Antitubercular Chemotherapy in Musculoskeletal Tuberculosis

Antitubercular chemotherapy is the mainstay of the treatment of osteoarticular tuberculosis. It is complemented by rest, nutritional support and splinting, as necessary.

The drugs and regimens are fundamentally similar to those for pulmonary TB. But there is a lack of consensus on the appropriate duration of treatment.

Overview of Osteoarticular Tuberculosis

The spine is probably the most common site of osseous involvement, followed by the hip and knee. In the spine, the usual involvement is vertebral bodies and intervertebral disks in the dorsolumbar regions. Other sites of involvement are less common.

Multifocal skeletal TB is an uncommon but known entity.

Mycobacterium tuberculosis is the usual causative organism and the skeletal focus is always secondary to another focus, usually in the lungs or in the mediastinal lymph nodes.

Osteoarticular tuberculosis has an insidious onset. Constitutional symptoms like low-grade fever, anorexia and weight loss may occur along with pain and tenderness in the affected part.

Muscle spasms and discharging sinuses may be present. Concomitant pulmonary tuberculosis may be present.

The diagnosis of osteoarticular TB is made by a clinicoradiological picture. Imaging modalities like X-ray, CT, MRI help to gauge the extent of the involvement.

Biopsy of the bony lesion, synovium or soft tissue masses may be needed in cases where the diagnosis is not certain.

Lab studies like the polymerase chain reaction (PCR) are useful adjuncts.

Management of Tuberculosis

The mainstay of treatment is multidrug antitubercular chemotherapy. Rest to the affected part, immobilization or surgery may be required in some cases.

The treatment aims to contain and eradicate the infection, provide pain relief and preserve function.

The treatment can be provided in an institution or on the domiciliary basis.

Surgical intervention is required when the patient is not responding to an adequate trial of antitubercular chemotherapy.

Multidrug resistance should be suspected if the disease activity does not subside after 4 to 6 months of uninterrupted combination chemotherapy.

Drugs Used in Antitubercular Chemotherapy

Following drugs are used in tuberculosis [these drugs are used for tuberculosis of bone and joints and other regions of the body.]

Isoniazid

This is the important first-line drug for use in preventive therapy and the primary drug for use in combination therapy for active TB. Bacteriostatic for resting bacilli but kills actively dividing ones. It is active against intracellular bacilli, extracellular bacilli, and bacilli in caseous lesions.

Its mechanism of action is not fully known, but isoniazid may inhibit the synthesis of mycolic acid, resulting in disruption of the bacterial cell wall. In patients receiving treatment for active TB, pyridoxine 25-50 mg orally once daily should be coadministered to prevent peripheral neuropathy.

Isoniazid has good CSF penetration.

Side effects are gastrointestinal disturbances,  hepatotoxicity [asymptomatic elevation of liver enzymes to fulminant hepatic failure], hypersensitivity, ANA-positive vasculitis, drug-induced lupus, agranulocytosis, pellagra; neurotoxicity-peripheral neuropathy, optic neuritis, convulsions, psychoses.

There is no cross-resistance with other antitubercular drugs except structurally related ethionamide.

Dosage

Isoniazid dosage in mg/kg. [Parenthesis indicate maximum dose]

 Daily regimens

Child             10-20 mg/kg (300 mg)

Adult   5 (300 mg)

Twice weekly regimens

Child   20-40 (900 mg)

Adult   15 (900 mg)

Thrice-weekly regimens

Child   20-40 (900 mg)

Adult   15 (900 mg)

Rifampin

Rifampin inhibits DNA-dependent RNA polymerase activity in bacterial cells but not in mammalian cells. It is bactericidal drug and active against intracellular, extracellular bacilli and bacilli in caseous lesions.

Side effects include gastrointestinal disturbances including pseudomembranous colitis, hepatotoxicity (transient elevation of liver enzymes common),  flu-like syndrome, shortness of breath, thrombocytopenic purpura, hemolytic anemia, acute renal failure; hypersensitivity reactions; orange discoloration of body fluids [and contact lenses] and  risk of hormonal contraceptive failure

This drug is given an empty stomach. Liver function and blood counts are frequently monitored.

Dosage

Rifampicin dosage in mg/kg. [Parenthesis indicate maximum dose]

Daily regimens

Child   10-20 (600 mg)

Adult   10 (600 mg)

Twice weekly regimens

Child  10-20 (600 mg)

Adult   10 (600 mg)

Thrice weekly regimens

Child   10-20 (600mg)

Adult   10 (600 mg)

Pyrazinamide

This is a pyrazine analog of nicotinamide that is either bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at the site of infection. Pyrazinamide’s mechanism of action is unknown.

It is especially active against intracellular bacilli and has very good CSF penetration.

Activity appears to be dependent on metabolism by a deamidase to pyrazinoic acid. Mechanism of action unknown

gastrointestinal disturbances, hepatotoxicity [asymptomatic elevation of liver enzymes to hepatic necrosis], urticaria, fever, arthralgia, sideroblastic anemia, and hyperuricemia.

