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Treatment of pulmonary tuberculosis
Netherlands Journal of Medicine 53 Ž1998. 7–14
Current practise Ž invited.
Treatment of pulmonary tuberculosis J.H. van Loenhout-Rooyackers a
a,)
, J. Veen
b
GGD Regio Nijmegen, Postbus 1120, 6501 BC Nijmegen, Netherlands b KNCV, Postbus 146, 2501 CC Den Haag, Netherlands
Received 6 January 1998; revised 16 March 1998; accepted 7 April 1998
Abstract Recently the duration of treatment for pulmonary tuberculosis in The Netherlands was shortened from nine to six months. A six months regimen containing isoniazid ŽH., rifampicin ŽR. and pyrazinamid ŽZ. daily for two months, followed by H and R daily for another four months Ž2HRZr2HR. has been proven effective for the treatment of pulmonary tuberculosis, provided the cause is a fully susceptible strain of M. tuberculosis. Worldwide there is an increase in drug-resistant tuberculosis. Since at the start of treatment susceptibility tests often are not available, a fourth drug must be added in the intensive phase. Ethambutol is the drug preferred. This means that one always starts with 4 drugs unless the patient is a contact of an index-case with proven susceptibility and one is sure that he will be compliant or ´ the patient is infected in the past before 1940, he received never tuberculostatic drugs and one is sure that there is no exogenous reinfection. If the patient has been treated previously and anti-tuberculosis drug resistance is likely, treatment regimens should contain at least two drugs with which he has not been treated before, while a fifth drug routinely must be added in the intensive phase. Amikacin is preferred, since there is no cross-resistance to streptomycin. Consensus on the duration of treatment for extra-pulmonary tuberculosis has not yet been reached, but basically the principles for treatment are the same. This is also true for HIV infected tuberculosis patients. In some serious clinical situations Žmeningitis, miliary, spine tb. duration of treatment still is 9–12 months. Early involvement of the public health nurse of the municipal health department ŽGGD. is necessary to ensure patient compliance and treatment supervision. q 1998 Published by Elsevier Science B.V. All rights reserved. Keywords: Pulmonary tuberculosis; Isoniazide; Rifampicine; Pyrazinamide
1. Introduction In 1996 the national Tuberculosis Policy Committee ŽCommissie voor Praktische Tuberculosebestrijding, CPT. and the Working Group on Tuberculosis of the Nederlandse Vereniging van Artsen voor
)
Corresponding author. Tel.: q31-24-3297114.
Longziekten en Tuberculose ŽNVALT. reached consensus on the treatment of pulmonary tuberculosis w1–4x. Hereafter the newly advised therapy regimens are discussed, emphasising the differences with the previous policy. A consensus report for the treatment of extra-pulmonary tuberculosis is underway. Few studies deal with the standardised treatment of extra-pulmonary tuberculosis, but the basic principles are similar to those of pulmonary tuberculosis.
0300-2977r98r$ – see front matter q 1998 Published by Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 8 . 0 0 0 6 7 - 9
8
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
2. Treatment objectives The objectives of treatment are two-pronged: to cure the patient in the shortest possible time, and to interrupt the chain of transmission of the tubercle bacilli. During therapy no drug resistance may be induced by treatment errors and no relapse may occur after the end of treatment. This means that treatment must be bactericidal and sterilising. A combination of drugs is needed to prevent the development of drug resistance, but also to affect tubercle bacilli which are at different levels of metabolic activity. The risk of relapse depends on the activity of each of the drugs, the combination used and the duration of treatment.
3. Activity of anti-tuberculosis drugs Mitchison developed a theoretical model using the localisation of tubercle bacilli Žintra- or extracellular., their metabolic activity Žmultiplying, dormant or semi-dormant bacilli. and the activity of each drug w5x. Because the targets for anti-tuberculosis drugs within the bacilli differ and to prevent resistance caused by spontaneous mutations, treatment of active tuberculosis starts with a combination of three or four drugs during the first two months Žinitial phase. and continues with two drugs Žcontinuation phase.. Isoniazid is bactericidal and acts both intracellular in the macrophages and extracellular in the necrotic tissue. Its mechanism is partly unclear, although it is known that the synthesis of mycolic acid, an important part of the cell wall, is inhibited w6x. Isoniazid quickly reduces the size of large populations of multiplying tubercle bacilli which are present in the wall of the tuberculous cavity. Rifampicin and pyrazinamid are less active there. Rifampicin is also bactericidal: it inhibits the RNA-polymerase, causing protein synthesis of the bacillus to come to a halt. It kills persistent semidormant bacilli during their short spurts of metabolic activity. This drug therefore is of great importance for the sterilisation of the process and thus for the prevention of relapse. Sterilisation reflects the power of the drug to kill the slowest metabolising bacillus, thereby ridding the lesion of all bacilli.
