MDR-TB IN A BELGIAN INFECTIOUS DISEASES UNIT
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Original Article
EPIDEMIOLOGY OF MDR-TB IN A BELGIAN INFECTIOUS DISEASES UNIT: A 15 YEARS REVIEW van Heurck R, Payen MC, De Wit S, Clumeck N CHU Saint-Pierre Infectious Diseases Department, Brussels, Belgium Correspondence and offprint requests to: R. van Heurck, [email protected]
ABSTRACT Introduction: For the last 20 years the world has seen the emergence of a growing epidemic of MDR-TB, followed by the appearance of XDR-TB. Both require longer, more expensive and more toxic treatments. MDR-TB and especially XDR-TB are associated with a lower cure rate than non MDR-TB. Materials and Methods: We reviewed retrospectively all cases of MDR-and XDR-TB managed at St Pierre University Hospital between 1996 and 2010. Epidemiological, clinical, bacteriological, treatment, follow up and outcome were collected and analysed. Results: We recorded 73 instances of MDR-TB and 11 XDR-TB for a total of 78 patients. All but 4 patients were of non Belgian origin. 10 patients were co-infected with HIV. A median of 4 active drugs (1-5) were used for a median of 448 days (329-616). 41 MDR-TB (56%) and 1 XDR-TB (1%) were considered as cured and 20 are still on treatment. Since 2007, increasing resistance to second line injectable drugs, fluoroquinolones and even linezolid (1 case) is observed. Extensive resistance was mainly found in patients who had previously been mismanaged with second line agents. Conclusions: This study illustrates the growing epidemic of MDR and XDR-TB, it emphasizes the importance of proper diagnosis and adequate management of TB in patients at risk for resistance and stresses the need for new therapies. Key words: pulmonary infectious disease, Tuberculosis control, transmigration, surveillance
INTRODUCTION For the last 20 years, the world has seen the emergence of MDR-TB (multidrug-resistant tuberculosis; strain resistant
doi: 10.2143/ACB.3269
to at least isoniazid and rifampicin) which has been followed a few years later by the appearance of XDR-TB (extensively drug resistant tuberculosis,MDR strain also resistant to any fluoroquinolone and any second line injectable drugs used in TB treatment). The World Health Organization (WHO) estimates that 390,000-510,000 cases of MDR-TB occurred in 2008 (1) (3.6% of the estimated total incidence of newly diagnosed TB) leading to 150000 deaths. MDR and XDR-TB require the use of second-line anti-tuberculous drugs which are more expensive, often more toxic and must be taken for a longer duration (2). Furthermore, cure rate of MDR-TB reaches only 50-70% compared to 85%-90% for susceptible TB. The aim of this study is to report the epidemiological, microbiological and clinical data of all cases of MDR and XDRTB that have been observed at Saint-Pierre University Hospital, Brussels, (Belgian reference center for tuberculosis) from January 1996 to December 2010.
MATERIALS AND METHODS TB diagnosis was confirmed by smear microscopy and culture of any suspected biological specimen. DST (drug susceptibility testing) for first-line drugs was performed for any Mycobacterium tuberculosis positive culture. If history suggested MDR-TB, an InnoLipa Test was performed to detect gene mutation conferring resistance to rifampicine (3). In case of resistance to any first-line drugs, the strain was sent to the National Reference Laboratory for extended DST, including second-line drugs. If a high suspicion of MDR-TB was present, empirical treatment was started based on previous treatment history. As soon as DST was obtained, an individualized treatment regimen was initiated. Of note, pyrazinamide and more recently a second generation fluoroquinolone are recommended whatever the results of DST (2, 4-6). The medical records of all patients diagnosed with culture bacteriologically confirmed MDR-TB and XDR-TB at
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Saint-Pierre University Hospital during the study period were retrospectively reviewed and the following data were collected: – Epidemiological data: age, sex, origin, social status, smoking habits, alcohol habits. – Clinical data: TB localisation, co morbidities (HIV status, HCV status, HBV status) – Classification of MDR-TB (based on patients’ file or their own recollection of the names of previous drugs): primary MDR-TB (patient who has received no or less than one month of antituberculous treatment), secondary MDR-TB previously treated with-first line drugs (patient who has been treated for one month or more with only first-line drugs), secondary MDR-TB previously treated with secondline drugs (patient who has been treated for one month or more with one or more second-line drugs, with or without first-line drugs) or MDR-TB with unknown past treatment. – In case of secondary MDR-TB, patients were classified according to the outcome of their previous treatment: relapse (a patient whose most recent treatment outcome was “cure” or “treatment completed” and who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy or culture), return after default (patient who returns to treatment, bacteriologically positive by sputum smear microscopy or culture, following interruption of treatment for two or more consecutive months), retreatment after failure (sputum smear positive at five months or later during treatment), transfer in (patient who has been transferred from another reporting and recording unit) or unknown. – Results of drug susceptibility testing (DST) for both first and second-line drugs – Number of drugs used, number of active drugs used (drug with either certain or almost certain effectiveness defined as susceptibility shown by DST and/or drug has not been used in this patient before), use of surgery. – Time to sputum culture conversion (interval between MDRTB treatment initiation and first out of three consecutive negative cultures) – Duration of hospitalisation, duration of follow up (interval between first out of three consecutive negative cultures and end of treatment) and duration of treatment – Outcome: cure, treatment completed (patient who has completed treatment according to programme protocol but does not meet the definition for cure because of lack of bacteriological results), death (patient who dies for any reason during the course of MDR-TB treatment), default, failure, transferred out (patient who has been transferred to another reporting and recording unit and for whom treatment outcome is unknown). – Adverse events Variables were compared using chi square or exact Fisher test.Wilcoxon or Kruscal Wallis test was used when continuous variable were compared. All statistical analysis was performed with SAS 9.2. software. This study has been approved by the local Ethics Committee.
ecember 2010. Figure 1 shows the reported numbers of D MDR-TB and XDR-TB episodes per year at St Pierre Hospital. MDR-TB and XDR-TB represented 1-2% of all tuberculosis cases seen at Saint Pierre University Hospital during this 15 year period. (10% of all Belgian TB cases were managed at St Pierre hospital, the number of MDR-TB that were managed at Saint Pierre University hospital were comprised between 6-84% for each year. After year 2003 at least 40% of all Belgian recorded cases were managed at Saint Pierre university Hospital) Five patients showed several episodes: one showed three episodes because the patient defaulted twice, one patient defaulted once, two patients showed treatment failure and needed treatment adaptation, one patient showed relapse. One MDR patient became XDR. Since DNA analysis is done on a regular base since 2002 in our National Reference Laboratory, it was possible to differenciante recurrence and reinfection among patients presenting several episodes. (same strain has been identified in all patients presenting several episodes but one. This analysis has not been done on one last patient (7-9).) Median age was 33 years (range 26-39) for MDR-TB and 30.5 years (range 26-37) for XDR-TB. Sex ratio was 2: 1 (men: women) for MDR-TB (46/22) and 3: 2 (women: men)for XDR-TB (6/4). Ninety-five % (74/78) of our patients were immigrants. Twenty-eight subjects were from Ex-USSR (35%) including 6 XDR-TB patients. Twenty-one subjects were from Asia (26%) including 4 XDR-TB patients, 19 from Africa (24%), 5 from Western Europe (6%), 3 from Central America (4%), and 2 from Middle East (3%) (Figure 2). Thirty-five patients were seeking asylum in Belgium (45%), 19 had no legal status in the country (24%). Two of the 4 belgian cases (3%) occurred in health care workers (one logistic assistant, one nursing auxilliary) transfered from 2 other hospitals to our institution. 10/ 78 subjects were HIV positive (12%)(9 MDR subject, 1 XDR subject), 12 were HCV positive (15%) (3 XDR-TB) and 1 XDR-TB patient was co infected with HCV and HIV. 10/77 tested subjects had chronic HBV (13%). Six patients actively consumed alcohol (8%) and 30 were smokers (40%) (including 2 XDR-TB patients).
RESULTS Population data
Seventy-three MDR-TB and 11 XDR-TB episodes occurring in 78 patients were recorded from January 1996 until
Acta Clinica Belgica, 2013; 68-5
Figure 1: Epidemic evolution. (XDR = Extensively Drug Resistant, MDR = Multi-Drug Resistant).
MDR-TB IN A BELGIAN INFECTIOUS DISEASES UNIT
Figure 3: Evolution of drug resistance through time.
Figure 2: Repartition of demographic origin at St Pierre University Hospital. (XDR = Extensively Drug Resistant, MDR = Multi-Drug Resistant).
Tuberculosis data
Forty out of the 84 episodes (including 2 XDR-TB) (48%) were primary cases without history of previous TB treatment. Thirty MDR-TB (41%) and 9 XDR-TB (82%) had been previously treated. Out of the 30 secondary MDR-TB, 14 had been treated with second line drugs (19%) and 16 with first line drugs (22%). For 5 MDR-TB (7%) previous treatments history was unknown. All of the secondary XDR-TB had been previously treated with second line drugs. Among the 39 episodes that had been treated before, 17 were treatment failures (11 MDRTB, 6 XDR-TB), 12 were relapses (11 MDR-TB, 1 XDR-TB) and 6 were treatment defaults (5 MDR, 1 XDR-TB). For the 4 remaining cases this information was not available. Seventy-nine out of the 84 episodes were pulmonary TB (93%), 10 presented lymph node invasion among which 3 had no pulmonary lesions. Miliary TB occured 6 times, pleuritis 7, gastro intestinal 4 times, and brain and osteitis once.
Drug susceptibility testing.
By definition, all strains were resistant to both rifampicin and isoniazid, 67% showed resistance to ethambutol, 67% to rifabutin, 64% to pyrazinamid, 62% to streptomycin, 33% to para –aminosalicylic acid, 29% to amikacin, 29% to prothionamid, 25% to ofloxacin, 14% to moxifloxacin, 12% to capreomycin, 11%to cycloserin, 6% to clarithromycin. One case was resistant to linezolid (patient had been previously treated with linezolid). Strains were resistant to a median of 6.5 drugs (4.5-9). As illustrated on Figure 3, median number of inactive drugs has increased progressively since 2004.
Management
Four active drugs (range 3-5) were used for each MDR-TB episode but the regimen was generally composed of 5 drugs (4-6) as pyrazinamide was often added. Quinolones were used in 76 out of the 84 episodes. Surgery was used in 8 cases (either in order to prevent persistent infection in extensively
destroyed pulmonary tissue or to eliminate focal lesion with pan-XDR strain); surgery was preferentially performed when bacillary load was controlled, except in case of treatment failure. However anti-tuberculosis treatment was not shortened in those patients. In 6 cases of XDR-TB no adequate treatment could be identified (if 3 or less active drugs were identified on the DST) and the combination of meropenem-clavulanate has been included in a salvage regimen. Concerning the other XDR cases, an adequate regimen of 4 active drugs could be built. Active treatment was given for a median of 448 days (range 329-616), with amikacin for a median of 89 days (range 41-166) and capreomycin for 211 days (range 68-649) (numbers based on the 84 episodes)
Evolution and final outcome
Among the 84 episodes, 41 MDR-TB and 1 XDR-TB episodes reached treatment completion, 3 MDR-TB and 2 XDRTB failed treatment, 1 MDR-TB patient died from stroke while still on therapy, 16 MDR-TB were lost to follow up. At the time of analysis 12 MDR-TB and 8 XDR-TB were still on therapy. As sputum collection is generally difficult to obtain when the evolution is favourable, no patient reached the WHO definition of cure in our series. Median time to sputum culture conversion was 69 days (range 37-116 days) for MDR-TB episodes and 97 days (range 85-188) for XDR-TB. This difference was statistically significant (Wilcoxon sum of square test, p = 0, 0391). Median time of hospitalisation was 105 days (range 61-149) for MDR-TB and 288 days (range 262-305) for a XDR-TB. Median time of treatment duration after sputum culture conversion reached 406 days (range 288-589). Among the six subjects who presented more than one MDR-TB episode, 1 reached treatment completion, 3 defaulted and 2 ended up in treatment failure. We recorded severe hepatotoxicity in 20% of the episodes (17/84). 7% of nephrotoxicity (6/83) and 29% of ototoxicity (24/83) with capreomycin or amikacin use, 32% of polyneuropathy (10/31) and 26% haematological side effects (8/31) with linezolid use and 9% of hypothyroidism (6/70) with prothionamide use. Most patients complained of gastro-intestinal disturbances but data on suspected drugs are generally not available. All of the above required treatment adaptation (interruption or dose reduction of the suspected drugs).
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DISCUSSION This retrospective study started in 1996 reviewed 84 episodes of MDR/XDR-TB that occurred in 78 subjects over 15 years in St Pierre University Hospital, Brussels with a growing number of recorded cases per year and an increasing proportion of XDR cases. Our findings are in accordance with other observations(1, 9). Most cases came from low income countries. Transmission of MDR TB in the Belgian population is limited with only 4 Belgian cases in this study. Ninety-five % of our cases were immigrants with a majority coming from Eastern Europe, Asia and Africa. The pattern of resistance differed according to the patients’ demographic origin. This is explained by the heterogeneous availability and use of anti-tuberculous agents around the world. All of our XDR-TB cases came either from Eastern Europe or Asia where second-line agents are readily available and often mismanaged leading to the selection of drug resistant mutants. Extensively resistant cases were found when second-line therapy has been used previously for more than a month (1, 9-13). We have observed one case resistant to Linezolid in a patient previously exposed to this drug. Linezolid has only been used since a few years in the treatment of TB with promising efficacy despite occurrence of side effects (14). This underlines once again the importance of adequate use of second-line drugs for MDR-TB (15). WHO’s guidelines about MDR-TB treatment remain difficult to comply with. In our cohort the recommended number of drugs was respected but not the duration of therapy (406 days after culture conversion compared with the 540 days after sputum culture conversion recommended by WHO in order to prevent relapse (2)). This illustrates the gap between recommandations and “real life”. The guidelines are issued from observational retrospectives studies which suggest that 18 to 24 month of therapy is associated with better outcome. In clinical practice, side effects and loss to follow up are barriers to this long treatment duration. Management of side effects and compliance are problematic especially with drugs like amikacine, capreomycin, linezolid or prothionamide (4). As our results show, these drugs induce a high percentage of side effects leading to treatment interruption or reconsideration. In our experience, total treatment interruption because of side effects has not occurred. Compliance to treatment was particularly difficult to ensure after discharge from the hospital as the vast majority of our patients were immigrants, illegal aliens or asylum seekers facing a lot of psycho-social problems. Financial issues were not a barrier since therapy was paid by the Belgian health care system. Considering the unfavourable outcome that remains associated with XDR-TB cases new therapeutic options have been looked at for the most resistant strains (12, 16). As in vitro efficacy of the combination of meropenem-clavulanate against susceptible as well as resistant M.tuberculosis strains has been demonstrated, we have used this compound in association with the remaining active drugs, in 6 XDR patients for whom no suitable active treatment could be found (3 or less active drugs shown by the antibiogram) (17, 18, 19). One case is now considered as cured after 19 month of this therapy. Four out of five additional cases are evolving favourably. One patient deceased from TB.
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In conclusion, we have observed a growing number of MDR-TB cases in St Pierre University Hospital since 1996. Eighty-four episodes were recorded, including 11 XDR-TB episodes over 15 years. This represents 1-2% of all TB cases being handled in our institution. MDR-TB cases are mostly found in immigrants usually in precarious social situations. Worst case figures came from Eastern Europe and Asia (all of our XDR cases) but we have also found 4 Belgian cases, including 2 health care workers. This means that resistant TB has to be suspected in all patients with risk factors whatever their demographic origin. Most of these cases are still treatable but at the price of enhanced complications and treatment toxicity. Despite the fact that new therapeutic options are hopefully to be expected in the future, early diagnosis and adequate management following WHO recommendations are cornerstone to struggle the MDR-TB epidemic.
CONFLICT OF INTEREST: None. REFERENCES 1. World Health Organisation. Anti-tuberculosis drug resistance in the world. Fourth global report. WHO/HTM/TB/2008.394.Geneva, Switzerland. 2. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency update 2008. WHO/HTM/TB/2008.402. Geneva, Switzerland. 3. Van Deun A, et al. Diagnosis of drug resistant tuberculosis: reliability and rapidity of detection. Int J Tuberc Lung Dis 2010; 14(2): 131-140. 4. Chiang C-Y, et al. Management of drug resistant tuberculosis. Int J Tuberc Lung Dis 2010; 14(6): 672-682. 5. Caminero J, et al. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 2010; 10: 621-629. 6. Falzon D, et al. WHO guidelines for the programmatic management of drug resistant tuberculosis: 2011 update. Eur Repir J 2011; 38: 516-528. 7. Krüüner A, et al. Use of molecular techniques to distinguish between treatment failure and exogenous reinfection with mycobacterium tuberculosis. Clin Inf Dis 2002; 35: 146-155. 8. Andrews J, et al. Exogenous reinfection as a cause of multidrug-resistant and extensively drug-resistant tuberculosis in ruralSouth Africa. J Inf Dis 2008; 198: 1582-1589. 9. World Health Organisation. Multidrug and extensively drug-resistant TB (M/ XDR): 2010 globalreport on surveillance and report, WHO/HTM/TB/2010. Geneva, Switzerland. 10. Caminero JA. Multidrug- resistant tuberculosis: epidemiology, risk factors and case finding. Int J Tuberc Lung Dis 2010; 14(4): 383-390. 11. Sarita S, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2004; 13: 380-387. 12. Gandhi N, et al. Multidrug-resistant and extensively drug resistant tuberculosis: a threat to global control of tuberculosis. Lancet 2010; 357: 1830-1843. 13. Dye, C. (2009), Drug resistant tuberculosis: biology, epidemiology and control, in Gillespie, S. (ed.), Antibiotic Resistance: From genes to global prevalence, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://hstalks.com/bio). 14. Anger H, et al. Linezolid use for treatment of multidrug-resistant and extensively drug-resistant tuberculosis, New York city 2000-2006, J Antimicrob Chemother 2010 65(4): 775-783. 15. World Health Organisation. The global plan to stop TB 2011-2015, Geneva, Switzerland. 16. Jacobson K, et al. Treatment outcomes among patients with extensively drugresistant tuberculosis: systematic review and meta analysis. Clin Inf Dis 2010; 51(1): 6-14. 17. Hugonnet J, et al. Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium Tuberculosis. Science 2009; 323: 1215-1218. 18. Dauby N, Muylle I, Mouchet F, Sergysels R, Payen MC. Meropenem/Clavulanate and linezolid treatment for extensively drug-resistant tuberculosis. Ped Inf Dis J 2011; 30(9): 812-813. 19. Payen MC, De Wit S, Martin C, Sergysels R, Muylle I, Van Laethem Y, et al. Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis [Case study]. The Int Journal of Tuberc and Lung Dis. 2012 16(4): 558-560.
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Original Article
EPIDEMIOLOGY OF MDR-TB IN A BELGIAN INFECTIOUS DISEASES UNIT: A 15 YEARS REVIEW van Heurck R, Payen MC, De Wit S, Clumeck N CHU Saint-Pierre Infectious Diseases Department, Brussels, Belgium Correspondence and offprint requests to: R. van Heurck, [email protected]
ABSTRACT Introduction: For the last 20 years the world has seen the emergence of a growing epidemic of MDR-TB, followed by the appearance of XDR-TB. Both require longer, more expensive and more toxic treatments. MDR-TB and especially XDR-TB are associated with a lower cure rate than non MDR-TB. Materials and Methods: We reviewed retrospectively all cases of MDR-and XDR-TB managed at St Pierre University Hospital between 1996 and 2010. Epidemiological, clinical, bacteriological, treatment, follow up and outcome were collected and analysed. Results: We recorded 73 instances of MDR-TB and 11 XDR-TB for a total of 78 patients. All but 4 patients were of non Belgian origin. 10 patients were co-infected with HIV. A median of 4 active drugs (1-5) were used for a median of 448 days (329-616). 41 MDR-TB (56%) and 1 XDR-TB (1%) were considered as cured and 20 are still on treatment. Since 2007, increasing resistance to second line injectable drugs, fluoroquinolones and even linezolid (1 case) is observed. Extensive resistance was mainly found in patients who had previously been mismanaged with second line agents. Conclusions: This study illustrates the growing epidemic of MDR and XDR-TB, it emphasizes the importance of proper diagnosis and adequate management of TB in patients at risk for resistance and stresses the need for new therapies. Key words: pulmonary infectious disease, Tuberculosis control, transmigration, surveillance
INTRODUCTION For the last 20 years, the world has seen the emergence of MDR-TB (multidrug-resistant tuberculosis; strain resistant
doi: 10.2143/ACB.3269
to at least isoniazid and rifampicin) which has been followed a few years later by the appearance of XDR-TB (extensively drug resistant tuberculosis,MDR strain also resistant to any fluoroquinolone and any second line injectable drugs used in TB treatment). The World Health Organization (WHO) estimates that 390,000-510,000 cases of MDR-TB occurred in 2008 (1) (3.6% of the estimated total incidence of newly diagnosed TB) leading to 150000 deaths. MDR and XDR-TB require the use of second-line anti-tuberculous drugs which are more expensive, often more toxic and must be taken for a longer duration (2). Furthermore, cure rate of MDR-TB reaches only 50-70% compared to 85%-90% for susceptible TB. The aim of this study is to report the epidemiological, microbiological and clinical data of all cases of MDR and XDRTB that have been observed at Saint-Pierre University Hospital, Brussels, (Belgian reference center for tuberculosis) from January 1996 to December 2010.
MATERIALS AND METHODS TB diagnosis was confirmed by smear microscopy and culture of any suspected biological specimen. DST (drug susceptibility testing) for first-line drugs was performed for any Mycobacterium tuberculosis positive culture. If history suggested MDR-TB, an InnoLipa Test was performed to detect gene mutation conferring resistance to rifampicine (3). In case of resistance to any first-line drugs, the strain was sent to the National Reference Laboratory for extended DST, including second-line drugs. If a high suspicion of MDR-TB was present, empirical treatment was started based on previous treatment history. As soon as DST was obtained, an individualized treatment regimen was initiated. Of note, pyrazinamide and more recently a second generation fluoroquinolone are recommended whatever the results of DST (2, 4-6). The medical records of all patients diagnosed with culture bacteriologically confirmed MDR-TB and XDR-TB at
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Saint-Pierre University Hospital during the study period were retrospectively reviewed and the following data were collected: – Epidemiological data: age, sex, origin, social status, smoking habits, alcohol habits. – Clinical data: TB localisation, co morbidities (HIV status, HCV status, HBV status) – Classification of MDR-TB (based on patients’ file or their own recollection of the names of previous drugs): primary MDR-TB (patient who has received no or less than one month of antituberculous treatment), secondary MDR-TB previously treated with-first line drugs (patient who has been treated for one month or more with only first-line drugs), secondary MDR-TB previously treated with secondline drugs (patient who has been treated for one month or more with one or more second-line drugs, with or without first-line drugs) or MDR-TB with unknown past treatment. – In case of secondary MDR-TB, patients were classified according to the outcome of their previous treatment: relapse (a patient whose most recent treatment outcome was “cure” or “treatment completed” and who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy or culture), return after default (patient who returns to treatment, bacteriologically positive by sputum smear microscopy or culture, following interruption of treatment for two or more consecutive months), retreatment after failure (sputum smear positive at five months or later during treatment), transfer in (patient who has been transferred from another reporting and recording unit) or unknown. – Results of drug susceptibility testing (DST) for both first and second-line drugs – Number of drugs used, number of active drugs used (drug with either certain or almost certain effectiveness defined as susceptibility shown by DST and/or drug has not been used in this patient before), use of surgery. – Time to sputum culture conversion (interval between MDRTB treatment initiation and first out of three consecutive negative cultures) – Duration of hospitalisation, duration of follow up (interval between first out of three consecutive negative cultures and end of treatment) and duration of treatment – Outcome: cure, treatment completed (patient who has completed treatment according to programme protocol but does not meet the definition for cure because of lack of bacteriological results), death (patient who dies for any reason during the course of MDR-TB treatment), default, failure, transferred out (patient who has been transferred to another reporting and recording unit and for whom treatment outcome is unknown). – Adverse events Variables were compared using chi square or exact Fisher test.Wilcoxon or Kruscal Wallis test was used when continuous variable were compared. All statistical analysis was performed with SAS 9.2. software. This study has been approved by the local Ethics Committee.