Baseline serum uric acid estimation and liver function monitoring recommended.

Dosage

Pyrazinamide dosage in mg/kg. [Parenthesis indicate maximum dose]

 Daily regimens

Child   15-30 (2 g)

Adult   15-30 (2 g)

Twice weekly regimens

Child   50-70 (4 g)

Adult   50-70 (4g)

Thrice-weekly regimens

50-70 (3 g)

Adult   50-70 (3 g)

Ethambutol

Ethambutol is bacteriostatic and active against intracellular bacilli, extracellular bacilli, and bacilli in caseous lesions.

It has poor penetration in CSF.

Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli).

It impairs cell wall synthesis by inhibiting incorporation of mycolic acid into the mycobacterial cell wall

No cross-resistance has been demonstrated.

Mycobacterial resistance is frequent with previous therapy.

Adverse effects of ethambutol include optic neuritis, which is usually reversible with discontinuation of the drug, optic neuritis-reduced visual acuity, loss of red-green discrimination

During the treatment, monthly eye examinations are recommended.

Drug not recommended in children below 6 years as these children cannot report visual symptoms. Peripheral neuropathy and hyperuricemia is also reported

Dosage

Ethambutol  dosage in mg/kg. [Parenthesis indicate maximum dose]

Daily regimens

Child   15-25 (2g)

Adult   15-25

Twice weekly regimens

Child   50

Adult   50

Thrice-weekly regimens

Child   25-30

Adult   25-30

Streptomycin

Streptomycin sulfate is an aminoglycoside which is used in antitubercular chemotherapy in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin).

Because of toxicity concerns., the drug is recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated. Then too, the drug is given only for short periods.

Bactericidal and active mostly against extracellular bacilli.

It has poor CSF penetration.

It inhibits protein synthesis by binding to the 30s Ribosomal Subunit.

Known adverse effects are ototoxicity (vestibular more than cochlear), nephrotoxicity,  rash and fever, neuromuscular blockade at high doses.

Dosage

Streptomycin dosage in mg/kg. [Parenthesis indicate maximum dose]

Daily regimens

Child   20-40 (1 g)

Adult  12-18 (1 g)

Twice weekly regimens

Child   25-30 (1.5 g)

Adult   25-30 (1.5 g)

Thrice-weekly regimens

Child   25-30 (1.5 g)

Adult   25-30 (1.5 g

Ethionamide

Ethionamide is a second-line bacteriostatic or bactericidal drug against M tuberculosis, depending on the concentration of the drug attained at the site of infection. It is recommended if treatment with first-line drugs is unsuccessful. Ethionamide can be used to treat any form of active TB.

It should be used only with other effective antituberculous agents.

It acts like nicotinamide analog and possibly inhibits incorporation of cysteine and methionine into proteins.

Dosage is 15-20 mg/kg PO in divided doses with meals. The maximum dose is 1 g.

Main adverse effects are gastrointestinal disturbances, neurotoxicity, visual disturbances, olfactory disturbances, peripheral neuropathy, convulsions, hepatotoxicity, hypersensitivity reactions,  alopecia, and gynecomastia.

Amikacin

Amikacin is a second-line drug used to treat patients with drug-resistant tuberculosis or those who do not tolerate first-line therapies. It binds irreversibly to the 30S subunit of bacterial ribosomes, blocking protein synthesis.

It is a bacteriocidal drug.

The usual dose is 15 mg/kg as an intramuscular injection. Maximum dosage is 1 g.

Adverse effects are ototoxicity, nephrotoxicity, pseudomembranous colitis and neuromuscular blockade at high doses.

Cycloserine

Cycloserine is a second-line tubercular drug which inhibits the cell wall synthesis. It is a bacteriostatic drug and a D-alanine analog.

The dose is 10-20 mg/kg orally in 2 divided doses. The maximum dose is 500 mg twice daily.

Side effects are a headache, dizziness, vertigo, drowsiness, tremor, convulsions, depression, psychosis, abnormal liver function, megaloblastic anemia, and rashes.

Capreomycin

Capreomycin is bacteriocidal drug obtained from Streptomyces Capreolus. Capreomycin is used only when first-line agents have been ineffective or cannot be used due to toxicity or resistance.

The dose is 15-30 mg/kg intramuscular, the maximum dose is  1 g per day.

Main adverse effects are pain and induration at the site of injection, ototoxicity, nephrotoxicity,  eosinophilia. Neuromuscular blockade can occur at high doses

Levofloxacin and other Fluoroquinolones

Levofloxacin, a second-line antituberculous drug, is used in combination with rifampin and other antituberculous agents in treating most cases of multidrug-resistant tuberculosis. It is the preferred oral agent for treating MDR-TB.

It causes inhibition of bacterial topoisomerase IV and DNA gyrase, which are required for DNA replication, transcription, repair, and recombination.