Pyrazinamid only works in an acid environment. The tubercle bacillus’ enzyme pyrazinamidase converts it into pyrazinoic acid. It lowers the pH in the macrophages, thereby killing the bacilli which are intracellular, but also is active in the acidified infectious foci Žcheese. w7x. Pyrazinamid therefore is especially important in the initial phase of treatment. It was used in the 1950s in high doses which proved to be too toxic. Since 1978, when was shown that lowered doses are also adequate, it is routinely used in each combination of anti-tuberculosis drugs. Aminoglycosides Žamikacin, kanamycin and streptomycin. block the synthesis of ribosomal RNA. These drugs are bactericidal in aerobic circumstances. Streptomycin has a bactericidal activity but this is limited to extra-cellular actively multiplying mycobacteria Že.g., in cavities.. Fluoridated chinolones like ciprofloxacin and ofloxacin are bactericidal: they inhibit the DNAgyrase of the bacillus. Their mechanism is comparable to that of isoniazid. In case of multi-drug resistance Žat least resistant to isoniazid and rifampicin. chinolones are drugs of first choice. Ethambutol influences the RNA-synthesis of the bacillus and inhibits mycolic acid to become part of the cell wall w8,9x. It is bacteriostatic in the dose of 15 mgrkg body weight and bactericidal in doses of 25 mgrkg body weight. The bactericidal dose is only used during the first 2 months of treatment since longer duration of higher doses increases the risk of ocular side effects. In therapeutic doses it is less effective than the previously described drugs. Other drugs used for the treatment of tuberculosis are clofazimin, prothionamid, rifabutin, cycloserin, thioacetazone and para-aminosalicylic acid.
4. Drug resistance After the introduction of streptomycin in 1940 it became apparent that mono-therapy quickly led to resistance. The same proved true for mono-therapy of isoniazid and rifampicin w10x. Combination therapy prevents the selection of spontaneous resistant mutants. The risk that mutants occur is largest when a high bacterial load is present as in cavernous pulmonary tuberculosis. If however the treatment is
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
9
Table 1 Distribution of drug resistance Ž%. among 809 bacteriologically confirmed tuberculosis cases, The Netherlands Žpatient cohort 1993, coverage 93%. w13x Drug
Asylumseekers Ž n s 106., %
Other foreigners Ž n s 365., %
Dutch Ž n s 338., %
Isoniazid ŽH. Streptomycin ŽS. Rifampicin ŽR.
13 19 3
6 9 2
2 3 1
adequate, risks are negligible. If treatment is inadequate due to erroneous dosages prescribed by the doctor or erroneous delivery by the pharmacist, or if the patient does not take drugs in the proper way, resistance may be induced by human failure w11x. More than in the past also in The Netherlands one has to reckon with resistant strains or with the induction of resistance by treatment errors. Risk groups for tuberculosis in The Netherlands are immigrants from countries with a high tuberculosis prevalence, where also the risk of drug resistance is large Žw12,13x, Table 1.. Homeless people and drug addicts belong to risk groups for tuberculosis and drug resistance. Their way of life increases the risk of treatment error. In view of the increased mobility Dutch travellers more then in the past run the risk to get infected with a resistant strain when travelling in foreign countries Žw13x, Table 2..
5. Duration of treatment and effectivity Isoniazid, rifampicin and pyrazinamid are essential for the treatment of tuberculosis and the combination is sufficient for the treatment of normal sensitive human bacilli. Before treatment starts the defi-
nite type of bacillus and its susceptibility pattern are not yet known. Since one has to reckon with the possibility of resistant strains we have to add a fourth drug to the combination in the intensive phase of treatment. As a fourth drug ethambutol is advised in stead of streptomycin, since next to isoniazid resistance, streptomycin resistance is also predominant. In everyday life it means that one always starts with 4 drugs unless one can assume with certainty that the disease was caused by a sensitive strain. Initial treatment with more than 4 drugs may be necessary if treatment in the past took place. A careful medical history taking into regard the drugs which were used, is of utmost importance. The new treatment scheme has to contain at least 2 drugs with which the patient has not been treated before. As a fifth drug amikacin is preferred since it has no cross-resistance to streptomycin. Treatment in the intensive phase must be daily and in one dose. Once the definite type and its susceptibility pattern are known, the medication may be adapted. If a strain is susceptible amikacin andror ethambutol can be discontinued. Pyrazinamid must be given for at least 2 months. It can be stopped after 2 months if sputum smear microscopy shows no further bacilli Žsputum conversion. and if one is
Table 2 Drug resistance should be suspected when Patients report prior treatment Patients have been in contact with drug-resistant tuberculosis index case Patients became infected and the resistance pattern of index case is unknown Patients belong to a high-risk group for resistance because their way of life increases the risk of treatment error Patients become smear-positive again after prior sputum conversion Patients do not respond to therapy as expected See Ref. w13x.
10 J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
Fig. 1. Treatment of the patient with pulmonary tuberculoses1. This flow-chart is only valid if no simultaneous resistance to isoniazid and rifampicin is present. Bacteriologic examination is repeated periodically. The treatment episode is ended by culture of the sputum specimen. Induction of sputum and bronchoscopy increase chances on a positive culture and ensuing suceptibility examination. This is especially important for patients with previous treatment for tuberculosis. H s Isoniazid, R s rifampicin, Z s pyrazinamid, E sethambutol, A samihacin. 1 Criteria for active tuberculosis, Table 3; for the diagnostic process, Table 4. 2 Resistance pattern of the source is still unknown. 3 Patient with normal susceptibility pattern.
