Drugs interact with Isoniazid .
Tuberculosis, caused by Mycobacterium tuberculosis (M.tb), remains the biggest infection burden in the word. Rifampin (RIF) and Isoniazid (INH) are the most effective antibiotics for killing M.tb. However, the resistance rate of rifampin and INH are high and lead to almost 35% treatment failure. Metformin enhanced anti tuberculosis efficacy in killing M. tuberculosis through several mechanism, firstly through autophagia mechanism and secondly by activating superoxide dismutase (SOD). Metformin activated mTOR and AMPK then induced more effective autophagy against M.tb. Superoxide Dismutase (SOD) is an enzyme produced in the host’s antioxidant defense system. SOD neutralizes reactive oxygen species (ROS) that excessively produced during phagocytosis process against M.tb. Excessive production of ROS associated with Th1 overactivation and leads into macrophage activity inhibition and excessive tissue damage. Metformin has ability in improving SOD level during inflammation.
- anti tuberculosis enhancement
Metformin is a biguanide salt hydrochloride consists of a molecular component of C4H11N5.HCl (
Metformin use oral anti-diabetic in type-2 DM patients for almost a decade , works through AMPK activation, thus increase insulin receptor sensitivity. AMPK activation also inhibits hepatic gluconeogenesis and glycogenolysis process and then glucose uptake may increase. This process may lead the increase of lactic acid production, especially when anaerobic glucose metabolism occurs. In addition, metformin effectively increase insulin activity in the musculoskeletal and liver by doing exercising or active physical activity thereby increasing energy requirements and metabolic responses throughout the body (Figure 1).
Since, metformin inhibits hepatic gluconeogenesis process, it also reduces metabolic acids flux thus lactic acid accumulated and may lead to metformin associated lactic acidosis (MALA)  as seen in Figure 2. However, MALA is rarely happened [3, 7].
Indications of metformin treatment in Type 2 DM patients is HbA1C levels within range of 7–8%. Moreover, metformin also use to improve insulin receptor resistance through the AMPK pathway in pre-diabetes type 2 patients with impaired glucose tolerance, obese patients and polycystic ovaries. Contra indication of metformin use: pregnancy and breastfeed, renal insufficiency, liver failure, heart failure lactic acidosis, severe infection, dehydration and alcoholism.
Metformin is excreted by the kidneys in an unchanged form, thus patient with renal dysfunction need to be carefully given . Some studies suggested metformin may still be given to patients with impaired renal function and does not require a dose adjustment whenever the GFR is>40% [9, 10].
2. Tuberculosis, its therapy and resistance mechanism
Tuberculosis (TB) is a chronic infection caused by
Tuberculosis continues to be difficult to treat, mainly due to three natural barriers: 1)
First-line anti-TB regiments are rifampicin, isoniazid (INH), ethambutol, pyrazinamide, use as anti-TB. Second line of anti-TB are fluoroquinolone (ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin), ethionamide, PAS, cyclomerize, amikacin, kanamycin, dan capreomycin . Herewith, we discussed more in First-line anti-TB.
Isoniazid is metabolized by hepatic arylamine NAT2. The patients’ clearance of INH classifies into three phenotypic groups: fast, intermediate, and slow acetylators. These acetylator groups relates to NAT2 genotype and influenced by race, not by sex or age. Fast acetylation is found in Inuit and Japanese, while slow acetylation is the predominant phenotype in most Scandinavians, Jews, and North African whites . The high acetyltransferase activity (fast acetylation) relates to high dose demand of INH. After NAT2 converts isoniazid to acetyl isoniazid, which is excreted by the kidney, acetyl isoniazid can also be converted to acetyl hydrazine and then to hepatotoxic metabolites by CYP2E1. Drug-Induced Hepatitis (DIH) associated INH occurs ~0.1% of all patients taking INH. Hepatic damage incidence increases with age but is rare in patients less than 20 years old. The risk is increased ~3% by coadministration INH with rifampicin. Most cases of DIH occur 4–8 weeks after initiation of anti TB therapy [2, 17]. Neuropathy, such as peripheral neuritis (most commonly paraesthesia of feet and hands) is more frequent in slow acetylators and in individuals with diabetes mellitus, poor nutrition, or anemia. To prevent neuropathy, pyridoxine is needed. Isoniazid may also induce syndrome resembling systemic lupus erythematosus. Isoniazid is a potent inhibitor of CYP2C19 and CYP3A and a weak inhibitor of CYP2D6. However, isoniazid induces CYP2E1. Herewith drugs that are metabolized by these enzymes will potentially be affected (Table 1) [1, 2].
