Find out more under Global TB challenges. TB treatment lasts at least six months. Treatment for TB is usually a mixture of four antibiotics:. After two months of being on this treatment, patients may then be moved on to a course of two antibiotics for four months: Rifampicin and Isoniazid. These can come in the same tablet, called Rifinah. Patients may begin to feel better within two weeks of beginning treatment, and people with pulmonary TB normally become non-infectious during this time.
This prevents symptoms from returning and the risk of bacteria becoming drug resistant. With any medication, it is possible to experience side effects. Most are nothing to worry about and will go away. The TB nurse or doctor should advise patients of these before they start treatment. In a very few cases people may experience jaundice, which is the yellowing of skin or eyes. If this happens, stop taking your medication and tell your doctor straight away.
Patients should always discuss any side effects with their doctor, as it may be possible to change TB medication. If you would like to find out more about the side effects of specific drugs, please download our leaflet About your TB drugs. Drug-resistant TB requires a longer course of treatment, with different combinations of drugs that can have more side effects. If you have TB of the lungs or throat, after two weeks of treatment you should no longer be infectious.
Gradually you will start to feel better. This may take weeks, but you will stop feeling sick and tired all the time. Isoniazid, Rifampicin Pyrazinamide and Ethambutol can all come in one tablet, called Voractiv. Isoniazid, Rifampicin and Pyrazinamide can all come in the same tablet, called Rifater. After two months of treatment you may change to two antibiotics, Rifampicin and Isoniazid. These can come in a single tablet, called Rifinah. With any medication, it is possible to have side effects.
Most are nothing to worry about and will go away. Your TB nurse or doctor should advise you of potential side effects before you start your treatment. In very few cases people may experience jaundice, which is the yellowing of skin or eyes. The impact of phenotypic drug resistance on TB treatment outcomes is particularly dire. In the absence of an effective vaccine, TB eradication is dependent on curing infected individuals who are either contagious or may become contagious after reactivation of latent infection.
The relative lack of protective immunity provided by natural infection makes control all the more dependent on complete bacterial eradication from the population, since individuals who are cured of TB remain vulnerable to reinfection [ 18 , 19 ]. Drug resistance, and the consequent need for long-term multidrug therapy have stymied TB eradication efforts particularly in poor countries with the highest disease burden.
Poor adherence to therapy also has led to an alarming increase in multidrug-resistant MDR and extensively drug-resistant XDR strains [ 20 ], which are associated with high morbidity and mortality [ 21 , 22 ]. A review of TB pathogenesis and pathology will facilitate the assessment of the models proposed for the mechanisms of phenotypic antibiotic resistance of MTB. MTB reaches the alveoli in small, aerosolized particles and is transported into tissues within host macrophages, which aggregate with other immune cells to form granulomas, the hallmark lesion of TB.
In immunocompetent individuals, there are two main outcomes of initial infection: the development of active TB or the establishment of a clinically asymptomatic latent infection. Active disease is associated with a wide range of granuloma structures [ 23—25 ], including bacteria-laden, necrotic caseating lesions undergoing central liquefaction and large open cavities. Patients with active disease also harbor lesions in various stages of healing, including closed granulomas with hard, central caseum, and fibrotic and calcified lesions.
These latter types of lesions with lower bacterial burdens [ 23 , 26 ] are the only lesion types detected in latent TB [ 23 ]. However, the actual physical location of viable bacteria during latent infection remains a topic of considerable debate. In latently infected individuals, viable bacteria or bacterial DNA have been detected outside of granulomas in apparently normal tissue [ 26 , 27 ].
In contrast, immunocompromised e. In summary, during active disease, numerous bacteria are found in highly organized, caseating, and cavitary lesions of immunocompetent individuals or in poorly organized, noncaseating granulomas of severely immunocompromised individuals, whereas the lesions present in latent TB contain few bacteria and viable bacteria may be present outside of discernible granulomas. The lesions characteristic of latency are also found in immunocompetent individuals with active disease.
The first step in understanding MTB phenotypic drug resistance is to address whether it is mediated by TB-specific mechanisms as has been widely postulated, or by mechanisms common to all bacteria. TB-specific models suggest that environmental conditions in specific granuloma types, in particular those associated with latent disease, induce nonreplicating bacterial populations and thereby antimicrobial resistance [ 29—33 ].
According to this model, exposure to these conditions leads to the expression of a discrete set of genes known as the dormancy regulon that are in turn responsible for maintaining the bacilli in the nonreplicating and hence resistant state [ 29 , 34—36 ].
The theory that TB-specific, environmentally induced mechanisms lead to sustained phenotypically drug-resistant bacterial populations has led to an emphasis on understanding specific host environments such as hypoxia and the specific bacterial gene expression programs they induce as a basis for developing drugs that intercept this host—bacterial interface [ 29—33 , 35—37 ].
The main argument favoring the environmentally induced in vivo dormancy program specific to MTB is based on observed differences in bacterial growth in vitro depending on the type of human lesion from which the bacteria were isolated [ 24 , 25 ].
These observations were interpreted to mean that the bacteria from the cavitary lesions were actively replicating and thus susceptible to the administered antibiotics.
Therefore, following antibiotic therapy, this niche became populated by the growth of the drug-resistant mutants that were selected for during drug treatment. In contrast, the bacteria in the closed lesions were thought to have been driven into a nonreplicating state by adverse conditions present within the lesion prior to antibiotic therapy. The nonreplicating state of the bacteria in these lesions was felt to account for both characteristics observed in vitro: the slower growth due to the need to overcome this dormant state as well as drug sensitivity owing to their never having been acted upon by the antibiotic in vivo.
These differences were felt to be unlikely to be due to a lack of drug exposure in the closed lesions, because several of the agents used have been shown to penetrate both types of lesions [ 23 , 38 ]. However, these findings could have had an alternate explanation, which was not considered. The slower growing, drug-sensitive bacteria could have been present in the open lesions but their in vitro detection masked by the more rapidly growing, drug-resistant bacteria.
If true, this would mean that the nonreplicating state is not specifically induced by the environment present in the closed lesions but is present in all bacterial populations and lesion types in vivo. Another problem with the TB-specific model is that it implicates the lesions that are associated with few bacteria in inducing bacterial phenotypic antibiotic resistance. This reduction, using a single drug, is comparable to that seen in treating high-burden, active disease with multidrug therapy, underscoring the importance of bacterial burden as one of the main determinants of successful treatment.
The high relapse rate of cavitary disease may also be related to poor penetration of the cavity by antibiotics, due to the dense, fibrous capsule surrounding these lesions [ 23 ]. However, some studies have shown that antibiotics do penetrate such lesions [ 23 , 38 ]. This point is underscored by the growth of resistant bacteria from these lesions in the studies described in the previous section [ 24 , 25 ]. All patients were HIV negative and were treated with six months of therapy consisting of streptomycin S , isoniazid H , rifampin R , and pyrazinamide Z during the intensive phase, followed by SHRZ or HR combinations in the continuation phase.
Data for the figure were obtained from references [ 78—80 , 91—95 ]. A Active TB associated with cavitary lesions requires longest duration of therapy to cure. An alternative explanation for the long duration of therapy required to treat active disease states associated with the highest bacterial burden e. However, this interpretation fails to explain the finding that HIV-infected individuals who tend to have poorly formed, noncaseating granulomas with high bacillary burdens [ 28 ] also require long durations of therapy Figure 2 and Table S1 [ 28 ].
Further, the lesion-specific model does not account for the findings that MTB exhibits nonreplicating states [ 42 , 43 ] and phenotypic drug resistance [ 44 ] during experimental infection of the mouse, an animal that forms poorly organized macrophage and lymphocyte aggregates that do not resemble human, caseating lesions.
The human treatment trial data are most readily explained by a model in which infections characterized by the highest organism burden be it in cavitary lesions, caseating lesions undergoing liquefaction, or poorly formed noncaseating granulomas typical of advanced HIV coinfection also have the highest number of phenotypically drug-resistant bacteria. Because high organism burden is associated with phenotypic resistance in other infectious diseases, we propose that the mechanisms are similar in MTB and other pathogenic bacteria.
We will describe the possible mechanisms briefly here; for more detailed reviews of specific mechanisms see references [ 15—17 , 45 , 46 ]. Killing rates of actively growing MTB cultures are dramatically greater than killing rates of stationary-phase MTB cultures, in which the bacteria are resistant to killing in the absence of genetic resistance mechanisms [ 9 , 10 ]. This phenomenon had previously been described in other bacterial systems and the term antibiotic indifference was coined to describe the finding that bacteria that are not dividing, due to some inhibitory environmental condition, are resistant to killing by most antibiotics [ 47 ].
This phenomenon is not limited to in vitro culture systems. For example, the dose of penicillin required to cure experimental infections in animals is proportional to the total bacterial burden both inoculum size and duration of infection. As the infection progresses, bacterial growth slows and eventually stops due to a variety of inhibitory conditions encountered in the host, rendering the residual population phenotypically antibiotic resistant [ 47—49 ].
One potential mechanism for MTB dormancy and phenotypic antibiotic tolerance in vivo is the development of antibiotic indifference in response to host defense mechanisms or nutrient deprivation. Although nutrient deprivation has long been proposed as one of the signals leading to mycobacterial dormancy, this mechanism need not be restricted to specific granuloma pathologies and is clearly not unique to MTB. In addition to drug indifference, non-inherited drug resistance can also be explained by the observation that populations of actively growing bacteria contain a specialized, nonreplicating subpopulation known as persister cells [ 50 ].
