Rifapentine (also known as cyclopentyl rifampicin and Priftin) is a medication recommended by the World Health Organization as a first-line treatment for TB. It was first synthesized in 1965 by the Italian company that developed rifampicin and approved by the U.S. Food and Drug Administration (FDA) as a treatment for pulmonary TB in 1998. Rifapentine is a long-acting derivative of rifampicin, and therefore is similar in structure to rifampicin. The primary benefit of rifapentine is that it simplifies TB treatment; its long-acting nature means that the drug is taken only once or twice weekly by patients. In addition, clinical studies have also demonstrated that rifapentine could potentially shorten the current six-month treatment regimen for latent TB. Rifapentine is not available for commercial use in South Africa. **Rifapentine (RPT)** Dosage ------ _Adults_ - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: Following the 2 month intensive phase, 600 mg orally once a week for at least 4 months _Children_ 15 years or older: - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: Following the 2 month intensive phase, 600 mg orally once a week for at least 4 months 12 years to less than 15 years weighing less than 45 kg: - Initial intensive phase dose: 450 mg orally two times a week with at least 72 hours between doses for 2 months. - Continuation phase dose: 450 mg orally once a week for at least 4 months following the initial phase 12 years to less than 15 years weighing 45 kg or more: - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: 600 mg orally once a week for at least 4 months following the initial phase _Notes on dosing_ - To be eligible for rifapentine therapy, patients must be more than 12 years of age; have culture- positive, noncavitary pulmonary tuberculosis; be infected with TB strains that are susceptible to rifampicin, isoniazid, and pyrazinamide; and be HIV negatve. Only HIV-negative patients should receive rifapentine - During the intensive phase, rifapentine should be administered in combination with daily companion drugs (such as ethambutol, pyrazinamide, and streptomycin). - The continuous phase of treatment may consist of rifapentine with isoniazid or an appropriate anti-TB medication. - Patients with resistance to rifampicin should not be given rifapentine, due to cross resistance between these drugs. How it works ------------ Rifapentine is similar in structure to rifampicin and uses a similar mechanism against TB bacteria. It kills TB bacteria by inhibiting bacterial RNA polymerase, which is the enzyme responsible for transcribing DNA into RNA (RNA is subsequently used to make bacterial proteins). By disrupting the bacterial RNA polymerase only, rifapentine eliminates TB bacteria while leaving human RNA polymerase unaffected. Rifapentine has a long half-life in serum and is therefore administered less frequently. Its half-life is 5 times that of rifampicin. Side effects ------------ Mild side effects include red, orange, or brown discoloration of skin, tears, sweat, saliva, urine, or tools, which is a harmless but potentially alarming side effect if the patient is not forewarned; nausea and loss of appetite; stomach pain; mild skin rash or itching; headache; and joint pain. Less common side effects include vomiting; diarrhea; blood in stools; and, in rare cases, liver problems. Pricing ------- Rifapentine (Brand: Priftin) 150 mg, 100 tablets: $363.48 / R2988 Price per tablet: $3.63 / R30 (exchange rate 21/09/2011) (Rifapentine is not available in South Africa) Clinical trials and approval ---------------------------- Rifapentine is recommended by the WHO as a first-line drug for the treatment of TB. It demonstrates excellent activity against TB bacteria in vitro , animal studies, and clinical trials. Rifapentine is as effective as rifampicin at eliminating TB bacteria. Clinical trials have demonstrated rifapentine to be safe and effective for the treatment of TB. Several studies, however, have suggested that patients treated with rifapentine have a slightly higher risk of relapse following the completion of treatment. A 2002 study in the USA and Canada administered rifapentine to a group of HIV positive patients with non drug-resistant TB who had completed a 2 month intensive phase of treatment. These patients received either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Rifapentine was shown to be safe and effective in HIV negative patients, which was the basis for the current CDC recommendation for using rifapentine and isoniazid in selected patients during the continuation phase of therapy. However, rates of relapse among rifapentine-receiving patients were slightly higher; crude rates of failure/relapse were 46/502 (9.2%) in patients administered rifapentine-isoniazid, and 28/502 (5.6%) in those given rifampicin-isoniazid[^Benator] Early on, this study had included a group of HIV-positive patients. However, recruitment in the HIV-positive study arm was stopped in 1997 after 4 of 36 patients in the rifapentine-isoniazid group experienced relapse with acquired rifampicin-monoresistant TB. Researchers have subsequently advised against administering rifapentine to patients co-infected with HIV and TB.[^Munsiff] A study in 2007 used the mouse model to compare the effectiveness of rifapentine- and moxiflocacin-containing regiments with that of the standard daily short course regimen with rifampicin, isoniazid, and pyrazinamide. Researchers found that replacing rifampicin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen and led to negativity in mice after only 2 months. They concluded that their results warrant urgent clinical investigation, and suggested that rifapentine should no longer be viewed solely as a long-acting substitute for rifampicin. According to the study’s authors, “our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 month duration of treatment to 3 months or less."[^Rosenthal] Rifapentine has also showed considerable promise as an effective treatment for latent TB. A study in 2005 demonstrated that a three-month, once-weekly regimen of rifapentine combined with either isoniazid or moxifloxacin were as active as the current treatment of daily isoniazid for 6–9 months.[^Nuermberger] In addition, a 10 year trial concluded in 2011 and sponsored by the international Centers for Disease Control and Prevention (CDC) recently demonstrated that a once-weekly regimen of rifapentine and isoniazid for just 3 months is as effective as a standard self-administered 9-month daily regimen of isoniazid alone, and has a significantly higher completion rate. The study was one of the largest ever conducted on latent TB preventative therapy, and consisted of 8053 participants in South Africa who were randomized to receive either 3 months of once-weekly rifapentine 900 mg plus isoniazid 900 mg (administered with directly observed supervision), or the current standard treatment regimen (9 months of self-administered daily isoniazid 300 mg). Of the study volunteers, 7 cases of TB occurred in the group assigned rifapentine, while 15 occurred in the standard treatment group. The rate of permanent drug discontinuation due to adverse side effects was slightly higher with the rifapentine/isoniazid regimen (4.7% vs 3.6%). Despite this, the rate of participants who completed treatment was substantially higher with the rifapentine regimen than with the standard regimen (82% vs 69%). This demonstrates that reducing the required treatment regimen from 270 doses to just 12 doses through rifapentine therapy could potentially lead to better rates of completion and patient compliance. Due to these encouraging results, the CDC has launched an effort to develop new guidelines on the use of the treatment regimen. In addition, current clinical trials are investigating the tolerability of the rifapentine-containing regimen amongst children and HIV positive patients.[^March] Advocacy issues --------------- - More clinical information is needed on the effectiveness, safety, and tolerability of rifapentine-containing regimens as a treatment for both active and latent TB in children and patients co-infected with HIV and TB. - The long-acting nature of rifapentine therapy simplifies TB treatment and has been shown to potentially lead to increased patient compliance. - It is recommended that the price of rifapentine therapy be reduced to increase access. [^Benator]: D Benator et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet. 2002 Aug 17; 360(9332): 528-534 [^Munsiff]: SS Munsiff et al. Rifapentine for the Treatment of Pulmonary Tuberculosis. Clin Infect Dis. (2006) 43(11): 1468-1475 [^Rosenthal]: IM Rosenthal et al. Daily Dosing of Rifapentine Cures Tuberculosis in Three Months or Less in the Murine Model. PLoS Med. 2007 Dec; 4(12): e344 [^Nuermberger]: E Nuermberger et al. Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model. Am J Respir Crit Care Med. 2005 Dec 1; 172(11): 1452-1456 [^March]: March, David. Simpler Combination Therapy as Good as Old Regimen to Prevent Full-Blown TB in People with and Without HIV. Johns Hopkins Medicine. 7 July 2011.

PA-824 is an experimental drug that is undergoing testing as a potential treatment for TB. Like OPC-67683, PA-824 is a nitroimidazole that has demonstrated bactericidal and sterilizing activity against drug-resistant and non drug-resistant TB. PA-824 has also shown activity against both active and latent TB. In a 2002 agreement with the former biotechnology company Chiron, the TB Alliance was granted exclusive rights to develop the drug as a treatment for TB. The TB Alliance is currently carrying out phase II clinical testing on PA-824. How it works ------------ PA-824 is a nitroimidazole. It is a prodrug, which means it needs to be activated before it becomes effective against TB bacteria. PA-824 is activated by either a bacterial enzyme or a cofactor, which is a compound that binds to a protein. This activation is the reason why PA-824 does not attack human cells. Human cells lack the bacterial enzyme and cofactor needed to convert PA-824 into its active form. PA-824 kills bacteria by inhibiting the synthesis of certain proteins and cell wall lipids (i.e. fat molecules) that are needed by bacteria for survival. Researchers believe that PA-824 acts this way against replicating, aerobic (i.e. requiring oxygen) bacteria only. PA-824 is also active against latent TB bacteria. In a latent state, bacteria are anaerobic and either non-replicating or replicating very slowly. In 2008 researchers from the National Institute of Allergy and Infectious Diseases (NIAID) found that PA-824 kills latent bacteria by releasing a gas called nitric oxide (NO), which poisons the bacteria. NO gas is produced naturally by specific immune cells after they engulf TB bacteria; this is one way the body fights TB infection. But this immune response is sometimes not sufficient to eliminate an infection. PA-824 mimics the body's natural immune response, but it is more specific and only releases the gas upon entering the TB bacteria. While PA-824 was originally designed to act against active, aerobic bacteria, this NO mechanism explains how PA-824 is also active against latent, anaerobic bacteria. TB bacteria in their latent state are surrounded by immune cells in structures called granulomas. Oxygen levels are low inside granulomas, so these structures are said to have an anaerobic environment. Researchers determined that NO gas is released in greater quantities in an anaerobic environment. Understanding how PA-824 acts against latent bacteria may help investigators design other TB drugs that use this same mechanism in low-oxygen conditions.[^Mohit] Pre-clinical studies -------------------- Pre-clinical studies demonstrated that PA-824 has potent bactericidal and sterilizing effects against drug-resistant and drug-susceptible TB. The drug’s Minimum Inhibitory Concentration (MIC, or the lowest concentration at which it is effective against bacteria) was found to be between 0.015 and 0.25 µ/ml for drug-sensitive strains and between 0.03 and 0.53 µ/ml for drug-resistant strains. A study in 2005 using the mouse model found that when PA-824 was used alone, it exhibited bactericidal activity during the intensive phase of therapy that was similar to an equivalent dose of isoniazid in humans. When combined with isoniazid, PA-824 prevented the selection of isoniazid-resistant mutants. Researchers were surprised to find that PA-824 also demonstrated potent activity during the continuation phase of therapy, during which it eliminated bacteria that had survived the initial two-month intensive phase.[^Sandeep] This is likely because the bacteria that outlast the intensive phase treatment inhabit an anaerobic environment that facilitates bactericidal action by PA-824.[^Lenaerts] Other studies using the mouse model demonstrated that PA-824, when administered by itself, had bactericidal activity slightly greater than rifampicin (20mg/kg), and comparable to moxifloxacin (100 mg/kg) and isoniazid (25 mg/kg). PA-824 administered alone also showed comparable activity to combination therapy with rifampin and isoniazid in mice and in vitro.[^Lenaerts2] Early studies incorporated PA-824 into standard combination therapies of first-line drugs to investigate its interaction with these drugs and its potential to shorten the current six-month treatment programme. Researchers found some evidence that PA-824 could potentially lead to a shorter regimen. A 2006 study replaced isoniazid with PA-824 in the first-line combination of isoniazid, rifampin, and pyrazinamide. Researchers found that this substitution led to a more rapid conversion to sputum-negative, and had more potent sterilizing effects – as demonstrated by significantly lower bacterial counts after two months of treatment. However, there was no difference in the proportion of mice that relapsed following treatment. Researchers were "unable to establish a clear role for PA-824 in a treatment-shortening regimen." [^Nuermberger] A 2008 study reported that the novel combination of PA-824, moxifloxacin, and pyrazinamide cured mice more rapidly than the first-line regimen of rifampin, isoniazid, and pyrazinamide. PA-824, moxifloxacin, and pyrazinamide in a combination regimen had potent sterilizing activity that accelerated the rate of conversion to sputum-negative. This suggested that PA-824 may substitute well for rifampicin during intensive phase therapy. Researchers concluded that, if these results are applicable to humans, "regimens containing this combination may radically shorten the treatment of multidrug-resistant tuberculosis." [^Nuermberger2] Pre-clinical studies on PA-824 revealed some other notable characteristics of the drug. Researchers found that PA-824 has a narrow spectrum of action; while it kills TB bacteria, it does not act against other types of bacteria. This has important implications for TB treatment, because it means that TB bacteria will not be able to develop resistance to PA-824 as a result of the medication being used widely as a treatment for other bacterial infections. Additionally, PA-824 may be particularly effective against latent TB bacteria when used in combination with moxifloxacin, a 2005 study suggested. This study examined the activity of various drug combinations against latent TB. Researchers were surprised to find that the combination of PA-824 (100 mg/kg) with moxifloxacin (100 mg/kg) was at least as active as the current treatment of isoniazid therapy.[^Nuermberger3] Phase I trials -------------- In phase I trials of PA-824 in healthy volunteers, no serious side effects were reported. A 2009 trial evaluated the safety and efficacy of PA-824 in two escalating-dose clinical studies, one single-dose and one multiple-dose study. The drug was well-tolerated in 58 healthy individuals who were given PA-824 for a period of 7 days, and no adverse events occurred. Pharmacokinetic properties of the drug supported a regimen of one dose per day.[^Ginsberg] Phase II trials --------------- The development of PA-824 experienced a setback when the U.S. Federal Drug Administration (FDA) put the medication on clinical hold following reports of PA-824 causing cataracts in monkeys. Phase I trials, however, found no evidence of this side-effect in human patients, most likely because the dose administered in animal studies far exceeded the comparable dose given to human patients. The FDA removed the clinical hold in July 2009. The following month, a phase II trial was initiated to examine the Early Bactericidal Activity (EBA) of PA-824. An EBA study investigates a drug's ability to quickly kill TB bacteria when administered alone. A randomized, controlled EBA study was conducted at two sites in South Africa and coordinated by Stellenbosch University, the University of Cape Town and the Global Alliance for TB Drug Development. TB-infected patients were separated into five different groups, with about 15 patients per group. Four groups received one of four oral doses of PA-824: 200, 600, 1,000, or 1,200mg per day for a period of 14 days. For the control group, 8 patients received the standard first-line TB treatment. Results were published in 2010. As researchers expected, PA-824 showed promising bactericidal activity. The results confirmed that PA-824 "could someday be incorporated into a regimen to treat drug-susceptible and drug-resistant TB more quickly and effectively." [^Diacon] However, investigators were surprised to find that each of the four PA-824 doses resulted in an essentially the same EBA, with a steady decrease in the number of TB bacteria in the sputum (~0.1 log drop in CFU per day for 14 days, as compared with 0.148 for the standard regimen). This means that maximum effectiveness was seen at the lowest dose tested: 200 mg. The lack of difference in bactericidal activity between 200 mg and 1200 mg contradicted pre-clinical studies in mice, where the activity of PA-824 was dose-dependent (i.e. increased with increasing doses). Researchers recommended more studies to test lower doses of the drug.[^Tyagi] A study published in 2011 conducted more experiments in mice and in vitro to examine the activity of lower doses of PA-824 against TB bacteria. Some of the bacterial cultures used were isolated from human patients. This study confirmed the earlier finding that 200 mg/day of PA-824 in humans is sufficient to achieve maximum bactericidal effects. The study showed that PA-824 could be active against TB bacteria in doses as low as 50 or 100 mg/day in humans. Based on pharmacokinetic results, researchers postulated that human patients require relatively lower doses of the drug than mice because PA-824 has a longer half-life in humans.[^Ahmad] Future developments ------------------- The TB Alliance is leading the development of PA-824 as a treatment for TB. A second EBA study was commenced in 2009 to explore the activity of PA-824 at lower doses (50 to 200 mg/day), but results have not yet been published. Another EBA study that will evaluate PA-824 as part of a novel three-drug combination is currently in its planning stages.[^Wingfield] Advocacy issues --------------- - The TB Alliance gained global exclusive rights to PA-824 and related compounds for the treatment of TB in an agreement with Chiron (now part of Novartis) in 2002. This agreement ensured that the technology would be made available royalty-free in endemic countries, and it was the first such arrangement between a private company and a nonprofit organization. - According to a TB Alliance statement, in 2007 the U.S. FDA approved a request for orphan drug designation for PA-824. The Orphan Drug Act is designed to reduce the costs of developing and registering drugs for some diseases and conditions that are rare in the U.S. The designation confers a number of benefits for the development of PA-824, including a waiver of the nearly $1 million fee usually paid on submission of a New Drug Application. The European Union has just approved similar Orphan Medical Product status for PA-824. The FDA also has granted PA-824 fast-track designation, which is designed to expedite the application and review process for products that have the potential to address a serious or life-threatening condition.[^TBAlliance] - Coordination between future research efforts to develop PA-824 and OPC-67683 is warranted due to the chemical similarities between these two nitroimidazole compounds. - It is taking an extraordinarily long time to push the drug through clinical trials. [^Mohit]: Joshi, Mohit. Experimental Drug Shows Promise Against Latent TB Bacteria. Top News Health. 28 Nov 2008. [^Sandeep]: T Sandeep. Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2005 June; 49(6): 2289-2293 [^Lenaerts]: AJ Lenaerts et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models. Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301 [^Lenaerts2]: AJ Lenaerts et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models. Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301 [^Nuermberger]: E Nuermberger et al. Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2006 Aug; 50(8): 2621-2625 [^Nuermberger2]: E Nuermberger et al. Powerful Bactericidal and Sterilizing Activity of a Regimen Containing PA-824, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2008 Apr; 52(4): 1522–1524 [^Nuermberger3]: E Nuermberger et al. Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model. Am. J. Respir. Crit. Care Med. 2005; 172: 1452-1456 [^Ginsberg]: AM Ginsberg et al. Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects. Antimicrob Agents Chemother. 2009 Sept; 53(9): 3720-3725 [^Tyagi]: S Tyagi et al. Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2005 June; 49(6): 2289-2293 [^Diacon]: AH Diacon et al. Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients. Antimicrob Agents Chemother. 2010 Aug; 54(8): 3402-3407 [^Ahmad]: A Ahmad et al. PA-824 Exhibits Time-Dependent Activity in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2011 Jan; 55(1): 239–245 [^Wingfield]: Wingfield, Claire. Tuberculosis Treatment Pipeline. I-Base, HIV Treatment Bulletin. July 2010. [^TBAlliance]: TB Alliance. TB Alliance Advances Two Drugs In Clinical Trials On Path To Faster, Better Tuberculosis Treatments. 11 August 2007.

