Prevalence of drug-resistant tuberculosis
In March 2010, the World Health Organization (WHO) released Multidrug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB): Global Surveillance and Response Report 2010, which showed that in 2008, there were an estimated 9.4 million new cases of TB and 440,000 cases of MDR-TB worldwide, of which one-third had died.
Nearly 50% of global MDR-TB cases are estimated to be from China and India, and in some regions, one in four TB patients will develop a condition that cannot be cured with standard drug therapy. An estimated 50 million people worldwide are infected with MDR-TB, with India, China, Russia, South Africa, and Bangladesh ranking as the top five countries for the total number of MDR-TB cases. XDR-TB exists in more than 50 countries worldwide.
China is one of the countries with high TB resistance rate, and the information of the fourth national TB epidemiological sampling survey shows that among the randomly selected TB strains, the total resistance rate is 27.8%, the initial resistance rate is 18.6%, the acquired resistance rate is 46.5%, and the multidrug resistance rate is 10.7%. 1.3 million new pulmonary TB cases and 180,000 retreatment cases were reported in China in 2007.
According to the results of the national baseline survey of drug-resistant TB from 2007 to 2008, the annual multidrug resistance rate of new pulmonary TB patients in China was estimated to be 8.32%, and the extensive drug resistance rate was 0.68%. 120,000 new cases of MDR-TB were estimated to occur each year nationwide, including 80,000 Tu-positive patients and nearly 10,000 XDR-TB patients.
Classification and definition of drug-resistant tuberculosis
Drug-resistant TB (DR-TB) is an in vitro test that confirms that patients are infected with human type Mycobacterium tuberculosis and are resistant to one or more anti-TB drugs, which is a general term for different types of drug resistance.
According to the classification of drug resistance species, it can be divided into single drug resistance (SDR, resistant to one anti-TB drug), multi-drug resistance (PDR, resistant to more than one anti-TB drug but not to both isoniazid and rifampin), MDR (resistant to both at least isoniazid and rifampin), XDR (resistant to both isoniazid and rifampin in addition to kanamycin, butamycin, curarubicin, and any of the injectable XDR (resistance to any of the injectable drugs of kanamycin, butylaminokanamycin, coleomycin and any of the fluoroquinolones of of ofloxacin, levofloxacin and moxifloxacin, in addition to resistance to isoniazid and rifampin) and total drug resistance (TDR, resistance to all existing first-line antituberculosis drugs and all second-line antituberculosis drugs tested for drug sensitivity).
Cross-resistance due to similar chemical structure of drugs is classified as unidirectional (e.g. after resistance to kanamycin, resistance to streptomycin, but if resistance to streptomycin is first, the patient can still be sensitive to kanamycin, so the drugs should be selected sequentially) and bidirectional (when resistance to one drug is developed, resistance to another drug is also developed, such as isoniazid and isoniazid, etc.).
Drug resistance is classified according to the occurrence of drug resistance and is classified as primary (drug resistance occurs in those who have never received treatment or have been treated for <1 month, mostly due to transmission from drug-resistant patients), initial [drug resistance occurs in those who claim (forget or conceal treatment history) to have never received treatment] and secondary (acquired) drug resistance (drug resistance occurs during treatment in those who were originally sensitive to the drug).
The genetic and strain characteristics of Mycobacterium tuberculosis are classified as natural (each wild bacterium has a very low mutation rate in its genes and can be naturally resistant to drugs in the absence of drugs, but the rate of resistance to various drugs varies, and secondary drug-resistant bacteria can develop due to inappropriate treatment) or intrinsic resistance (naturally insensitive to certain drugs, which is passed from generation to generation and develops and disappears independent of drug exposure).
Others include transient drug resistance, which refers to a small number of drug-resistant bacteria cultured during the course of treatment (usually at 4-5 months), but is not clinically or bacteriologically significant and can still be treated successfully without changing the treatment regimen.
