1. What is the classification of anti-tuberculosis drugs?
In 2006, WHO classified them into five major categories: Class 1 first-line antituberculosis drugs, including isoniazid (abbreviated as H, same below), rifampicin (R) (9.2.9), rifapentine (L), pyrazinamide (Z) and ethambutol (E); Class 2 injectables, including streptomycin, kanamycin (K), amikacin (A) and capreomycin (C); Class 3 fluoroquinolones, including ciprofloxacin (C), ofloxacin (O) (see 9.2.14), levofloxacin (V) (see 9.2.14), moxifloxacin (MO), and gatifloxacin (G); Class 4 oral antibacterial agents, including ethionamide (Eth), propylthioisonicotinamide (Pth), sodium p-aminosalicylate (P), and cycloserine (Cs); Class 5 – drugs of uncertain efficacy Drugs, including ampicillin clavulanic acid complex), clofazimine, clarithromycin and linezolid.
2. What is the clinical evaluation of anti-tuberculosis drugs?
The following three effects of anti-tuberculosis drugs are evaluated.
(1) Early bactericidal activity: Among the anti-tuberculosis drugs, isoniazid has the strongest early bactericidal activity, followed by rifampicin and streptomycin.
(ii) Sterilization activity: Among the first-line drugs, pyrazinamide and rifampicin have the strongest sterilization activity.
③Prevention of drug resistance: Studies have proved that a large number of sensitive flora often have a small number of genetically mutated drug-resistant bacteria at the same time, and in the course of single drug treatment, the sensitive flora are killed, and the drug-resistant strains become the dominant flora. 3). Therefore, isoniazid and rifampin have the strongest effect in preventing drug resistance in combination with drugs, followed by ethambutol.
3.What is the principle of application of anti-tuberculosis drugs?
Mycobacterium tuberculosis is a “hardy” pathogenic bacterium, with lipid-rich cell wall as its natural barrier, and has the characteristics of persistence, latency, hibernation and mutation after invading the human body, which makes tuberculosis become chronic and prolonged clinically and requires a long course of combined chemotherapy. Otherwise, it is easy to relapse and even develop into drug-resistant TB, multidrug-resistant TB (MDR-TB), or even severe multidrug-resistant TB (XDR-TB), which is difficult to treat. Therefore, the treatment of tuberculosis must follow the principles of “early, combined, regular, complete and appropriate”.
4. How to treat primary bacillary-positive TB?
Possible bacterium for primary treatment: Mycobacterium tuberculosis. Preferred: 2HRZE/4HRE, i.e. a six-month course of isoniazid, rifampin, pyrazinamide and ethambutol for the first 2 months and isoniazid, rifampin and ethambutol for the last 4 months. Suboption.
1. 2HL2ZE/4HL2E; that is, a six-month course of isoniazid, rifapentine, pyrazinamide and ethambutol for the first 2 months and isoniazid, rifapentine and ethambutol for the second 4 months.
2) 2HRZE/4H3R3E3; that is, a six-month course of treatment with isoniazid, rifampicin, pyrazinamide and ethambutol for the first 2 months and isoniazid, rifampicin and ethambutol for the last 4 months and can be used for 3 doses a week. 3) 9HRE, a 9-month course of treatment with isoniazid, rifampicin and ethambutol.
Note: Primary treatment means never treated before or <1 month of regular treatment. Mycopositive: including sputum smear (+) and/or culture (+).
5. How to treat primary treatment of bacillary-positive tuberculosis?
Possible germs for primary treatment of bacillus-negative TB: Mycobacterium tuberculosis. Preferred: 2HRZE/4HR. i.e. a six-month course with isoniazid, rifampicin, pyrazinamide and ethambutol for the first 2 months and isoniazid and rifampicin for the last 4 months. Suboptions.
1. 2HRZ/4HR; that is, a six-month course with isoniazid, rifampin and pyrazinamide for the first 2 months and isoniazid and rifampin for the last 4 months.
2. 2H3R3Z3/4H3R3. i.e., using a six-month course with isoniazid, rifampicin and pyrazinamide for the first 2 months and isoniazid and rifampicin for the last 4 months, both before and after 3 doses a week.
Note: No bacteriologically confirmed (i.e., sputum smear and culture are negative) active pulmonary TB.
6.What is the regimen for relapsed tuberculosis treated for the first time?
