Clinical Investigations Pharmacological

Introduction

Tuberculosis is one of the oldest diseases in human history. Originating from the Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium africanum bacteria, the disease has the ability to spread to the skeletal muscles. This assignment will examine the key pathophysiology of a patient with spinal tuberculosis and analyse the clinical rationale of the investigations and pharmacological interventions of several antibiotics used related to pyogenic discitis. This essay will be based on Mohammed Khan which is a pseudonym and is anonymous to ensure confidentiality is not breached.

Case study

Mohammed Khan is a 44-year-old Asian male who was admitted onto a renal ward at the local hospital. Based on the electronic patient record Mr Khan’s presentation to accident and emergency department with symptoms of shortness of breath, severe back pain, unwell for 2 days at home, feeling hot and cold, having rigors, coughing which the patient states have been productive for last five weeks, green sputum and has been vomiting for the last two days, non-bilious and reduced mobility. Mr Khan’s past medical history includes end-stage renal disease and on haemodialysis three times a week, Type 1 diabetes mellitus, fluid overload/pulmonary oedema and known to have ischemic heart disease.

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Mr Khan has had multiple admissions in recent months including ICU admission. He has had previous bilateral pleural effusion that was resolved. He was treated for pneumocystis pneumonia (PCP) which was not an entirely convincing clinical picture. Mr Khan’s most recent admission stated that he was unwell with febrile illness and predominantly respiratory symptoms. He has back pain, fever, high CRP, and as stated before later found to have L1/L2 osteomyelitis/ discitis. Despite antibiotic therapy, there has been a progression of back pain and deterioration of his mobility. Mr Khan was administered with isoniazid and rifampicin which are taken during the whole course of therapy. The first line of medications used in Mr Khan’s case was oral rifampicin and isoniazid. He started with 900mg tablets of rifampicin 100mg of isoniazid and pyrazinamide to begin with.

Pathophysiology of spinal TB

Khan was diagnosed with osteomyelitis which manifests as tuberculosis spondylitis, also known as Pott’s disease. The spine is the most recurrent site of musculoskeletal tuberculosis, and ordinarily related symptoms are back pain and lower limb weakness (Jain & Dhammi 2007). Pott’s disease is a form of tuberculosis that occurs outside the lungs whereby disease is seen in the vertebrae, a kind of tuberculosis arthritis of the intervertebral joints (Subramani et al. 2017). There are two distinct types of spinal TB, the classic form or spondylodiscitis, and an increasingly common atypical form which is spondylitis without disc involvement (Jain 2010).

Jain (2010) state that the involvement of the intervertebral disc in an adult is secondary to spread from the adjacent infected vertebra and that the basic lesion and is a combination of osteomyelitis and arthritis which usually affects multiple vertebrae. The typical site of involvement is the anterior aspect of the vertebral body adjacent to the subchondral plate. A possible effect in spinal TB can include any of the following progressive bone destruction leading to vertebral collapse and kyphotic deformity of the spine, spinal cord compression, neurological insults, including paraplegia, spinal canal narrowing by abscesses and cold abscess formation (Tuli 2013).

The manifestation of spinal tuberculosis emerges with the inflammation of the vertebra and joints. This causes loss of weight and appetite, night sweats, fever, generalized body pain, and feeling fatigue. Severe back pain is a well-known indication that TB has spread to the spine (Chen at al. 2016). The intensity of pain is typically localized to the site of involvement and is most common in the thoracic region. The pain may be aggravated by spinal motion, coughing and weight bearing, because of advanced disc disruption and spinal instability, nerve root compression, or pathological fracture (Rajasekaran et al. 2014). Schimer et al (2010) also mention symptoms and signs of spinal TB which include stiffness and spasm of muscles, local pain, a cold abscess, gibbus, local tenderness, and a prominent spinal deformity. These symptoms of spinal tuberculosis manifest in Mr Khan who recorded severe back pain, fever, cold, coughing and reduced mobility.

Early diagnosis is crucial in detecting and developing therapeutic plans for patients with spinal tuberculosis. Studies recommend that early diagnosis of spinal TB can lead to effective treatment plans and management of the patient’s condition (Shetty et al 2016). Difficulties are however present when patients manifesting symptoms of spinal TB instead seek anti-inflammatory medicines over the counters instead of undergoing tests for identification of the spinal TB and consecutive treatment with antibiotics.

