Despite the availability of several effective antibiotics, TB continued to be a widespread disease and the causative agent of death. Outbreaks of drug resistance and HIV epidemic added more complications and challenge for the treatment of the disease causing the mortility rate to increase.
i.Persistence and Resistance
Persistence and resistance are the two factors that made the treatment of the Tuberculosis difficult. Persistence is defined by the ability of the Tuberculosis to survive despite the use of antibiotics, even if they are not genetically drug resistance they still are able to survive causing a prolonged treatment where a combination of three drugs are required to cure the patient and prevent relapse (3). Drug resistance on the other side is defined by the loss of bacterial susceptibility to drugs due to genetic mutations in the genome of the bacterium. Resistance to drugs comes in different flavors, some strains are resistance to one drug which still enable the cure of the disease but a prolonged treatment is required, some other strains are resistance to multiple drugs (MDR-TB), these strains are resistance to the first-line agents such as isoniazid (INH) and rifampicin, however, some strains are more devil known as extensively drug-resistance bacteria (XDR), that is MDR-TB and also resistant to floroquinolones one of the second-line agents ( ). There was some highly lethal outbreaks of XDR-TB in south Africa (14). It is known now that resistance strains of Tuberculosis are evoloving continuously. Certainly, it is very important to understand the physiology and persistence of M. tuberculosis and the potential causes of drug resistence for the development of a rapidly effective drug.
Potential causes of Drug Resistence
Anti-TB drug resistance to Rifampicin which is one of the first-line agents is caued by alteration of the beta subunit of the RNA polymerase that is encoded by rpoB gene. On the contrary, resistance to INH is considered more complicated sine the mutation in several gene have been implicated such as reductase, Enoyl acyl carrier protein (acp) and catalase-peroxidase (katG) (10,11). It was also shown that in some cases the resistance to Rifampicin is accompined by resistance to INH. There are several factors that are associated with drug resistance including previous treatment of TB, inadequate or incomplete treatment, lack of information on the sensitivity of the bacterium, side effects of drugs and their malabsorption. Other causes involve absence of reliable laboratory support, where facility for culture growing and sensitivity testing are not available. Host genetic factors play also a role in increasing the susceptibility to the development of MDR-TB ( ). HIV infection although it does not appear to be a predisposing factor for the development of MDR-TB but there is a chance to acquire MDR-TB due to increase hospital visits.
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Treatment of MDR-TB is very difficult and required reliable sensitivity tests and the use of floroquinolone one of the second-line agents with a close monitoring to assess the response to the treatment. Some newer anti-TB drugs such as PA-824 showed potent bactericidal activity in animal infection model (57). In some cases where treatment is not effective surgery is recommended but in this case a prolonged treatment after the surgery is required ( ). Other used therapy for the treatment of MDR-TB is the use of cytokines such as Aerosolized INF-g, low dose recombinant human interleukin-2.
Multidrug Resistant Mycobacterium Tuberculosis and HIV Infection
Mutidrug resistant TB is becoming highly spread with ~425,000 new cases occur annually ( ). Persistence MDR require prolong treatment, usually 24 months, where drug-susceptible patients require 6-8 months of treatment. Alternatively, dru resiatnce TB require the use of the second line agents which is very expensive and are more toxic and patients have a higher mortality rates compared to the drug susceptible TB patients. Patients infected with M. tuberculosis, HIV infection is a very strong risk factor for the development of either drug susceptible or drug resistance TB after M. tuberculosis infection. In Sub-saharan Africa, the rate of HIV infection with TB infected person increased to 5-10% annually over the past decade (11). TB is also known to accelerate the cause of HIV infection in HIV patient. Both dieses are killer since HIV increase the prevelance of MDR in TB patient. Therefore, a better understanding of the relationship between HIV and anti-TB drug resistance is very urgent.
i.Association between HIV and MDR-TB
It was shown that the outbreaks of HIV and MDR-TB patients in the late 1980 and early 1990 was due to the poor infection control practices in hospitals and prisons were patients of HIV and TB were together leading to 72-98% of death in a period of 4-16 weeks ( ). The issue was complicated due to the lack of highly active antiretroviral therapy and lack or improper diagnosis of anti-TB drug resistance. Several studies conducted in South Africa and United States reported an association of HIV and anti-TB drug resistance, where an association between HIV and resistance to streptomycin was shown (48, 51). In addition, in the study conducted in the United States it was shown that patients with advance HIV disease were at high risk for infection with drug resistance TB (51).
ii. Impact of MDR-TB on HIV treatment
HIV infected persons who developed MDR-TB are at a high risk of death and the case is even worse for XDR-TB. In one study conducted in the United States, 62% of HIV-infected patients with MDR-TB died during treatment compared to 26% of HIV infected patients with TB or without MDR-TB (113). It is obvious that treatment of MDR-TB in HIV infected patient is difficult and challenging because treatment of MDR-TB required at least four drugs including floroquinolones, an inject able agent such as kanamycin and two agents from the second line agents to which the patient TB retain susceptibility. An added complication is the overlapping toxicity of the HIV antiretroviral therapy and the MDR-TB drugs in addition to the interaction of the different used drug for the treatment such as malabsorption of the TB drugs. This leads to difficulty in the overall management of disease treatment. Surgery is one option in these cases, however, very careful considerations such as infection control and post surgical management in highly recommended.
iii Control of TB-HIV infection
In order to minimize the complications of HIV/MDR-TB, addressing the TB control program deficiency is a must by improving the adherence to the TB treatment completion. Accurate and rapid diagnosis of TB-resistent strain and close monitoring of treatment response. Better understanding of the interaction of MDR-
TB and HIV infection is important and can be achieved through surveillance among patients with TB, such as HIV testing of patient sputum collected for anti-TB drug resistence survey. It is also critical to increase the laboratory capacity as outlined by WHO to reduce the MDR and XDR prevelance for a rapid and accurate diagnosis in association with implementation of quality assurance processes, adequate supervision of personnel, more rapid technology that provide quick results in few days (161). Separation of HIV patients from MDR-TB patients is required as well as the isolation and separation of MDR-TB from TB patients and general population in the hospital. Finally, conducting a proper research for addressing the association of HIV infection and malabsorption of TB drugs. In addition to the identification of new TB drugs to expand the treatment options (171, 181).
Iv TB Drug Discovery
Based on the prevalence of drug resistance TB and the high mortality rates associated with this disease, it becomes clear that defining the precise targets of the discovered compounds is very crucial for effective treatment of this disease. In one hand, it is not that simple and on the other hand the recent availability of whole-genome sequencing is providing a rapid method for finding targets, in addition to the use of DNA microarrays that can provide an expression profile for the response of the Mycobacteria to number of drugs and different environment conditions such as low oxygene or carbon starvation that thought to be one of the reasons behind the persistence of the bacteria which leads to treatment failure ( ).
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One of the suggested ways to minimize resistance of bacteria to drugs is to generate a drug that hits multiple bacterial proteins. In fact, High throughput screening against bacterial target proteins has contributed to the finding of the new clinical drug candidates by evaluating thousands of candidate compounds and their efficacy against both drug sensitive and drug-resistance strains ( 116,47 ). As an alternative to this screening, some groups have focused on specific targets compounds that have a known structure by searching for homologs to know inhibitors for example in Saccharomyces secevicease and test their inhibition in an enzyme assay ( ). Another study have focused on defying the X-ray crystallography structure of some TB patient proteins which would provide a good tool for screening massive number of compounds for binding to these defined protein structures (38).
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