use of a combination therapy for the treatment of TB. Drugs for treating TB are usually classified as first- and second-line drugs. Traditionally, there are five first-line drugs: INH, RIF, PZA, EMB, and SM. Second-line drugs include the aminoglycosides kanamycin and amikacin, the polypeptide capreomycin, PAS, cycloserine, the thioamides ethionamide and prothionamide and several fluoroquinolones such as moxifloxacin, levofloxacin and gatifloxacin. Some reports, however, include SM among the second-line drugs, since its use has declined in recent years, due to the high rates of resistance, and also, because other more effective drugs have been incorporated into the anti-tuberculosis treatment. Similarly, new drugs such as the rifamycin derivatives rifapentine and rifabutin can be considered among the first-line drugs, and in the near future, it is quite likely that some fluoroquinolones could be incorporated into the standard anti-tuberculosis treatment, thus being considered as first-line drugs. The current short-course treatment for the complete elimination of active and dormant bacilli involves two phases: · initial phase: three or more drugs (usually isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin) are used for two months, and allow a rapid killing of actively dividing bacteria, resulting in the negativization of sputum · continuation phase: fewer drugs (usually isoniazid and rifampicin) are used for 4 to 7 months, aimed at killing any remaining or dormant bacilli and preventing recurrence 18.2.2. Dosing There are five first-line drugs: INH, RIF, EMB, PZA, and SM. For standard regimes, first-line drugs should be used at the doses summarized in Table 18-1 (data from Martindale 2004, and Centers for Disease Control and Prevention 2003a). Table 18-1: Recommended doses for first-line antituberculosis drugs Drug Adults or Childrena Daily dose (max. dose) Three times per week (max. dose) Twice per week (max. dose) INHb Adults 5 mg/kg (300 mg) 10-15 mg/kg (900 mg) 15 mg/kg (900 mg) Children 10-15 mg/kg (300 mg) 20-30 mg/kg (900 mg) RIF Adults 10 mg/kg (600 mg) 10 mg/kgc (600 mg) 10 mg/kgc (600 mg) Children 10-20 mg/kg (600 mg) 10-20 mg/kg (600 mg) PZAd Adults 18.2-26.3 mg/kg (1-2 g) 27.3-39.5 mg/kg (1.5-3 g) 36.4-52.6 mg/kg (2-4 g) Children 15-30 mg/kg (2 g) 50 mg/kg (2 g) EMBd Adults 14.5-21.1 mg/kg (800-1,600 mg) 21.8-31.6 mg/kg (1.2-2.4 g) 36.4-52.6 mg/kg (1.2-2.4 g) Children 15-20 mg/kg (1 g) 50 mg/kg (2.5 g) SM Adults 15 mg/kge (1 g) Children 20-40 mg/kg (1 g) 20 mg/kg (1 g) a : Patients under 15 years of age. b : INH can be given also once per week, on a 15 mg/kg basis, up to a maximal dose of 900 mg c : For RIF, some manuals also recommend higher doses (10-15 mg/kg) intermittently (two-three days per week) having a maximum of 900 mg (Martindale 2004) d : For PZA and EMB, doses have to be calculated precisely depending on the weight range (for details, see CDC 2003a) e : SM: doses should be reduced to 10 mg/kg in people over 59 years old When resistance to any of these first-line drugs is found or highly suspected, or when adverse effects to first-line drugs develop during therapy, the treatment should include other drugs known as second-line drugs (details of second-line drugs can be found in section 18.3). The doses and periodicity of second-line drugs and other drugs are given in Table 18-2 (Centers for Disease Control and Prevention 2003a). Table 18-2: Recommended doses for second-line anti-tuberculosis drugs Drug Adults or childrena Dose (max. dose) Days per week Rifapentineb Adults 10 mg/kg (600 mg) One Rifabutinc Adults 5 mg/kg (300 mg) Two, three or seven Cycloserine Adults and children 10-15 mg/kg (1 g) Seven Ethionamide Adults and children 15-20 mg/kg (1 g) Seven Amikacin Kanamycin Capreomycin Adults 15 mg/kg (1 g) One, two, three or seven Children 15-30 mg/kg (1 g) Two or seven PAS Adults 8-12 g Seven Children 200-300 mg/kg (10 g) Seven Levofloxacind Adults 500-1,000 mg Seven Moxifloxacind Gatifloxacind Adults 400 mg Seven a : Patients under 15 years of age. b : This drug has not been approved for use in children. c : Doses of rifabutin may need to be adjusted in HIV-positive patients receiving antiretroviral therapy. d : This drug has not been approved for long-term use in children and adolescents. 