Assessment for spinal TB involves a number of tests which can help identify the presence of the disease in patients. A positive skin test and elevated erythrocyte sedimentation (ESR) may be crucial and applied in the diagnosis of spinal TB (de Modeiros et al 2007). Other tests include biopsy evaluation and DNA amplification (polymerse chain reaction). Jain (2010) states that biopsy plays a valuable role in the diagnosis of spinal tuberculosis infection and thus was applicable in the assessment of Mr Khan’s condition. Mr Khan had two biopsies which were culture negative. Each biopsy was taken after antibiotic washout. Histology was suggestive of infection rather than malignancy or granuloma. First biopsy smear and cultures negative for TB. The second biopsy smears negative and TB culture in progress. The second biopsy was also sent for polymerase chain reaction (PCR) but this was negative. However, Rajasekaran et al (2016) argue that culturing the organisms is slow and may be inaccurate, despite multiple attempts. Nevertheless, it is still a valuable diagnostic method resulting in recognising the causative bacteria.

While the Biopsy method of assessment is quite useful, other assessment methods can be more effective especially in detecting advanced cases of spinal TB. Voster et al (2014) states that conventional radiography’s gives a very good overview, computed tomography (CT) the disco-vertebral lesions and also paravertebral abscesses, while studies show MRI is known to be useful in determining the spread of the disease to the soft tissues and to determine the extent of spinal cord involvement (Jain 2010). Magnetic resonance imaging (MRI) plays an important role in early detection of spinal TB than other techniques and more effective treatment. In fact, a combination of CT and MRI has been identified to result in effective revelation of the involved vertebrae and attachments (Rasouli et al 2012). The technology can also exhibit the degree of intervertebral disc reduction, the scope of central lesions and spinal cord compressions (Jain & Ravi 2016).

Due to the limitations of biopsy in effectively detecting the extent of the spread of Spinal TB, CT technology was further applied to Mr Khan as recommended with the NICE (2016) guidelines. Results from the CT examinations revealed that there was a loss in the inferior endplate lucency/bone within the L1 vertebral body which was not present on the previous biopsy examination. These appearances did raise the possibility of discitis/spondylitis, however, there was no visible paravertebral soft tissue mass seen. No other focal bony lesions were identified at `that point. The conclusions of the CT appearances do raise the possibility of L1/2 discitis/spondylitis. Management of spinal TB is commonly achieved by the administration of antibiotics usually in a triple combination of chemotherapy (WHO 2017). However, chemotherapy drugs are more effective if the lesion is limited to the vertebrae. Mr Khan, as pointed out above was administered with a dosage of isoniazid, rifampicin, and pyrazinamide, a standard treatment requirement according to NICE (2016) guidelines. These individual drugs exhibit different pharmacokinetics upon administration to the patients.

This is an anti-tuberculosis drug which is semisynthetic antibiotic derivative of rifamycin SV. This drug is usually a red-brown crystalline powder that is slightly soluble in water. Upon administration, rifampicin is readily absorbed in the gastrointestinal tract. A 600 mg single dose of rifampicin has a biological half-life of 3.35 ± 0.66 hours in the serum. Rifampicin half-life increases with increase in dosage and repetitive drug administration. The half-life of rifampicin doesn’t differ to patients with renal failure at dosage ≤ 600mg daily and thus no dosage adjustments need to be made (Mukherjee et al. 2015). The drug is widely distributed throughout the body and it accumulates in effective concentrations in many body fluids such as cerebrospinal fluid and body organs.

Rifampicin drug functions by inhibiting the DNA-dependent RNA polymerase activity in Mycobacterium tuberculosis bacteria (Mukherjee et al 2015). This interaction doesn’t inhibit the mammalian enzyme. Additionally, rifampicin exhibits different drug interaction behaviour. Rifampicin has the potential of inhibiting plasma concentration of antiviral drugs such as atazanavir and thus should not be co-administered together. Additionally, rifampicin has the potential to accelerate the metabolism of anticonvulsants, and antifungals (Mukherjee et al 2015).

