9 Drug Therapy for Spinal Tuberculosis
Introduction
Tubercular infection of the spine is an infection of the vertebral elements by Mycobacterium tuberculosis or its variants. Like all infections, antimicrobial chemotherapy remains the cornerstone of treatment. The unique microbiological characteristics of the bacteria include a special cell wall that makes it resistant to conventional antibiotics, a slow multiplication rate that necessitates a need for long-term therapy, early development of drug resistance with monotherapy, and the presence of a dormant phase of the bacteria that is unaffected by drugs. All these factors contribute to difficulties in eradicating the bacteria from the site of infection. Chemotherapy of spinal tuberculosis is therefore a challenge due to the special bacterial features, the need for long-term multidrug therapy, and rising the incidence of drug resistance.
History
It is useful to study the history of chemotherapy in order to understand the evolution of treatment regimens and the duration of chemotherapy for tuberculosis (TB). Until the 1940s, there was no drug available for the treatment of TB. The development of streptomycin in 1943 by a team led by Selman Waksman was a landmark in the treatment of TB. The first trial of streptomycin efficacy, in 1947, was conducted by the Medical Research Council (MRC) of the United Kingdom, 1 which is credited as being the first randomized controlled trial in the world, because it used a statistically based random sampling method.
A second drug, para-aminosalicylic acid (PAS), was evaluated to treat pulmonary TB in Sweden, 2 which led to the MRC’s second clinical trial in 1948. The antituber culous properties of isoniazid were observed in 1952. The MRC conducted a further trial of chemotherapy for TB in 1956, in which patients were given chemotherapy for varying lengths of time, from 6 months to 3 years. Introduction of rifampin in 1966 and pyrazinamide in the early 1970s further reduced the relapse rates.
Chemotherapy for osteoarticular TB was based on the experience gained in the treatment of pulmonary TB. Initially, there was apprehension that the antituberculous drugs may not be reaching minimum inhibitory concentration (MIC) levels in the osseous tissues and abscesses from mycobacterial infections. However, studies have shown that MIC levels are reached in the osseous tissues and abscesses. In the tuberculous joints as well as in the cold abscesses, the concentrations were much higher than those considered to have an inhibitory effect on the bacilli in clinical material. 3 In a study on drug concentrations in healing lesions, Kumar 4 found that the anti-TB drugs penetrated the fibrous tissue surrounding the tuberculous spinal lesions at a therapeutically adequate concentration.
The goals of chemotherapy in TB of the spine are as follows:
Cure the patient of the infection from mycobacteria.
Prevent development of drug-resistant TB.
Prevent development or aid recovery of a neurologic deficit.
Prevent disability from a mycobacterial infection.
Prevent relapse of a mycobacterial infection.
The unique nature of the bacilli and the pathogenesis of spinal tubercular infection makes it difficult task to achieve these goals.
Issues in Osteoarticular Tuberculosis
The following subsections discuss the issues peculiar to the nature of infection in spinal TB.
The Nature of Osteoarticular Spinal Tuberculosis
Spinal infection is always a secondary TB and is a paucibacillary disease. The disease evolves slowly, and the degree of destruction of bone depends on multiple factors, from host immunity to virulence of the organism. Clinical features such as pain, swelling, weight loss, fever, and malaise are all nonspecific. Cold abscesses and discharging sinuses, neurologic deficit, and kyphosis may all take time to appear. Neurologic deficit may be the result of active disease or may appear late due to an internal gibbus after healing of the disease. The early radiological manifestation may be completely nonspecific. The radiological response to treatment also is slow, and follow-up radiographs may take months before showing signs of healing. Blood investigations are also nonspecific. All these features make it difficult for the clinician to decide on the criteria to initiate antitubercular drugs. In endemic zones, a middle path is recommended in which patients are followed up with conservative chemotherapy, and a decision regarding pursuing surgery is based on the specific indications 5 ; chemotherapy is continued for the appropriate duration.