Possible germs for retreatment TB (initial): Mycobacterium tuberculosis. Preferred: 2HRZES/6HRE, i.e. an 8-month regimen with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin for the first 2 months and isoniazid, rifampicin and ethambutol for the last 6 months. Secondary options: 1) 2H3R3Z3E3S3/5H3R3E3; i.e., a 7-month course with isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin for the first 2 months and isoniazid, rifampin and ethambutol for the second 5 months, both before and after using 3 times a week therapy. 2) 2HRZES/5HRE, i.e., a 7-month course with isoniazid, rifampin, pyrazinamide, ethambutol 2) 2HRZES/5HRE, i.e. a 7-month course with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin for the first 2 months and isoniazid, rifampicin and ethambutol for the second 5 months, using daily regimens before and after.
Note: Retreatment refers to having received >1 month of chemotherapy or failure of initial treatment or initial relapse after treatment.
7. What regimen is used for recurrent relapsed TB?
Possible germs for relapsed TB (recurrent): Mycobacterium tuberculosis (may have become resistant to some anti-tuberculosis drugs). First choice: 2HRZES/6HRE, which is an 8-month course of isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin for the first 2 months and isoniazid, rifampin, and ethambutol for the last 6 months. Secondary choice: A chemotherapy regimen containing 3-4 sensitive drugs (including amikacin, quinolones, etc.) was selected based on the results of drug sensitivity testing and previous drug history.
Note: Drug sensitivity testing is required to guide drug use.
8.What are the treatment options for multidrug-resistant tuberculosis?
The treatment of multidrug-resistant tuberculosis is complicated, and drug sensitivity testing is required to guide the use of drugs.
1.If the causative agent is at least resistant to isoniazid, rifampin or above Mycobacterium tuberculosis, the first choice is: 3-6 months intensive period with streptomycin (or amikacin, ciprofloxacin), pyrazinamide, ethambutol, levofloxacin (or moxifloxacin), propylthiouracil (or sodium p-aminosalicylate) and 18 months continuation period with pyrazinamide, ethambutol, levofloxacin, propylthiouracil (or p-aminosalicylate). sodium salicylate). Secondary choice: Adjustment according to the drug sensitivity results, previous drug history, patient’s liver and kidney function, etc.
2. If the causative organism is resistant to isoniazid and rifampicin, preferred: 6ZESVPTH(or P)/18ZEVPth(or P), i.e. a 24-month course with pyrazinamide, ethambutol, streptomycin, levofloxacin and propylthiouracil (or sodium p-aminosalicylate) for the first 6-month intensive period. In the second 18 months, pyrazinamide, ethambutol, streptomycin and prothiouracil (or sodium p-aminosalicylate) were used in the continuation period.
3. When the causative organism is resistant to isoniazid, rifampicin and streptomycin, the preferred option is: 6ZEA(or C)VPth(or P)/18ZEVPth(or P) i.e. a 24-month course with pyrazinamide, ethambutol, amikacin (or ciprofloxacin), levofloxacin and prothiouracil (or sodium p-aminosalicylate) for the first 6-month intensive period and pyrazinamide, ethambutol, levofloxacin and prothiouracil (or sodium p-aminosalicylate) for the second 18-month continuation period. Ethambutol, levofloxacin and propylthiisonicotinamide (or sodium p-aminosalicylate) for the latter 18-month continuation period.
4. When the causative agent is resistant to isoniazid, rifampicin and ethambutol, the preferred option is: 6ZCSSVPth(or P)/18CS(or P)VPT(or P), i.e., a 24-month course with pyrazinamide, cycloserine, streptomycin, levofloxacin and prothiouracil (or sodium p-aminosalicylate) for the first 6-month intensive period and cycloserine, prothiouracil (or Sodium p-aminosalicylate).
5. For pathogenic bacteria resistant to isoniazid, rifampicin, ethambutol and streptomycin, preferred: 6ZCS(or P)A(or C)VPth/18ZCSVPthP, i.e., a 24-month course with pyrazinamide, cycloserine (or sodium p-aminosalicylate), amikacin (or ciprofloxacin), levofloxacin and prothioisonicotinamide for the first 6-month intensive period, and pyrazinamide, cycloserine, levofloxacin, prothiouracil and sodium p-aminosalicylate.