18.2.3. Treatment regimens There are many different anti-tuberculosis regimens described in the literature, mostly matching the premises, indications and doses indicated in the sections above (Centers for Disease Control and Prevention 2003a, World Health Organization 2003). Several drug regimens are recommended depending on many factors, such as disease localization and severity, result of sputum smear microscopy, human immunodeficiency virus (HIV) co-infection, prevalence of drug resistance in the setting, availability of drugs, cost of treatment and medical supervision, whether the patient has previously received any anti-tuberculosis drug, the country’s budget, health coverage by public health services, and qualifications of health staff at the peripheral level. Then, the selection of a particular drug regimen must be done considering all these factors. The World Health Organization (WHO) has established four TB diagnostic categories, assuming from a public health perspective that the highest priority of national TB programs is to identify and cure those patients with sputum smear-positive pulmonary TB, i.e. infectious TB patients (World Health Organization 2003). Category I comprises those patients with a high priority for treatment who are new smear-positive patients, new smear-negative pulmonary TB patients with extensive parenchymal involvement, patients with concomitant HIV/acquired immunodeficiency syndrome (AIDS) disease or severe forms of extrapulmonary TB. Patients with a lower priority for treatment are classified as follows: Category II (relapse, treatment failure or default), Category III (new smear-negative pulmonary TB other than in Category I and less severe forms of extrapulmonary TB) and Category IV (chronic sputum-positive TB after re-treatment and proven or suspected MDR-TB). Preferred and optional treatment regimens for each category, as recommended by the WHO, are detailed in Table 18-3 at http://www.tuberculosistextbook.com/pdf/Table 18-3.pdf . In addition to these guidelines for TB treatment, there are other alternatives. For example, the Center for Disease Control and Prevention (CDC) of the United States (US) also suggests continuation phases consisting of INH and rifapentine once per week for four months for patients in Category I (Centers for Disease Control and Prevention 2003a). This treatment can be used when sputum is negative for acid-fast bacilli (AFB) after the first two months of treatment but should be extended to nine months if the result of the culture at that time point is sill positive. These guidelines apply only to HIV-negative patients as regimens containing rifapentine should not be administered to HIV/AIDS patients. In general, the duration of the continuation phase must be estimated once the first two months of treatment (initial phase) have been completed. If the patient had cavitations on initial chest radiography and cultures are still positive after two months of treatment, the continuation phase should be extended to 31 weeks (seven months). When drug resistance develops, patients should be treated with a new combination containing at least three drugs that they had never received before (or that do not show cross-resistance with those to which resistance is suspected). In these conditions, the treatment is longer, more toxic, more expensive and less effective than regimens containing first-line drugs, and should be directly observed. In children, drug regimens similar to those described above for adults can be given, although EMB is not recommended because of its ocular toxicity. Rifapentine has not been approved for pediatric use. In case of pregnancy, similar drug regimens can be prescribed, although SM and other second-line aminoglycosides must not be given because they are ototoxic for the fetus. Also, there has been concern about the use of PZA. Then, a drug regimen of nine months of INH and RIF supplemented with EMB during the first months has been proposed. All antituberculosis drugs are compatible with breast feeding, although babies should be given chemoprophylaxis for at least three months after the mother is considered non-infectious. Since HIV/AIDS patients have a higher probability of acquiring TB (either pulmonary or extrapulmonary) or other mycobacterial opportunistic infections, particular drug regimens have been designed for treating active TB disease in them (Tuberculosis Coalition for Technical Assistance 2006). Also, the severity of adverse effects of anti-mycobacterial drugs (due to the interactions with anti-retroviral drugs) and mortality is higher among HIV-positive patients. Although, in general, HIV-positive patients respond well to a standard short-course treatment of TB, treatment failure due to malabsorption of antimycobacterial drugs has been reported. The WHO recommends not using SM or thiacetazone in HIV-positive patients in order to prevent the adverse effects of these drugs, often enhanced by anti-retroviral drugs; EMB can be used