OPC-67683 (also known as delamanid) is an experimental drug that has shown potent activity against drug-resistant and drug-susceptible TB. Along with another experimental medication called PA-824, OPC-67683 belongs to a class of drugs called nitroimidazoles. Interest in nitroimidazoles arose because of research into another antibiotic called [metronidazole](http://www.medicinenet.com/metronidazole/article.htm "Metronidazole"). The Japanese company Otsuka Pharmaceutical has been investigating this class of compounds for more than a decade. Early clinical trials demonstrated OPC-67683 to be a potent bactericidal and sterilizing drug. It is currently undergoing phase II trials to determine its role in TB treatment. How it works ------------ OPC-67683 kills TB-causing bacteria by disrupting the cell wall. It does so by preventing the synthesis of a molecule called mycolic acid, an essential mycobacteria cell wall component. Isoniazid also works by preventing the synthesis of mycolic acid. The difference between OPC-67683 and isoniazid lies in the type of mycolic acid molecule that each drug inhibits. OPC-67683 inhibits the synthesis of methoxy- and keto-mycolic acid but not a-mycolic acid. Isoniazid acts on all subclasses of mycolic acid.[^Tomioka] Pre-clinical trials ------------------- A study in 2006 conducted by Otsuka Pharmaceutical showed that OPC-67683 has potent activity against drug-resistant and drug-susceptible TB _in vitro_ and in mice. For the in vitro component, researchers tested the drug’s ability to inhibit bacterial growth in dishes of both drug-susceptible and MDR TB bacteria. Using the mouse model, researchers administered OPC-67683 to TB-infected mice, some of which were immunocompromised. The results from the in vitro and mouse models demonstrated that OPC-67683 was more potent at a smaller concentration than other first-line TB drugs. The in vitro experiment showed it to be effective against drug-susceptible and MDR TB bacteria at a low concentration of 0.006-0.024 µ/ml. Whereas no TB bacteria colonies were found after 4 months of treatment with the OPC-67683-containing regimen, colonies were still detected after 6 months of treatment with the standard intensive phase regimen. The mouse model showed OPC-67683 to be effective at low doses in vivo. It reduced the number of bacteria in the lungs of normal and immunocompromised mice at lower concentrations than the standard first-line drugs. The combination of OPC-67683 (2.5 mg/kg) with rifampicin (5 mg/kg) and pyrazinamide (100 mg/kg) eradicated TB bacteria more quickly - by at least 2 months - than the current intensive phase regimen of rifampicin (5mg/kg), isoniazid (10mg/kg), ethambutol (100 mg/kg), and pyrazinamide (100mg/kg). These early results, if reproducible in human patients, suggest that OPC-67683 could potentially shorten TB treatment time. [^Matsumoto] Another study in 2007 investigated the in vitro sterilizing activity of OPC-67683, i.e. its ability to completely eliminate an infection, against drug-susceptible bacteria. Researchers found that, at the highest dose levels tested (1.0 µg/ml), OPC-67683 was superior to isoniazid and equal to rifampicin.[^Saliu] These pre-clinical studies revealed some potentially important attributes of OPC-67683. Firstly, the drug was found to have no cross-resistance with any other first-line TB drug. In addition, OPC-67683 is likely safe and effective when used in combination with antiretrovirals. Researchers found that OPC-67683 had no effects on a specific class of liver enzymes (called cytochrome P450 enzymes) that metabolize antiretrovirals. In addition, these liver enzymes did not affect the activity of OPC-67683. This indicates OPC-67683 is unlikely to cause problems or lose its effectiveness when given with drugs that are metabolized by this enzyme. These studies also found that the killing of TB bacteria by OPC-67683 is concentration-dependent. Unlike other first-line medications like isoniazid and rifampicin, which are effective against TB bacteria regardless of the drug concentration, OPC-67683 is only bactericidal at a minimum threshold concentration. Researchers postulated that this may be because, at low concentrations, OPC-67683 is metabolized by TB bacteria to an intermediate compound with slightly different chemical properties. According to the authors of the 2007 study, this chemical transformation could account for the observation that, in some TB bacterial cultures, OPC-67683 at low concentrations lost its effectiveness against the bacteria after 4-5 days. Interestingly, these studies also found that OPC-67683 is highly effective against intracellular bacteria, i.e. bacteria hidden within human cells, and therefore could be used to fight latent TB. TB is remarkably difficult to kill because bacteria are able to hide in different parts of the body, including white blood cells called macrophages. TB bacteria hiding in cells are in a latent state. While researchers are currently investigating exactly where and how bacteria hide in the body, they do know that OPC-67683 is effective against intracellular bacteria. The 2006 study determined that the in vitro intracellular activity of OPC-67683 was better than that of isoniazid and PA-824 and, at a concentration of 0.1 μg/ml, as good as that of rifampicin at a concentration of 3 μg/ml. This intracellular activity is believed by researchers to be an indication that OPC-67683 could be used as a treatment for latent TB.[^Matsumoto] OPC-67683 has another potentially useful property: it is effective against both aerobic and anaerobic bacteria. When TB bacteria are in an aerobic state, they require oxygen for survival and are active and self-replicating. In an anaerobic state, TB bacteria do not use oxygen and are often found hiding inside cells. Experts believe that this anaerobic state is similar to the state of TB bacteria that survive TB treatment with first-line drugs. First-line medications rifampicin and isoniazid are active against aerobic but not anaerobic bacteria, while metronidazole is active only against anaerobic bacteria. Researchers have postulated that, because OPC-67683 is active against bacteria in both states, it could be used to treat both active and latent TB, and to shorten the duration of the standard treatment programme. [^Anderson] Phase I trials -------------- Phase I and Early Bacterial Activity (EBA) studies of OPC-67683 have been completed. Studies of the drug in doses of up to 400mg showed that it was tolerated well by healthy volunteers, and no serious side effects were reported.[^Shi] A phase I trial was undertaken by researchers at the University of Stellenbosch in South Africa to examine the EBA of OPC-67683. Results were published in July 2011. In this study, 48 patients infected with drug-susceptible pulmonary TB were randomly assigned to receive OPC-67683 at a dose of 100, 200, 300 or 400 mg daily for 14 days. Sputum was collected from these patients and analyzed to determine OPC-67683’s EBA, i.e. its bactericidal effects early on in treatment. Researchers found that the average EBA of all dosages of OPC-67683 was significant from day 2 onward, meaning that it didn’t begin eliminating TB bacteria prior to the second day of treatment. The EBA of OPC-67683 did not differ significantly between dosages, although patients who received a dose of either 200 or 300 mg experienced a slightly greater decline in the number of TB bacilli in their sputum than those who received 100 mg or 400 mg of the drug. The effectiveness of the medication appeared to plateau at 300 mg, which researchers believed was due to limited absorption in doses exceeding 300 mg. Overall, the medication was tolerated well in patients, with no serious side effects.[^Diacon] Phase II trials --------------- Phase II clinical trials are currently being planned and undertaken to test the safety and efficacy of OPC-67683 in patients. A phase II study was conducted by Otsuka Pharmaceutical to evaluate the effectiveness of OPC-67683 in the treatment of MDR TB. It was completed in October 2010 but results have not yet been published. In this study, researchers randomly assigned a group of 481 patients infected with MDR TB to one of three groups. Group 1 received an Optimized Background Regimen (OBR, which refers to the standard treatment programme) for MDR TB in addition to 100 mg of OPC-67683 twice daily. Group 2 received the OBR plus 200 mg of OPC-67683 twice daily. Group 3 received the OBR in addition to a placebo. The study lasted for 56 days. Researchers are examining the results to determine how effective OPC-67683 was at inducing patients to convert to sputum-negative during the 56 days of treatment, and whether the medication caused any adverse side effects.[^Otsuka] Another phase II study led by Otsuka Pharmaceutical is active but not yet recruiting participants. This study aims to assess the safety and efficacy of OPC-67683 in patients with MDR TB. OPC-67683 will be given to patients at a total dose of 500-800 mg per day. Researchers will evaluate the medication’s safety and side effects in patients during a period of nine months, and the rate of sputum culture conversion over a period of 24 weeks. The study is expected to be completed by December 2011.