9. What treatment regimen is used for acute blood-borne disseminated pulmonary tuberculosis?
Acute blood-borne disseminated pulmonary tuberculosis is treated with a 12-month regimen. Preferred: 2-3HRZES/9-10HRE regimen, i.e. the first 2-3 months of intensive period with five combinations of isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin, followed by 9-10 months with three combinations of isoniazid, rifampin and ethambutol. Secondary option: 2HRZE (or S)/10HRE regimen, which is a quadruple combination of isoniazid, rifampicin pyrazinamide and ethambutol or streptomycin for the first 2 months of intensification, and a triple combination of isoniazid, rifampicin and ethambutol for the second 10 months.
10.What treatment plan is used for tuberculous pleurisy, tuberculous peritonitis and tuberculous pericarditis?
A 12-month course of treatment is preferred for tuberculous multiplasmonitis: 2HRZE(or S))/10HRE regimen, i.e. isoniazid, rifampicin pyrazinamide and ethambutol or streptomycin in quadruple combination for the first 2 months of intensive period, and isoniazid, rifampicin and ethambutol in triple combination for the last 10 months. Fluid should also be pumped aggressively. Glucocorticoids may be used in cases of high fever and rapid and uncontrollable growth of pleural fluid. In case of medium or large amount of pericardial fluid, fluid should be drained by puncture and glucocorticoids should be used to reduce pericardial adhesions and thickening.
11.What are the adverse effects of isoniazid and what should be noted clinically?
Isoniazid is used in combination with other anti-tuberculosis drugs for various types of tuberculosis and some non-tuberculous mycobacterial diseases. In clinical use, attention should be paid to.
(1) This product should be used with caution or at a reduced dose in cases of psychosis, epilepsy, hepatic impairment and severe renal impairment.
(2) Isoniazid is cross-allergic to ethanethioninamide, pyrazinamide, nicotinic acid or other drugs with related chemical structures.
(3) When applied in large doses, it can cause a large amount of vitamin B6 to be excreted in urine, inhibit the decarboxylation of glutamate into γ-aminotyrosine in the brain and cause convulsions, and also cause multiple lesions in the peripheral nervous system. Therefore, adults take oral vitamin B650-100mg a day at the same time to help prevent or reduce the symptoms of peripheral neuritis and/or vitamin B6 deficiency. If mild tingling of the hands and feet and dizziness occur, vitamin B1 or B6 can be taken. If severe cases or vomiting of blood occur, the drug should be stopped immediately.
(4) The dosage of isoniazid should not be reduced if the renal function is decompensated but the blood creatinine value is <6mg/100ml. If the renal function is severe or the patient is slow acetylated, the dosage should be reduced so that the blood concentration of isoniazid does not exceed 1mg/L 24 hours after administration. In anuric patients, the dose of isoniazid can be reduced to half of the usual dose.
(5) The dose should be reduced in patients with decompensated liver function.
(6) Liver function, including serum bilirubin, AST and ALT, should be checked regularly before and during the course of treatment, and any prodromal symptoms of hepatitis should be paid close attention during the course of treatment.
(7) If symptoms of optic neuritis appear during the course of treatment, immediate eye examination is required, and regular review is required.
(8) Patients with slow acetylation are more likely to have adverse reactions, so a lower dose is appropriate.
(9) Isoniazid can cross the placental barrier, resulting in higher fetal blood concentrations than maternal blood concentrations. It should be avoided in pregnant women. If it is indicated, the advantages and disadvantages must be fully weighed.
(10) The concentration of isoniazid in breast milk can reach 12 mg/L, which is similar to the blood concentration; if the decision to use the drug is made after weighing the pros and cons fully during breastfeeding, it is advisable to stop breastfeeding.
(11) Neonates have poor hepatic acetylation capacity, resulting in prolonged elimination half-life; adverse reactions should be closely observed when administered to neonates.
(12) Patients over 50 years of age have a higher incidence of hepatitis caused by the use of drugs, and it is necessary to pay closer attention to changes in liver function during treatment, and reduce the dose if necessary or use preparations to protect liver function at the same time as appropriate. The adverse reactions are: the incidence of adverse reactions at commonly used doses is low. When the dose is increased to 6mg/kg, the incidence of adverse reactions increases significantly, mainly for peripheral neuritis and hepatotoxicity, although the addition of vitamin B6 can reduce toxic reactions, but also can affect the efficacy.
(1) Liver: It can cause mild transient liver damage such as AST and ALT elevation and jaundice, the incidence is about 10%-20%. Hepatotoxicity is related to the metabolite of this product, acetylhydrazine, and the accumulation of acetylhydrazine in the liver is increased in fast acetylation, so it is easy to cause liver damage. Drinking alcohol while taking the drug can increase liver damage. Toxic reactions manifest as poor appetite, abnormal weakness or flaccidity, nausea or vomiting (prodromal symptoms of hepatotoxicity) and dark urine, yellow staining of eyes or skin (hepatotoxicity).
(2) Nervous system: Peripheral neuritis is mostly seen in slow acetylators and is significantly related to the dose. More patients show unstable gait, numbness pins and needles, burning sensation or pain in hands and feet. This reaction is more likely to occur in lead poisoning, arteriosclerosis, hyperthyroidism, diabetes, alcoholism, malnutrition, and pregnant women. Other toxic reactions such as euphoria, euphoria, insomnia, loss of autonomy, toxic encephalopathy or toxic psychosis are rare, and serious toxic reactions such as optic neuritis and atrophy have been reported occasionally.
(3) Metabolic reactions: including fever, polymorphic rash, lymphadenopathy, vasculitis, etc.. Once it occurs, the drug should be immediately discontinued, and if it is needed again, it should start with a small dose and gradually increase the dose.
(4) Hematological system: granulocytopenia, eosinophilia, thrombocytopenia, methemoglobinemia, etc. may be present.
(5) Other: dry mouth, vitamin B6 deficiency, hyperglycemia, metabolic acidosis, endocrine dysfunction, etc. have been reported occasionally.
12.What should be noted when ethambutol is used clinically?
When ethambutol is used clinically, attention should be paid to.
(1) Use with caution for gout, optic neuritis, and renal hypofunction.
(2) During treatment should be examined for.
(1) Eyes, visual field, visual acuity, red-green discrimination, etc., should be checked once a day before and during the course of treatment, especially in patients with a long course of treatment and a dose of more than 15mg/kg a day.
② Ethambutol can increase serum uric acid concentration and cause gout attack. It should be measured regularly.
(3) It can be taken with food, and the daily dose should be taken in a single dose.
(4) When used alone, it can rapidly produce drug resistance, and must be combined with other anti-tuberculosis drugs.
(5) The dose should be calculated according to the patient’s body weight.
(6) The dose should be reduced when used in patients with reduced renal function or in the elderly.
(7) It can cross the placental barrier, and the fetal blood concentration is about 30% of the mother’s blood concentration. It should be used with caution in pregnant women.
(8) It can be distributed in breast milk, and should be used with caution in lactating women.
13.What should be noted when pyrazinamide is used clinically?
Pyrazinamide should be used with attention to.
(1) Cross-allergy, patients allergic to ethylthioisonicotinamide, isoniazid, nicotinic acid or other drugs with similar chemical structure may also be allergic to pyrazinamide.
(2) Interference to diagnosis: It can interact with sodium nitrocyanide to produce red-brown color and affect the result of urine ketone determination; it can increase the value of AST and ALT, blood uric acid concentration determination.
(3)Use with caution in diabetes, gout or severe hepatic decompensation.
(4) Increase the blood uric acid, which may cause acute gout attack and must be measured regularly.
(5) Pregnant patients with tuberculosis can be treated with isoniazid, rifampin and ethambutol for 9 months first, and can be considered if they are resistant to any of the above drugs and may be sensitive to pyrazinamide.
14.What should I pay attention to when using rifapentine clinically?
Rifapentine should be used clinically with attention to.
(1) Cross-sensitivity with other rifapentine.
(2) Use with caution in alcoholism and liver function impairment.
(3) When leukocytopenia and thrombocytopenia are caused after administration, avoid procedures such as tooth extraction, and pay attention to oral hygiene and dental flossing with caution until the blood picture returns to normal.
(4) During the application process, the changes of blood picture and liver function should be checked frequently.
(5) If rifampicin has been taken intermittently due to the production of circulating antibodies and metabolic reactions, such as blood pressure drop or shock, acute hemolytic anemia, thrombocytopenia or acute interstitial tubulointerstitial nephritis, it should not be used again.
(6) It should be taken with water on an empty stomach (1 hour before a meal); patients with gastrointestinal irritation symptoms on rifampicin may be switched to rifapentine.
