| Treatment for tuberculosis should be | | | | tuberculosis. |
| administered by a medical practitioner | | | | Some people recommend monthly |
| experienced and trained in the treatment | | | | surveillance until cultures convert to |
| of tuberculosis. The standard "short" | | | | negative; this does not form any part of |
| course treatment for tuberculosis where | | | | the UK or WHO recommendations for TB. If |
| the sensitivities of the organism are | | | | cultures are positive or symptoms do not |
| not known, is isoniazid, rifampicin, | | | | resolve after three months of treatment, |
| pyrazinamide and ethambutol for two | | | | it is necessary to re-evaluate the |
| months, then isoniazid and rifampicin | | | | patient for drug-resistant disease or |
| alone for a further four months. The | | | | nonadherence to drug regimen. If |
| patient is considered cured at six | | | | cultures do not convert to negative |
| months (although there is still a | | | | despite three months of therapy, |
| relapse rate of 2 to 3%). | | | | consider initiating directly observed |
| If the organism is known to be fully | | | | therapy. |
| sensitive, then treatment is with | | | | Non-compliance |
| isoniazid, rifampicin and pyrazinamide | | | | Patients who take their TB treatment in |
| (omitting ethambutol) for two months, | | | | an irregular and unreliable way are at |
| then isoniazid and rifampicin for four | | | | greatly increased risk of treatment |
| months. | | | | failure, relapse and the development of |
| Rationale and evidence for regimens | | | | drug-resistant TB strains. |
| Tuberculosis has been treated with | | | | There are variety of reasons why |
| combination therapy for over fifty | | | | patients fail to take their medication. |
| years. Drugs are not used singly (except | | | | The symptoms of TB commonly resolve |
| in latent TB or chemoprophylaxis), and | | | | within a few weeks of starting TB |
| regimens that use only single drugs | | | | treatment and many patients then lose |
| result in the rapid development of | | | | motivation to continue taking their |
| resistance and treatment failure. The | | | | medication. Regular follow-up is |
| rationale for using multiple drugs to | | | | important to check on compliance and to |
| treat TB are based on simple | | | | identify any problems patients are |
| probability. The frequency of | | | | having problems with their medication. |
| spontaneous mutations that confer | | | | Patients need to be told of the |
| resistance to an individual drug are | | | | importance of taking their tablets |
| well known: 1 in 107 for EMB, 1 in 108 | | | | regularly, and the importance of |
| for STM and INH, and 1 in 1010 for RMP. | | | | completing treatment, because of the |
| A patient with extensive pulmonary TB | | | | risk of relapse or drug-resistance |
| has approximately 1012 bacteria in his | | | | developing otherwise. |
| body, and therefore will probably be | | | | One of the main complaints is the |
| harboring approximately 105 | | | | bulkiness of the tablets. The main |
| EMB-resistant bacteria, 104 | | | | offender is PZA (the tablets being the |
| STM-resistant bacteria, 104 | | | | size of horse tablets). PZA syrup may be |
| INH-resistant bacteria and 102 | | | | offered as a substitute, or if the size |
| RMP-resistant bacteria. Resistance | | | | of the tablets is truly an issue and |
| mutations appear spontanously and | | | | liquid preparations are not available, |
| independently, so the chances of him | | | | then PZA can be omitted altogether. If |
| harbouring a bacterium that is | | | | PZA is omitted, the patient should be |
| spontaneously resistant to both INH and | | | | warned that this results in a |
| RMP is 1 in 106, and the chances of him | | | | significant increase in the duration of |
| harbouring a bacterium that is | | | | treatment (details of regimens omitting |
| spontaneously resistant to all four | | | | PZA are given below). |
| drugs is 1 in 1011. This is, of course, | | | | The other complaint is that the |
| an oversimplification, but it is a | | | | medicines must be taken on an empty |
| useful way of explaining combination | | | | stomach to facilitate absorption. This |
| therapy. | | | | can be difficult for patients to follow |
| There are other theoretical reasons for | | | | (for example, shift workers who take |
| supporting combination therapy. The | | | | their meals at irregular times) and may |
| different drugs in the regimen have | | | | mean the patient waking up an hour |