[^Otsuka2] Future developments ------------------- Otsuka is currently planning a phase III clinical trial that is expected to be completed in 2015. This will be a multicenter, randomized, placebo-controlled trial conducted globally at approximately 15 different sites qualified to treat MDR TB. There will be two parallel groups of patients in this study. In the first group, MDR TB infected patients will receive either the standard MDR treatment programme (OBR) plus a placebo, or the OBR plus 100 mg of OPC-67683 twice daily for 2 months followed by 200 mg once daily for 4 months. For the second group, researchers will examine the safety and efficacy of OPC-67683 in a group of HIV positive patients taking antiretrovirals.[^Otsuka3] Although early studies demonstrated OPC-67683 to be a potentially effective treatment for both drug-resistant and drug-susceptible TB, Otsuka Pharmaceutical has chosen to direct its initial focus on testing the drug as a treatment for MDR TB. Given that the current success rate for treating MDR TB is only about 70%, the drug will likely be licensed more quickly as a treatment for MDR TB. Otsuka has committed to conducting clinical trials for OPC-67683 once the drug has been licensed for drug-resistant TB.[^Boogaard] Advocacy Issues --------------- - More clinical information is needed to determine the effectiveness of OPC-67683 as a treatment for MDR and XDR TB in addition to drug-tolerant and latent TB. Its optimal formulation has yet to be established. - It is recommended that more resources be committed to clinical trials on TB medications. Research is hampered by issues such as a dearth of investigators experienced in conducting TB trials that adhere to international standards for clinical research, and by a lack of such internationally accepted standards. Larry Geiter from Otsuka Pharmaceutical acknowledged that investigators have yet to agree even on research methods within TB trials, such as a standard way to cultivate TB bacteria in the laboratory. There is also a lack of formal guidelines for benchmarks to be fulfilled by researchers seeking to secure drug licenses. For example, the U.S. FDA has yet to publish formal guidelines on TB drug licensing, guidelines that are well established for other diseases like hypertension.[^Anderson] - If phase II data shows OPC-67683 is likely effective, it should be offered on a compassionate care basis to people with MDR and XDR TB in conjunction with TMC207 and standard MDR TB treatment. [^Tomioka]: H. Tomioka et al. Antituberculous Drug Development and Novel Drug Targets: Present Status of the Development of New Antimycobacterial Agents. Expert Rev Resp Med. 2008; 2(4): 455-471 [^Matsumoto]: M Matsumoto et al. OPC-67683, a Nitro-dihydro-imidazooxazole Derivative with Promising Action Against tuberculosis In Vitro and in Mice. PLoS Med. 2006 Nov; 3(11): 466 [^Saliu]: OY Saliu et al. Bactericidal Activity of OPC-67683 Against Drug-Tolerant Mycobacterium tuberculosis. J Antimicrob Chemother. 2007 Nov; 60(5): 994-8 [^Matsumoto]: M Matsumoto et al. OPC-67683, a Nitro-dihydro-imidazooxazole Derivative with Promising Action Against tuberculosis In Vitro and in Mice. PLoS Med. 2006 Nov; 3(11): 466 [^Anderson]: Anderson, Tatum. Working for the ‘Dark Side’ Against TB. TropIKA.net. 29 Jan 2009. [^Shi]: R Shi et al. Development of New Anti-tuberculosis Drug Candidates. Tohoku J. Exp. Med. 2010; 22(1): 97-106 [^Diacon]: AH Diacon et al. Early Bactericidal Activity of Delamanid (OPC-67683) in Smear-Positive Pulmonary tuberculosis Patients. Int J Tuberc Lung Dis. 2011 Jul; 15(7): 949-954 [^Otsuka]: Otsuka Pharmaceutical. A Placebo-controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB). Clinical Trials.gov: A Service of the U.S. National Institutes of Health. 31 Aug 2011. [^Otsuka2]: Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis. Clinical Trials.gov: A Service of the U.S. National Institutes of Health. 22 Jun 2011. [^Otsuka3]: Otsuka Pharmaceutical. Safety and Efficacy Trial of Delamanid for 6 Months in Patients With Multidrug Resistant Tuberculosis. 26 Aug 2011. [^Boogaard]: J van den Boogaard et al. New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Antimicrobial Agents and Chemotherapy. 2009 Mar; 53(3): 849-862 [^Anderson]: Anderson, Tatum. Working for the ‘Dark Side’ Against TB. TropIKA.net. 29 Jan 2009

TMC207 (also known as bedaquiline, R207910 or the ‘J’ compound) is an experimental anti-TB drug. Discovered by Johnson & Johnson, TMC207 is the first compound in a new class of potent anti-TB drugs, the first new class in 60 years. Studies have shown that it is effective against both drug-resistant and susceptible TB. A recently completed phase II trial found that it reduces the time it takes for sputum to become negative in patients, meaning that it has the potential to shorten the duration of TB treatment. Clinical phase II trials are currently being carried out to evaluate the effectiveness of TMC207 for TB treatment. How it works ------------ TMC207 is categorized as a diarylquinoline. This is an entirely new class of TB drug that works by inhibiting an enzyme that is vital for the production of energy, or ATP, in TB bacteria. This enzyme is called ATPase. TMC207 binds to ATPase and prevents it from supplying energy for the bacterial cell, which kills the bacterium. Pre-clinical trials ------------------- Researchers at Johnson & Johnson published their first report on TMC207 in 2005. They found that TMC207 was effective against both drug-sensitive (i.e. non-resistant) and drug-resistant TB bacteria in vitro. In mice, the drug was found to exceed the effectiveness of isoniazid and rifampicin when taken alone. When substituted for first-line drugs in the standard treatment programme, the activity of each new combination with TMC207 was improved.[^Andries] A study published in 2006 examined TMC207 as a treatment for MDR TB using the mouse model. Mice were treated with various combinations of TMC207 with the standard regimen of second-line drugs (amikacin, pyrazinamide, moxifloxacin, and ethionamide). Combinations that included TMC207 were found to be more effective against MDR TB than the current regimen in nearly every case.[^Lounis] A study in 2008 examined the activity of TMC207 against TB bacteria in mice lungs. Most notably, the study found that using a triple combination of TMC207 with rifapentine and pyrazinamide achieved outstanding bactericidal activity, with lung culture negativity in 9 of 10 mice.[^Veziris] These early studies revealed some potentially important attributes of TMC207. Firstly, the mouse model suggested a synergistic interaction between TMC207 and pyrazinamide, meaning that these drugs may be more powerful when given in combination than either drug alone. More studies are needed to investigate this. Secondly, the drug showed activity against both drug-resistant and non drug-susceptible strains of TB, meaning that it could work as a treatment for MDR / XDR TB. Additionally, in-vitro studies of TMC207 showed that the drug is a potent sterilizing agent, meaning that it is able to effectively eliminate TB bacteria. If the behavior of TB bacteria has this same property in-vivo (in human patients), then TMC207 could shorten the duration of TB treatment. This would be a much-needed change to what is currently a very lengthy and cumbersome treatment programme. The sterilizing ability of TMC207 also might make it a powerful drug in the struggle to eradicate TB.[^Matteelli] Phase I trials -------------- A phase I trial, the first stage of testing in human patients, was completed in South Africa. Results were published in 2008. The study examined the Early Bactericidal Activity (EBA), meaning its activity against TB early on, in 75 different TB-infected patients who had not had prior TB treatment. Of these patients, 31% were HIV positive. For seven days, these patients took either 600mg rifampicin, 300mg isoniazid, or a particular dose of TMC207. Researchers found that the bactericidal activity (i.e. ability to eliminate TB bacteria) of TMC207 at a dose of 7400 mg daily was similar to that of the other two first-line drugs, rifampicin and isoniazid. They found that TMC207 took slightly longer to start eliminating TB bacteria, with bactericidal effects beginning on day 4. In addition, the drug was well tolerated in patients, with no serious side effects.[^Rustomjee] Another phase I trial is currently being carried out at University Hospitals (UH) Case Medical Center in the U.S. This trial will give TMC207 to 32 healthy individuals to test for the drug’s safety and tolerability. The study will also examine whether TMC207 has any drug interactions with other TB medications, such as rifabutin and rifampicin.[^TB Online] Researchers believe that there may be a drug-drug interaction between TMC207 and rifampicin, which is of major concern given that rifampicin is a first-line TB drug. An enzyme (called CYP3A4) that metabolizes - and thereby activates - TMC207 is inhibited by rifampicin. This means that when both drugs are used together, rifampicin may prevent TMC207 from working properly. A study among 16 volunteers indicates that rifampicin might indeed make TMC207 less powerful.[^Lounis] More studies are needed to investigate this interaction. Phase II trials --------------- In a phase II trial, experimental drugs are given to a larger group of patients than in phase I. A phase II trial for TMC207 is currently being carried out in South Africa. The study is coordinated by teams of researchers at the Univ. of Stellenbosch, Univ. of Witwatersrand, Aurum Health, Medical Research Council, and Tibotec. This trial has two stages. The first stage has already been completed, and results were published in 2009. The purpose was to determine whether TMC207 was effective in reducing the time it took for patients to convert to sputum-negative. A group of 47 patients, all of whom were HIV negative and had been newly diagnosed with MDR TB, were randomly assigned to two groups. The first group received TMC207 at a dose of 400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks. The second group received the standard five-drug, second-line regimen for treating MDR TB, and a placebo was used instead of TMC207. Researchers found that TMC207 reduced the time it took for sputum to convert to negative in patients. At the end of the trial, 9% of patients who took the placebo were sputum-negative, as compared to 48% of those who received TMC27. TMC207 eliminated TB bacteria more quickly, and it was shown to be safe and well tolerated in patients. The only side effect that was significantly more common in the group that took TMC207 was nausea (26% vs. 4%). Researchers concluded that “the clinical activity of TMC207 validates ATPsynthase as a viable target for the treatment of tuberculosis.”[^Diacon] The second stage of this two-part trial will be a multinational study of patients in South Africa, Peru, Latvia, India, Brazil, Thailand, The Philippines and Russia. Because the first part of the study showed that TMC207 is highly effective against TB, the study’s second stage will be open label and non-randomised. Future developments ------------------- Johnson & Johnson’s research subsidiary, Tibotec, is managing the clinical development of TMC207 to determine whether the drug can be used in the treatment of MDR / XDR TB. Tibotec will elaborate a program whereby developing countries can gain access to TMC207. In addition, Tibotec has given the TB Alliance a royalty-free license to develop TMC207 for drug-sensitive TB. Current and future clinical trials of TMC207 will examine the potential use of TMC207 in the treatment of children with MDR TB; for the treatment of latent TB infection; for use in combination with antiretrovirals; and as a shortened treatment regimen for drug-sensitive TB.[^Matteelli] Advocacy Issues --------------- - More clinical information is needed on the use of TMC207 in TB patients with HIV co-infection. - Organizations in South Africa have called for TMC207 to be made immediately available for compassionate use. They recommend that clinicians in South Africa apply to the Medicines Control Council (MCC) for Section 21 authorizations to use bedaquiline. These authorizations are already being used to procure access to PAS, a less effective and harder to tolerate medication than TMC207.[^TAC] [^Andries]: K Andries et al. A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis. Science. 2005 Jan 14; 307(5707): 223-7 [^Lounis]: N Lounis et al. Combinations of R207910 with Drugs Used To Treat Multidrug-Resistant Tuberculosis Have the Potential to Shorten Treatment Duration. Antimicrobial Agents and Chemotherapy. 2006 Nov; 50(11): 3543-3547. [^Veziris]: N Veziris et al. A Once-Weekly R207910-Containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis. Am J Respir Crit Care Med. 2009 Jan 1; 179(1): 75-9 [^Matteelli]: A Matteelli et al. TMC207: the First Compound of a New Class of Potent Anti-Tuberculosis Drugs. Future Microbiol. 2010 June; 5(6): 849-858. [^Rustomjee]: R Rustomjee et al. Early Bactericidal Activity and Pharmokinetics Of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2008 Aug; 52(8): 2831-5. [^TB Online]: The Medical News. [TMC207 represents first new class of anti-TB drugs in the past 60 years](http://www.tbonline.info/posts/2011/8/1/uh-case-medical-center-commence-phase-1-clinical-t/ "UH Med Centre"). [^Lounis]: N Lounis. Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model. Antimicrob Agents Chemother. 2008 Oct; 52(10):3568-72 [^Diacon]: AH Diacon et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405 [^Matteelli]: A Matteelli et al. TMC207: the First Compound of a New Class of Potent Anti-Tuberculosis Drugs. Future Microbiol. 2010 June; 5(6): 849-858 [^TAC]: [Mobilize Against TB](http://www.tbonline.info/posts/2011/8/30/addressing-tb-crisis-south-africa/ "TAC").

Rifabutin (also known as mycobutin) is effective for the treatment of tuberculosis (TB). It is most commonly used as a replacement for rifampicin, one of the strongest first-line drugs. Rifabutin has been demonstrated to be as effective as rifampicin for TB treatment. A major drawback of rifabutin is its high cost, although in 2009 the U.S. pharmaceutical company Pfizer did agree to lower the cost significantly in developing markets. Rifabutin is the only rifamycin that does not appear to have a significant impact on the p450 exzyme, which is involved in the metabolisation of some antiretrovirals. It is therefore receommended for use with antiretrovirals but it has not been well studied and the dosages for adults and children are not well understood. Dosage ------ _Adults:_ 300 mg orally once a day. If nausea or vomiting becomes a problem, 150 mg orally every 12 hours is an alternative. _Adults with liver damage (creatinine clearance < 30 ml/min):_ 150 mg orally once a day (regular dose should be reduced by 50%). _Children:_ 5 mg/kg/day orally has been used in a limited number of cases. More testing is needed to determine correct dosing. _Notes on dosing:_ - Rifabutin is most often used as an alternative to rifampicin. Therapy normally lasts 18 to 24 months. - Dose adjustments may be necessary when taken with protease inhibitors or non-nucleoside reverse transcriptase inhibitor. The dose should be increased to 450 mg or 600 mg when given with efavirenz. How it works ------------ Rifabutin works by blocking the RNA-polymerase of the bacteria that cause TB infection. RNA polymerase is an enzyme that uses copies of DNA to create RNA transcripts, which are then turned into proteins. By blocking RNA polymerase, Rifabutin prevents bacteria from synthesizing vital proteins. Side effects ------------ Potential side effects of rifabutin include diarrhea, nausea/vomiting, changes in taste, and rash. Rifabutin may cause urine, sweat, or saliva to turn a brown-orange color, which is a harmless but potentially alarming side effect. In rare cases, Rifabutin has been associated with the blood disorder neutropenia. Like all antibiotics, it may cause a severe intestinal condition (Clostridium difficile-associated diarrhea) to develop during treatment, or in the months after treatment has stopped. Clinical studies and approval ----------------------------- Rifabutin was discovered by scientists at the drug company Achifar in 1975, and was approved by the FDA in 1992. It is now recommended by the WHO as a first-line treatment for TB. It was added to the Essential Medicines List by the WHO in 2009. Multiple studies have shown that rifabutin and rifampicin are similarly effective for the treatment of active TB, with some evidence that rifabutin may cause the conversion of sputum from positive to negative to occur more quickly than rifampicin.[^Grassi] More studies, particularly those that include HIV/TB co-infected patients and elderly patients, are needed to determine when and how rifabutin should be administered. A major benefit of rifabutin is that it has fewer drug-drug interactions than rifampicin. Rifampicin interacts with certain antiretroviral medications such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors. In HIV positive patients taking these drugs, rifabutin is usually a safer medication to use. However, rifabutin therapy has important drawbacks that should be considered before prescribing the medication. Firstly, some antiretroviral drugs can affect rifabutin concentrations in the body. For patients taking antiretroviral therapy, healthcare providers must follow a set of somewhat complex guidelines for the proper administration of rifabutin. Secondly, the changes in rifabutin dosage can be problematic in patients that stop taking the antiretroviral medications that interact with rifabutin. This is because the rifabutin dose may lose its effectiveness in these patients.[^CDC] Advocacy issues --------------- - Until recently, rifabutin was too expensive for use in many countries. In 2009, the U.S. pharmaceutical company Pfizer agreed to a deal, brokered by the Clinton HIV/AIDS initiative, to lower the price of rifabutin by 60 percent of the price in Western countries at the time. The price was made available throughout developing markets in Africa, Asia, Eastern Europe, the Middle East, and the Caribbean. The drug is no longer protected by patent, and is sold by at least two other generic manufacturers, Lupin of India and Med Shine Pharma of China. - Further research is needed to establish the safety and efficacy for elderly and pediatric patients. [^Grassi]: C Grassi et al. Use of Rifabutin in the Treatment of Pulmonary Tuberculosis. Clinical Infectious Diseases. 1996; 22 (Suppl 1). [^CDC]: Centers for Disease Control and Prevention. [Managing Drugs Interactions in the Treatment of HIV-related Tuberculosis](http://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/rifabutin_therapy.htm "CDC"). July 2010.

Imipenem is an intravenous antibiotic that was developed in 1980. It is always administered as a combination of equal quantities of imipenem and cilastatin. Cilastatin helps imipenem work more effectively by preventing the breakdown of the antibiotic in the kidneys. Imipenem has a broad spectrum of activity and has been shown to be effective against the bacteria that cause TB. The imipenem/cilastatin combination is marketed by Merck & Co. under the names Primaxin, Tienam, and Zienam. Dosage ------ _Adults:_ 1000 mg IV every 12 hours _Adults with liver damage:_ - For creatinine clearance 20–40 ml: 500 mg every 8 hours - For creatinine clearance < 20 ml/min: 500 mg every 12 hours _Children:_ - < 1 wk of age: 25 mg/kg every 12 hrs - 1-4 wks of age: 25 mg/kg every 8 hrs - 4 wks-3 mos. of age: 25 mg/kg every 6 hrs _Notes on dosing:_ - Care should be taken when increasing the amoxicillin dose. Taking two tablets of 250mg/125mg of amoxicillin/clavulanate is not the same as taking one tablet of 500mg/125 mg, because doing so would result in a double dose of clavulanate. - The maximum recommended daily dose of clavulanic acid in adults is 500mg. - Children weighing <40 kg should not receive film-coated tablets with250 mg of amoxicillin, since this preparation contains a high dose of clavulanate. - Ampicillin/clavulanate is best tolerated and well absorbed when taken at the start of a meal. How it works ------------ Imipenem inhibits cell wall synthesis in bacteria, so that the bacteria break up and die. Side effects ------------ The most common side effects of imipenem/cilastatin are mild diarrhea, nausea, and vomiting. More severe and less common side effects include confusion, hallucinations, seizure, light-headedness, skin rash, chest pain, and fast or irregular heartbeat. Clinical studies and approval ----------------------------- Imepenem/cilastatin is categorized by the WHO as a Group 5 medication with an “unclear role” in the treatment of drug-resistant TB. Group 5 medications like imepenem/cilastatin should be used after drug options from Groups 1-4 have been exhausted or are unavailable. This is because there is a lack of clinical evidence establishing the effectiveness of imepenem/cilastatin for TB treatment. A study done at the Univ. of California San Francisco investigated the effectiveness of imipenem in a mouse model of TB and in humans with MDR TB. TB-infected mice were treated with isoniazid or imipenem to compare the efficacy of the two drugs. Ten MDR TB-infected patients were treated with imipenem in combination with other first or second-line drugs. The results of the study, which were published in 2005, indicate that imepenem/cilastatin is active against drug-resistnat TB. Although it is less effective then isoniazid, imipenem significantly reduced infection with TB bacteria and improved the survival rates of mice. Among the patient group, eight of ten individuals responded positively to imipenem therapy and experienced sputum conversions to negative. Seven of those remained negative when taken off therapy. The study concluded that imipenem has “antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.”[^Chambers] The effectiveness of imipenem/cilastatin as a treatment for TB has also been suggested by other reports of at least three patients with drug-resistant TB in the U.S. who have had their infections eliminated with a combination of imipenem and a drug called amikacin. These patients had no recurrence in 12 months of follow-up.[^Journal] Pricing ------- Imipenem 500 mg and Cilastatin Sodium 500 mg injection, 120 ml vial (for IV infusion): R121.10 Advocacy issues --------------- - Further studies are needed to establish the effectiveness of imipenem/cilastatin in the treatment of drug-resistant TB. - There is no pediatric formulation of the medication, and its safety and effectiveness in pediatric patients below the age of 12 have not been established. - Using the medication for an “off-label” purpose such as TB treatment poses liability issues that may become an issue for healthcare providers if patients respond adversely. [^Chambers]: H. Chambers et al. Imipenem for Treatment of Tuberculosis in Mice and Humans. Antimicrob Agents Chemoth. 2005; 49(7): 2816-2821. [^Journal]: Journal of Antimicrobial Therapy. 2006; 58(5): 916-929.

Thioacetazone (also known as thiacetazone, thiosemicarbazone, benzothiozane and amithiozone) has been used for TB treatment since the 1960s. Thioacetazone is never used alone to treat TB, because by itself it is weak and ineffective against the bacteria. It is only used as a combination with first-line TB medications, such as isoniazid and rifampicin. It is used primarily to prevent the development of bacteria that are resistant to first-line drugs, and to treat patients infected with drug-resistant TB. Thioacetazone is extremely cheap. However, it is associated with adverse patient reactions. These reactions are more severe, sometimes leading to death, in individuals co-infected with HIV. As a result, Thioacetazone is used rarely. It is prescribed for TB treatment in certain countries in Asia, Africa, and Latin America, where access to other TB medications is limited. It is unavailable for use in South Africa. Dosage (as a medication administered in combination with isoniazid) ------------------------------------------------------------------- _Adults:_ 150 mg thioacetazone + 300 mg isoniazid daily. _Children:_ - Children up to 10 kg: 50 mg of isoniazid and 25 mg of thiacetazone once a day. - Children 10 to 20 kg: 100 mg of isoniazid and 50 mg of thiacetazone once a day. - Children 20 to 30 kg: 200 mg of isoniazid and 100 mg of thiacetazone once a day. - Children 30 to 40 kg: 250 mg of isoniazid and 125 mg of thiacetazone once a day. _Notes on dosing:_ - Thioacetazone is most often administered as a combination with isoniazid, particularly during the continuation phase of long-term regimens. - A major benefit is its ability to prevent failure and relapse in patients with initially isoniazid-resistant strains. - Thioacetazone is generally used as a replacement for ethambutol in countries where access to ethambutol is restricted. There is no advantage to using thioacetazone as a replacement for ethambutol. How it works ------------ Thioacetazone is referred to as a bacteriostatic medication. A medication that is bacteriostatic does not kill bacteria, but rather stops them from reproducing. Thioacetazone is bacteriostatic even at very high concentrations. It stops TB bacteria from spreading by interfering with processes that are vital to the functioning of the cell wall in bacteria. Side Effects ------------ Some common symptoms of thioacetazone include nausea, vomiting, diarrhea, loss of appetite, skin rashes, aching joints and muscles, clumsiness or unsteadiness, and a tingling or burning sensation in the hands and feet. Some uncommon side effects are blurred vision, seizures, fever, and mood changes. Liver problems (indicated by darkening of urine and/or yellowing of skin) are rare, but more frequent in patients over the age of 50. Rare cases of exfoliative dermatitis, thrombocytopenia, agranulocytosis, and aplastic anemia have been recorded. Adverse reactions are more common and severe in HIV-positive patients, and can sometimes lead to death. There has been a significant number of cases in which Thioacetozone has led to the development of a skin condition called severe cutaneous hypersensitivity in patients co-infected with HIV. Severe cutaneous hypersensitivity, which includes a condition called Stevens-Johnson syndrome, refers to when the skin’s epidermis (outer layer) begins to separate from the dermis (inner layer). For this reason, thioacetazone should not be given to HIV positive patients. Pricing ------- Thiacetazone 50 mg and isoniazid 100 mg, 1000 tablets: R33.55 / US $4.71 (exchange rate 09/09/2011)[^drug prices] (A combination of thioacetazone and isoniazid is almost as cheap as isoniazid alone). Clinical studies and approval ----------------------------- Thioacetazone is categorized by the WHO as a Group 5 medication, only to be used when medication regimens involving drugs from Groups 1-4 are not possible. The WHO placed thioacetazone in Group 5 because, even though the drug is known to be active against TB, “its role in the treatment of DR-TB is not well established.” More studies are needed to determine whether thioacetazone is effective in the treatment of MDR / XDR TB. Thioacetazone is not recommended for patients known, or suspected, to be infected with HIV. The serious risk of adverse skin reactions, particularly in HIV co-infected patients, has been well documented. A 1991 study in Zambia monitored, over an 18 month period, the drug reactions in 237 TB-infected children receiving some combination of medications that included thioacetazone. 22 (9%) of these children developed hypersensitivity skin reactions. These reactions were seen mostly in HIV-infected children 2-4 weeks after beginning treatment. 12 of the 22 children, all of whom were HIV-positive, developed Steven Johnson syndrome. The mortality rate among these children was 91%.[^Chintu] Another study done in Tanzania in 1995 examined patients of all ages receiving TB treatment. The study determined that the frequency of death from using thioacetazone was 3.1 per 1000 patients. Over half of the adverse reactions to the medication happened within 20 days of starting the drug. The study concluded that, because the frequency of death was lower than previously thought, “improved management might allow retention of thiacetazone in the armamentarium of national tuberculosis programmes even where infection with HIV is prevalent.”[^Ipuge] When prescribing thioacetazone, it is important to keep in mind that the medication has cross-resistance with some other anti-TB drugs. Cross-resistance between two different drugs means that a patient who has an infection that is resistant to one drug will also be resistant to the other drug. Advocacy issues --------------- - Further studies are needed to determine the effectiveness of thioacetazone for the treatment of MDR / XDR TB. - The extremely low cost of thioacetazone is particularly beneficial in developing countries that do not have access to higher-cost medications. The low cost may promote compliance because patients are better able to afford their medications. - The use of thioacetazone is very controversial due to the terrible and relatively common side effects in patients co-infected with HIV. Some institutions, such as the U.S. Centers for Disease Control, suggest that the risks of the drug outweigh the benefits. MSF has suggested that thioacetazone be used only for treatment of pregnant women who are HIV-negative and need the treatment.[^Bouros] - Lowering the cost of other TB medications, such as ethambutol, would reduce the need for riskier medications such as thioacetazone. [^drug prices]: [International Drug Price Indicator Guide](http://erc.msh.org/dmpguide/resultsdetail.cfm?language=english&code=IST100T&s_year=2009&year=2009&str=50%20mg%2B100%20mg&desc=Thiacetazone%2BIsoniazid&pack=new&frm=TAB-CAP&rte=PO&class_code2=06.2.4.&supplement=&class_name=%2806.2.4.%29Antituberculosis%20medicines%3Cbr%3E "Prices") [^Chintu]: C. Chintu et al. Cutaneous hypersensitivity reactions due to t heacetazone in the treatment of tuberculosis in Zambian children infectd with HIV-I. Arch Dis Child. May 1993; 68(5): 665-668. [^Ipuge]: YA Ipuge et al. Adverse cutaneous reactions to thiacetazone for tuberculosis treatment in Tanzania. Lancet. Sep. 1995; 346(8976):657-60 [^Bouros]: Bouros, Demosthenes. Pleural Disease. CRC Press, 2004. P677.

Clinical studies have suggested that high-dose isoniazid may be active against drug-resistant TB. The WHO recommends high-dose isoniazid as a medication with “unclear efficacy” against MDR / XDR TB. High doses are perhaps effective for treating patients infected with strains of bacteria that are resistant to low doses of isoniazid. High dose isoniazid also may make patients with bacterial resistance to other first-line medications susceptible to these drugs. More clinical studies are needed to establish the effectiveness of this medication. Dosage ------ _Adults:_ 1000 to 1500 mg per day _Children:_ Pediatric dosage has not been determined How it works ------------ Isoniazid inhibits the synthesis of a compound that is required for the cell wall in TB-causing bacteria. By doing so, it disrupts the cell wall, killing bacteria and preventing them from growing. Bacteria can mutate and develop resistance to low doses of isoniazid. This is called low-level isoniazid resistance, and is defined as an infection that is resistant to the critical concentration of 0.1µg/ml but susceptible to the higher concentration of 0.4µg/ml. However, in a bacterial population classified as low-level resistant, sometimes not all of the bacteria have this resistance. This means that there could be both resistant and non-resistant bacteria infecting a single patient. Using high dose isoniazid may be effective against TB in two different ways. Firstly, it may kill the bacteria in a population that are not resistant to isoniazid. Secondly, it may also kill the bacteria that have low-level isoniazid resistance, because these bacteria might not have developed resistance to high doses of the drug. Side effects ------------ Isoniazid may cause fevers, rashes, and, in rare cases, conditions such as peripheral neuropathy, neurotoxicity, hepatoxocity (damage to the liver), psychosis, and convulsions. These side effects may be more pronounced with high dose isoniazid. In those taking the medication, there is a slightly higher risk of liver damage and peripheral neuropathy. Pyridoxine (vitamin B6) deficiency is also sometimes observed. Clinical trials and approval ---------------------------- High dose isoniazid is classified by the WHO as a Group 5 medication with unclear efficacy, only to be used when regimens involving drugs from Groups 1-4 are not possible. There is currently debate over whether high dose isoniazid should be used for the treatment of drug-resistant TB. Many experts believe that high-dose isoniazid can be used to treat a TB infection that is resistant to low doses of isoniazid. This may be because all or part of the bacterial population has resistance to only low doses of the drug. In addition, it has been shown that bacteria that are resistant to low doses of isoniazid are sometimes resistant to two other first-line drugs, ethionamide and pyrazinamide. However, bacteria that are resistant to higher doses of isoniazid are often NOT resistant to these drugs. Therefore, giving high dose isoniazid to patients who are resistant to ethionamide and pyrazinamide may make these patients responsive to these drugs; this is because the high dose isoniazid, by killing bacteria that are resistant to low dose isoniazid, may also be eliminating resistance to ethionamide and pyrazinamide.[^Moulding] Clinical studies of the use of high dose isoniazid in the treatment of MDR / XDR TB have produced mixed results. One study in 1999 that tested high dose isoniazid in mice suggested that high doses of the drug might not be useful as a treament. When both low and high doses of isoniazid were given to different groups of mice, researchers found that raising the dose of isoniazid was not more active in fighting drug-resistant TB than low dose isoniazid.[^Cynamon] However, a more recent study done in 2008 in India produced more encouraging results. This study examined high dose isoniazid in HIV negative patients infected with MDR TB. The study was controlled, meaning that patients were randomly assigned to different groups. Group 1 received high dose isoniazid (16‐18mg/kg), Group 2 received normal dose isoniazid (5mg/kg), and Group 3 received a placebo. Patients of every group also received a combination of other TB drugs: anamycin, levofloxacin,prothionamide, cycloserine, p‐aminosalicylic acid. Researchers found that patients who received high dose isoniazid became sputum-negative (meaning that there were no detectable TB bacilli in their sputum) 2.38 times more quickly than patients who did not receive the medication. On average, patients in Group 1 became sputum-negative after 3.4 months. This period for Group 2 was 6.4 months, and for Group 3 was 6.6 months. When tested after six months of receiving treatment, Group 1 patients were 2.37 times more likely to be sputum-negative than those not receiving the high dose drug. The study concluded that the treatment programme for drug-resistant TB can be improved by using high dose isoniazid.[^Katiyar] Pricing ------- There is no formulation for high dose isoniazid. Please refer to prices for [low dose isoniazid](http://www.tbonline.info/posts/2011/8/22/isoniazid/ "Isoniazid"). Advocacy issues --------------- - Information on the use of high dose isoniazid as a treatment for drug-resistant TB is mostly based on experience and opinion rather than clinical trials. The clinical studies done thus far have produced mixed results. More studies are needed to determine the effectiveness of high dose isoniazid therapy, particularly in patients co-infected with HIV and TB. - No information is available on the use of high dose isoniazid in children and elderly patients. [^Moulding]: TS Moulding. Should Isoniazid be used in Retreatment of Tuberculosis Despite Acquired Isoniazid Resistance? AM Rev Respir Dis. Mar 1981; 123(3):262-4 [^Cynamon]: M.H. Cynamon et al. High-Dose Isoniazid Therapy for Isoniazid-Resistant Murine Mycobacterium tuberculosis Infection? Antimicrob Agents Chemother. Dec 1999; 43(12): 2922-2924. [^Katiyar]: SK Katiyar et al. A Randomised Controlled Trial of High-Dose Isoniazid Adjuvant Therapy for Multidrug-Resistant Tuberculosis. Int J Tuberc Lung Dis. Feb 2008; 12(2): 139-45.

