Clinical Pharmacology & Prescribing
“42 year old female with multibacillary leprosy”
Leprosy is an infectious disease caused by the acid-fast Gram-positive bacteria Mycobacterium leprae. It is a chronic condition which is thought be transmitted between individuals through sputum or nasal secretions (for example, sneezing), and has a long incubation period – it can reside dormant in the body for between two to six years before a patient exhibits symptoms1. The area most commonly affected is the periphery, including the skin, the nervous system, the lining of the nose, and the mucosa of the mouth and eyes, and it is thought to be due to temperature preference of the bacteria that result in the expression of these symptoms (optimal growth appears to be around skin temperature of 30°C as opposed to core body temperature of around 37°C). The bacteria appear to be particularly partial to nerve tissue, and are found to multiply abundantly in the space around the neurones. When the bacteria die, they release chemicals which cause serious nerve inflammation which applies great pressure to the axons and results in their irreversible damage. From this it follows that the sense of feeling is lost, and often muscle damage can occur as a consequence of the neuronal destruction2.
The disease manifests itself mainly by the formation of lesions, especially in the mouth and on the skin. These can either be flat (macules) or raised (papules), and are noticeably devoid of sensation (hypoanaesthetic) due to neuropathy induced by the microorganism. On observation, the lesions appear depigmented which makes leprosy difficult to diagnose initially, as it may be confused with other melanin-deficient conditions such as vitiligo3. Lesions often progress to an ulcerative state and cause skin tissue necrosis, which can culminate in disments such as the loss of extremities including the fingers, toes, and occasionally the nose ( 1). These disments have long term implications, often leading to serious social problems long after the disease has been cured. For those who experience neuropathy, careful counselling is required as they will never regain the feeling in their affected limbs. This is because nerve tissue cannot replicate, and therefore cannot repair itself. Advice on how to continue life as normally as possible will include being aware of hot or sharp objects to avoid sustaining further tissue damage4.
The condition was first discovered to be a consequence of M. leprae infection by Gerhard Armauer Hansen in 18735, and it is for this reason that leprosy is occasionally referred to by its eponymous name, Hansen's Disease. It is thought to have been prevalent for thousands of years with the first known cases being documented as far back as 600 BC, which makes it one of the longest suffered diseases in history3. It also has a strong social impact, with sufferers being known to be excluded from families and villages due to the fear of contagion, and extradited to so-called ‘leper colonies.' These are not so common in current times, although still exist in endemic countries such as Egypt, where despite being cured of the disease many patients choose to remain in the colony. Some feel more comfortable in this environment as they have been there so long they can't imagine going back to life outside the colony6. In a report published by the WHO in 2009, the current incidence of leprosy globally was found to be 249,007 whilst the registered prevalence was 213,036 spread across 121 countries. Detection of new cases has shown a steady decline since 2002, with a 40.12% reduction overall from 2002 to 2008, and most recently, a 3.54% between 2007 and 2008, based on reports from 126 countries across the world. The majority of new cases in 2008 were found in South-East Asia (67.27% of total world prevalence), with the highest number of new diagnoses (53.89%) being made in India7.
Diagnosis itself depends on the number of skin lesions, and areas where loss of sensation is experienced, as well as the results of skin smears or lesion biopsies which should be positive for M. leprae. However, skin smears often do not give a definitive diagnosis as the bacteria live and grow under the epidermal layer. As a consequence, slit-skin smears are being used more frequently8. These are smears where the lesion is cut to a depth of approximately 3 mm, and scrapings are taken from the edge of the cut for analysis. The samples taken cannot be grown in vitro and as such are cultured using a mechanism known as the mouse foot-pad test. Here, the sample is injected into the feet of mice where the bacteria can multiply, before being transferred to a microscope slide for analysis2. Since mycobacteria are acid-fast bacilli, they stain using a Ziehl-Neelsen stain and if present appear as red rod-shaped bacilli on a background of blue cells ( 2).
There are two types of leprosy, and depending on which type is expressed will influence which drug regimen and duration of treatment to be prescribed. Paucibacillary (PB, or tuberculoid) leprosy is when the host mounts a substantial immune response against the infection, and is diagnosed by the presence of between one and five skin lesions which are hypoanaestheic but with few bacilli present, and it is treated with dual-therapy drugs2. The main difference between this and multibacillary (MB, or lepromatous) leprosy is that the number of skin lesions must be greater than five and tend to exhibit ‘foamy' macrophages which are full of M. leprae bacteria2. These factors impact on the drug treatment which increases to triple therapy3,9.