|No||Coadministration Drug||CYP isoform||Adverse Effects|
|2.||Carbamazepine||CYP3A inhibition||Neurological toxicity|
|3.||Diazepam||CYP3A and CYP2C19 inhibition||Sedation and respiratory depression|
|4.||Ethosuximide||CYP3A inhibition||Psychotic behaviors|
|5.||Isoflurane and enflurane||CYP2C19 inhibition||Decreased effectiveness of INH|
|6.||Phenytoin||CYP2C19 inhibition||Neurological toxicity|
|7.||Theophylline||CYP3A inhibition||Seizures, palpitation, nausea|
|8.||Vincristine||CYP3A inhibition||Limb weakness and tingling|
|9.||Warfarin||CYP2C9 inhibition||Bleeding (higher risk with INH doses >300 mg/d|
The aim of combination anti TB are 1) increasing bactericidal activity from the very beginning of therapy and 2) preventing pathogen resistance, therefore, patients could be cured. Prevent to death, prevent to recurrence, and cutting off the transmission chains by eradicated Mtb [8, 19]. Rifampicin and isoniazid have the highest bactericidal activity against Mtb, compared to other anti-TB. However, rifampicin and isoniazid are also easily becoming resistance.
Herewith some mechanism of anti-TB resistance: 1) Anti-TB amenable to penetrate into Mtb wall’s cell, due to its rich of lipopolysaccharide and mannose; 2) Mtb becomes dormant easily in anaerobic, thus anti-TB, except rifampicin and fluoroquinolone, which aims to inhibit metabolic processes became ineffective in dormant conditions; 3) Alteration of the enzymes that responsible for activating pro-drugs (pyrazinamide and isoniazid); 4) DNA of Mtb mutases; 5) Target protein’s structure alters thus the efficacy of rifampicin, ethambutol, streptomycin, fluoroquinolone and macrolide declined (Figure 3).
Based on in vitro studies, Rifampicin inhibits Mtb at a concentration of 0.06–0.25 mg/L. The prevalence of rifampicin resistance isolates (1 in every 107 to 108 CFU bacilli). Pyrazinamide has antimicrobial activity in vitro at an acidic pH of 5.8–5.95 and 80–90% of clinical isolates have an MIC (minimum inhibitory concentration) of 100 mg/L. Pyrazinamide resistance occurs due to single point mutations (pncA gene). The minimum inhibitory concentration (MIC) of isoniazid is 0.025–0.05 mg/L. The prevalence of isoniazid resistance occurs at 1 in every 106 CFU bacilli. The inhibition of ethambutol is 0.5–2 mg/L and resistance occurs due to the embB gene mutase. Based on this, to prevent anti-TB resistance, it is given in combination .
Despite of those anti-TB resistance, Mtb also has ability to manipulate host immune response, both innate and adaptive immune systems or known with escape mechanism (Figure 4). Mtb has ability to avoid intracellular killing inside macrophages (phagocytosis) .
3. Immune response against
Several epidemiological models of family members who have long shared the bedroom with subjects with TB infection have clearly demonstrated that 5 to 20% of them do not get infected (resilient individuals or resisters), or become transiently infected (early sterilization or early clearance) . An individual defined as resilient after close and prolonged contact with the negativity both of the skin reactivity test and of the IFN-g release assay (IGRA) which persists for at least 1 year. On the other side, the study of TB susceptibility, has reported onto various components of human immunity to mycobacteria. Different genetic polymorphisms which modulate the host immune response in favor of TB infection and disease progression have been identified in human leukocyte antigens (HLA), toll like receptors (TLR), vitamin D receptors (VDR), cytokines with their receptors and many other functional immune components .