Clarithromycin was synthesized by researchers at the Japanese company Taisho Pharmaceutical in the 1970s and approved by the FDA in 1991. Clarithromycin is not effective against TB when used by itself, but some evidence shows that the drug can work against MDR / XDR TB when used in combination with other anti-TB medications. Dosage ------ The optimal dosage for clarithromycin for treatment and prevention of TB in adults is 500 mg orally every 12 hours. How it works ------------ Clarithromycin interferes with bacterial growth by inhibiting the synthesis of bacterial proteins. It does so by binding to the bacterial ribosome, the enzyme that builds proteins from RNA transcripts. Side effects ------------ The most common side effects are abnormal taste, diarrhea, headache, indigestion, nausea, stomach pain, and vomiting. Less common side-effects include headaches, hallucinations, dizziness, and rash. In rare cases, the medication may cause jaundice or kidney problems. Clinical evidence and approval ----------------------------------- Clarithromycin is categorized by the WHO as a Group 5 medication with an “unclear role” in the treatment of drug-resistant TB.[^Truffot] Group 5 medications like clarithromycin should only be used after other drug options from Groups 1-4 have been exhausted or are unavailable. There is a lack of clinical studies establishing its effectiveness for TB treatment. TB treatment is therefore an “off-label” use of the medication. Multiple studies have demonstrated that Clarithromycin by itself is inactive against the bacteria that cause TB. However, the drug shows promise as a medication to be used synergistically, i.e. with other antibiotic medications. A 1995 in-vitro study at Creighton Univ. Medical Centre tested the effectiveness of Clarithromycin, when combined with other standard anti-TB drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), against 12 strains of drug-resistant tuberculosis. Results showed that combinations of clarithromycin with other anti-TB drugs can make resistant TB strains susceptible to drugs and eliminate TB bacteria. The study concluded that “the ability of clarithromycin…to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggests that this combination may be efficacious in the treatment of multidrug-resistant M. tuberculosis infections.”[^Cavaliere] Interestingly, a study published in 2000 found that certain drugs that inhibit the synthesis of bacterial cell walls can successfully reverse resistance to clarithromycin in strains of TB bacteria, making these bacteria once again susceptible to treatment.[^Bosne-David] This finding could have practical applications for the treatment of MDR / XDR TB. Pricing (per lowest unit, i.e. single tablet or injection) ----------------------------------------------------------- • 500 mg tablet, 14 tablets: R30.01 • 125 mg/5 ml suspension, 50 ml bottle: R16.31 Advocacy issues ---------------- - Further studies are needed to establish the effectiveness of clarithromycin in the treatment of TB. - No pediatric formulation is available, and more research is needed to determine the safety and efficacy in children. - Using the medication for an “off-label” purpose such as TB treatment poses liability issues that may become a problem for healthcare providers if patients experience complications. [^Truffot]: C. Truffot-Pernot et al. Clarithromycin Is Inactive against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1995; 39(12): 2827 [^Cavaliere]: S. Cavaliere et al. Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1995; 39(7): 1542-1545. [^Bosne-David]: S. Bosne-David et al. Intrinsic resistance of Mycobacterium tuberculosis to clarithromycin is effectively reversed by subinhibitory concentrations of cell wall inhibitors. Journal of Antimicrobial Chemotherapy. 2000; 46(3): 391-395.

Amoxicillin with clavulanate (also known as clavulanic acid) is a broad-spectrum drug combination that is potentially effective in treating drug-resistant tuberculosis. Trade names for amoxicillin/clavulanate include Augmentin, Clavamox, and CLAMP. The combination was developed in 1978 by British scientists at the pharmaceutical company Beecham, and protected by patent in 1984. Amoxicillin is only effective against TB when administered with clavulanate because without it, the bacteria that cause TB are resistant to amoxicillin. More studies are needed to determine the medication’s effectiveness in the treatment of MDR / XDR TB. Dosage ------ _Adults:_ 2000 mg as amoxicillin/125 mg clavulanate twice daily (daily total is 4000 mg amoxicillin / 250 mg clavulanate) _Adults with liver damage:_ - For creatinine clearance 10–30 ml/min: 1000 mg as amoxicillin twice daily - For creatinine clearance < 10 ml/min: 1000 mg as amoxicillin once daily. _Children:_ 80 mg/kg/day, with the amoxicillin component divided twice daily _Notes on dosing:_ - Care should be taken when increasing the amoxicillin dose. Taking two tablets of 250mg/125mg of amoxicillin/clavulanate is not the same as taking one tablet of 500mg/125 mg, because doing so would result in a double dose of clavulanate. - The maximum recommended daily dose of clavulanic acid in adults is 500mg. - Children weighing <40 kg should not receive film-coated tablets with250 mg of amoxicillin, since this preparation contains a high dose of clavulanate. - Ampicillin/clavulanate is best tolerated and well absorbed when taken at the start of a meal. How it works ------------ In the amoxicillin/clavulanate combination, amoxicillin is the active antibacterial medication. It is a type of penicillin that kills bacteria by preventing them from synthesizing cell walls. Amoxicillin does not work against TB bacteria when used by itself, because the bacteria contain an enzyme (called β-lactamase) that allows them to be resistant to the amoxicillin. This resistance can be overcome by combining amoxicillin with clavulanate. Clavulanate inactivates this enzyme and therefore prevents amoxicillin from being degraded. Side effects ------------ Amoxicillin and clavulanate is generally well tolerated in patients. The majority of side effects are mild, and, on average, less than 3% of patients discontinue the medications due to side effects. The most frequently reported adverse effects are diarrhea (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%), and vaginitis (1%).[^NIH] The incidence of side effects, particularly diarrhea, tends to increase with higher doses. Rare side effects include headache; white patches in mouth or throat; and mucocutaneous candidiasis. Overdose of clavulanate has been associated with cholestatic hepatoxicity. Clinical evidence and approval ------------------------------ Amoxicillin/clavulanate is recommended by the WHO as a medication with an “unclear role” in the treatment of drug-resistant tuberculosis. It is categorized in Group 5 as a medication, to be used only when regimens involving drugs from Groups 1-4 are not possible. Clinical studies of the medication’s effectiveness against MDR / XDR TB have produced conflicting reports. In 1991, a U.S. report suggested that amoxicillin/clavulanate might be effective in the treatment of drug-resistant tuberculosis. The report describes two patients in the U.S. with MDR TB who were treated successfully when amoxicillin/clavulanate were added to a regimen of second-line drugs. Case 1 was a female with TB that was resistant to isoniazid, ethambutol, rifampicin, and pyrazinamide. Within three days of beginning treatment with amoxicillin/clavulanate at a dosage of two 500mg tablets every 6 hours, her symptoms began to subside. Her sputum became negative after three weeks of treatment, and she was successfully maintained on a regimen of amoxicillin/clavulanate, capreomycin, and cycloserine for 18 months. Case 2 was a male with TB that was resistant to isoniazid, rifampicin, and pyrazinamide, and sensitive to streptomycin, ethionamide, and cycloserine. He was given isoniazid, streptomycin, ethionamide, and cycloserine for 2 months with no improvements in his condition. After he began taking amoxicillin/clavulanate at adose of 500mg every 6 hours, his sputum converted to negative within a month. This study was limited because amoxicillin/clavulanate was given to patients as part of a multidrug regimen, which makes it difficult to draw firm conclusions about any one drug. Researchers concluded that amoxicillin/clavulanate might have a role to play in TB treatment, and suggested the need for clinical trials.[^Nadler] An in-vitro study done in 2001 examined what is called the early bactericidal activity (EBA) of amoxicillin/clavulanate. EBA refers to how effectively a drug reduces the amount of bacteria in a patient’s sputum during the first 2 days of treatment. Researchers studied this property of the medication by taking sputum samples from patients infected with non-resistant TB. Some patients received amoxicillin/clavulanate at a dose of 3000mg/750mg while others received no drug. The study did not find a significant difference between numbers of bacteria in sputum samples between the two groups, indicating that the amoxicillin/clavulanate was not killing the bacteria. The study concluded that “it is unlikely that the combination of amoxicillin/clavulanic acid has an important place in the treatment of tuberculosis with the exception of those patients with multidrug-resistant tuberculosis who are otherwise therapeutically destitute.”[^Chambers] An in-vitro study in 2004 examined the effectiveness of amoxicillin/clavulanate in a group of Iranian patients infected with MDR TB strains. There were more than 90 TB strains tested, and some were resistant to medications while others weren’t. Researchers were surprised to find that all 90 strains were resistant to the amoxicillin/clavulanate at a concentration of 32μg/ml. At a drug concentration of 64μg/ml, 51 of 90 strains were resistant. At a concentration of 512μg/ml, 29 strains were resistant. The results of the study suggested that the medication might be suitable as a second-line anti-TB drug at a minimum concentration of 64μg/ml. However, researchers were unable to draw firm conclusions, and recommended more clinical trials.[^Varsochi] Pricing(given for lowest dose formulations only) ------------------------------------------------ - Amoxicillin 125mg, Clavulanic Acid 31.25mg/5ml suspension: R11.50 - Amoxicillin 250mg and Clavulanic Acid 125mg tablet, 15 tablets: R16.41 - Amoxicillin 500mg and Clavulanic Acid 100 mg, powder for injection, vial: R113.80 (Available as suspension, tablet, and injection) Advocacy issues --------------- Further studies are needed to establish the effectiveness of amoxicillin/clavulanate in the treatment of drug-resistant TB. [^NIH]: National Institute of Health. Guide to Amoxicillin Clavulanate Potassium. November 2006. [^Nadler]: J. Nadler et al. Amoxicillin-Clavulanic Acid for Treating Drug-Resistant Mycobacterium tuberculosis. Chest. April 1991; 99(4): 1025-1026 [^Chambers]: HF Chambers et al. Activity of Amoxicillin/Clavulanate in Patients with Tuberculosis. Clin Infect Dis. Apr 1998; 26(4): 874-7 [^Varsochi]: M. Varshochi et al. In-Vitro Susceptibility of Mycobacterium tuberculosis to Amoxicillin-Clavulanate. Iranian Journal of Clinical Infectious Diseases. 2006; 1(3): 121-125