Like drug-indifferent bacteria, these persister cells remain genetically drug sensitive but are phenotypically drug resistant, and their number increases with total organism burden [ 51 ]. Although the initial establishment of the persister population is likely to be stochastic [ 52 ], the magnitude of this population may be further influenced by specific conditions operant in vivo such as growth in macrophages [ 53 ] or biofilms [ 54 ].
For example, Legionella pneumophila grown in macrophages is more antibiotic resistant than broth-grown bacteria, suggesting that intramacrophage growth enriches phenotypically antibiotic-resistant populations [ 53 ]. This might occur because host-killing mechanisms may also target actively replicating bacteria [ 46 ]. Further, bacteria that have incurred DNA damage, perhaps as a result of host-killing mechanisms, undergo replication arrest to allow for DNA repair, rendering them transiently insensitive to antibiotic killing [ 55 ].
Some antibiotics actually induce DNA repair systems [ 56 ], halting bacterial division and theoretically rendering these bacteria even more resistant to therapy. The molecular mechanisms of persister formation are beginning to be elucidated and include growth arrest secondary to the action of toxin—antitoxin modules [ 57 , 58 ].
The toxin portion of these modules acts to cleave mRNAs positioned in the ribosome, leading to translational and growth arrest [ 59 ]. Although a potential role for relA in mycobacterial phenotypic drug resistance has not been shown, relA is required for chronic infection in the mouse model of TB [ 64 ], suggesting a possible connection to mechanisms of resistance to both host- and antibiotic-mediated killing. Studies of other chronic bacterial infections suggest that biofilm formation is responsible for the relative in vivo resistance to antibiotic killing [ 65 ].
Biofilms are multicellular bacterial communities encased in a matrix and bacteria within biofilms are phenotypically resistant to antibiotic killing when compared to growing planktonic cells [ 66 ].
Examples of important biofilm infections in humans include Pseudomonas aeruginosa lung infections in cystic fibrosis, endocarditis, and device-related infections.
Key aspects of MTB biology are reminiscent of biofilm behavior. For example, MTB in liquid culture grows as large clumps of cells known as cords. The ability to cord in culture correlates with virulence [ 67—69 ], suggesting that the capacity to grow in a multicellular community is an important determinant of MTB survival in the host.
MTB may also be found in a biofilm-like state in vivo. For example, large clumps of bacteria reside in an acellular matrix in certain human lesions, such as caseating lesions undergoing liquefaction [ 23 ]. Biofilms of other mycobacterial species have been shown to be phenotypically antibiotic resistant [ 70 , 71 ] and M. Canetti G, [ 23 ] A seminal text describing the pathology of human pulmonary tuberculosis with particular focus on the bacillary content of different types of lesions.
Vandiviere HM et al. Balaban NQ et al. Keren I et al. The phenotypic resistance to antibiotics exhibited by bacteria within biofilms is likely multifactorial.
Proposed mechanisms of resistance include poor antibiotic penetration of the biofilm, expression of biofilm genes that confer resistance, and the presence of different microenvironments in the biofilm that lead to different growth rates and thus differing antibiotic sensitivity [ 45 , 65 ].
One prominent school of thought is that the biofilm environment may also enrich the formation of persister cells [ 54 , 73 ]. New drugs that target nonreplicating bacteria are likely to revolutionize TB therapy. Such agents have the potential not only to treat MDR and XDR strains but also to dramatically shorten the duration of curative therapy. Shorter treatment times will likely translate into higher patient adherence, reduced transmission, and decreased drug resistance, leading in turn to diminished mortality and substantial gains in tuberculosis control efforts.
A major obstacle for such truly short-course therapy is the development of phenotypic antibiotic resistance in vivo. This phenomenon is common to all bacteria and these resistant populations may be enriched under a variety of conditions that are operant in vivo, such as intracellular growth, DNA damage, exposure to other antimicrobials, and biofilm formation. In addition to studying possible TB-specific mechanisms of phenotypic drug resistance, we suggest that the study of mycobacterial persister formation and biofilm-like growth states may lead to drug discovery.
Additionally, a better understanding of mechanisms of phenotypic antibiotic resistance in other pathogenic bacteria will likely have implications for MTB therapy. Given our current understanding, the development of antibiotics that are effective against non-dividing bacteria is of potential great importance [ 75 ].
Promising candidates under investigation include the ATP synthase inhibitor R [ 76 ]; however, MTB mutants resistant to this agent have been found even before clinical trials have been completed [ 77 ]. Development of additional drugs that target bacterial or host programs that induce phenotypic antibiotic resistance mechanisms will be aided by a better understanding of the physiology of this MTB population and the conditions that induce or enrich it.
LR thanks Ira Tager for first stimulating her interest in this area during her infectious diseases fellowship. Author contributions.
LEC and LR designed the study. LEC also completed the primary literature review and constructed all tables and figures in the manuscript. Lynn E. Paul H. PHE and LR declare that they have no competing interests. National Center for Biotechnology Information , U.
PLoS Med. Published online Mar
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