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Tuberculosis and a focus on rifampicin

A 47-year-old woman was admitted to hospital with acute onset dyspnoea and right-sided pleuritic chest pain. She was diagnosed with a PE (pulmonary embolism) in the right lower lobe, which was complicated by left lower lobe pneumonia, and accompanied by anaemia and thrombocytopenia.

A 47-year-old woman was admitted to hospital with acute onset dyspnoea and right-sided pleuritic chest pain. She was diagnosed with a PE (pulmonary embolism) in the right lower lobe, which was complicated by left lower lobe pneumonia, and accompanied by anaemia and thrombocytopenia.

She had recently been diagnosed with HIV infection and pulmonary tuberculosis (see Panel 1: About tuberculosis), on the basis of a sputum smear obtained by BAL (broncho-alveolar lavage), which tested positive for AFB (acid fast bacilli). Sensitivity analysis indicated that the TB was fully sensitive to the four standard antitubercular drugs, which had already been started.

Panel 1: About tuberculosis  

Monica Schroeder/SPL

There are around 9,000 cases of TB reported in the UK each year. According to Public Health England, most cases occur in urban centres, in young adults, those from countries with high TB burdens and those with social risk factors (eg, overcrowding).

Tuberculosis usually affects the lungs but can infect other parts of the body (extrapulmonary TB). Only the pulmonary form of TB is infectious — the bacteria are spread by coughing and sneezing and the inhalation of air-borne droplets. The illness develops slowly and symptoms appear some time after infection. Most patients receiving treatment are considered no longer infectious after two weeks.

Symptoms Symptoms depend on the site of infection but typical symptoms of “active” pulmonary TB include a persistent cough (more than three weeks) with phlegm (may contain blood), weight loss, night sweats, fever, fatigue and loss of appetite. Latent TB is symptomless. Bone pain is a symptom of skeletal TB, headaches and vomiting are symptoms when TB infects the brain or spinal cord, and abdominal pain and diarrhoea can be symptoms of gastrointestinal TB.

Treatment Usual treatment of TB consists of:

- Isoniazid and rifampicin daily for six months, plus

- Pyrazinamide and ethambutol daily for the first two months

Resistance Large mycobacterial populations contain a number of resistant mutants. Where treatment consists of a single drug, rapid suppression of susceptible mycobacteria allows resistant mutants to dominate the population. Low drug concentrations perpetuate this effect among large bacterial populations, the emergence of resistance increasing in line with population size.1,2 The use of combination therapy throughout the period of high mycobacterial burden prevents this situation from developing.

During the continuation phase of treatment, resistance ceases to be an issue, the mycobacterial population being small enough to contain no resistant mutants, and dual therapy is sufficient.1

With the inexorable rise in the incidence of drug resistance and the development of new agents, we may find that the future of TB therapy lies in more individualised regimens.

Vaccination The Bacillus Calmette-Guérin vaccine is not currently given as part of the routine NHS childhood vaccination schedule unless a baby is thought to have an increased risk of coming into contact with TB (eg, those born in inner-city areas with high TB rates). The vaccination may be recommended for older children at risk (eg, those children who have come into close contact a patient with pulmonary TB) but it is rarely given to anyone over the age of 16 years because it tends to be less effective in adults, although it may be used in healthcare workers.

 

Subsequently highly active antiretroviral therapy (HAART) was also initiated and, after a month, viral load dropped to 1,150 HIV RNA copies/ml, from 68,000 copies/ml at diagnosis, indicating good compliance.

Medication on admission was as follows:

  • Rifinah 300 (rifampicin 300mg, isoniazid 150mg) po ii od
  • Ethambutol 800mg po od (body weight 48.8kg)
  • Pyrazinamide 2g po od
  • Pyridoxine 25mg po od
  • Truvada (tenofovir 245mg, emtricitabine 200mg) i po od
  • Efavirenz 600mg po od
  • Co-trimoxazole 480mg po od for PCP (Pneumocystis jirovecii pneumonia) prophylaxis

The standard dosing of rifampicin and pyrazinamide suggest that this patient’s weight had dropped following initiation of therapy — a reduced daily dose of 450mg and 1.5g, respectively, is generally recommended for those weighing less than 50kg.3 In this case, however, the higher doses were continued because the patient was suffering no adverse effects and it was thought that the benefits outweighed the risks. Our consultant favours the use of Rifinah (rifampicin and isoniazid) over Rifater (rifampicin, isoniazid and pyrazinamide) because it leads to less confusion when switching to dual therapy after the first two months.