Dangers of drug-resistant tuberculosis
The existence of multidrug-resistant, extensively drug-resistant or even fully drug-resistant bacilli, in particular, greatly reduces the success rate of treatment and even makes it incurable because there are few and expensive drugs available.
In addition, some patients with incurable MDR-TB act as a source of infection and continue to cause the spread of drug-resistant tuberculosis bacteria, increasing the number of patients with primary MDR-TB.
Causes of drug resistance development
Inappropriate anti-TB treatment
Inappropriate treatment regimens provided by health providers
(1) The guidelines are reasonable but not followed, such as adding a new drug to a regimen that has failed or giving the wrong regimen, or repeatedly treating “community-acquired pneumonia” with fluoroquinolones, resulting in drug resistance to these drugs;
② Inadequate training of physicians in drug resistance treatment;
(3) Inadequate monitoring and management.
Inadequate supply and quality of drugs
① Poor quality and lack of supervision;
② Disruption of supply;
③ Poor storage conditions;
④ Inadequate or unreasonable doses of drugs.
Improper medication administration by patients
① Poor compliance, special groups such as patients with neuropsychiatric diseases do not cooperate with treatment;
② Lack of general knowledge about TB treatment, stopping medication just because symptoms improve;
③ Inability to pay for medication and monitoring costs;
④ inconvenience in collecting medication;
⑤ Concealing medical history and continuing to work or go to school without taking rest;
(6) Gastrointestinal disorders or other diseases that affect the absorption of drugs;
(7) Unhealthy lifestyle, substance dependence, and non-cooperation with treatment.
Presence of drug-resistant gene of tuberculosis bacilli
Mycobacterium tuberculosis can continue to survive and reproduce by regulating the enzyme system and changing the metabolic pathway under the action of drugs; or by eliminating sensitive bacteria through the action of drugs, so that non-sensitive bacteria are relatively prominent; or by changing the structure of a specific position in the DNA molecule of the bacterium (observation confirms that the development of drug resistance is consistent with the mutation rate).
More than 95% of genetic mutations in M. tuberculosis are directly caused by drugs. mdr-tb is an accumulation of mutations in drug-resistant genes of M. tuberculosis to individual drugs, and the vast majority can be cured with reasonable treatment, but inadequate and irrational treatment will lead to proliferation of drug-resistant bacteria, eventually leading to a clinically significant increase in drug-resistant bacteria.
Principles for the development of chemotherapy regimens for drug-resistant tuberculosis
SDR and PDR-TB should develop reasonable treatment regimens according to the current status of drug resistance, especially for patients with isoniazid or rifampicin resistance, as the resistant drug is the main bactericidal agent of the retreatment regimen, which will pose a serious threat to the effectiveness of the retreatment regimen. Therefore, it is necessary to take into account not only the WHO protocol, but also our national conditions and patient compliance, and select at least 4 sensitive drugs to form an appropriate treatment regimen for 12-18 months.
In case of resistance to isoniazid, rifampin or ofloxacin, sensitive drugs with different mechanisms of action, such as ethambutol and para-aminosalicylic acid, should be selected. In case of sensitivity to isoniazid, rifampin or ofloxacin, similar drugs such as isoniazid salicylate tablets, rifapentine or levofloxacin can be selected in order to reduce adverse effects and to increase the dose appropriately. Successful cure of SDR and PDR-TB in retreatment is an important link to stop the production of MDR-TB, and the principle of maximum cure should be adhered to.
MDR-TB WHO and China have treatment guidelines. 2011 WHO guidelines emphasize that all TB patients should have drug sensitivity testing before treatment, and monthly sputum smear and culture during treatment is the best strategy to clarify the success of treatment at an early stage. Sputum smear should be checked monthly and sputum culture quarterly after negative sputum bacteria. Monitor for adverse effects throughout.
Standardized treatment regimens for MDR-TB should not include ethambutol and Group V two drugs. See MDR-TB chemotherapy regimen for others.