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
11
Table 3 American Thoracic Society criteria for active tuberculosis Response to tuberculostatic treatment and at least 2 of the next 3 criteria are fulfilled: 1 one or more of the next clinical findings: fever ) 388C during at least one week night sweats more than one week weight loss ) 20% bodyweight cough dyspnea hemotysis lymphadenopathy ) 4 weeks 2
One or more of the next microbiologic criteria acid-fast bacilli in Ziehl–Neelsen stains growth of M. tuberculosis, Lowenstein–Jensen ¨ granulomas with caseous necrosis by histological examination.
3
Radiographic criterium chest X-ray suspect for tuberculosis Žinfiltration, pleural opacity, hilar lymphadenopathy.
certain that the strain is sensitive Žw1x, Fig. 1 and Tables 3 and 4.. During the continuation phase the patient is treated with at least 2 drugs for which the bacillus is susceptible, mostly being isoniazid and rifampicin if no resistance is present. How long should the continuation phase with isoniazid and rifampicin be continued? A nine month during treatment regimen without pyrazinamid, but with isoniazid, rifampicin and either ethambutol or streptomycin caused a bacteriological proven relapse in 3 of 298 patients Ž1% or 0.2–2.9% with a 95%
confidence interval. w14x. It was expected that the addition of pyrazinamid to isoniazid and rifampicin could shorten the duration of treatment. After reintroduction of pyrazinamid in therapeutic adequate dosages after 1978 most countries reduced the total duration of treatment from 9 to 6 months. A treatment duration of 6 months with isoniazid, rifampicin and pyrazinamid for pulmonary tuberculosis patients, infected by a susceptible strain showed a relapse in 116 of 4833 patients, i.e., 2.4% ŽC.I.s 2.0–2.8. w2x. The American Thoracic Society ŽATS. accepts a relapse rate of less than 5% w15x. In The Netherlands,
Table 4 Diagnostic process Medical history Žsymptoms of tuberculosis, contact of patients with tuberculosis, born or travelling in countries with high prevalence of tuberculosis. Clinical examination. Microbiological examination. acid-fast bacilli in Ziehl–Neelsen or Auramine stains growth of M. tuberculosis, Lowenstein–Jensen or 7H10. ¨ polymerase chain reaction ŽPCR. on DNA and RNA. In the future it will be possible to distinguish between visible and viable bacteria DNA-fingerprinting by restriction fragment length polymorphism ŽRFLP. analysis to identify clusters of identical fingerprints Histological examination Žalso Ziehl–Neelsen or Auraminestain.. PPD Žreaction of mantoux. Chest X-ray Serological examination Žnot yet valuable.
12
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
using the tuberculosis registration cards kept by the Health Inspectorate, it was calculated that the percentage of Dutch inhabitants with a relapse of pulmonary tuberculosis in the period 1984–1990, in whom the relapse occurred within 5 years after the previous episode, was 44 out of 1792 Ž2.5%, CI s 1.8–3.2. w16x. This well below the 5% level of the ATS. The shorter the duration of treatment the better the patients’ compliance. The CPT decided that also in the Netherlands treatment of pulmonary tuberculosis, when caused by fully susceptible bacilli, can be decreased to 6 months duration by shortening the continuation phase. This however can only be done when treatment compliance is perfect. The public health nurse of the municipal health services ŽGGD. therefore has to supervise the patient during treatment.
been done in the same way as with pulmonary tuberculosis. Objective criteria for treatment outcome, like sputum conversion or improvement of the radiological image, as in pulmonary tuberculosis, are lacking. During therapy even new glands and tuberculomas may evolve or enlarge. The basic principles of treatment however are the same, although in milliary tuberculosis, tuberculous meningitis and tuberculosis of the bones generally duration is increased to 9–12 months w17–19x. Depending on the localisation, adjuvant interventions like bed rest and surgery may be needed. If during the diagnostic process tuberculosis is considered, material for further diagnosis always need to be sent for sputum smear microscopy and bacteriological culture. More than in the past one has to reckon with the presence of resistant strains.
6. Extra-pulmonary tuberculosis
7. Corticosteroids
Clinical trials into the effectivity of standardised treatment of extra-pulmonary tuberculosis have not
In general corticosteroids play no role in the treatment of tuberculosis. Only in tuberculous
Fig. 2. The approach to treatment of TB in HIV-infected patients who also need protease inhibitors w23,24x.
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
meningitis and pericarditis it is suggested to be effective w20,21x.
13
start of the treatment. Treatment compliance ultimately is only guaranteed if medication is taken under direct supervision.