A major problem with treating leprosy is that the mycobacteria which cause the disease are very complex, and demonstrate resistance to drug treatment. The outer layer of the bacterial cell wall has an intricate network of fatty acids (often described as a ‘waxy' coat) and a high concentration of mycolic acids which provides a barrier to drug penetration into the bacterial cystoplasm, therefore, complex drug treatment regimens are required.
As mentioned previously, there are two different drug regimens licensed for treating the two different varieties of leprosy, and these have been used successfully since the 1960's to treat, and in the majority of cases, cure the disease11. Dual therapy consists of a supervised monthly dose of 600 mg of rifampicin (reduced to 450 mg in adult patients who are emaciated or weigh less than 35 kg), in combination with a self-administered daily dose of 100 mg dapsone (reduced to 1 – 2 mg/kg or up to 50 mg daily for adults less than 35 kg). This regimen is known as PB-MDT (paucibacillary leprosy multi drug therapy) and is reserved purely for PB leprosy. It should be continued for six months. If a break in treatment occurs for some reason then there is no need to start the course of treatment from the beginning, and it may be recommenced immediately from the same point as it was terminated in order to complete the full duration of treatment9.
Triple therapy comprises the same drugs and doses as dual therapy, but with an additional third drug – clofazimine. This drug is only licensed in the UK for the treatment of leprosy, and should be administered as a supervised monthly dose of 300 mg, as well as a self-administered dose which can either be 50 mg every day, or 100 mg on alternate days. This regimen is known as MB-MDT (multibacillary leprosy multi drug therapy) and is reserved purely for MB leprosy. The BNF 58 states that it should be continued for two years however, the World Health Organisation (WHO), who have provided free MDT ( 3) for all endemic countries since 1995, suggest a twelve month regimen3,9. This reduced duration has been employed to reduce the risk of drug resistance, especially to rifampicin since studies have revealed no significant reduction in bactericidal effectiveness when the duration of treatment was cut3.
Dapsone was the first drug to be introduced for the treatment of leprosy in the 1940's and was administered as the sole treatment for about a decade. As such the bacteria began to develop a substantial degree of resistance to it, with the first case being discovered in 195312. It is for this reason that additional drugs were required, and in the 1960's rifampicin and clofazimine were developed and introduced as part of a MDT regimen. MDT is now required to eradicate dormant bacteria, and reduce new resistant strains from developing. This is achieved by the shorter duration of treatment, as well as by the use of combination therapy. However, despite these methods drug resistance continues to rise, resulting in multi-drug resistant (MDR) leprosy, providing the rationale for research and development of new drug treatments. Ideally, the duration of treatment should be further shortened in order to provide more effective treatment and better patient compliance.
Complications such as type I (reversal) or type II (erythema nodosum leprosum) adverse reactions can occur as a consequence of inflammation of the nerve fibres caused by the death of the bacteria, either from the national expiration of the bacteria's life cycle, or by lysis induced by the drugs. These types of reaction require subsequent drug treatment. Both types I and II can be treated with prednisolone using an initial dose of 40 – 60 mg daily, although thalidomide may also be used in severe type II reactions on a named-patient basis only9.
Mode of Action of Antileprotics
Dapsone is a sulphone and was first used to treat of leprosy in 1949. It superseded its predecessor, promin, by demonstrating greater efficacy in the clinic, and appears to be bacteriostatic. It acts by competitively inhibiting the bacterial enzyme dihydropteroate synthase (DHPS), thereby inhibiting folate synthesis in the mycobacteria, and by doing so interrupting the metabolism of the microorganism12. Resistance has developed towards this mechanism by genetic mutation of the bacterial DNA. The primary site of mutation appears to be the folP1 gene which codes for the DHPS enzyme. This modifies the ability of dapsone to bind to DHPS, and so the bacteria continue to multiply regardless of the presence of dapsone.
Rifampicin is a rifamycin which acts by inhibiting the growth of mycobacteria by binding irreversibly to the RNA polymerase enzyme required for bacterial mitosis9,12. Since DNA replication has effectively been halted by this, the bacteria cease dividing and die. It is therefore seen to act as a bactericidal agent against mycobacteria, and can be used to treat additional diseases caused by this type of infection (for example tuberculosis, caused by M. tuberculosis). Resistance appears to occur when there is a mutation on the rpoB gene, which encodes for the β-subunit of the RNA polymerase enzyme – the region where rifampicin binds. When this is structurally modified, the drug has reduced affinity for the enzyme and the bacteria are unaffected. Resistance is seen to be more prevalent when rifampicin is given as monotherapy, as opposed to part of a MDT regimen14.