Isoniazid is a hydrazide of isonicotinic acid and is usually colourless or white crystalline powder. The drug is freely soluble in water and slightly soluble in alcohol. Following the oral administration, isoniazid is instantly absorbed in the gastrointestinal tract and its peak concentration in the blood is achieved 1 to 2 hours after administration (Shetty et al. 2016). The liver is the main organ for the metabolism of the isoniazid drugs which are metabolized through acetylation and dehydrazination. Isoniazid works by inhibiting the biosynthesis of mycolic acids, the major components of cell walls of the Mycobacterium tuberculosis (Mukherjee et al 2015).

However, a drug interaction is also manifest with isoniazid drugs. Isoniazid drugs are known to inhibit the metabolism of anticonvulsants, benzodiapens, and haloperidol. Continuous antacid administration may inhibit the absorption of isoniazid. Corticosteroids have been identified to inhibit the concentration of isoniazid by increasing the acetylation rate (Mukherjee et al. 2015).

These drugs are mainly administered at the beginning of the dosage for the treatment of spinal TB. This drug is a pyrazine analogue of nicotinamide and usually appears as a white crystalline powder. After administration, pyrazinamide drug is well absorbed in the gastrointestinal tract, attaining peak concentration within 2 hours (Mukherjee et al. 2015). Unlike the other two, the exact mechanism of pyrazinamide against Mycobacterium tuberculosis is not well known.

Rifampicin, isoniazid and pyrazinamide drugs have potential side effects associated with their administration. Common side effects include nausea, vomiting, drowsiness, and fatigue (Jain & Ravi 2016). Furthermore, Rifampicin has been associated with transient abnormalities in liver functioning, thrombocytopenia in cases of high dosage and occasional pruritus (Shetty et al 2016). Isoniazid has been linked with peripheral neuropathy, pancreatitis, and agranulocytosis. Pyrazinamide, on the other hand, is capable of causing sideroblastic anaemia, mild arthralgia, and anorexia. it is, therefore, possible that fever, high CRP, vomiting, and nausea experienced by Khan are manifestations of side effects of rifampicin, isoniazid and pyrazinamide drugs, much as they are signs of tuberculosis.

Effectiveness of drugs in managing spinal TB

While chemotherapy through the use of rifampicin, isoniazid and pyrazinamide drugs is a common method for managing spinal tuberculosis and is the recommended dose according to NICE (2016) guidelines, the drugs have limited ability to manage serious conditions of the disease since their action against the bacteria is limited and also possible drug interaction further inhibit their potential (Schimer 2010). Alan et al. (2015) emphasize that the anti-TB drugs may not be helpful to patients with risk of instability, the progression of neurological deficit and refractory to medical treatment. For these reasons, other interventions have been developed including surgery. Modern surgical management of spinal TB is achieved through a number of options like anterior spinal fusion, anterior-posterior spinal fusion, and posterior spinal fusion (Rajasekaran et al 2016).

As supported with studies, the combination of surgery and chemotherapy has been identified to effectively manage the spinal TB conditions. An Anterior surgery approach allows for direct access to the lesions and full decompression of spinal cord whereas the posterior approach provides an assurance for superior posterior stabilization (Alam et al 2015). The study by Alam et al. (2015) has identified that the surgical treatment of spinal TB is effective and safe with good radiological outcomes.

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Conclusion

The tuberculosis bacillus bacteria are responsible for causing the complications have been identified to have a serious immunodeficiency impact on the immunity of the patients. Bearing in mind that the bacteria can only be controlled, there are intervention measures to manage the condition. As has been discussed in this paper, oral medication can be administered to the patients with the condition and control the condition.

References

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  • Jain A, Ravi S. (2016): Tuberculosis of spine. In: Weinstein SL, Buckwalter JA, eds. Turek’s Orthopaedics. Philadelphia, PA: Wolters Kluwer; 1412-1617.
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  • Subramani S, Shetty AP, Kanna RM, Shanmuganathan R. (2017): Ossified ligamentum flavum causing neurological deficit above the level of post-tuberculous kyphotic deformity. Journal of Clinical Orthopedic Trauma; 8:174-177.
  • Tuli SM, 2013; Historical aspects of Pott’s disease (spinal tuberculosis) management, European Spine Journal. 22 (suppl 4):529-538
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