Transcriptomic studies have described a TB signature of neutrophil-driven IFN-inducible genes in Mtb, including IFN-g but also type I IFNs, reflecting disease extension and response to treatment and highlighting the previously under-appreciated role of IFN-ab signaling in TB pathogenesis. Beyond host factors, bacterial virulence constitutes the other major player when evaluating the risk of TB infection. Differential Mtb gene expression in the different phases of infection also contributes to the bacterial virulence besides bacterial strain or burden in respiratory secretion. Mtb lacks virulence factors such as toxins, and its immune-escaping ability depends on the alteration of lipid metabolism, metal-transporter proteins, and protease, which inhibit the antimicrobial effectors of macrophages .
Macrophages are the first line of immune defense, so they can prevent the infection but only if the ratio of forces lies clearly to their advantage . Otherwise, they favor its development because they become first a niche for the slow replication of the Mtb and then the sanctuary for the persistence of the infection inside the phagosome during the latent infection phase. Mtb expresses an extremely wide variety of virulence factors that counteract macrophage ability in suppressing the pathogen. Among Mtb strategies we can include the intracellular trafficking inhibition, autophagy inhibition, cytosol entry ability, the induction of host cell death and the neutralization of toxic components as reactive oxygen species [15, 21].
Whilst IFN-γ is a key element in the containment of Mtb within the Macrophage, it is now widely recognized that performing this function requires the presence of vitamin D. IFN-γ axis is struggling against the ESX-system to enhance phagolysosome activity, vitamin D deficiency abets the Mtb replication . IFN-γ is the chief cytokine involved in the protective immune response against mycobacterial infection [24, 25, 26]. The main function of IFN-γ is macrophage activation, thus in this study autophagy marker was also high , it referred to its mycobactericidal functions. Predominantly IFN-γ is also contributed to less severe forms of pulmonary TB . Moreover, IFN-γ also enhances the antigen presentation through the induction of the expression of molecules from the major histocompatibility complex (MHC) class I and II and promoting the differentiation of CD4 T lymphocytes to the Th1 subpopulation [26, 29]. Furthermore as conclusion, MET through mTOR inhibition enhances macrophage’s autophagy activity thus Th1-related IFN-γ activity increases and in this study, DM-TB coinfection patients represented by BTA conversion. However, IFN-γ relates to CD8 T lymphocytes or cytotoxic T-cells activity which contributes to lung tissue damaged, thus IFN-γ activity needs to be controlled [28, 29].
IL-10 is produced by macrophages and Th-2 during
Nitric oxide (NO) within macrophages play less important role in human. On the other hand, reactive oxygen species (ROS) play a well-documented role in the immune response to Mtb, which increases susceptibility in patients displaying mutations in a catalytic subunit of NADPH-oxidase 2 involved in ROS production on phagolysosome membrane. Mtb affects NADPH- oxidase activity through nucleoside diphosphate kinase (Npk) interaction with small GTPases involved in NADPH-oxidase assembly and functioning [21, 32].
Dendritic cells (DCs) play a fundamental role in the immune defense system due to antigen presentation, co- stimulating activity and the large cytokine production capacity with activity on the lymphocytes cluster of differentiation (CD) 4. DCs role in immune response against TB remains controversial. DCs soon become a niche for the Mtb. CD209, also called DC- specific intercellular adhesion molecule 3-grabbing non-integrin receptor (DC-SIGN), represents the gateway of Mtb into the DC .
The T lymphocytes immune response begins when Mtb spreads inside the lymph nodes, but its arousal lies in the early activation of the innate immune system. Inside the lymph nodes, T lymphocytes undergo a process of activation and expansion of the specific populations for the Mtb antigens. However, at this point, the largest part is done and the infection is now established. The development of a hypersensitivity response (delayed-type) to intradermal injected tuberculin (DHT) or purified protein derivative indicates cellular immune response in 2–6 weeks after Mtb infection. It is important to underline that DHT positivity does not correlate with protective response to TB, and the disease can occur in people with adequate DHT response [34, 35].