Clofazimine belongs to the riminophenazine class of drugs, and also exhibits bactericidal effects. It is currently only licensed for use in the UK to treat MB leprosy. It is thought to bind directly to the guanine and cytosine residues of the bacterial DNA, thereby inducing cell lysis12. An additional benefit of using this drug is that is also exhibits anti-inflammatory action against type II (erythema nodosum leprosum) reactions which can occur in leprosy and result in serious nerve damage3,9. Despite being used since the 1960's, there appears to be no significant development of resistance to clofazimine over the past four decades, which is obviously advantageous in treating and curing this disease especially since long term therapy is currently required.
Potential New Drug Treatments
Minocycline is a tetracycline antibiotic which as been shown to exhibit some efficacy against M. leprae. It exhibits its bactericidal activity by interfering with the microorganism's protein synthesis after binding to the 30S ribosomal subunit in susceptible bacteria. In a study by Gelber and his colleagues in 1992, it was found that after three months of daily treatment of 100 mg of minocycline, no patient in the trial was found to possess any remaining organisms still capable of growth15. However, an additive effect was found to occur when used in conjunction with the known antileprotic rifampicin16. In current practice, minocycline is only used to treat single-lesion PB leprosy due to the superior action of the preceding antileprotic MDT regimens, but can be seen to provide a beneficial effect in this particular manifestation of the disease12.
Ofloxacin belongs to the fluoroquinolone class of antibacterials which bind to the
α-subunit of the DNA gyrase enzyme, thereby preventing DNA replication. Mutation of the gyrA gene which codes for the enzyme is seen to be the primary factor in development of resistance by the mycobacteria. Clinical trials have shown single-dose ofloxacin to be moderately bactericidal against M. leprae, but Ji and cohorts found in a 1994 trial with dapsone and clofazimine that over 99% of the viable bacteria had been killed after 14 days treatment with ofloxacin alone (in 400 mg and 800 mg daily doses) or in combination with 100 mg of dapsone and 50 mg of clofazimine daily, as well as an monthly dose of 300 mg of clofazimine as is standard in the current MB leprosy MDT regimen3,17. Over 99.99% of viable bacteria were eradicated after 56 days treatment, either alone or in combination with dapsone and clofazimine.
After being withdrawn from the market in the early 1960's due to serious teratogenic effects, thalidomide was reintroduced on a named-patient basis strictly for the treatment of the type II reactions in the late ‘60s18. Further studies in the 1970's deduced that using corticosteroids such as prednisolone were just as, if not more, effective than thalidomide, and reduced the incidence of remission of these type II reactions19,20. However, thalidomide is still used to treat these types of reactions in patients who are steroid-dependant, but is strictly regulated and only used in men and post-menopausal women to exclude any chance of pregnancy9.
The patient in this scenario is a 42 year old woman suffering from multibacillary leprosy. There are a number of factors which will impact on the choice of treatment for her, including her age, sex, weight and type of leprosy. Since MB leprosy has been diagnosed, the patient should be commenced on triple-drug MB-MDT. Providing the patient weighed over 35 kg, she should be given a monthly dose of 600 mg of rifampicin with a 300 mg dose of clofazimine and 100 mg of dapsone on the first day of treatment, then 50 mg of dapsone with 50 mg of clofazimine for a further 27 days. The drugs would most likely be provided in a device similar to the pink blister pack seen in 3. Treatment should be continued for 12 months, and then the patient should be tested to determine if any viable microorganisms remain. If any are found, then the treatment may be continued for a further 12 months9.
Should the patient experience any lepra reactions (either type I or II) then she should be treated with a corticosteroid such as prednisolone in a dose of 40 – 60 mg for a week, before being reduced by 5 mg a week until she is weaned off completely9. Thalidomide should be avoided in this patient as she is likely to be pre-menopausal (she is under the age of 50) although it should be checked to see if she has undergone the menopause, since it can occur earlier in some women. The chance of teratogenic effects on a foetus if she were to become pregnant is too great a risk to take, and there is currently little evidence to support any greater efficacy of using thalidomide over prednisolone, hence the rationale for corticosteroid treatment19.