It is best not to start antiretroviral therapy at the same time as TB treatment in order to avoid drug interactions and to reduce the likelihood of toxicity. This also reduces the risk of immune reconstitution inflammatory syndrome (IRIS; see Panel 2).

Panel 2: IRIS

Restoration of immune responses following initiation of highly active antiretroviral therapy may lead to activation of latent  disease, such as tuberculosis, mycobacterium avium-intracellulare, herpes simplex, varicella zoster, cytomegalovirus or John Cunningham virus, or other opportunistic infection.4

In the case of mycobacterial infection immune reconstitution inflammatory syndrome takes the form of cutaneous delayed-type hypersensitivity to tuberculin (TB protein) occurring within two months of the initiation of HAART, and usually within two to three weeks. Delayed-type hypersensitivity responses are mediated by T-lymphocytes and involve granulomatous inflammation and tissue necrosis.4 (Granulomas are a small clump of cells formed if the immune system tries to fight off infection but cannot remove it. In effect, a granuloma walls off the infection. However, this also shields the infection from the immune system and antibiotic attack.) HIV infects and destroys T-cells. Impaired T-cell function inhibits granuloma formation.

With the introduction of HAART, restored T-cell function enables the immune system to mount a response against the pre-existing infection, leading to paradoxical clinical deterioration. Up-regulation of infected macrophages at inflammatory sites re-establishes granuloma formation and results in rapid enlargement of lymph nodes. Signs and symptoms of the response include fever, nausea and vomiting, diarrhoea, intrathoracic and cervical lymphadenopathy, and pulmonary infiltrates that may or may not be accompanied by hypercalcaemia.5 In cases of latent cerebral TB, raised intracranial pressure can be fatal.

Common practice is to start TB therapy first (to reduce the bacterial load, thus reducing the risk of IRIS) and to delay HAART at least until completion of the initial two months’ aggressive TB therapy, as recommended by the British HIV Association (BHIVA).6 However, where the CD4+ count is dangerously low, the chance of successful TB eradication is hampered by the patient’s impaired ability to mount an effective immune response. The risk of vulnerability to opportunistic infections is also prolonged. So, where the CD4+ count is below 100, as in this case (49 cells/µl at presentation; rising to 90 cells/µl by date of admission), initiation of HAART?and TB therapy are separated by two weeks.

The pneumonia was successfully treated with a 10-day course of intravenous piperacillin/tazobactam, followed by oral co-amoxiclav for a further seven days. Tinzaparin (9,000 units subcutaneously daily) was prescribed for management of the PE (to be continued for six months) in preference to warfarin therapy in view of its interaction with rifampicin.

Once the patient had completed over a month’s antiretroviral therapy without adverse effects, Truvada and efavirenz were switched to one Atripla tablet daily to reduce the pill burden. (Atripla is not licensed for initiation of antiretroviral therapy.)

Tuberculosis treatment

The standard combinat­ion of medicines used in the treatment of TB has arisen as a consequence of their diverse mechanisms of action; their complementary activities are exploited in order to reduce the risk of resistance and limit the duration of treatment.

 

Isoniazid disrupts bacterial cell walls. Of all the antitubercular drugs it exhibits the greatest early bactericidal activity (EBA),7 producing rapid mycobacterial suppression and 95 per cent kill within five days.1

EBA is a measure of the fall in colony-forming units (log10 CFU) per millilitre of sputum per day over the first few days of treatment, which is the period of most prolific replication. It gives an indication of drug activity against replicating, but not dormant, organisms and is often used to evaluate efficacy in new drugs.

The mechanism of action of pyrazinamide is uncertain, but the drug is active in acid environments such as within macrophages. This means it is effective against dormant bacteria that hide in such cells to avoid the host’s immune system, and it prevents the relapse that could occur upon their emergence over the first couple of months.8

Ethambutol, which has the second best EBA but poor sterilising ability, increases permeability of bacterial cell walls and is included in the regimen in case of resistance to isoniazid.1

Rifampicin (see Panel 3) possesses the most powerful sterilising ability, acting preferentially against the more slowly metabolising bacilli that remain after five days, with some effect against semi-dormant, slowly dividing bacilli.1,2 It inhibits RNA synthesis by steric block of the active site of bacterial, but not mammalian, DNA-dependent RNA polymerase, in particular the ß-subunit, for which it possesses high affinity. Anchoring itself within the binding groove by means of van der Waals interactions,2 rifampicin specifically inhibits formation of the second or third phosphodiester bond in the RNA transcription process,27 terminating the chain at two to three nucleotides.25

Panel 3: About rifampicin 

 

Rifampicin structure is based on a napthoquinone (Dr Tim Evans/SPL)

Rifampicin is a semi-synthetic derivative of rifamycin, a natural product, which was isolated in 1957 from a strain of the fungus Amycolatopsis rifamycinica (originally Streptomyces mediterranei) obtained from a soil sample from the French Riviera.

