Tuberculous Meningitis Medication

First-line therapy includes isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), streptomycin (SM), and ethambutol. Second-line therapy includes ethionamide, cycloserine, para-aminosalicylic acid (PAS), aminoglycosides, capreomycin, and thiacetazone.

Potential new agents include oxazolidinone and isepamicin. Fluoroquinolones useful in the treatment of TBM include ciprofloxacin, ofloxacin, and levofloxacin. A new rifamycin called rifapentine has been developed.

Trials for novel agents for the treatment of tuberculosis (TB) are under way. Long-acting rifamycin derivatives and potent fluoroquinolone antibiotics have been studied, and they lead the way for improved regimens against active and latent TB. The recent rapid increase in knowledge of mycobacterial pathogenesis is likely to lead to the advent of potent new drugs in latent disease and against the phenomenon of persistence. Without a doubt, sustained and increased funding for basic research plays a key role in eradicating this global epidemic altogether.

Finally, because of the intensity of the inflammatory and fibrotic reactions at the meningeal site, adjunctive corticosteroid therapy, in addition to standard antituberculous therapy, is recommended in tuberculous meningitis (TBM).

Studies have confirmed the benefit of adjunctive corticosteroid therapy on survival and intellectual outcome in children with TBM, with enhanced resolution of basal exudates but no effect on intracranial pressure (ICP) or the incidence of basal ganglia infarction.^[31]

Wasay, in his 2006 editorial, discusses at length central nervous system (CNS) TB and the paradoxical response.^[32] The paradoxical response to antituberculous therapy is well known; it usually develops after approximately 2 weeks of treatment. It is characterized by the clinical or radiological worsening of preexisting tuberculous lesions or the development of new lesions not attributable to the normal course of disease in a patient who initially improved with antituberculous therapy.

Up to 10% of patients with CNS TB report the paradoxical response, and this number may be as high as 30% in HIV-infected patients.^{[33, 34]}

The paradoxical response has been attributed as a component of immune reconstitution inflammatory syndrome or immune restoration syndrome, which results from an exuberant inflammatory response toward incubating opportunistic pathogens.^[35] An increase in the incidence and severity of the paradoxical response is noted in HIV-infected patients on highly active antiretroviral therapy.^[36] Patients demonstrating a paradoxical response are more likely to have lower baseline lymphocyte counts, followed by a surge.^[37]

Class Summary

Any regimen must contain multiple drugs to which the mycoplasma is susceptible. In addition, the therapy must be taken regularly and continued for a sufficient period. First-line therapy includes isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), streptomycin (SM), and ethambutol. Second-line therapy includes ethionamide, cycloserine, para-aminosalicylic acid (PAS), aminoglycosides, capreomycin, and thiacetazone.

Capreomycin (Capastat)

Capreomycin is a second-line drug for concomitant use with other appropriate anti-TB drugs when first-line drugs are ineffective or cannot be used because of toxicity.

Cycloserine (Seromycin)

Cycloserine is a second-line anti-TB drug effective against Mycobacterium tuberculosis. It is a competitive antagonist of the racemase enzyme involved in bacterial cell wall synthesis. It is also active against other mycobacteria such as Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium malmoense. It is indicated in TB resistant to first-line drugs, in combination with other drugs.

Ethambutol (Myambutol)

Ethambutol is bactericidal at 25 mg/kg at pH between neutral and alkaline. It is bacteriostatic at 15 mg/kg. Its site of action is extracellular. It acts on rapidly growing pathogens in cavity walls. It is also effective in slow-growing pathogens. Ethambutol is indicated as a first-line anti-TB drug.

Ethionamide (Trecator)

Ethionamide is bacteriostatic against M tuberculosis. It is also active against atypical mycobacteria such as Mycobacterium kansasii, some strains of Mycobacterium avium complex, and Mycobacterium leprae. It is indicated as a second-line anti-TB agent.

Isoniazid (Laniazid, Nydrazid)

INH is bactericidal against actively dividing pathogens but bacteriostatic against nondividing organisms. It is highly effective against M tuberculosis. It is indicated for treatment of all forms of TB. Usually, preventive therapy with INH is delayed in pregnant women until delivery unless the patient is likely to have been infected recently. There have been reports of severe and potentially fatal hepatitis related to isoniazid therapy. Hepatic enzymes, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), should be measured prior to the initiation of therapy and monitored at monthly intervals during treatment.