(7) Used alone for the treatment of tuberculosis may rapidly develop bacterial resistance, and must be used in combination with other anti-tuberculosis drugs.
(8) Patients may have orange-red color in urine and stool, saliva, sputum and tears after taking it.
(9) Breastfeeding women should suspend breastfeeding after the decision to use the drug after weighing the pros and cons.
(10) In elderly patients with reduced liver function, the dosage should be reduced.
(11) The safety of application in children under 5 years of age has not been determined.
15.What should I pay attention to when using sodium p-aminosalicylate clinically?
The clinical use of p-aminosalicylic acid sodium should pay attention to.
(1) Cross-allergic reactions: Patients who are allergic to other salicylates including methyl salicylate (wintergreen oil) or other p-aminophenyl groups (such as certain sulfonamides and dyes) may also be allergic to this product.
(2) Interference with diagnosis: False positive urine glucose determination by copper sulfate method; False positive urine urobilinogen determination (reaction of aminosalicylates with Ehrlich’s reagent to produce orange turbidity or yellow color, and the results of some commercially available test strips based on the above principle can also be affected); Increased normal values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Normal values are increased.
(3) Use with caution in patients with congestive heart failure, gastric ulcer, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and severe hepatic or renal impairment.
(4) Pregnant and lactating women should use after weighing the pros and cons.
(5) Children should take it strictly according to the dosage.
16.What should I pay attention to when using Pasirenz in clinical practice?
Pasirenz should be used with the following precautions.
(1) Pasirenz should be taken continuously for at least 3 months. If there is no adverse reaction, the drug should not be discontinued in the middle of the course, and should only be discontinued after clinical confirmation of recovery.
(2) Pregnant women, people with poor liver and kidney function, and people with history of psychosis, epilepsy and traumatic brain injury should use with caution.
(3) Liver function tests should be performed regularly during the drug administration. A small number of patients may experience transient aminotransferase elevation in the first two months of drug administration. AST and ALT may return to normal with continued use of the drug under hepatoprotective therapy. If they continue to be elevated, the drug should be discontinued.
(4) If symptoms of optic neuritis appear during the course of treatment, immediate eye examination and regular review are required.
(5) The concomitant administration of vitamin B6 can prevent and control peripheral neuritis and other adverse reactions of the nervous system.
(6) Antacids, especially aluminum hydroxide, can inhibit the absorption of this product and should not be taken together.
(7) This product can enhance the effect of coumarin anticoagulants, certain antiepileptic drugs, antihypertensive drugs, anticholinergics, tricyclic antidepressants, and need to pay attention when combined.
(8) Use with caution in pregnant and lactating women.
17.What should I pay attention to when using propylthiouracil in clinical practice?
When using prothiouracil, attention should be paid to.
(1) Cross-allergy, patients who are allergic to isoniazid, pyrazinamide, nicotinic acid or other drugs with similar chemical structure may be allergic to prothiouracil.
(2) Use with caution in patients with diabetes mellitus and severe hepatic decompensation.
(3) During treatment shall be performed.
(1) Measure alanine aminotransferase and aspartate aminotransferase before administration and every 2 to 4 weeks during the course of treatment, but an increase in the value of the above tests does not necessarily predict the occurrence of clinical hepatitis and may recover during the continuation of treatment;
(2) Eye examinations should be performed immediately if vision loss or other symptoms of optic neuritis occur during the course of treatment and should be reviewed regularly.
(4) Not recommended for children under 12 years of age. Its adverse reactions are.
(1) Higher incidence include: mental depression (central nervous system toxicity).
(2) Less frequent are: gait instability or numbness, pins and needles, burning sensation, pain in hands and feet (peripheral neuritis), mental confusion or other mental changes (central nervous system toxicity), eye or skin yellowing (jaundice, hepatitis).
(3) The rare occurrences include blurred or diminished vision, combined or uncomplicated eye pain (optic neuritis), menstrual disorders or fear of cold, decreased libido (in men), dry and rough skin, hypothyroidism, joint pain, and stiffness and swelling.
(4) The following should be noted if they persist: diarrhea, increased salivation, drooling, loss of appetite, metallic taste in the mouth, nausea, mouth pain, stomach pain, stomach upset, vomiting (gastrointestinal disorder, central nervous system toxicity), vertigo (including when rising from a recumbent or sitting position), drowsiness, weakness (central nervous system toxicity).