Drugs for tuberculosis pdf

Four years later, the discovery of streptomycin, a new synthetic drug, called para-aminosalicylic acid PAS , was presented as an alternative drug for the treatment of tuberculosis. Following the poor results of the monotherapy, in , the first regimen based on the combination of streptomycin, PAS, and isoniazid was proposed. In , pyrazinamide was discovered, but at the prescribed dosages, the rate of hepatic toxicity was significantly high.

Ethambutol and rifampicin were introduced in and , respectively. The duration of therapy varied from 1 to 2 yr. The Madras study started in India in On the basis of the microbiological characteristics of M. Other factors can contribute to the successful outcome of the antituberculosis therapy, including the chemical features of the infection site. An adequate combination of effective drugs can reduce the probability of failure, relapse, and selection of resistant strains.

To achieve those clinical and public health outcomes, it is necessary to prescribe antituberculosis drugs with an adequate dosage, for a specific time of exposure, and whose efficacy has been proved in in vitro tests i. In particular, to avoid the emergence of resistant strains, it is necessary to prescribe at least two effective drugs.

Duration of drug exposure is different according to the susceptibility of the isolated strains. In general, two different steps in the treatment of tuberculosis can be recognized—initial or bactericidal phase and continuation or sterilizing phase.

During the first step of treatment, mycobacteria with a high replication rate are killed, and, consequently, with the histological pulmonary restoration and the reduction of the inflammation process, symptoms and clinical signs resolve clinical recovery.

From a public health perspective, this phase is crucial because the treated patient becomes noninfectious and the probability of selection of drug-resistant strains decreases it is directly correlated to the fast-growing bacteria. The continuation phase is oriented to the elimination of semidormant bacteria, whose size is significantly reduced if compared with that at the beginning of the antituberculosis therapy; this quantitative feature, related to the low replication rate, is associated with a low probability of emergence of drug-resistant mycobacteria.

In cases of drug-susceptible tuberculosis, two potent medicines are sufficient e. On the other hand, the regimen prescribed during the initial phase is more complex: two bactericidal drugs isoniazid with streptomycin or rifampicin , ethambutol to inhibit monoresistant strains and to reduce the mycobacterial burden, and pyrazinamide, whose action is mainly focused to the semidormant mycobacteria. The intensive phase has a duration of 4 mo, whereas the sterilizing phase has a duration of 2 mo.

On this basis, the choice of the antituberculosis drugs in the different phases is not random but is based on the epidemiology e. The antituberculosis drug armamentarium is characterized by molecules with two main different mechanisms of action—bactericidal effect and sterilizing effect.

The first one is crucial in the intensive phase and allows a relevant reduction of the bacterial load; the indirect consequence of this activity is the reduction of the probability of selecting drug-resistant strains. The most important drugs prescribed for that aim are isoniazid, pyrazinamide, rifampicin, and streptomycin. The sterilizing activity is relevant in the initial phase and in the continuation phase, but primarily in the continuation phase because it is oriented to kill mycobacteria in a dormancy state.

Antituberculosis drugs deemed helpful in this phase are pyrazinamide and rifampicin. These general principles are accepted worldwide, and the standardized regimens recommended by the World Health Organization in its guidelines have their roots in this biological rationale World Health Organization ; Migliori et al. The World Health Organization classified antituberculosis drugs into five classes following several criteria, among them their efficacy and their chemical characteristics.

The drugs usually prescribed for the drug-susceptible tuberculosis are included in the first class, whereas the drugs with unclear efficacy are included in the fifth class. In particular, the following drugs are integrated in the first class: ethambutol, isoniazid, pyrazinamide, and rifampicin. The second class includes amikacin, capreomycin, kanamycin, and streptomycin; old- and new-generation fluoroquinolones are included in the third class.

The antituberculosis drugs in the fourth class are cycloserine, ethionamide, para-aminosalicylic acid, prothionamide, terizidone, and thioacetazone. During the 2-mo intensive phase, patients should be administered a combined regimen including ethambutol, isoniazid, pyrazinamide, and rifampicin.

Only isoniazid and rifampicin are prescribed during the 4-mo continuation phase. As mentioned above, a higher efficacy of antituberculosis regimens longer than 6 mo for individuals both with and without HIV infection was not shown; a different scenario has been found in the treatment of the latent tuberculosis infection, in which the duration of the treatment is longer in HIV-infected patients.

Microbiological monitoring of the efficacy of the prescribed regimen is mandatory; sputum smear and culture conversion should be evaluated, particularly at the end of the intensive and continuation phases of treatment. Previously treated cases i. To prescribe an effective regimen tailored on the phenotypic profile of the mycobacterial isolates, a rapid and conventional drug-susceptibility testing is required before the initiation of therapy.

It is crucial to monitor the potential adverse events to avoid the interruption of the prescribed therapy Table 3. The World Health Organization recommends the prescription of an empiric regimen for those who are identified as relapsers or defaulters, in case of a low multidrug resistance prevalence—ethambutol, isoniazid, pyrazinamide, rifampicin, and streptomycin in the intensive phase, followed by ethambutol, isoniazid, pyrazinamide, and rifampicin for 30 d; the last 5-mo phase is characterized by ethambutol, isoniazid, and rifampicin, for a total duration of 8 mo Table 4.

In tuberculosis meningitis, streptomycin is suggested. Intermittent regimens proved a similar efficacy, with a slightly higher relapse rate at 2 and 5 yr and a lower proportion of adverse events World Health Organization Extrapulmonary tuberculosis is a paucibacillary disease, and therapeutic regimens are the same as those prescribed for the pulmonary forms.

Severe extrapulmonary disease, characterized by the neurological, abdominal, bilateral pleural, pericardial, bone, or joint or systemic involvement, needs four drugs in the intensive phase and sometimes a treatment duration of 9 mo e.

In case of relevant inflammation, the prescription of steroids is recommended. However, the prognosis strictly depends on the precocity of the administration of the antituberculosis drugs World Health Organization The clinical and public health management of drug-resistant tuberculosis is complicated. The therapeutic approach, as well as the prognosis, is significantly associated with the resistance pattern Falzon et al.

It has been clearly shown that the multidrug resistance i. The so-called second- and third-line antituberculosis drugs are less efficacious, more toxic, and more expensive than the first-line drugs. It is straightforward that the adequate treatment of drug-resistant tuberculosis can prevent the emergence of new serious drug-resistant forms, which could have a worst prognosis and less alternative therapeutic options. Furthermore, another relevant feature of an adequate and early treatment is the low probability of transmission of drug-resistant mycobacterial strains in a specific setting, such as a hospital or a community.

Nevertheless, to obtain a clinical and a microbiological cure, it is mandatory to treat individuals for a long period because of the lesser effectiveness of the second- and third-line drugs.

The prolonged exposure to medicines, characterized by a poor safety and tolerability profile, reduces the adherence of the patient. This pathogenetic step could be crucial for the emergence of new drug-resistant mycobacterial strains and their spread in the community. One of the most important points in the management of the drug-resistant strains is the prescription of an efficacious drug regimen, which should be based on the results of the drug-susceptibility testing. The current availability of rapid molecular tests, which can assess the resistances of mycobacterial strains to isoniazid and rifampicin, can allow the administration of an early tailored antituberculosis regimen.

The rapid identification of a multidrug-resistant case can allow an immediate prescription of an empiric and specific antituberculosis drug regimen. This molecular method might avoid the administration of an inappropriate treatment and, consequently, indirectly favor the clinical recovery of patients and the reduction of their infectiousness World Health Organization a.

The World Health Organization suggests the prescription of at least four active drugs during the intensive phase. In particular, the backbone of the administered regimen should include pyrazinamide, one of the injectable second-line drugs amikacin, capreomycin, or kanamycin , a new-generation fluoroquinolone, ethionamide or prothionamide , and cycloserine or PAS.

Other drugs should be prescribed in case of resistances to one or more of the backbone drugs. The duration of the first phase of the treatment should depend on the culture conversion, but it should last at least 8 mo, whereas the duration of the second phase should be longer than 20 mo. The World Health Organization guidelines issued in WHO b showed significant differences if compared with those issued in ; in particular, the suggested duration of the intensive phase is longer i.

If feasible, pyrazinamide should be added up to a backbone regimen of four second-line antituberculosis drugs, in which ethionamide and new-generation fluoroquinolones are the preferred medicines. Furthermore, monthly monitoring of the culture conversion is relevant to assess the efficacy of the prescribed therapy World Health Organization New therapeutic options have been proposed in recent years for the management of the drug-resistant mycobacterial strains, including new molecules and drugs prescribed for other diseases.

Several drugs, approved for infectious diseases other than tuberculosis, showed in vitro and in vivo antimycobacterial activity; among them, imipenem-cilastatin, linezolid, and meropenem-clavulanate have had a relevant role in individuals with drug-resistant tuberculosis in the last few years. The new molecules recently approved or in the last clinical trial phases are bedaquiline a new diarylquinoline, previously called TMC , delamanid previously called OPC , sutezolid PNU , and PA Bedaquiline and delamanid have recently received a marketing approval.

Bedaquiline-containing regimens increase by 12 times the probability of culture conversion in multidrug-resistant tuberculosis cases and prevent the emergence of further resistances to the drugs included in the backbone regimens. It reduces the time to culture conversion in the first 6 mo of exposure hazard ratio: 2. The safety and tolerability profile is good if compared with other antituberculosis drugs i. However, the frequency of nausea was significantly higher during some clinical trials if compared with that in the control group Diacon et al.

Delamanid-containing regimens showed a short- and long-term efficacy in terms of culture conversion. The most important adverse event that occurred in patients exposed to this novel nitroimidazole was QT prolongation, although not associated to relevant cardiac events Diacon et al. In particular, sutezolid, belonging to the same chemical family of linezolid, showed its ability in the reduction of the colony forming units Shaw and Barbachyn ; Wallis et al. The early bactericidal activity showed by PA, a new nitroimidazo-oxazine, was superior to that of bedaquiline in the first clinical trials Diacon et al.

Antibiotics licensed for bacterial infections other than tuberculosis proved their efficacy in the treatment of the multidrug-resistant and extensively drug-resistant tuberculosis cases. However, it has been proved that the therapeutic monitoring of its blood levels TDM can allow a dosage adjustment, followed by the reduction of the probability of occurrence of adverse events.

TDM was helpful in understanding the best dosage to be administered to patients on the basis of the blood drug concentration. It was clear that a daily dosage of mg is toxic if compared with a mg dosage. On the other hand, a mg daily dosage is less efficacious Migliori et al. Meropenem-clavulanate and cotrimoxazole showed their efficacy in some observational studies.

Treating and curing drug-resistant TB is complicated. Inappropriate management can have life-threatening results. Drug-resistant TB should be managed by or in close consultation with an expert in the disease. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Tuberculosis TB. Section Navigation. Facebook Twitter LinkedIn Syndicate.

Treatment for TB Disease. Minus Related Pages. Drug Susceptible TB Disease Treatment Regimens Regimens for treating TB disease have an intensive phase of 2 months, followed by a continuation phase of either 4 or 7 months total of 6 to 9 months for treatment. Missed doses can lead to treatment failure, relapse, and acquired drug resistance.

If doses are missed then therapy is equivalent to once weekly, which is inferior. Continuation Phase of Treatment The continuation phase of treatment is given for either 4 or 7 months. The 7-month continuation phase is recommended only for the following groups: Patients with cavitary pulmonary TB caused by drug-susceptible organisms and whose sputum culture obtained at the time of completion of 2 months of treatment is positive; Patients whose intensive phase of treatment did not include PZA; Patients with HIV who are not receiving antiretroviral treatment ART during TB treatment; and Patients being treated with once weekly INH and rifapentine and whose sputum culture obtained at the time of completion of the intensive phase is positive.

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