Items tagged with Treatment

Streptomycin (post with image)

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Amoxicillin / Clavulanate (post with image)

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

Clarithromycin (post with image)

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.

High Dose Isoniazid (post with image)

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.

Thioacetazone (post with image)

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.