In an attempt to formulate a more stable product, a series of structural modifications were conducted, culminating, in 1959, in the production of orally active hydrazones, of which 3-(4-methyl piperazinyl-imminomethyl)-rifamycin SV was the most stable and potent.2 Demonstrating high efficacy and good tolerability, it was named “rifampicin” and introduced in 1967.

The target enzyme RNA polymerase is highly conserved among prokaryotes accounting for rifampicin’s broad spectrum of activity, covering Gram positive cocci, including meticillin-resistant Staphylococcus aureusNeisseria gonorrhoeae and Haemophilus influenzae. In order to limit the development of resistance, use is largely restricted to serious infections with few effective treatments, such as TB.

Dosing considerations Along with aminoglycosides and fluoroquinolones, rifamycins exhibit concentration-dependent antimicrobial activity, which is associated with a prolonged post-antibiotic effect (PAE), the ability to suppress bacterial regrowth despite levels falling below the minimum inhibitory concentration (MIC).9 Rifampicin exerts a PAE of several days in vitro, which allows intermittent therapy, as in the three-times-a-week regimens employed in directly observed therapy.10,11 Thrice-weekly regimens appear effective and tolerable, but attempts to reduce to weekly by the use of higher dosing have led to significant adverse reactions. Doses of 900mg or 1,200mg given as part of a once- or twice-weekly regimen over prolonged periods gave rise to an influenza-like syndrome.12

The original dosing (10mg/kg) was based on the minimum effective dose, established as being the most cost-effective at a time when  the drug was new and expensive.13 This has been standardised to 600mg daily for individuals weighing 50kg or more, and 450mg for those whose body weight is less than 50kg, and continues to be the accepted standard dose. However, despite remaining above the MIC of 0.15mg/L for 10 hours,14 this dose produces serum concentrations towards the lower end of the concentration-response curve.10,15,16

The higher daily doses required for the treatment of leishmaniasis (600mg bd), brucellosis (900mg od) or staphylococcal infections (600mg bd) are well tolerated. Treatment courses are shorter (28 days, 45 days and up to 12 weeks, respectively), but it has been reported that some patients have been able to tolerate high-dose rifampicin for up to a year.17

The efficacy of concentration-dependent activity is best described by the AUC:MIC quotient.18 A dose of 600mg of rifampicin gives a value of 120 against Mycobacterium tuberculosis,10,16 but to achieve one log10 reduction in CFU requires an AUC:MIC ratio of 271.18

Given that CYP450 induction is maximal at 300mg16 and first-pass metabolism saturates at 450mg,19 doses above these would be expected to produce logarithmic increases in bactericidal activity18,20,21 without any increase in drug interactions. Diacon et al22 observed a doubling of EBA over two and five days using doses of 1,200mg daily but the study was too short to assess long-term tolerability. A small study (n=50) in Indonesia demonstrated that an increase in dose of 30 per cent (13mg/kg) produced a 49 per cent increase in Cmax and 65 per cent in AUC compared with standard dosing, and without any flu-like symptoms or any associated reduction in tolerability during six months. Peak levels above 8mg/L were achieved in 96 per cent of subjects compared with 79 per cent of the 10mg/kg group.23 Similarly, doses under 600mg (450mg and 300mg) have been found to be less effective, due, in part, to the reduction in the AUC:MIC ratio but also to the greater relative protein-binding.24

The influenza-like syndrome, together with concerns over the incidence of hepatotoxicity, discouraged clinicians from using daily doses greater than 600mg long-term for TB. However, the syndrome has subsequently been attributed to an immune complex-mediated hypersensitivity involving rifampicin antibodies produced during the interval between doses, rather than the dose itself.12 Moreover, the incidence of raised liver transaminases and bilirubin levels is common; it is not dose-related and severe hepatotoxicity is rare.22

Resistance Because resistance to rifampicin develops rapidly — within six to eight weeks of monotherapy — it is always used in combination with other agents. In 95 per cent of cases, rifampicin resistance arises from single point mutations of the rpoB gene that encodes the ß-subunit binding site on RNA polymerase, resulting in decreased affinity for the drug.25,26 Isolated rifampicin resistance is uncommon. Resistance more frequently occurs in combination with isoniazid resistance as MDR (multi-drug resistant) TB.