End Point of Treatment
The problem in chemotherapy of spinal TB is the assessment of the end point of activity of the disease. Sputum examination in pulmonary TB is a key factor that helps in assessing the response to chemotherapy, whereas in spinal TB, there are no easily available investigations to periodically assess the response to chemotherapy. Currently, a combination of clinical improvements in symptoms, hematological assessment of blood inflammatory markers, and magnetic resonance imaging (MRI) features of vertebral healing are used to assess the healing and to assess the end point of the chemotherapy.
The classic radiographic signs of healing include sclerosis in the previously osteopenic bones, fusion of vertebrae in the case of paradiskal TB, and the filling up or sclerosis of the lytic lesions. However, this process may take a long time. Also, the process of radiological change continues well beyond bacteriological sterility of the lesion.
An MRI with contrast has been used by some surgeons to evaluate the activity of the disease. 6 But MRI can only demonstrate the vascularity or the fluid in the area and not the bacteriological sterilization. The return of normal signal characteristics may take a long time. There could also be paradoxical worsening of lesions during successful TB treatment. This phenomenon is called a paradoxical response or an immune reconstitution inflammatory syndrome (IRIS), and is well known to occur with or without human immunodeficiency virus (HIV) co-infection. 7 So when an MRI is done 2 or 3 months after the start of chemotherapy, it may show an increase in abscess collection. This may lead the surgeon to conclude that the patient is not responding to treatment, whereas this is only an immune response to the tubercular protein. Recent reports on the use of positron emission tomography (PET)/computed tomography (CT) to assess activity of the disease, however, are encouraging. The PET/CT technology enables detailed analysis of changes in individual tuberculous lesions over time and monitoring of the response of these lesions to treatment. 8
Drug Treatment in Tuberculosis
Drug-Sensitive Tuberculosis Treatment
Chemotherapy initiated in the early stages of the disease will reduce the risks of deformity, neurologic deficit, and disability.
There are three important determinations to make regarding drug treatment for TB:
Which drugs?
Which regimen?
What duration?
Which Drugs?
The World Health Organization (WHO) 9 has classified drugs used in the treatment of TB as follows:
Group 1: first-line oral agents: isoniazid, rifampin, ethambutol, pyrazinamide, and rifabutin
Group 2: injectable agents: kanamycin, amikacin, capreomycin, and streptomycin
Group 3: fluoroquinolones, moxifloxacin, levofloxacin, gatifloxacin, and ofloxacin
Group 4: oral bacteriostatic second-line agents: ethionamide, protionamide, cycloserine, terizidone, and para-aminosalicylic acid
Group 5: agents with unclear efficacy: clofazimine, linezolid, amoxicillin-clavulanate, thiacetazone, clarithromycin, and carbapenems
The various drugs in these groups along with their dosages and key adverse effects are summarized in Tables 9.1, 9.2, 9.3, 9.4, 9.5. These groupings have now been reevaluated and modified based on drugs that are effective in multidrug-resistant (MDR) or extensive drug resistant (XDR) TB. 10
Some of these drugs are bactericidal and some are bacteriostatic; some are effective against intracellular bacteria, and some are active only against extracellular bacteria. Isoniazid, rifampin, streptomycin, and ethambutol act on extracellular rapidly multiplying (< 108) bacteria. Rifampin acts on extracellular slowly multiplying (< 105) bacteria also. Pyrazinamide acts on both intra- and extracellular bacteria in an acidic environment (< 105). Lesions may also harbor bacteria that are dormant and not multiplying at all. As yet there are no drugs available to eliminate these bacteria.
In the early active phase of the disease, the bacteria are rapidly multiplying and their numbers are large. Treatment at this intensive phase entails using drugs that are effective against both intra- and extracellular bacteria. A drug such as pyrazinamide is mainly effective in an acidic medium and is most effective in the first 2 months of treatment. There is no additional advantage to continuing pyrazinamide beyond the first 2 months. 11 The 5-year total relapse rates for patients with drug-susceptible strains were 3.4% for a pyrazinamide series compared with 10.3% for a non-pyrazinamide series (p < 0.001). 11 This highlights the importance of including pyrazinamide in the combinations used.
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