The process of maturation of the phagosome of macrophages is facilitated and increased by IFN-γ, the production of which is mostly dependent on the T lymphocytes CD4+ with a minor support of lymphocytes CD8+ and T lymphocytes with γδ receptor. However, IFN-γ is inadequate to control the infection alone, and it requires the association of other molecules such as IL-6, IL-1, and TNF-α. It is known that TNF-α boosts the production of NO by macrophages and stimulates the production of the chemokines CCL5, CCL9, CXCL10, and CCL2, which then attract immunity cells at the site of infection [21, 36].
T lymphocytes CD8+ had no role in controlling the infection and Mtb disease. An activity against Mtb is conceivable considering that T lymphocytes CD8+ recognize Mtb antigens through class I molecules of the major histocompatibility complex (MHC), and produce IL-2, IFN-γ and TNF-α, which have a well-known role in controlling Mtb. This direct cell-to-cell contact determines the apoptosis of the Mtb- infected cell (especially macrophages) depriving Mtb from its natural growth environment and at the same time reducing its viability by unknown mechanism . On the other hand, lymphocytes CD8+ produce IL-10 and TGF-β which instead favor the development of the Mtb infection.
4. Host-directed therapy for tuberculosis
The effectiveness of anti-TB are also influenced by the host immune response due to the interaction of anti-TB. Immuno-modulators’ adjunctive therapy that enhance TB might able to shorten treatment durations and improve TB outcomes [38, 39]. To identify new host-directed therapy (HDT) for TB patients is WHO’s priority for TB management. Nowadays, Host-directed therapy (HDT) provides a largely unexploited approach as adjunctive anti-TB therapy. Firstly, HDT may impair Mtb replication and survival by disrupting Mtb manipulation of macrophage pathways, thus rendering the bacteria more sensitive to host defenses. The current search for novel therapeutics has focused on the use of repurposed drugs aimed at optimizing the host’s response against the mycobacterium . HDT has been proposed as adjuvant therapy for TB infection to improve the efficacy of current treatment outcomes. One possible solution to antibiotic resistance and non-replicating bacterial death problem is targeting the host instead of the pathogen.
Several studies about corticosteroids, TNF blockers, thalidomide, and non-steroidal anti-inflammatory (NSAIDs) have been conducted to determine the function of these immunomodulatory agents as an adjunct of OAT therapy [39, 41]. One of HDT mechanism is autophagy due to its ability in inhibiting the TB infection process [39, 41]. The process of activating autophagy from formation to maturation and then fusion with lysosomes for phagolysosome or autophagy processes requires many activators and protein (ATGs), one of the proteins representing phagolysosome or autophagy is MAP1LC3B/ATG8.
5. Mechanism of action of Metformin as candidate for host-directed therapy in patients with diabetes mellitus: tuberculosis coinfection
Metformin (MET) is a Food and Drug Administration (FDA)-approved drug, biguanide the oral anti diabetic agent, well-known for its glucose-lowering effect on type 2 diabetes (T2D) individuals [1, 2]. A group of studies have reported the potential role of MET as an adjunctive therapy for TB [32, 42, 43]. However, the exact mechanism of how MET modulates the cellular interaction between Mtb and macrophages is not well known. Therefore, we pursued to amalgamate the evidence base on MET as an adjunctive therapy for TB infection using a scoping study methodology to identify gaps to be attained in future research.
Metformin (MET) is the most commonly prescribed drug for type 2 diabetes mellitus. MET through in silico studies, in vitro studies and in vivo studies using animal models, expressed as important role for anti-tuberculosis through immunomodulatory mechanism [42, 43, 44], as it is seen in Figure 5.
Metformin hydrochloride (MET), recently known has possibilities of utilizing as a combination drug with existing antibiotics for TB therapy [15, 44] and by an extensive in vitro study, MET was reported controlling the growth of drug-resistant Mtb strains via production of mitochondrial reactive oxygen species and facilitates phagosome-lysosome fusion [3, 42]. Thus, MET is known as one of highly potential HDT due to target autophagy by AMPK activation or known as mTOR inhibitor [42, 43].