8. HIV-infected tuberculosis patients References For HIV-infected patients with pulmonary tuberculosis the same treatment schedules apply as for patients without HIV infection w17x. There is an increased risk for adverse effects and mal-absorption. Measurement of the serum concentration of the drugs may be needed. In cases where treatment is sub-optimal, duration of treatment must be increased. There are insufficient data about the treatment of extrapulmonary tuberculosis in HIV infected patients. Treatment must always be individualised. Rifampicin lowers the serum concentration of the protease inhibitors, thereby contributing to resistance against these drugs. Anti-retroviral drugs in their turn increase the level of rifampicin inducing the risk of toxicity Žw22–24x, Fig. 2..
9. Conclusion Treatment duration for pulmonary tuberculosis used to be 9 months with three drugs in the intensive phase. Consensus has been reached for the treatment of pulmonary tuberculosis which differs in the following aspects: Ži. The total duration of therapy can be shortened from 9 to 6 months by decreasing the continuation phase by three months. However, this is only possible with proven susceptibility and if treatment compliance is guaranteed. Žii. If in the initial phase of treatment the susceptibility pattern of the tubercle bacillus is unknown not 3 but 4 drugs are given in the initial phase. The fourth drug to be added is ethambutol. Žiii. If treatment for tuberculosis was given for a previous episode, it may be necessary to give more than 4 drugs; amikacin is advised as a fifth drug. To decrease the risk of treatment errors and to increase patient compliance, the public health nurse of the municipal health services’ tuberculosis department must supervise every patient right from the
w1x Rapport KNCV. De behandeling van longtuberculose. Met hoeveel middelen en hoe lang. Februari 1996. KNCV Den Haag. w2x van Loenhout-Rooyackers JH, Veen J, Verbeek ALM. Verkorting van de therapieduur bij patienten met longtuber¨ culose van 9 naar 6 maanden verdedigbaar op grond van gepubliceerde gegevens. NTVG 1996;140:2181–2187. w3x Broekmans JF, van Herwaarden CLA. De behandeling van lo n g tu b ercu lo se: k o rter en k rach tig er. N T V G 1996;140:2160–2163. w4x van Loenhout-Rooyackers JH, van Lambregts-Weezenbeek CSB, Veen J. De behandeling van tuberculose anno 1997. Gebu 1997;7:75–81. w5x Mitchison DA. Mechanisms of drug action in short-course chemotherapy. Bull Int Union Tuberc Lung Dis 1985;60:34– 37. w6x Takayama K, Schnoes JK, Armstrong EL, Boyle RW. Site of inhibitory action of isoniazid in the synthesis of mycolic acids in Mycobacterium tuberculosis. J Lipid Res 1975;16:308–372. w7x Crowle AJ, Sbarbaro JA, May MH. Inhibition by pyrazinamide of tubercle bacilli within cultured human macrophages. Am Rev Respir Dis 1986;134:1052–1058. w8x Crowl AJ, Sbarbaro JA, Judson FN, May MH. The effect of ethambutol on tubercle bacilli within cultured human macrophages. Am Rev Respir Dis 1985;132:742–745. w9x Takayama K, Armstrong EL, Kunugi KA, Kilbum JO. Inhibition by ethambutol of mycolic acid transfer into the cell wall of Mycobacterium smegmatis. Antimicrob Agents Chemother 1979;16:240–242. w10x Costello HD, Caras GJ, Snider DE Jr. Drug resistence among previously treated tuberculosis patients, a brief report. Tubercle 1980;121:313–316. w11x Rapport KNCV. Richtlijnen met betrekking tot de behandeling en preventie van multiresistente tuberculose in Nederland. September 1993. Den Haag. w12x van Lambregts-Weezenbeek CSB, van Klingeren B, Veen J. Resistentie bij Mycobacterium tuberculosis in Nederland. NTVG 1996;140:2187–2191. w13x van Lambregts-Weezenbeek CSB. Drug-resistant tuberculosis in the Netherlands; Trifle or threat? Thesis University of Amsterdam, 1998. w14x Fox W. Whither short-course chemotherapy?. Br J Dis Chest 1981;75:331–357. w15x American Thoracic Society, Guidelines for short-course tuberculosis chemotherapy. Am Rev Respir Dis 1980;121:611– 614. w16x van Loenhout-Rooyackers JH. Verslag van een management en beleidsstage. Sociale geneeskunde, tak algemene gezond-
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w17x
w18x w19x w20x
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14 heidszorg groep IX–X, 1990–1993. Utrecht: Stichting Sociale Gezondheidszorg, 1993. ATS, Treatment of tuberculosis and tuberculosis infection in adults and children. AM J Crit Care Med 1994;149:1359– 1374. Dutt AK, Stead WW. Treatment of extra-pulmonary tuberculosis. Semin Respir Infect 1989;4:225–231. Rom WN, Garay SM. Tuberculosis. 1st edn. USA: Little Brown, 1996. Strang JL, Kakaza HH, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987;ii:1418–1422.
w21x O’Toole RD, Thornton GF, Mukherjee MK, Nath RL. Dexamethasone in tuberculous meningitis. Relationship of cerebrospinal fluid effects to therapeutic efficacy. Ann Intern Med 1969;70:39–48. w22x Gebu 1996; 30: 141-4. w23x CDC, Clinical update: Impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin. MMWR 1996;45Ž42.:921–925. w24x Approach to treatment of TB in HIV-infected patients who also need protease inhibitors. ‘‘Dear Colleague’’ letter. 8 September 1996. NYCDOH Bureau of TB Control.