Common side effects the patient may experience from her treatment include nausea and vomiting, for which an antiemetic such as metoclopramide (10 mg up to three times a day) may be prescribed. If this doesn't relieve her symptoms, then she should be hospitalised for further investigations9. Other side effects include abdominal pain, headache, fatigue, intermittent flu-like symptoms (which coincide with the monthly dose of rifampicin), discolouration of lesions, rash, discolouration of urine and faeces, and rarely serious adverse reactions such as haeomlysis, methaemoglobinaemia, toxic epidermal necrolysis or Stevens-Johnson syndrome (these rare effects are dose dependent and do not tend to occur at the dosages used in leprosy treatment)9.
There is currently not enough evidence to support the use of other drugs (minocycline, ofloxacin and so on) or to change the MDT regimens, despite the cost of MDT. Currently, the WHO reimburses the National Health Service (NHS) should a patient require treatment, with the cost per patient per month being somewhere in the region of £50 for MB-MDT3. For a patient to be completely cured the price of medication would amount to around £600 to £1,200, but this would be more cost-effective in the long term because there is a good chance that the patient would be completely cured, and would not require long-term nursing or occupational therapy.
The success of leprosy treatment really depends on how quickly the disease is diagnosed and treatment initiated, as well as the degree to which the patient complies with the drug therapy. It is no longer a disease which should be feared since it is curable, but it will still take time for the stigma surrounding the disease to completely disappear.
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2. OHCM (Oxford Handbook of Clinical Medicine). Leprosy. In: Chapter 10 – Infectious Diseases. Oxford: Oxford University Press; 2007. p.416-417
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6. BBC (British Broadcasting Corporation) News – Egypt leper colony grows into successful community [Internet]. Accessed: February 2010. Available from: http://news.bbc.co.uk/1/hi/world/middle_east/8521577.stm
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9. BNF 58. Section 5.1.10 Antileprotic Drugs. London: BMJ Group & RPS Publishing; 2009. p.326
10. Original image for 2: Accessed: January 2010. Available from: http://tinyurl.com/yhehd96
11. WHO | Leprosy Key Facts [Internet]. Accessed: January 2010. Available from: http://www.who.int/mediacentre/factsheets/fs101/en/index.html
12. Matsuoka M. Drug Resistance in Leprosy. Jpn. J. Infect. Dis. 2010; 63(1): 1-7
13. WHO | WHO Multidrug Therapy (MDT) [Internet]. Accessed: February 2010. Available from: http://www.who.int/lep/mdt/en/index.html
14. Dietrich M, Gaus W, Kern P, Meyers WM. An International Randomized Study with Long-Term Follow- Up of Single versus Combination Chemotherapy of Multibacillary Leprosy. Antimicrobial. Ag. Chemo. 1994; 38(10): 2249-2257
15. Gelber RH, Fukuda K, Byrd S, Murray LP, Siu P, Tsang M, Rea TH. A clinical trial of minocycline in lepromatous leprosy. BMJ. 1992; 304(1): 91-92
16. Ji B, Perani EG, Grosset JH. Effectiveness of Clarithromycin and Minocycline Alone and in Combination against Experimental Mycobacterium leprae Infection in Mice. Antimicrobial. Ag. Chemo. 1991; 35(3): 579-581
17. Ji B, Perani EG, Petinom C, N'Deli L, Grosset JH. Clinical Trial of Ofloxacin Alone and in Combination with Dapsone plus Clofazimine for Treatment of Lepromatous Leprosy. Antimicrobial. Ag. Chemo. 1994; 38(4): 662-667
18. Pannikar V. The Return of Thalidomide: New Uses and Renewed Concerns. Lepr. Rev. 2003; 74(3): 286-288
19. Van Veen NHJ, Lockwood DNJ, Van Brakel WH, Ramirez Jr J, Richardus JJ. Interventions for erythema nodosum leprosum (Review). Cochrane Database Syst. Rev. 2009: (3); 1-53
20. Villahermosa L, Fajardo Jr TT, Abalos RM, Balagon MV, Tan EV, Cellona RV et al. A Randomized, Double-Blind, Double-Dummy, Controlled Dose Comparison of Thalidomide for Treatment of Erythema Nodosum Leprosum. Am. J. Trop. Med. Hyg. 2005: 72(5); 518-526