| different modes of action: INH and EMB | | | | earlier than usual everyday just to take |
| are bacteriostatic (they stop the | | | | medication. The rules are actually less |
| bacteria replicating, but do not kill | | | | stringent than may physicians and |
| them); RMP is bacteriocidal (it actually | | | | pharmacists realise: the issue is that |
| kills bacteria). | | | | the absorption of RMP is reduced if |
| All TB regimens in use were 18 months or | | | | taken with fat; so the patient can in |
| longer until the appearance of | | | | fact have his or her medication with |
| rifampicin. In 1953, the standard UK | | | | food as long as the meal does not |
| regimen was 3SPH/15PH or 3SPH/15SH2. | | | | contain fat or oils (e.g., a cup of |
| Between 1985 to 1970, EMB replaced PAS. | | | | black coffee or toast with jam and no |
| RMP began to be used to treat TB in 1968 | | | | butter). Taking the medicines with food |
| and the BTS study in the 1970's showed | | | | also helps ease the nausea that many |
| that 2HRE/7HR was efficacious. In 1984, | | | | patients feel when taking the medicines |
| a BTS study showed that 2HRZ/4HR was | | | | on an empty stomach. |
| efficacious, with a relapse rate of less | | | | It is possible to test urine for |
| than 3% after two years. In 1995, with | | | | isoniazid and rifampicin levels in order |
| the recognition that INH resistance was | | | | to check for compliance. The |
| increasing, the BTS recommended adding | | | | interpretation of urine analysis is |
| EMB or STM to the regimen: 2HREZ/4HR or | | | | based on the fact that isoniazid has a |
| 2SHRZ/4HR, which are the regimens | | | | longer half-life than rifampicin: |
| currently recommended. The WHO also | | | | urine positive for isoniazid and |
| recommend a six month continuation phase | | | | rifampicin patient probably fully |
| of HR if the patient is still culture | | | | compliant |
| positive after 2 months of treatment | | | | urine positive for isoniazid only |
| (approximately 15% of patients with | | | | patient has taken his medication in the |
| fully-sensitive TB) and for those | | | | last few days preceding the clinic |
| patients who have extensive bilateral | | | | appointment, but had not yet taken a |
| cavitation at the start of treatment. | | | | dose that day. |
| Monitoring and DOTS | | | | urine positive for rifampicin only |
| DOTS stands for "Directly Observed | | | | patient has omitted to take his |
| Therapy, Short-course" and is a major | | | | medication the preceding few days, but |
| plank in the WHO global TB eradication | | | | did take it just before coming to |
| programme. The WHO advises that all TB | | | | clinic. |
| patients should have at least the first | | | | urine negative for both isoniazid and |
| two months of their therapy observed | | | | rifampicin patient has not taken either |
| (and preferably the whole of it | | | | medicine for a number of days |
| observed): this means an independent | | | | In countries where doctors are unable to |
| observer watching tuberculosis patients | | | | compell patients to take their treatment |
| swallow their anti-TB therapy. The | | | | (e.g., the UK), some say that urine |
| independent observer is often not a | | | | testing only results in unhelpful |
| healthcare worker and may be a | | | | confrontations with patients and does |
| shopkeeper or a tribal elder or similar | | | | not help increase compliance. In |
| senior person within that society. DOTS | | | | countries where legal measures can be |
| is used with intermittent dosing (thrice | | | | taken to force patients to take their |
| weekly or 2HREZ/4HR3). The WHO does not | | | | medication (e.g., the US), then urine |
| recommend twice weekly dosing (2HREZ | | | | testing can a useful adjunct in assuring |
| 4HR2), not because it is ineffective, | | | | compliance. |
| but because there is no margin for error | | | | RMP colours the urine and all bodily |
| (accidentally omitting one dose per week | | | | secretions (tears, sweat, etc.) an |
| results in once weekly dosing, which is | | | | orange-pink colour and this can be a |
| ineffective). | | | | useful proxy if urine testing is not |
| Treatment with properly implemented DOTS | | | | available (although this colour fades |
| has a success rate exceeding 95% and | | | | approximately six to eight hours after |
| prevents the emergence of further | | | | each dose). |
| multi-drug resistant strains of | | | | |