Current practise Ž invited.
Treatment of pulmonary tuberculosis J.H. van Loenhout-Rooyackers a
a,)
, J. Veen
b
GGD Regio Nijmegen, Postbus 1120, 6501 BC Nijmegen, Netherlands b KNCV, Postbus 146, 2501 CC Den Haag, Netherlands
Received 6 January 1998; revised 16 March 1998; accepted 7 April 1998
Abstract Recently the duration of treatment for pulmonary tuberculosis in The Netherlands was shortened from nine to six months. A six months regimen containing isoniazid ŽH., rifampicin ŽR. and pyrazinamid ŽZ. daily for two months, followed by H and R daily for another four months Ž2HRZr2HR. has been proven effective for the treatment of pulmonary tuberculosis, provided the cause is a fully susceptible strain of M. tuberculosis. Worldwide there is an increase in drug-resistant tuberculosis. Since at the start of treatment susceptibility tests often are not available, a fourth drug must be added in the intensive phase. Ethambutol is the drug preferred. This means that one always starts with 4 drugs unless the patient is a contact of an index-case with proven susceptibility and one is sure that he will be compliant or ´ the patient is infected in the past before 1940, he received never tuberculostatic drugs and one is sure that there is no exogenous reinfection. If the patient has been treated previously and anti-tuberculosis drug resistance is likely, treatment regimens should contain at least two drugs with which he has not been treated before, while a fifth drug routinely must be added in the intensive phase. Amikacin is preferred, since there is no cross-resistance to streptomycin. Consensus on the duration of treatment for extra-pulmonary tuberculosis has not yet been reached, but basically the principles for treatment are the same. This is also true for HIV infected tuberculosis patients. In some serious clinical situations Žmeningitis, miliary, spine tb. duration of treatment still is 9–12 months. Early involvement of the public health nurse of the municipal health department ŽGGD. is necessary to ensure patient compliance and treatment supervision. q 1998 Published by Elsevier Science B.V. All rights reserved. Keywords: Pulmonary tuberculosis; Isoniazide; Rifampicine; Pyrazinamide
1. Introduction In 1996 the national Tuberculosis Policy Committee ŽCommissie voor Praktische Tuberculosebestrijding, CPT. and the Working Group on Tuberculosis of the Nederlandse Vereniging van Artsen voor
)
Corresponding author. Tel.: q31-24-3297114.
Longziekten en Tuberculose ŽNVALT. reached consensus on the treatment of pulmonary tuberculosis w1–4x. Hereafter the newly advised therapy regimens are discussed, emphasising the differences with the previous policy. A consensus report for the treatment of extra-pulmonary tuberculosis is underway. Few studies deal with the standardised treatment of extra-pulmonary tuberculosis, but the basic principles are similar to those of pulmonary tuberculosis.
0300-2977r98r$ – see front matter q 1998 Published by Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 8 . 0 0 0 6 7 - 9
8
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
2. Treatment objectives The objectives of treatment are two-pronged: to cure the patient in the shortest possible time, and to interrupt the chain of transmission of the tubercle bacilli. During therapy no drug resistance may be induced by treatment errors and no relapse may occur after the end of treatment. This means that treatment must be bactericidal and sterilising. A combination of drugs is needed to prevent the development of drug resistance, but also to affect tubercle bacilli which are at different levels of metabolic activity. The risk of relapse depends on the activity of each of the drugs, the combination used and the duration of treatment.
3. Activity of anti-tuberculosis drugs Mitchison developed a theoretical model using the localisation of tubercle bacilli Žintra- or extracellular., their metabolic activity Žmultiplying, dormant or semi-dormant bacilli. and the activity of each drug w5x. Because the targets for anti-tuberculosis drugs within the bacilli differ and to prevent resistance caused by spontaneous mutations, treatment of active tuberculosis starts with a combination of three or four drugs during the first two months Žinitial phase. and continues with two drugs Žcontinuation phase.. Isoniazid is bactericidal and acts both intracellular in the macrophages and extracellular in the necrotic tissue. Its mechanism is partly unclear, although it is known that the synthesis of mycolic acid, an important part of the cell wall, is inhibited w6x. Isoniazid quickly reduces the size of large populations of multiplying tubercle bacilli which are present in the wall of the tuberculous cavity. Rifampicin and pyrazinamid are less active there. Rifampicin is also bactericidal: it inhibits the RNA-polymerase, causing protein synthesis of the bacillus to come to a halt. It kills persistent semidormant bacilli during their short spurts of metabolic activity. This drug therefore is of great importance for the sterilisation of the process and thus for the prevention of relapse. Sterilisation reflects the power of the drug to kill the slowest metabolising bacillus, thereby ridding the lesion of all bacilli.
Pyrazinamid only works in an acid environment. The tubercle bacillus’ enzyme pyrazinamidase converts it into pyrazinoic acid. It lowers the pH in the macrophages, thereby killing the bacilli which are intracellular, but also is active in the acidified infectious foci Žcheese. w7x. Pyrazinamid therefore is especially important in the initial phase of treatment. It was used in the 1950s in high doses which proved to be too toxic. Since 1978, when was shown that lowered doses are also adequate, it is routinely used in each combination of anti-tuberculosis drugs. Aminoglycosides Žamikacin, kanamycin and streptomycin. block the synthesis of ribosomal RNA. These drugs are bactericidal in aerobic circumstances. Streptomycin has a bactericidal activity but this is limited to extra-cellular actively multiplying mycobacteria Že.g., in cavities.. Fluoridated chinolones like ciprofloxacin and ofloxacin are bactericidal: they inhibit the DNAgyrase of the bacillus. Their mechanism is comparable to that of isoniazid. In case of multi-drug resistance Žat least resistant to isoniazid and rifampicin. chinolones are drugs of first choice. Ethambutol influences the RNA-synthesis of the bacillus and inhibits mycolic acid to become part of the cell wall w8,9x. It is bacteriostatic in the dose of 15 mgrkg body weight and bactericidal in doses of 25 mgrkg body weight. The bactericidal dose is only used during the first 2 months of treatment since longer duration of higher doses increases the risk of ocular side effects. In therapeutic doses it is less effective than the previously described drugs. Other drugs used for the treatment of tuberculosis are clofazimin, prothionamid, rifabutin, cycloserin, thioacetazone and para-aminosalicylic acid.
4. Drug resistance After the introduction of streptomycin in 1940 it became apparent that mono-therapy quickly led to resistance. The same proved true for mono-therapy of isoniazid and rifampicin w10x. Combination therapy prevents the selection of spontaneous resistant mutants. The risk that mutants occur is largest when a high bacterial load is present as in cavernous pulmonary tuberculosis. If however the treatment is
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
9
Table 1 Distribution of drug resistance Ž%. among 809 bacteriologically confirmed tuberculosis cases, The Netherlands Žpatient cohort 1993, coverage 93%. w13x Drug
Asylumseekers Ž n s 106., %
Other foreigners Ž n s 365., %
Dutch Ž n s 338., %
Isoniazid ŽH. Streptomycin ŽS. Rifampicin ŽR.
13 19 3
6 9 2
2 3 1
adequate, risks are negligible. If treatment is inadequate due to erroneous dosages prescribed by the doctor or erroneous delivery by the pharmacist, or if the patient does not take drugs in the proper way, resistance may be induced by human failure w11x. More than in the past also in The Netherlands one has to reckon with resistant strains or with the induction of resistance by treatment errors. Risk groups for tuberculosis in The Netherlands are immigrants from countries with a high tuberculosis prevalence, where also the risk of drug resistance is large Žw12,13x, Table 1.. Homeless people and drug addicts belong to risk groups for tuberculosis and drug resistance. Their way of life increases the risk of treatment error. In view of the increased mobility Dutch travellers more then in the past run the risk to get infected with a resistant strain when travelling in foreign countries Žw13x, Table 2..
5. Duration of treatment and effectivity Isoniazid, rifampicin and pyrazinamid are essential for the treatment of tuberculosis and the combination is sufficient for the treatment of normal sensitive human bacilli. Before treatment starts the defi-
nite type of bacillus and its susceptibility pattern are not yet known. Since one has to reckon with the possibility of resistant strains we have to add a fourth drug to the combination in the intensive phase of treatment. As a fourth drug ethambutol is advised in stead of streptomycin, since next to isoniazid resistance, streptomycin resistance is also predominant. In everyday life it means that one always starts with 4 drugs unless one can assume with certainty that the disease was caused by a sensitive strain. Initial treatment with more than 4 drugs may be necessary if treatment in the past took place. A careful medical history taking into regard the drugs which were used, is of utmost importance. The new treatment scheme has to contain at least 2 drugs with which the patient has not been treated before. As a fifth drug amikacin is preferred since it has no cross-resistance to streptomycin. Treatment in the intensive phase must be daily and in one dose. Once the definite type and its susceptibility pattern are known, the medication may be adapted. If a strain is susceptible amikacin andror ethambutol can be discontinued. Pyrazinamid must be given for at least 2 months. It can be stopped after 2 months if sputum smear microscopy shows no further bacilli Žsputum conversion. and if one is
Table 2 Drug resistance should be suspected when Patients report prior treatment Patients have been in contact with drug-resistant tuberculosis index case Patients became infected and the resistance pattern of index case is unknown Patients belong to a high-risk group for resistance because their way of life increases the risk of treatment error Patients become smear-positive again after prior sputum conversion Patients do not respond to therapy as expected See Ref. w13x.
10 J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
Fig. 1. Treatment of the patient with pulmonary tuberculoses1. This flow-chart is only valid if no simultaneous resistance to isoniazid and rifampicin is present. Bacteriologic examination is repeated periodically. The treatment episode is ended by culture of the sputum specimen. Induction of sputum and bronchoscopy increase chances on a positive culture and ensuing suceptibility examination. This is especially important for patients with previous treatment for tuberculosis. H s Isoniazid, R s rifampicin, Z s pyrazinamid, E sethambutol, A samihacin. 1 Criteria for active tuberculosis, Table 3; for the diagnostic process, Table 4. 2 Resistance pattern of the source is still unknown. 3 Patient with normal susceptibility pattern.
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
11
Table 3 American Thoracic Society criteria for active tuberculosis Response to tuberculostatic treatment and at least 2 of the next 3 criteria are fulfilled: 1 one or more of the next clinical findings: fever ) 388C during at least one week night sweats more than one week weight loss ) 20% bodyweight cough dyspnea hemotysis lymphadenopathy ) 4 weeks 2
One or more of the next microbiologic criteria acid-fast bacilli in Ziehl–Neelsen stains growth of M. tuberculosis, Lowenstein–Jensen ¨ granulomas with caseous necrosis by histological examination.
3
Radiographic criterium chest X-ray suspect for tuberculosis Žinfiltration, pleural opacity, hilar lymphadenopathy.
certain that the strain is sensitive Žw1x, Fig. 1 and Tables 3 and 4.. During the continuation phase the patient is treated with at least 2 drugs for which the bacillus is susceptible, mostly being isoniazid and rifampicin if no resistance is present. How long should the continuation phase with isoniazid and rifampicin be continued? A nine month during treatment regimen without pyrazinamid, but with isoniazid, rifampicin and either ethambutol or streptomycin caused a bacteriological proven relapse in 3 of 298 patients Ž1% or 0.2–2.9% with a 95%
confidence interval. w14x. It was expected that the addition of pyrazinamid to isoniazid and rifampicin could shorten the duration of treatment. After reintroduction of pyrazinamid in therapeutic adequate dosages after 1978 most countries reduced the total duration of treatment from 9 to 6 months. A treatment duration of 6 months with isoniazid, rifampicin and pyrazinamid for pulmonary tuberculosis patients, infected by a susceptible strain showed a relapse in 116 of 4833 patients, i.e., 2.4% ŽC.I.s 2.0–2.8. w2x. The American Thoracic Society ŽATS. accepts a relapse rate of less than 5% w15x. In The Netherlands,
Table 4 Diagnostic process Medical history Žsymptoms of tuberculosis, contact of patients with tuberculosis, born or travelling in countries with high prevalence of tuberculosis. Clinical examination. Microbiological examination. acid-fast bacilli in Ziehl–Neelsen or Auramine stains growth of M. tuberculosis, Lowenstein–Jensen or 7H10. ¨ polymerase chain reaction ŽPCR. on DNA and RNA. In the future it will be possible to distinguish between visible and viable bacteria DNA-fingerprinting by restriction fragment length polymorphism ŽRFLP. analysis to identify clusters of identical fingerprints Histological examination Žalso Ziehl–Neelsen or Auraminestain.. PPD Žreaction of mantoux. Chest X-ray Serological examination Žnot yet valuable.
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using the tuberculosis registration cards kept by the Health Inspectorate, it was calculated that the percentage of Dutch inhabitants with a relapse of pulmonary tuberculosis in the period 1984–1990, in whom the relapse occurred within 5 years after the previous episode, was 44 out of 1792 Ž2.5%, CI s 1.8–3.2. w16x. This well below the 5% level of the ATS. The shorter the duration of treatment the better the patients’ compliance. The CPT decided that also in the Netherlands treatment of pulmonary tuberculosis, when caused by fully susceptible bacilli, can be decreased to 6 months duration by shortening the continuation phase. This however can only be done when treatment compliance is perfect. The public health nurse of the municipal health services ŽGGD. therefore has to supervise the patient during treatment.
been done in the same way as with pulmonary tuberculosis. Objective criteria for treatment outcome, like sputum conversion or improvement of the radiological image, as in pulmonary tuberculosis, are lacking. During therapy even new glands and tuberculomas may evolve or enlarge. The basic principles of treatment however are the same, although in milliary tuberculosis, tuberculous meningitis and tuberculosis of the bones generally duration is increased to 9–12 months w17–19x. Depending on the localisation, adjuvant interventions like bed rest and surgery may be needed. If during the diagnostic process tuberculosis is considered, material for further diagnosis always need to be sent for sputum smear microscopy and bacteriological culture. More than in the past one has to reckon with the presence of resistant strains.
6. Extra-pulmonary tuberculosis
7. Corticosteroids
Clinical trials into the effectivity of standardised treatment of extra-pulmonary tuberculosis have not
In general corticosteroids play no role in the treatment of tuberculosis. Only in tuberculous
Fig. 2. The approach to treatment of TB in HIV-infected patients who also need protease inhibitors w23,24x.
J.H. Õan Loenhout-Rooyackers, J. Veen r Netherlands Journal of Medicine 53 (1998) 7–14
meningitis and pericarditis it is suggested to be effective w20,21x.
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start of the treatment. Treatment compliance ultimately is only guaranteed if medication is taken under direct supervision.
8. HIV-infected tuberculosis patients References For HIV-infected patients with pulmonary tuberculosis the same treatment schedules apply as for patients without HIV infection w17x. There is an increased risk for adverse effects and mal-absorption. Measurement of the serum concentration of the drugs may be needed. In cases where treatment is sub-optimal, duration of treatment must be increased. There are insufficient data about the treatment of extrapulmonary tuberculosis in HIV infected patients. Treatment must always be individualised. Rifampicin lowers the serum concentration of the protease inhibitors, thereby contributing to resistance against these drugs. Anti-retroviral drugs in their turn increase the level of rifampicin inducing the risk of toxicity Žw22–24x, Fig. 2..
9. Conclusion Treatment duration for pulmonary tuberculosis used to be 9 months with three drugs in the intensive phase. Consensus has been reached for the treatment of pulmonary tuberculosis which differs in the following aspects: Ži. The total duration of therapy can be shortened from 9 to 6 months by decreasing the continuation phase by three months. However, this is only possible with proven susceptibility and if treatment compliance is guaranteed. Žii. If in the initial phase of treatment the susceptibility pattern of the tubercle bacillus is unknown not 3 but 4 drugs are given in the initial phase. The fourth drug to be added is ethambutol. Žiii. If treatment for tuberculosis was given for a previous episode, it may be necessary to give more than 4 drugs; amikacin is advised as a fifth drug. To decrease the risk of treatment errors and to increase patient compliance, the public health nurse of the municipal health services’ tuberculosis department must supervise every patient right from the
w1x Rapport KNCV. De behandeling van longtuberculose. Met hoeveel middelen en hoe lang. Februari 1996. KNCV Den Haag. w2x van Loenhout-Rooyackers JH, Veen J, Verbeek ALM. Verkorting van de therapieduur bij patienten met longtuber¨ culose van 9 naar 6 maanden verdedigbaar op grond van gepubliceerde gegevens. NTVG 1996;140:2181–2187. w3x Broekmans JF, van Herwaarden CLA. De behandeling van lo n g tu b ercu lo se: k o rter en k rach tig er. N T V G 1996;140:2160–2163. w4x van Loenhout-Rooyackers JH, van Lambregts-Weezenbeek CSB, Veen J. De behandeling van tuberculose anno 1997. Gebu 1997;7:75–81. w5x Mitchison DA. Mechanisms of drug action in short-course chemotherapy. Bull Int Union Tuberc Lung Dis 1985;60:34– 37. w6x Takayama K, Schnoes JK, Armstrong EL, Boyle RW. Site of inhibitory action of isoniazid in the synthesis of mycolic acids in Mycobacterium tuberculosis. J Lipid Res 1975;16:308–372. w7x Crowle AJ, Sbarbaro JA, May MH. Inhibition by pyrazinamide of tubercle bacilli within cultured human macrophages. Am Rev Respir Dis 1986;134:1052–1058. w8x Crowl AJ, Sbarbaro JA, Judson FN, May MH. The effect of ethambutol on tubercle bacilli within cultured human macrophages. Am Rev Respir Dis 1985;132:742–745. w9x Takayama K, Armstrong EL, Kunugi KA, Kilbum JO. Inhibition by ethambutol of mycolic acid transfer into the cell wall of Mycobacterium smegmatis. Antimicrob Agents Chemother 1979;16:240–242. w10x Costello HD, Caras GJ, Snider DE Jr. Drug resistence among previously treated tuberculosis patients, a brief report. Tubercle 1980;121:313–316. w11x Rapport KNCV. Richtlijnen met betrekking tot de behandeling en preventie van multiresistente tuberculose in Nederland. September 1993. Den Haag. w12x van Lambregts-Weezenbeek CSB, van Klingeren B, Veen J. Resistentie bij Mycobacterium tuberculosis in Nederland. NTVG 1996;140:2187–2191. w13x van Lambregts-Weezenbeek CSB. Drug-resistant tuberculosis in the Netherlands; Trifle or threat? Thesis University of Amsterdam, 1998. w14x Fox W. Whither short-course chemotherapy?. Br J Dis Chest 1981;75:331–357. w15x American Thoracic Society, Guidelines for short-course tuberculosis chemotherapy. Am Rev Respir Dis 1980;121:611– 614. w16x van Loenhout-Rooyackers JH. Verslag van een management en beleidsstage. Sociale geneeskunde, tak algemene gezond-
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w17x
w18x w19x w20x
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w21x O’Toole RD, Thornton GF, Mukherjee MK, Nath RL. Dexamethasone in tuberculous meningitis. Relationship of cerebrospinal fluid effects to therapeutic efficacy. Ann Intern Med 1969;70:39–48. w22x Gebu 1996; 30: 141-4. w23x CDC, Clinical update: Impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin. MMWR 1996;45Ž42.:921–925. w24x Approach to treatment of TB in HIV-infected patients who also need protease inhibitors. ‘‘Dear Colleague’’ letter. 8 September 1996. NYCDOH Bureau of TB Control.