The order of drug selection in the WHO 2014 edition of the Partner Manual for Planning and Management Guidelines for Drug-Resistant Tuberculosis differs from the 2008 planning and management guidelines in that the 2008 guidelines start with the first group of drugs and go sequentially to the fifth group, and in the 2014 guidelines, the selection starts with the second group first, followed by the second and third groups, and finally the first and and fifth groups, with the following five steps of selection.
In the first step, select the second group of injectable drugs (amikacin, capreomycin, kanamycin).
In the second step, the third group of fluoroquinolones (levofloxacin, moxifloxacin) is selected.
Fluoroquinolones are considered to be one of the most effective drugs for MDR-TB; the following are recommended for quinolones.
1, MDR-TB treatment regimens should include fluoroquinolones and are considered to have better anti-tuberculosis activity than the newer generation of fluoroquinolones.
2, avoid using different quinolones at the same time to reduce cardiotoxicity.
3.Levofloxacin is considered to be twice as active as oxyfloxacin in anti-tuberculosis and active against oxyfloxacin-resistant tuberculosis bacteria.
4.Ciprofloxacin is no longer recommended for anti-tuberculosis treatment.
5, Gatifloxacin can be used to treat MDR-TB, but because of the more serious side effects, try not to choose this drug without sufficient evidence to support the safety of gatifloxacin. Prefer to choose levofloxacin and moxifloxacin.
In the third step, a fourth group of drugs (ethionamide, prothiamin, cycloserine, terizidone, and para-aminosalicylic acid) was selected. Since the results of drug sensitivity tests for group IV drugs are not accurate, try to select two or more group IV drugs to ensure that at least four “potentially effective anti-tuberculosis drugs” are selected.
Isoniazid low-level resistance is mostly related to inhA mutation, when it is not recommended to use ethionamide or propylthiouracil, but can use high-dose isoniazid; isoniazid high-level resistance is mostly related to katG mutation, when it is not recommended to use high-dose isoniazid, but can choose ethionamide or propylthiouracil.
The new manual states that “potentially effective antituberculosis drugs” must meet the following four criteria.
1. Not previously used in a regimen where treatment has failed.
2. Sensitivity testing suggests sensitivity (isoniazid, rifampin, Group II and Group III drugs in Group I).
3. no cross-resistance with drugs known to be resistant.
4, in the absence of drug sensitivity test or drug sensitivity test results are not reliable, you can refer to the results of the local drug resistance epidemiological survey.
The fourth step is to select the first group of drugs (ethambutol, pyrazinamide).
The new guidelines give more prominence to pyrazinamide in drug-resistant regimens. Theoretically, pyrazinamide is effective against intracellular tuberculosis bacteria in an acidic environment, and the results of drug susceptibility tests for pyrazinamide are not sufficiently reliable, so even if drug susceptibility tests suggest pyrazinamide resistance, it can still be used as a drug for MDR-TB treatment, and WHO recommends that all patients with drug-resistant TB should be selected for pyrazinamide, and the full course of treatment can be The WHO recommends that pyrazinamide should be used in all patients with drug-resistant TB and can be used for the full course of treatment. If the lesion is mild, pyrazinamide can be used only in the intensive phase, as can a second group of injectable drugs. Hepatotoxicity and other serious adverse effects should be noted during the use of pyrazinamide. Ethambutol should not be used routinely for MDR-TB, but may be used when there is good evidence that it may be effective.
In the fifth step, a fifth group of drugs (bedaquiline, dilamanid, clofazimine, linezolid, amoxicillin clavulanate potassium, clarithromycin, high-dose isoniazid, imipenem cistatin, meropenem clavulanate potassium, and aminothiourea) is selected. If the number of “potentially effective antituberculosis drugs” selected in the previous 4 steps does not reach 4 or more, a fifth group of drugs needs to be selected to complete the list, and sometimes 2 or more drugs from the fifth group are needed.
The results of drug sensitivity tests for Group V drugs are inaccurate, and with the exception of bedaquiline and dilamanid, none of the other Group V drugs are registered for the treatment of tuberculosis. There is a wealth of laboratory and clinical data to support the effectiveness of Group V drugs such as linezolid and clofazimine.
The following points should be noted in the development of drug-resistant regimens.
1. group IV drugs are recommended for once-daily administration, and multiple daily doses are often used clinically to avoid adverse drug reactions
2. the initial dose of all anti-tuberculosis drugs can be adequate.
3. if adverse drug reactions (e.g. cycloserine, ethionine/propylthiol, para-aminosalicylic acid) are not tolerated, patients can start with a dose of 2 times a week and gradually increase the dose
4. group II injectable drugs should be administered once daily, or less frequently if not tolerated, preferably until sputum cultures turn negative
5. all oral antituberculosis drugs are recommended for daily use if tolerated
6. pyrazinamide should be used throughout
7. for patients with suspected multidrug resistance, isoniazid may still be used if only rifampicin resistance results are currently available until isoniazid resistance results are obtained.
The choice of drug dose should be based on age and weight, and a reasonable individualized treatment plan should be developed to avoid adverse drug reactions as much as possible.