Rifampicin has good EBA, although it is lower than that of isoniazid. However, its bactericidal activity is more sustained, being maintained against the logarithmic growth phase,1 and against intracellular bacteria in anaerobic environments, such as within macrophages or closed caseous tuberculous lesions. Its inclusion in the regimen for TB from 1981 facilitated the shortening of the treatment course from nine to six months, improving compliance and quality of life.

Lack of response

Pulmonary TB is usually no longer considered contagious after the first two weeks of treatment and following a negative sputum smear for AFB. However, this patient’s sputum smears were repeatedly positive over the first two months and the TB appeared unresponsive to the standard four-drug therapy (rifampicin and isoniazid, plus pyrazinamide and ethambutol) by the time it would usually be appropriate to reduce to the two-drug (rifampicin and isoniazid) continuation phase.

The focus of improving treatment was centred on rifampicin because, having the greatest sterilising ability, it exerts the greatest influence over eradication of the infection.

In the absence of resistance (confirmed by the sensitivity analysis), four possible reasons for a lack of response to antituberculous medication are: poor compliance, drug interactions, malabsorption and inter-individual pharmacokinetic variation. In this case, the first explanation was considered unlikely and ruled out by nursing staff who directly observed administration. The other three explanations are considered below.

Drug interactions Several components of the standard TB regimen influence the activity of metabolic enzymes. They interact with one another and with other medicines. Rifampicin is a potent inducer of hepatic drug metabolism enzymes, including cytochrome P450s, uridine diphosphate glucuronyl transferases, glutathione epoxide transferases and monoamine oxidases, and of the efflux transporter P-glycoprotein (P-gp). Its ability to reduce the concentration of many drugs is well known. (A pharmacokinetic study has identified co-trimoxazole as being one such drug,28 and it may have been advisable to double the patient’s dose to 960mg daily to provide more effective PCP prophylaxis. However, either dose is supported by BHIVA and 480mg is used as standard for HIV patients in my hospital trust.)

In contrast, drugs that affect the concentration of rifampicin are few — simultaneous administration of para-aminosalicylic acid or ketoconazole may reduce absorption29 (an effect that can be lessened by separating administration by 12 hours) but neither apply in this case. The combination product Rifater (rifampicin co-formulated with isoniazid and pyrazinamide) can impair rifampicin absorption but this effect is counterbalanced by the increased dosage provided by the weight-based dosing structure.30 An increase in rifampicin concentration by co-trimoxazole has been reported31 but this would be considered beneficial in this patient.

In this case, other than a potential for reduction in efavirenz concentration by rifampicin, no interactions would be expected or were identified using the University of Liverpool HIV interactions checker.32 For patients weighing more than 50kg the manufacturers recommend increasing the dose of efavirenz to 800mg33 for the duration of rifampicin therapy, although BHIVA favours delaying dose adjustment until 60kg is reached.6 Because this patient did not regain weight she was continued on standard dose efavirenz, and this proved sufficient — after three months of HAART, her viral load became undetectable.

Malabsorption Peak rifampicin levels were measured and found to be consistently low, 3.6mg/L on one occasion, and 2.7mg/L on another, even after two months. The therapeutic concentration quoted in the literature varies between 4mg/L and 24mg/L, with most favouring 8–24mg/L. The laboratory quoted range of 4–8mg/L34 has been described as adequate, although 8–15mg/L is considered ideal and concentrations falling below 4mg/L are classified by some as very low. In an article in Drugs, Peloquin recommends a dose increase where levels lie below 6mg/L.30

Although rifampicin is readily absorbed from both stomach and duodenum, absorption can be variable.35 Food, in particular a meal with high fat content, decreases the peak concentration (Cmax) by about one third and delays time to peak concentration (Tmax) from two to four hours, while reducing the area under the concentration curve (AUC) to a lesser and more variable extent.14,30 In general, patients are advised to take anti-TB medicines on an empty stomach, half to one hour before breakfast.

In view of the ability of rifampicin to induce its own metabolism over the first six days of treatment, levels should not be measured for two weeks after starting therapy to ensure attainment of steady state. In order to be sure of capturing the peak, a series of levels are measured at intervals of one, two and four hours after the dose.30,32 To rule out malabsorption in this patient, we decided to convert to intravenous therapy: rifampicin and isoniazid may be directly converted (ie, 600mg daily and 300mg daily, respectively), and, although an unlicensed intravenous preparation of ethambutol exists, levofloxacin 500mg was substituted. Pyrazinamide, having no intravenous counterpart, was continued orally.

One week later peak rifampicin levels reached 7.3mg/L, achieving 9.9mg/L at three weeks and yet the patient was still unresponsive. So the fourth explanation, wide inter-individual variation in metabolism,36 which is common with oral antibiotics,19 was also considered.