The Centers for Disease Control (CDC) reported in November 2010 the results of a national project on monitoring severe adverse events associated with the treatment of latent tuberculosis infection (LTBI). This report was published in the Morbidity and Mortality Weekly Report. The report includes 17 cases of severe INH-associated liver injury identified from 2004-2008. INH-induced liver injury may occur in persons of any age and at any time during treatment. It is important to discontinue isoniazid treatment immediately if patients develop symptoms of nausea, vomiting, abdominal discomfort, or fatigue.^[38]

Prothionamide

Prothionamide is a thionamide derivative, active against M tuberculosis. Its action is similar to that of ethionamide, with which it is considered interchangeable. Resistance develops quickly if it used alone. It is better tolerated than ethionamide. Prothionamide is indicated as a second-line anti-TB drug. It is not available in the United States.

Pyrazinamide (Tebrazid)

PZA has bactericidal action against M tuberculosis in the acidic environment present in macrophages and inflamed tissue; it works both intracellularly and extracellularly. Together with RIF, it provides the greatest sterilizing action, with a reduction in the replace rate. It reduces tubular secretion of uric acid. PZA is indicated as part of multidrug regimens during the first 2 months; it may be continued if necessary.

Rifampin (Rifadin, Rimactane)

RIF has bactericidal action against a wide range of organisms, including intracellular organisms and semidormant or persistent ones. Generally, it is reserved for the treatment of TB and leprosy and opportunistic atypical mycobacterial infections such as those in patients with AIDS or HIV infection. RIF inhibits DNA-dependent RNA polymerase enzyme, resulting in suppression of nucleic acid synthesis. It is indicated as part of multidrug anti-TB regimens.

Streptomycin

SM sulfate has bactericidal action and inhibits bacterial protein synthesis. Susceptible organisms include M tuberculosis, Pasteurella pestis, Pasteurella tularensis, Haemophilus influenzae, Haemophilus ducreyi, donovanosis (granuloma inguinale), Brucella species, Klebsiella pneumonia, Escherichia coli, Proteus species, Aerobacter species, Enterococcus faecalis, and Streptococcus viridans (in endocarditis, with penicillin). SM sulfate is always given as part of a total anti-TB regimen.

Para-aminosalicylic acid (Sodium PAS)

Para-aminosalicylic acid is a weak bacteriostatic agent that is available as an enteric-coated granule designed for gradual drug release. It is believed to competitively inhibit conversion of aminobenzoic acid to dihydrofolic acid and/or to inhibit iron uptake. In treatment of clinical TB, PAS should not be given alone.

Thiacetazone

Although not available in the United States, thiacetazone is used in many developing countries because it is inexpensive. Although it is related to INH biochemically, it is bacteriostatic and more toxic than INH. It is commonly combined in a single tab containing 300-400 mg of INH and 150 mg of thiacetazone.

Rifapentine (Priftin)

Rifapentine possesses in vitro activity superior to that of RIF against isolates of M tuberculosis and M avium complex. Both rifapentine and its metabolite are protein bound. Rifapentine is FDA approved for the treatment of pulmonary tuberculosis.

Class Summary

The aminoglycosides bind reversibly to 1 of 2 aminoglycoside binding sites on the 30S ribosomal subunit, causing an inhibition of bacterial protein synthesis. Examples of aminoglycosides used in the treatment of tuberculosis include amikacin and kanamycin.

Kanamycin (Kantrex)

Kanamycin is an aminoglycoside containing 1 or 2 amino sugars linked to an aminocyclitol nucleus. The nucleus is 2-deoxystreptamine. Kanamycin is bactericidal and is believed to inhibit protein synthesis by binding to the 30S ribosomal subunit. It is effective against extracellular mycobacteria.

Amikacin (Amikin)

Amikacin is an aminoglycoside containing 1 or 2 amino sugars linked to an aminocyclitol nucleus. The nucleus is 2-deoxystreptamine. Amikacin is highly bactericidal against M tuberculosis in vitro.

