DESARROLLO DEL CRONOGRAMA

The 2016 WHO guidelines for the treatment for DR-TB are a revision of the 2011 guidelines. In an article by Pontali et al. (2013), a study in MDR-TB patients showed that the use of amikacin, kanamycin, capreomycin, moxifloxacin, ethionamide/prothionamide, and cycloserine were all correlated with considerably higher probabilities of treatment success (Pontali et al., 2013). These 2011 guidelines were amended slightly in 2016 specifically with regard to the classes of drugs, duration of treatment and the role of surgery.

Ahuja et al. (2012) conducted a patient meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. This analysis was based on the retrospective analysis of 9153 patient records from individuals with

resistance to at least isoniazid and rifampicin, from 32 observational reviews investigating the effect of type, number of drugs and cycle of treatment on the outcome (Ahuja et al., 2012).

From this examination, the general treatment success in this group was 54%. The study showed that the probability of treatment success is uppermost using at least four in-vitro susceptible drugs in the intensive phase of treatment and at least three susceptible drugs during the continuation phase for patients who had not received second-line drugs

for effective treatment and the possible benefit of ethionamide and prothionamide in DR-TB.

The most significant chance for positive treatment outcomes was with an intensive phase (including an injectable in the) for seven to eight and a half months, and a total treatment duration of 25–27 months. This study underlines the massive challenges of DR-TB treatment.

These guidelines DR-TB for management are based on retrospective, observational data, where just half of the patients successfully completed treatment (Ahuja et al., 2012).

2.7.3.1. Drugs.

Treatment for DR-TB (both RR-TB and MDR-TB) involves the inclusion of four categories or groups (A to D) of drugs. In patients with DR-TB, a regimen with at least five effective TB drugs during the intensive phase is recommended, including pyrazinamide and four core second-line TB medications - one chosen from group A, one from group B, and at least two from group C2 (Table 2.2). If this regimen cannot be given for some reason, an agent from group D2 and other agents from D3 may be added to bring the total to five effective TB regimens.

Table 2.2

WHO recommended medication for the treatment of RR-TB and MDR-TB (WHO, 2016b)¹

Category of Medication Name of Medication Abbreviation of Medication A. Fluoroquinolones² Levofloxacin

Moxifloxacin Gatifloxacin

Lfx Mfx Gfx B. Second-line injectable agents Amikacin

Capreomycin C. Other core second-line

agents²

(not part of the core MDR-TB regimen

Note. ¹The intention of this regrouping is to guide the design of conventional regimens; for shorter regimens lasting 9-12 months the composition is usually standardised (See Section A);

2Medicines in Groups A and C are shown by decreasing order of usual preference for use (subject to other considerations);

3In some cases, streptomycin may substitute other injectable agents. Resistance to streptomycin alone does not qualify for the definition of XDR-TB;

4Carbapenems and clavulanate are meant to be used together; clavulanate is only available in formulations combined with amoxicillin

5HIV-status must be tested and confirmed to be negative before thioacetazone is started.

Class B consists of the aminoglycosides, which are bactericidal aminoglycosidic aminocyclitols. They are used for the treatment of TB but also used for advanced bacterial infections (Schacht, 1993). Aminoglycosides investigated explicitly in the current study, kanamycin, as well as polypeptides, specifically capreomycin, have been shown to be toxic;

both ototoxic and nephrotoxic (Njuguna, 2013). Nephrotoxicity results from acute tubular necrosis as these drugs appear to concentrate in the renal tubular cell (Alamadi & Rutka, n.d).

Ototoxicity, a significant public health concern is occurring in the DR-TB population, specifically in South Africa (Njuguna, 2013).

In the industrialised world, aminoglycosides are limited generally to treat severe infections, due to their toxicity. In the developing world, such as South Africa,

aminoglycosides are used more frequently because of their low-cost potent antibacterial activities, outrivalling more expensive antibiotics with less severe side effects (Huth et al., 2011). Despite their toxicity, they are still in the WHO (2016b) guidelines for the treatment of DR-TB.

The WHO does not recommend alternate and more recent drugs such as bedaquiline and delamanid for routine use in MDR-TB treatment. However, they remain as options in cases where acceptable schedules are impossible to design with medications from the other groups (WHO, 2014b). In South Africa, they are referred to as third-line-drugs and are currently only available at designated sites and are only available to patients with specific criteria (NDoH, 2015).

Further, for the HIV positive population, along with the complicated DR-TB

medication regimen, the inclusion of antiretroviral therapy (ARV) is a necessary factor in the HIV infected patients’ treatment. ARV is advocated for all patients with HIV and DR-TB needing second-line anti-tuberculosis drugs, irrespective of CD4 count, promptly (within the first eight weeks) following initiation of TB treatment (WHO, 2011).

2.7.3.2. Duration.

Currently, in the treatment of patients with DR-TB, the WHO suggests an intensive phase of eight months for most patients, and modifications to the duration may ensue

according to the patient’s response to therapy (conditional recommendation, very low-quality indication) with a total treatment duration of 20 months (WHO, 2014b).

According to the WHO, where a shorter duration is based on a qualified

recommendation with very low-quality evidence, the updated guidelines in 2016 include a shorter duration. They include patients with RR-TB or MDR-TB who have not previously received treatment with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered implausible. For these patients, a shorter MDR-TB regimen of nine to 12 months may be utilised instead of a conventional regimen (WHO, 2016b).

The optimal duration for treatment of patients with DR-TB, however, differs between individuals as it depends on a variety of factors, such as the extent of the disease, the immune status of the patient, and the virulence and the drug resistance of the causative strain of M.

tuberculosis. Personalization of the duration of treatment for DR-TB would be highly beneficial. Until recently there has been little interest in the identification of biosignatures that could eventually lead to individual recommendations for the duration of anti-TB therapy (Heychendorf et al., 2014).

2.7.3.3. Surgery.

In patients with RR-TB and MDR-TB, elective partial lung resection (lobectomy or wedge resection) may transpire alongside a recommended MDR-TB regimen (WHO, 2016b).