Moreover, MET is not metabolized by P450 enzymes [1, 2, 45], thus it has no interaction with rifampicin that could decrease the therapy efficacy. However, interaction MET and Rifampicin increases the expression of organic cation transporter (OCT1) and hepatic uptake of metformin, leading to an enhanced glucose lowering [46, 47]. MET is also expected enhanced Isoniazid (INH) efficacy due to SOD activity . INH a pro-drug, its activation is requiring an interaction with Kat-G produced by
5.1 Metformin dan superoxide dismutase (SOD)
Superoxide Dismutase (SOD) is an enzyme produced by the host antioxidant defense system. Increased reactive oxygen species (ROS) as respiratory burst in TB infection results in macrophage phagocytosis process against Mtb. Massive production of ROS also associated with Th1 overactivation, macrophage activity inhibition, and tissue damage. Hyperglycaemia condition could increase ROS production, therefore SOD levels could also increase in DM patients . KatG gene activates INH from pro-drug to active drug. Apparently, SOD contributes during this mechanism, higher SOD related to better of INH’s in inhibiting Mtb . MET has ability in improving SOD level during inflammation [50, 51]. Based on this, the addition of MET provides synergism effects to increase the effectiveness of INH in treating TB infection. MET also has a synergistic effect with RIF through increasing the expression of organic cation transporter (OCT)-1. The OCT-1 expression plays a role in inhibiting transcription Mtb [9, 44]. Moreover, target of glycemic level for DM-TB patients is also need to be adjusted, therefore synchronized with SOD production .
5.2 Metformin induced autophagy
Mtb has an escape mechanism through inhibition of host macrophage cells’ autophagy [20, 38]. Improving the autophagia process will improve anti-TB in eliminating Mtb. MET activates Adeno Monophosphate Kinase (AMPK) and subsequent phosphorylation of unc-51-like kinase 1 (ULK1) , then AMPK works as mTOR inhibitor and enhances autophagy [37, 39, 42, 43]. Therefore, MET from pharmacodynamics aspect has no effect to Mtb but works on host immune regulation [6, 15].
interferon gamma (IFN-γ), interleukin (IL)-10 and its ratio
In chronic TB infection, IFN-γ level increases as the body cellular immune response. Currently, IFN-release assay (IGRA) is used as a diagnostic tool for latent TB infection and as an indicator of therapeutic success in active TB infectionf [26, 53, 54]. IL-10 is a negative feedback regulator on the immune response produced by Th2 to inhibit excessive production of pro-inflammatory cytokines. IL-10 barriers the macrophage function, due to suppression of MHC class II molecules and reduces co-stimulator expression [55, 56, 57].
MET associated AMPK activation, through thioredoxin-interacting protein (TXNIP) decreases activation of inflammatory mediators and transcription factors, including NF kappa B which encodes proinflammatory mediators [58, 59]. In addition, in intracellular infections such TB MET through AMPK is also stimulated macrophage autophagy [15, 52], therefore MET accelerates Mtb elimination process without excessive inflammatory processes that can damage the tissue .
6. Side effects of Metformin that might occur
Gastrointestinal disorders (anorexia, nausea, vomiting and diarrhea) is one of the most common MET’s side effect. Impaired absorption of vitamin B12, impaired liver and or kidney function or in elderly people [1, 2]. Increased levels of lactate or known as Metformin-associated lactoacidosis (MALA) although the occurrence is low, must still be prevented. MALA is a life-threatening event. However, in Diabetes Tuberculosis coinfection patients, MALA could be prevented by determining patients criterias, including: 1) has minimal - moderate advaced pulmonary lesions in X-ray chest examination; 2) has oxygen saturation has at least above 92%; 3) has normal liver function (SGOT, SGPT) and normal kidney function (BUN, SK). Providing consultation, information and education related to the symptoms of lacto-acidosis is also needed during MET additional therapy. MET may increase lactate but rarely increase the risk of DM-TB coinfection patients experience MALA . Therefore, MET is relatively safe to use for DM-TB coinfection patients .
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