Class Summary

Several fluoroquinolones have shown in vitro activity against M tuberculosis. The target of the quinolones is the enzyme DNA gyrase. Ofloxacin and ciprofloxacin are compounds of this family that are licensed for use in the United States. However, neither of these drugs are FDA approved for the treatment of TB.

The minimal inhibitory concentration of ofloxacin and ciprofloxacin is approximately 1 mcg/mL for a wide range of strains of M tuberculosis, compared with a peak serum concentration of 4.3 mcg/mL 1-2 h after a 750-mg dose of ciprofloxacin, and a 4.6 mcg/mL peak serum concentration after multiple 400-mg doses of ofloxacin. One study showed a similar minimal inhibitory concentration for ofloxacin in the macrophage model, and minimal bactericidal concentration was found to be 2 mcg/mL; however, the bactericidal activity of ofloxacin was less than that of RIF. Another study found identical minimal bactericidal concentration levels of 2 mcg/mL for both ciprofloxacin and ofloxacin in 7H12 broth medium. In general, quinolones are well tolerated.

The quinolones are cleared primarily by renal excretion; adjust dosage for those with CrCl less than 50 mL/min. Few long-term studies have been preformed on the use of quinolones, but one review found that toxicity is dependent more on dose than on duration of therapy.

Data on the use of these agents for the treatment of TB are limited. A study from Japan reported patients who had chronic cavitary lung TB were excreting bacilli resistant to various anti-TB agents. Of 17 patients who received ofloxacin in combination with other anti-TB agents as single doses of 300 mg/d for 6-8 months, 14 patients showed a decrease in culture positivity and 5 had a negative conversion. No adverse effects were observed.

Another study of ofloxacin reported 22 patients receiving 300 or 800 mg of ofloxacin in a single daily dose for 9 mo to 1 y. All patients tolerated the drug well, and indications were noted of higher efficacy at higher doses.

Prudent use of antituberculous drugs is a must to decrease drug resistance. Infection with Mycobacterium tuberculosis resistant to the standard drugs causes grave concerns, threatening a return to the prechemotherapeutic days. In addition to isoniazid resistance, multidrug-resistant tuberculosis has emerged, accounting for almost half a million cases of tuberculosis. Extensively drug-resistant tuberculosis (resistant to several additional second-line drugs) has emerged, which makes the treatment difficult and costly, in addition to having a poor prognosis.

Ciprofloxacin (Cipro, Cipro XR)

Ciprofloxacin has been shown to have in vitro activity in M tuberculosis, but data on clinical use of these agents in TB are limited. Ciprofloxacin is not approved in United States for treatment of TB. It probably has greater efficacy at higher doses. The target is the enzyme DNA gyrase. Ciprofloxacin is generally well tolerated. Toxicity is related more to duration of therapy than to dose. The agent is cleared primarily by renal excretion; adjust dosage for creatinine clearance of less than 50 mL/min.

Ofloxacin (Floxin)

Ofloxacin is a broad-spectrum fluoroquinolone that inhibits DNA gyrase. It has good gram-positive coverage and excellent gram-negative coverage but poor anaerobic coverage.

Levofloxacin (Levaquin)

Levofloxacin is a fluoroquinolone antibiotic that is used in the treatment of tuberculosis in combination with rifampin and other antituberculosis agents.

Class Summary

The use of corticosteroids in adults is controversial; they may be indicated in the presence of increased intracranial pressure (ICP), altered consciousness, focal neurological findings, spinal block, and tuberculous encephalopathy. Treatment of tuberculoma consists of high-dose steroids and continuation of antituberculous therapy, often for a prolonged course. In tuberculous radiculomyelitis (TBRM), as in other forms of paradoxical reactions to anti-TB treatment, evidence shows that steroid treatment might have a beneficial effect.

Studies have shown that young children with TBM can be treated safely for 6 months with high doses of anti-TB agents without overt hepatotoxicity and with a low risk of relapse. Children must be treated for 12 months with combination antibiotic therapy and adjunctive corticosteroids. The rationale behind the use of adjuvant corticosteroids lies in reducing the harmful effects of inflammation as the antibiotics kill the organisms.

Prednisone

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dexamethasone (Baycadron, DexPak 10-Day TaperPak)

Dexamethasone has many pharmacologic benefits but significant adverse effects. It stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas.