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