Inter-individual variation Contributing factors to inter-individual variation in metabolism include:

  • Food
  • First-pass metabolism
  • Protein binding
  • Metabolic enzyme polymorphisms

The effect of food on bioavailability, as has already been mentioned, is inconsistent, being more pronounced for low doses than high doses, which may be explained by the degree of protein binding. Having poor water-solubility, most (97 per cent) rifampicin circulates bound to plasma proteins,37 therefore higher doses are associated with a greater free fraction and, consequently, greater activity. In addition, rifampicin is a substrate for P-glycoprotein and is subject to intestinal and hepatic first-pass metabolism, both of which may adversely affect absorption and bioavailability, but evidence for this is scarce.38

Having high molecular weight and poor water solubility at physiological pH,2,37 rifampicin is eliminated by hepatic phase I and phase II metabolism and excreted predominantly via bile. Most undergoes progressive deacetylation to an active metabolite, 25-O-desacetyl-rifampicin, involving entero-hepatic circulation. Although N-acetyl transferases that effect acetylation reactions are well known to possess polymorphic variants,39 deacetylation involves hydrolysis by esterases, which are not known to be subject to such polymorphisms.

However, it appears that additional metabolic pathways may exist. Rifampicin therapy has been reported to stimulate proliferation of hepatocyte smooth endoplasmic reticulum, a structure involved not in oxidation but in glucuronidation.19 In contrast to hepatic esterases, the enzymes responsible for glucuronide conjugation, UDP glucuronyl transferases, do occur in a number polymorphic forms.40 This, combined with a degree of malabsorption, may have contributed to the inadequate response to therapy in this patient.

Discha­rge

Having established an increase in rifampicin levels using intravenous therapy, it was necessary to switch the patient back to oral medication in order to prepare her for discharge. Increasing the dose of rifampicin to 900mg daily seemed a reasonable option, with continued monitoring of liver function.
­The patient was discharged on rifampicin 900mg od, isoniazid 300mg od, pyrazinamide 2g od, levofloxacin 500mg bd and pyridoxine 25mg od.

Ethambutol was substituted for levofloxacin at the first clinic visit and quadruple therapy continued for four months followed by two months of dual therapy. The patient suffered no adverse effects and her LFTs (liver function tests) remained acceptable. No mycobacteria were isolated from sputum cultures after four months of therapy.

The patient completed her therapy and made a good recovery.

Key points

- Symptoms of pulmonary tuberculosis include a cough for more than three weeks, night sweats, fatigue and weight loss.

- Treatment consists of combination therapy (four drugs for the first twomonths, then two drugs for four months). This helps to prevent resistance.

- Pharmacists should support adherence and there are a number of resources available (eg, leaflets from TB Alert) to help.

Case comment: Adele Gothard, lead infectious diseases pharmacist 

Adele Gothard

This is an excellent case to demonstrate the complexity of HIV and tuberculosis co-infected patients. There are often drug-drug interactions and adherence issues to consider alongside the increasing benefits of treating HIV within two weeks of starting TB therapy. Managing a patient with immune reconstitution inflammatory syndrome is even more complex and due attention should always be given to preventing this condition.

Resources It is interesting how different units manage TB in terms of preference to fixed dose combinations and simplicity. This patient will have had a high pill burden. It would have been important to ensure she was fully informed about what the medicines are for and how to take them appropriately, and there are many resources out there to assist the pharmacist. For example, nine leaflets in 21 languages, covering TB topics from vaccination to contact tracing, are available from the charity TB Alert (www.tbalert.org)  An “HIV & TB” booklet is also available from www.aidsmap.com. 

Interactions I would agree in this case to leave the patient on co-trimoxazole 480mg od. There is a possible interaction but because the patient had thrombocytopenia when she was admitted, which can be a side effect of co-trimoxazole I think it important to keep on this dose. I would keep monitoring the full blood count and, if necessary, switch to an alternative Pneumocystis jirovecii pneumonia prophylaxis.

MDR TB According to a paper in Lancet Infectious Diseases (online 4 March 2014), between 2000 and 2012 the number of multi-drug resistant (MDR) TB cases in the UK increased from 28 per year to 81 per year. MDR TB would have been a differential diagnosis in this patient if sensitivities had not been confirmed. MDR TB presents numerous challenges to the multidisciplinary team in terms of pill burden, adverse events and a paucity of drug interaction data.

Further reading

  • The World Health Organization Treatment of TB guidelines, 4th edition. 2010.
  • National Institute for Health and Care Excellence. Clinical guideline 117. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. 2011.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11135743

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