instead. Rifamycins (rifampicin, rifabutin, etc.) have clinically relevant interactions with some drugs used in the antiretroviral therapy, since they induce the metabolism of anti-retroviral agents such as zidovudine, non-nucleoside reverse transcriptase inhibitors, and HIV protease inhibitors, whose concentrations may fall to sub-therapeutic levels (see section 18.5 below). Then, rifamycin-free regimens have been suggested. They consist of INH, EMB, PZA, and SM, daily for two months, followed by INH, PZA, and SM two or three times weekly for seven months. However, it has also been described that the use of RIF throughout antituberculosis treatment improves outcome in HIV patients. Chemoprophylaxis of TB is indicated for asymptomatic patients having a positive tuberculin skin test (TST) but not showing active disease (latent TB infection), especially when they are at risk of developing the disease (for example, HIV-positive patients) (Balcells 2006, Centers for Disease Control and Prevention 2003b, Stout 2004). This is aimed at preventing the occurrence of TB. Prophylaxis is most frequently achieved by the administration of INH only, at doses of 300 mg daily for six to nine months (although there is a risk of developing INH resistance). When resistance to INH is suspected, other regimens include RIF, PZA or EMB, can be administered, although there is a greater chance of having adverse effects. In TB prophylaxis, RIF can be given concurrently with INH, reducing the prophylaxis treatment to three months. It is of prime importance to ensure the patient’s adherence to the antituberculosis treatment in order to achieve complete elimination of the bacilli (and hence avoid disease relapse), and also to prevent the emergence of drug resistance. For this reason, the antituberculosis treatment has to be supervised. Both the patient’s adherence and supervision are often difficult to manage when the antituberculosis treatment has to be administered on a daily basis. Alternative treatments based on an intermittent administration of drugs (three times, twice and even once per week) facilitate the patient’s adherence and the supervision of treatment. Intermittent treatment is possible because antituberculosis drugs have a marked post-antibiotic effect. After the tuberculous bacillus has been exposed to drugs, there is a lag period (up to several days) during which its growth is interrupted even after the drug concentration has fallen to sub-inhibitory levels. Thus, there is no need to maintain a continuous inhibitory drug concentration to kill the bacilli or prevent growth. 18.2.4. Drug preparations Most drugs used in antituberculosis treatment – INH, RIF, rifapentine, rifabutin, PZA, EMB, and ethionamide (ETH) – are commercially available as tablets or capsules and can therefore be taken orally. INH is also available as an elixir, in granules for pediatric use, and in aqueous solution for intravenous or intramuscular injection. RIF is available in powder for preparing suspensions for oral administration, and also in aqueous solution for intravenous or intramuscular injection. The exceptions are the aminoglycosides – SM, kanamycin, and amikacin – and capreomycin, which are only available as aqueous solutions for intravenous or intramuscular injection. PAS is usually available as granules for mixing with food; tablets and solutions for intravenous administration can also be found. The fluoroquinolones are available as tablets or as aqueous solutions for intravenous injections. The three main drugs used in the standard antituberculosis regimen – INH, RIF, and PZA – can also be found in fixed-dose combination preparations (Centers for Disease Control and Prevention 2003a, Panchagnula 2004, World Health Organization 2003). There are several combinations, containing for example, INH and RIF, INH and EMB, INH, RIF and PZA, and INH, RIF, PZA and EMB. When available, the use of combination preparations is recommended. Indeed, by reducing the number of tablets to be taken, they facilitate the patient’s adherence to treatment and supervision of therapy. Most importantly, this form of preparation minimizes the possibility of monotherapy and therefore, reduces the risk of drug resistance development. 18.3. Drugs: structure, pharmacokinetics and toxicity In this section, we describe the structure, general properties, pharmacokinetics, and toxicity of the main drugs used in the treatment of TB. More detailed information on drugs can be found in pharmacological books (Martindale 2004), reports on TB treatment (Centers for Disease Control and Prevention 2003a) or highly specialized reports (Douglas 1999, Forget 2006, Launay-Vacher 2005, Nuermberger 2004a, Saukkonen 2006, Zhang 2005). 18.3.1. Isoniazid Structure and general properties INH is a pro-drug that requires processing by the bacterial catalase-peroxidase to become active. Once activated, it inhibits the biosynthesis of mycolic acids, which are essential components of the mycobacterial cell wall. This drug is bactericidal against metabolically active bacilli and bacteriostatic against resting bacilli. INH is active against M. tuberculosis, M. bovis and M. kansasii. Susceptible M. tuberculosis strains show minimal inhibitory concentrations (MIC) between 0.02 and 0.2 mg/L. Isoniazid (isonicotinic acid hydrazide; C8H7N3O, MW: 137.1) is one of the most powerful drugs against TB. It is a white crystalline powder freely soluble in water. Solutions can be sterilized by autoclaving Pharmacokinetics INH is readily absorbed from the gastrointestinal tract (although absorption is reduced by food) or following intramuscular injections. Peak concentrations of 3-8 mg/L appear in blood between 1-2 hours after ingestion of 300 mg of INH. It diffuses into all body tissues, including cerebrospinal fluid. The plasma half-life ranges from 1 to 6 hours. INH is metabolized in the liver and the small intestine: first, an N-acetyltransferase acetylates INH producing acetylisoniazid; this product is hydrolyzed to isonicotinic acid and monoacetylhydrazine, and the latter compound is further acetylated to diacetylhydrazine. None of these INH-derived metabolites have any antituberculosis activity. Within the population, there are two groups of patients, depending on whether INH is acetylated slowly or rapidly, a characteristic that is genetically determined. Plasma INH concentrations are lower in rapid acetylators than in slow acetylators, although this difference does not affect the efficacy of the treatment. INH and its metabolites are excreted in the urine. Toxicity INH is well tolerated at recommended doses, although slow acetylators can accumulate higher INH concentrations and then have a higher risk of developing adverse effects. Between 10 % and 20 % of patients may develop transient increases in liver enzymes at the beginning of treatment, and sometimes develop hepatic damage. In these cases, administration of INH should be stopped. Liver function should be monitored before and during treatment, especially in those patients with a history of hepatic or renal dysfunction, in whom doses of INH should be reduced to prevent further damage. Neurological or hematological adverse effects and hypersensitivity reactions occur less frequently. A daily dose of 10 mg of pyridoxine hydrochloride is recommended to reduce neurotoxicity and to treat adverse effects caused by INH. 18.3.2. Rifampicin Structure and general properties Rifampicin, often spelled rifampin, (5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)f ormimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)-naphtho[2,1-b]furan-1,11(2H)-dione21-acetate; C43H58N4O12; MW 822.9) is a red-brown crystalline powder poorly soluble in water; it is dissolved in methyl alcohol and can be stored at room temperature protected from light. RIF inhibits gene transcription, by interacting with the beta subunit of the ribonucleic acid (RNA) polymerase enzyme. It is bactericidal against dividing mycobacteria and also has some activity against non-dividing bacilli. M. tuberculosis strains are normally susceptible to 0.1-2 mg/L. The introduction of RIF, thus, allowed reduction of the duration of standard antituberculosis treatments from one year to nine months. This was later reduced to six months after incorporation of PZA. RIF is also active against a wide range of microorganisms, including staphylococci, Neisseria spp. Haemophilus influenzae and Legionella spp. Pharmacokinetics This drug is readily absorbed from the gastrointestinal tract (food may delay or decrease RIF absorption); within 2 to 4 hours after ingestion of a dose of 600 mg, peak plasma concentrations may reach 7-10 mg/L. It also can be given intravenously. In blood, RIF is bound to plasma proteins, and distributes into body tissues and fluids, including cerebrospinal fluid and breast milk, and crosses the placenta. The half-life of RIF ranges from 2 to 5 hours. RIF is metabolized in the liver, and excreted in the bile, feces and urine. Toxicity RIF is well tolerated, although adverse effects may arise during intermittent therapy or when restarting an interrupted treatment. Adverse effects include diverse alterations in the gastrointestinal tract, skin, kidney and nervous system. It may also produce thrombocytopenia. RIF will cause a red-orange coloration of body fluids such as urine, tears, saliva, sweat, sputum and feces; it may result in the coloration of soft contact lens. Since it is metabolized in the liver, hepatic functions should be controlled before starting treatment and monitored regularly until the therapy ends. Special care should be taken in patients with pre-existing liver diseases. A moderate increase in alkaline phosphatase can be observed. 18.3.3. Pyrazinamide Structure and general properties Pyrazinamide (pyrazinoic acid amide, C5H5N3O; MW: 123.1) is a white crystalline powder, soluble in water. PZA is a bactericidal drug active only against M. tuberculosis, having no in vitro activity against other mycobacteria or any other microorganism. Susceptible strains have MICs of 20 mg/L at pH 5.6. It is active against persisting and non-dividing bacilli, even against those residing intracellularly, being almost inactive at neutral pH. The introduction of PZA into treatment regimens for TB allowed reduction of the duration of such regimens to six months. PZA is a pro-drug that requires conversion into pyrazinoic acid to be effective; this is done by mycobacterial pyrazinamidases. Pharmacokinetics PZA is given orally and is readily absorbed from the gastrointestinal tract. Serum concentrations reach a peak level of about 66 mg/L two hours after administration of a dose of 3 g. It is distributed in all body tissues and fluids, including the cerebrospinal fluid and breast milk. The half-life of PZA is about 9-10 hours. PZA is hydrolyzed in the liver, being converted to pyrazinoic acid, which is further hydroxylated and finally excreted in the urine. Toxicity PZA is hepatotoxic in a dose-dependent manner. Following a daily dose of 3 g of PZA, 15 % of patients may develop liver alterations, such as transient increases in liver enzymes, hepatomegaly, splenomegaly and jaundice. Hepatitis has been reported in less than 3 % of cases. It may also produce hyperuricemia, leading to attacks of gout. Therefore, it is contra-indicated in patients with liver damage, and it is advisable to test liver function before and regularly during treatment. It also should not be given to patients having a history of gout or hyperuricemia. 18.3.4. Ethambutol Structure and general properties Ethambutol (N,N’-ethylenebis(2-aminobutan-1-ol) dihydrochloride; C10H24N2O2,2HCl; MW: 277.2) is a white crystalline powder soluble in water and alcohol that must be stored preserved from air. This drug is used to treat TB and other opportunistic infections caused by non-tuberculous mycobacteria such as Mycobacterium kansasii. The MICs of sensitive M. tuberculosis strains range from 0.5 to 8 mg/L. EMB is only active against dividing mycobacteria, being bacteriostatic. Since EMB affects the biosynthesis of the cell wall, it has been suggested that it contributes towards increasing the susceptibility of M. tuberculosis to other drugs. Pharmacokinetics EMB is given orally, as it is well absorbed in the gastrointestinal tract (and not affected significantly by food), although a part is excreted in the feces. After absorption, it is distributed in most tissues and diffuses into the cerebrospinal fluid and breast milk; it also crosses the placenta. Following a dose of 25 mg/kg body weight a peak concentration of 5 mg/L in serum is reached after 4 hours. The half-life is about 3 to 4 hours. Only a fraction of EMB is metabolized in the liver; the unchanged drug and its metabolites are excreted in the urine. Toxicity EMB produces retrobulbar neuritis with a reduction in visual acuity, constriction of visual field, central or peripheral scotoma, and green-red color blindness (Fraunfelder 2006). This may affect one or both eyes. The severity of these effects depends on the dose and duration of treatment. Usually, normal vision is recovered a few weeks after the end of the treatment, although in some cases, this recovery may not occur until some months after the completion of treatment. Consequently, EMB is contraindicated in patients with optic neuritis, and should be used with care in patients with visual disorders. Optical examinations are advisable before and during treatment. EMB is not usually given to children under six years of age because of the difficulty in monitoring visual acuity, unless resistance to INH or RIF is highly suspected. Other adverse effects include a reduction of urate excretion (hence producing gout), gastrointestinal disorders and hypersensitivity skin reactions. 18.3.5. Streptomycin Structure and general properties Streptomycin (O-2-deoxy-2-methylamino- a-L-glucopyranosyl-(1-2)-O-5-deoxy- 3-C-formyl-a-L-lyxofuranosyl- (1-4)-N,N-diamidino-D-streptamine; C21H39N7O12; MW: 581.6). It is a white-whitish crystalline powder, highly hygroscopic and soluble in water that must be stored in airtight containers. SM, an antibiotic produced by some strains of Streptomyces griseus, was the first drug with antituberculosis activity to be discovered. It is mainly used in the treatment of TB (most M. tuberculosis strains are susceptible to 1-8 mg/L of streptomycin). It can also be used in the treatment of other bacterial infections such as those produced by Yersinia pestis, Francisella tularensis, and Brucella spp. Pharmacokinetics SM, like most aminoglycosides, is poorly absorbed from the gastrointestinal tract, and therefore it must be administered by intramuscular injection. Because of the toxicity of SM (see below) and the introduction of other drugs that can be administered orally for the treatment of TB, the use of SM has decreased, being relegated to the treatment of infections caused by drug-resistant strains. Two hours after an injection of 1 g SM, drug levels in blood may reach up to 50 mg/L, where one third of it circulates bound to plasma proteins. The half-life for SM is about 2.5 hours. SM and the other aminoglycosides diffuse well into most extracellular fluids, maybe with the exception of the cerebrospinal fluid. They diffuse quite readily into the perilymph of the inner ear, causing ototoxic effects (see below). Aminoglycosides also tend to accumulate in specific body tissues such as the kidneys. Streptomycin does not appear to be metabolized, and is excreted unchanged in the urine. The concurrence of other diseases may affect the pharmacokinetics of SM and this may become relevant since there is a relatively small difference between the therapeutic and toxic concentrations of aminoglycosides. For example, patients with renal impairment will have increased plasma concentrations of SM, whereas in patients having diseases that cause expanded extracellular fluid volume or increased renal clearance (such as ascites, cirrhosis, heart failure, malnutrition or burns), SM concentrations will be reduced. Toxicity Like most aminoglycosides, SM has ototoxic effects affecting vestibular rather than auditory (cochlear) function, which manifest as dizziness and vertigo. It is less nephrotoxic than other aminoglycosides, although it may produce renal failure when administered with other nephrotoxic agents. Regular assessment of both auditory and renal function is recommended. In case of severe adverse effects, SM can be removed by hemodialysis. Paresthesia, neurological symptoms such as peripheral neuropathies, optic neuritis and scotoma, and hypersensitivity skin reactions have also been observed after SM injections. 18.3.6. Other drugs against tuberculosis Drugs in this group are interesting for one or more of the following features: · widely used in the past but in our days its use has been relegated by the incorporation of more effective and/or less toxic drugs · used when resistance to first-line antituberculosis drugs is suspected or confirmed, and are usually denominated second-line drugs · used when severe adverse effects to other antituberculosis drugs develop · have been developed recently and, because of their usefulness for the treatment of TB, are potential first-line drugs that could be incorporated soon into standard (and maybe shorter) antituberculosis regimens · allow intermittent doses, hence facilitating patient’s adherence to anti-tuberculosis treatment Para-aminosalicylic acid This compound and its salts are active only against M. tuberculosis, which can be inhibited by 1 mg/L of this drug. It is bacteriostatic. PAS can be given orally, in a daily dose of 10-12 g divided into two or three doses. It is well absorbed in the gastrointestinal tract and distributes well throughout the body, although it is poorly distributed in the cerebrospinal fluid. It is metabolized in the intestine and in the liver, and it is excreted mainly in the urine. PAS may produce gastrointestinal side-effects such as nausea, vomiting, diarrhea, and hypersensitivity reactions, and should be administered with care in patients with liver or renal impairment. PAS can be used safely during pregnancy but is not recommended because of the gastrointestinal intolerance. The use of PAS has largely decreased since the introduction of RMP and EMB; however, due to its low cost, it is still in use in low-resource countries. Capreomycin This polypeptide is bacteriostatic against several mycobacteria including M. tuberculosis; susceptible strains are inhibited by 10 mg/L of capreomycin. Doses, usually of 1 g