Tuberculosis medical therapy special conditions

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; João André Alves Silva, M.D. [3] Ammu Susheela, M.D. [4]

Overview

Medical therapy for tuberculosis in special conditions include HIV co-infection and extrapulmonary manifestations. Different approaches are taken for patients taking ART and those who do not take ART. Although WHO recommends the same drug regimen for pulmonary and extrapulmonary manifestations, various stages of skeletal tuberculosis are managed differently. For patients with renal or liver diseases, the first line of drugs are substituted with second-line drugs to prevent complications.

HIV Coinfection

Depending on the treatment status of each patient, different approaches may be taken:

Patients Not Taking ART

• After the diagnosis of TB in HIV-positive patients, not taking antiretroviral therapy (ART), the priority is to initiate treatment for TB, along with co-trimoxazole and ART.
• These patients should be treated with the same regimen as HIV-negative patients, with the exception that the optional 3 times/week of intensive phase treatment, is mandatory for HIV-positive patients. This leads to a decrease in incidence of TB relapse and resistance to rifampicin, often seen in HIV-positive patients.
• The retreatment regimens are the same for HIV-positive and HIV-negative patients.

According to the WHO, the following recommendations should be applied to these patients:

• Patients with TB, who are known to be HIV-positive, and all TB patients who live in areas where HIV is prevalent, should be treated with at least the intensive phase of the TB treatment.

• During the continuation phase of the treatment, these patients should also receive a daily dose.

• In the impossibility of taking the daily dose, a continuation phase of 3 times/week is acceptable. Regarding the duration of therapy, some experts recommend prolongation of TB treatment in certain HIV-positive patients.
• HIV-positive patients with TB should receive TB treatment, at least for the same period of time as HIV-negative patients.

Patients Taking ART

Besides improving the survival rate of HIV-positive patients, antiretroviral therapy can decrease TB rates by about 90% at the individual level, 60% population level, and 50% reduction in recurrence rates. People with active TB and HIV must be initiated with ART irrespective of CD4 cell count. By the first 8 weeks of starting TB treatment, ART must be initiated to reduce the complications.

Co-trimoxazole

Preventive therapy with co-trimoxazole should be initiated as early as possible in all TB patients who are HIV-positive, and should be continued during the entire treatment of TB. Co-trimoxazol reduces the mortality rate of HIV-positive tuberculous patients, as well as infections by Pneumocystis jirovecii and malaria. After TB treatment has been complete, continuation of co-trimoxazol should be evaluated according to each country's guidelines.

Extrapulmonary

Tuberculous Lymphadenitis

The infectious disease society of America(IDSA) recommends treatment for 6 months for the drug-susceptible organisms.

• The regimen includes isoniazid, rifampin, pyrazinamide and ethambutol for 2 months followed by isoniazid and rifampin for another 4 months.
• Surgical excision as an adjuvant to antibiotic therapy for TB lymphadenitis caused by the drug-resistant organism.

Studies have shown that steroids used for local discomfort and adjuvant immunotherapy with anti tumor necrosis factor agents can be beneficial but no specific recommendation has been made.

Skeletal Tuberculosis

The mainstay of treatment for skeletal tuberculosis is antibiotics and surgery. The selection of antibiotics for skeletal tuberculosis is the same as that of pulmonary tuberculosis.

Stage	Treatment
Stage 1 (synovitis)	Chemotherapy    Rest    Restriction of movements    Splinting
Stage 2 (Early arthritis)	Chemotherapy    Rest    Restriction of movements    Splinting    Synovectomy
Stage 3 (Advanced arthritis)	Chemotherapy    Osteotomy    Arthrodesis    Arthroplasty
Stage 4 (Advanced arthritis)	Chemotherapy    Osteotomy    Arthrodesis    Arthroplasty
Stage 5	Chemotherapy    Osteotomy    Arthrodesis    Arthroplasty

Tuberculous Meningitis

The treatment of TB meningitis is 2 months of isoniazid, ethambutol, pyrazinamide, and rifampicin, followed by rifampicin and isoniazid alone for a further ten months. Steroids help reduce the risk of death or disabling neurological deficit.[6] Steroids can be used in the first six weeks of treatment, but must be used with caution in individuals who also have HIV. A few patients may require immunomodulatory agents such as thalidomide. Treatment must be started as soon as there is a reasonable suspicion of the diagnosis. Treatment must not be delayed while waiting for confirmation of the diagnosis. Hydrocephalus occurs as a complication in about a third of patients with TB meningitis and will require a ventricular shunt. Aspirin may be used as an adjuvant therapy to reduce complications. BCG vaccination has been proved to prevent tuberculous meningitis.

Miliary Tuberculosis

Miliary tuberculosis is a grave condition that must be treated immediately. A delay in treatment may cause serious complications and even death. 8-9 months is the time of treatment for the susceptible organisms. Treatment of miliary tuberculosis includes 6 months of daily or intermittent treatment. . Expert opinion suggests that corticosteroid therapy may be useful for treating respiratory failure caused by disseminated tuberculosis but there are no data to support its use.

Tuberculosis Peritonitis

Medical therapy for tuberculous peritonitis involves the multi drug regimen of tuberculosis consisting of 5 major drugs as the first line of treatment including isoniazid, ethambutol, pyrazinamide, streptomycin and rifamppicin. Corticosteroids can be added to the treatment to reduce the complications. Response to treatment is manifested as disappearance of ascitis and resolution of symptoms . All lab based values return to normal baseline within 3 months of treatment initiation. .

Tuberculous Pericarditis

A 2 months course of isoniazid, pyrazinamide, rifampicin, and ethambutol followed by 4 months course of isoniazid and rifampicin is shown to be effective . For patients with pericardial tuberculosis, a 6-month regimen is recommended. Corticosteroids is recommended as adjunctive therapy for tuberculous pericarditis during the first 11 weeks of antituberculosis therapy. In a randomized, double-blind, controlled trial, patients in the later effusive--constrictive phase who received prednisolone had a significantly more rapid clinical resolution compared with patients given a placebo. Prednisolone did not reduce the risk of constrictive pericarditis. It is recommended that daily adjunctive prednisolone or prednisone alone treatment be given to adults and children with tuberculous pericarditis. Following are the dosage recommendations:

• Adults: Prednisone 60 mg/day given for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and finally 5 mg/day for week 11 (the final week)
• Children: Doses should be proportionate to their weight, beginning with about 1 mg/kg body weight and decreasing the dose as described for adults.

Renal Tuberculosis

Drug regimen is similar to other types of tuberculosis with a multidrug antibiotic therapy with antitubercular drugs. According to the 4th edition of WHO recommendations;

• Pulmonary and extrapulmonary disease should be treated with the same regimens.
• Continuation phase for 6-9 months regimens that include INH and RIF are highly recommended.
• Prolongation of therapy also should be considered for patients with tuberculosis in any site that is slow to respond.
• The addition of corticosteroids is recommended for patients with tuberculous pericarditis and tuberculous meningitis.
• In tuberculous meningitis, ethambutol should be replaced by streptomycin.

Statandard Regimens For New TB Patients With Drug-Susceptible TB Intensive Initial Phase ▸ Initial Phase: 2 months of HRZS † Continuation phase ▸ Continuation Phase: 6-9 months ‡ of HR ‡ In this group decisions to prolong the continuation phase should be made on an individual basis.

Renal Insufficiency and End-Stage Renal Disease

For patients undergoing hemodialysis, administration of all drugs after dialysis is preferred to facilitate DOT and to avoid premature removal of drugs such as PZA and cycloserine. To avoid toxicity it is important to monitor serum drug concentrations in persons with renal failure who are taking cycloserine or EMB. There is little information concerning the effects of peritoneal dialysis on the clearance of antituberculosis drugs.

Liver Disease

INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than three times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease a regimen with only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months; however, there are no data to support this recommendation.

In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury.

Hepatitis and Anti-TB medications

WHO Recommendation for Anti-TB drug-induced hepatitis is:

• If TB treatment has been stopped, Wait for liver function tests to normalize and resolution of the clinical symptoms (nausea, abdominal pain) before reintroducing the anti-TB drugs.
• If the liver function tests are not available, it is advisable to wait for extra 2 weeks after resolution of jaundice and upper abdominal tenderness before restarting TB treatment.
• If the signs and symptoms do not resolve and the liver disease is severe, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started (or continued) for a total of 18-24 months.
• Reintroducing one drug at a time is the optimal approach, especially if the patient’s hepatitis was severe.
• Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. But if symptoms recur or liver function tests become abnormal again as the drugs are reintroduced, the last drug added should be stopped.
• Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most effective agent . After 3–7 days, isoniazid may be reintroduced. In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide.

Alternative regimens in Anti-TB induced Hepatitis

It depends on which drug is implicated as the cause of hepatitis.

• If rifampicin is implicated, a suggested regimen without rifampicin is 2 months of Isoniazid, Ethambutol and Streptomycinfollowed by 10 months of Isoniazid and Ethambutol.
• If Isoniazid cannot be used, 6-9 months of Rifampicin, Pyrazinamide and Ethambutol can be considered.
• If Pyrazinamide is discontinued before the patient has completed the intensive phase, the total duration of isoniazid and rifampicin therapy may be extended to 9 months.
• If neither isoniazid nor rifampicin can be used, the non-hepatotoxic regimen consisting of Streptomycin, ethambutol and afluoroquinolone should be continued for a total of 18-24 months.
• Hepatitis during the intensive phase of TB treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol: once hepatitis has resolved, restart the same drugs EXCEPT replace pyrazinamide with streptomycin to complete the 2-month course of initial therapy, followed by Rifampicin and Isoniazid for the 6-month continuation phase.
• Hepatitis during the continuation phase: once hepatitis has resolved, restart Isoniazid and Rifampicin to complete the 4-month continuationphase of therapy.