Moxifloxacin and ofloxacillin are other fluoroquinolones used in antitubercular chemotherapy, usually in drug-resistant tuberculosis.

Rifapentine

Rifapentine inhibits RNA polymerase in M. tuberculosis. Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of M tuberculosis organisms.

It is used twice weekly as part of a multiple drug regimen for 2 months during the intensive phase of TB treatment, then once weekly for 4 months, along with isoniazid or other appropriate drugs.

It is also indicated for adults and children aged 2 years or older with latent TB in combination with isoniazid as once-weekly DOT therapy for 12 weeks. It should not be used in individuals with HIV infection or with positive TB cultures after 2 months of treatment.

Rifabutin

This is derived from rifamycin and inhibits DNA-dependent RNA polymerase, preventing chain initiation. It is used for TB treatment in individuals on specific HIV medications when rifampin is contraindicated (most protease inhibitors).

Para-aminosalicylic Acid

This is a bacteriostatic agent that is used as a second-line agent against M tuberculosis. It inhibits folate biosynthesis by interfering with the incorporation of p-aminobenzoic acid.

The dose is 150 mg/kg orally in divided doses with meals. The maximum dose is 12 g per day.

The adverse effects are gastrointestinal disturbances,  hypersensitivity reactions, arthralgia, agranulocytosis, leucopenia, eosinophilia, lymphocytosis, atypical mononucleosis, thrombocytopenia, and hemolytic anemia

Bedaquiline

Diarylquinoline is a diarylquinoline that inhibits mycobacterial adenosine 5′-triphosphate (ATP) synthase.

It is used in drug-resistant tuberculosis.

Thiacetazone (oral)

It is a bacteriostatic second-line drug. The usual dose is 150 mg per oral.

Gastrointestinal disturbances, skin reaction including exfoliative dermatitis, hepatotoxicity and myelosuppression are common side effects.

Treatment Regimen for Osteoarticular Tuberculosis

Treatment of tuberculosis, in general, is divided into two phases, an intensive phase where more drugs are used to kill the bacteria and a  continuation phase where the lesser number of drugs are used.

The intensive phase is intended to bring about rapid clinical amelioration and achieve non-infectivity. Continuation phase aims to eliminate residual bacilli and prevent relapse.

For fresh cases of osteoarticular tuberculosis WHO recommends two months therapy with isoniazid, rifampin, pyrazinamide and ethambutol for two months and followed by isoniazid and rifampin for 4 months.

[2H₃R₃Z₃E₃ + 4H₃R₃] is the preferred regimen is thrice weekly.

However for previously treated recurrence/failures, the intensive phase is for 3 months.  Streptomycin injections are added in the intensive phase for the first two months

2H₃R₃Z₃E₃S₃ + 1H₃R₃Z₃E₃ + 5H₃R₃E₃ 

For new cases, WHO recommends the treatment for a minimum of 6 months.

Many clinicians had conventionally been treating osteoarticular tuberculosis for longer durations and still recommend to continue the continuation phase until there is adequate radiological evidence of healing

Recent studies have reported that 6 months of therapy is probably sufficient for the majority of patients.

The United States Centers for Disease Control recommend that for infants and children with miliary TB or bone and joint TB treatment should last at least 12 months.

For adults with these forms of extrapulmonary TB, the patient’s response to therapy should be monitored closely. If the response is slow or inadequate, treatment may be prolonged on a case-by-case basis.

Treatment of Drug-Resistant Tuberculosis

Drug Resistant tuberculosis is discussed here.

Adverse Reactions and Toxicity

If a reaction occurs but its nature does not single out a particular drug, the treatment may be continued by replacing the offending drug with a suitable alternative, or with a reduced number of drugs if none is suitable. The resumed regimen is considered to be a new start to the treatment. This prolongs the duration of therapy but, on the other hand, reduces the chance of recurrence.

Prognosis

The prognosis, in general, is good with adequate treatment regimens sustained for an appropriate length of time. In some series, children appear to fare better than adults.

References

• Matar MJ, Cabral DA, Petty RE. Isolated tuberculous monoarthritis mimicking oligoarticular juvenile rheumatoid arthritis. J Rheumatol 2001;28:204-6.
• Andronikou S, Jadwat S, Douis H. Patterns of disease on MRI in 53 children with tuberculous spondylitis and the role of gadolinium. Pediatr Radiol 2002;32:798-805.
• Teklali Y, El Alami ZF, El Madhi T, Gourinda H, Miri A. Peripheral osteoarticular tuberculosis in children: 106 case reports. Joint Bone Spine 2003;70:282-6.
• van Loenhout-Rooyackers JH, Verbeek AL, Jutte PC. Chemotherapeutic treatment for spinal tuberculosis. Int J Tuberc Lung Dis 2002;6:259-65.
• Treatment of TB Infection and Disease. CDC Module 4. Available at: http://www.phppo.cdc.gov/phtn/tbmodules/modules1-5/m4/4-m-05.htm.