ecember 2010. Figure 1 shows the reported numbers of D MDR-TB and XDR-TB episodes per year at St Pierre Hospital. MDR-TB and XDR-TB represented 1-2% of all tuberculosis cases seen at Saint Pierre University Hospital during this 15 year period. (10% of all Belgian TB cases were managed at St Pierre hospital, the number of MDR-TB that were managed at Saint Pierre University hospital were comprised between 6-84% for each year. After year 2003 at least 40% of all Belgian recorded cases were managed at Saint Pierre university Hospital) Five patients showed several episodes: one showed three episodes because the patient defaulted twice, one patient defaulted once, two patients showed treatment failure and needed treatment adaptation, one patient showed relapse. One MDR patient became XDR. Since DNA analysis is done on a regular base since 2002 in our National Reference Laboratory, it was possible to differenciante recurrence and reinfection among patients presenting several episodes. (same strain has been identified in all patients presenting several episodes but one. This analysis has not been done on one last patient (7-9).) Median age was 33 years (range 26-39) for MDR-TB and 30.5 years (range 26-37) for XDR-TB. Sex ratio was 2: 1 (men: women) for MDR-TB (46/22) and 3: 2 (women: men)for XDR-TB (6/4). Ninety-five % (74/78) of our patients were immigrants. Twenty-eight subjects were from Ex-USSR (35%) including 6 XDR-TB patients. Twenty-one subjects were from Asia (26%) including 4 XDR-TB patients, 19 from Africa (24%), 5 from Western Europe (6%), 3 from Central America (4%), and 2 from Middle East (3%) (Figure 2). Thirty-five patients were seeking asylum in Belgium (45%), 19 had no legal status in the country (24%). Two of the 4 belgian cases (3%) occurred in health care workers (one logistic assistant, one nursing auxilliary) transfered from 2 other hospitals to our institution. 10/ 78 subjects were HIV positive (12%)(9 MDR subject, 1 XDR subject), 12 were HCV positive (15%) (3 XDR-TB) and 1 XDR-TB patient was co infected with HCV and HIV. 10/77 tested subjects had chronic HBV (13%). Six patients actively consumed alcohol (8%) and 30 were smokers (40%) (including 2 XDR-TB patients).
RESULTS Population data
Seventy-three MDR-TB and 11 XDR-TB episodes occurring in 78 patients were recorded from January 1996 until
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Figure 1: Epidemic evolution. (XDR = Extensively Drug Resistant, MDR = Multi-Drug Resistant).
MDR-TB IN A BELGIAN INFECTIOUS DISEASES UNIT
Figure 3: Evolution of drug resistance through time.
Figure 2: Repartition of demographic origin at St Pierre University Hospital. (XDR = Extensively Drug Resistant, MDR = Multi-Drug Resistant).
Tuberculosis data
Forty out of the 84 episodes (including 2 XDR-TB) (48%) were primary cases without history of previous TB treatment. Thirty MDR-TB (41%) and 9 XDR-TB (82%) had been previously treated. Out of the 30 secondary MDR-TB, 14 had been treated with second line drugs (19%) and 16 with first line drugs (22%). For 5 MDR-TB (7%) previous treatments history was unknown. All of the secondary XDR-TB had been previously treated with second line drugs. Among the 39 episodes that had been treated before, 17 were treatment failures (11 MDRTB, 6 XDR-TB), 12 were relapses (11 MDR-TB, 1 XDR-TB) and 6 were treatment defaults (5 MDR, 1 XDR-TB). For the 4 remaining cases this information was not available. Seventy-nine out of the 84 episodes were pulmonary TB (93%), 10 presented lymph node invasion among which 3 had no pulmonary lesions. Miliary TB occured 6 times, pleuritis 7, gastro intestinal 4 times, and brain and osteitis once.
Drug susceptibility testing.
By definition, all strains were resistant to both rifampicin and isoniazid, 67% showed resistance to ethambutol, 67% to rifabutin, 64% to pyrazinamid, 62% to streptomycin, 33% to para –aminosalicylic acid, 29% to amikacin, 29% to prothionamid, 25% to ofloxacin, 14% to moxifloxacin, 12% to capreomycin, 11%to cycloserin, 6% to clarithromycin. One case was resistant to linezolid (patient had been previously treated with linezolid). Strains were resistant to a median of 6.5 drugs (4.5-9). As illustrated on Figure 3, median number of inactive drugs has increased progressively since 2004.
Management
Four active drugs (range 3-5) were used for each MDR-TB episode but the regimen was generally composed of 5 drugs (4-6) as pyrazinamide was often added. Quinolones were used in 76 out of the 84 episodes. Surgery was used in 8 cases (either in order to prevent persistent infection in extensively
destroyed pulmonary tissue or to eliminate focal lesion with pan-XDR strain); surgery was preferentially performed when bacillary load was controlled, except in case of treatment failure. However anti-tuberculosis treatment was not shortened in those patients. In 6 cases of XDR-TB no adequate treatment could be identified (if 3 or less active drugs were identified on the DST) and the combination of meropenem-clavulanate has been included in a salvage regimen. Concerning the other XDR cases, an adequate regimen of 4 active drugs could be built. Active treatment was given for a median of 448 days (range 329-616), with amikacin for a median of 89 days (range 41-166) and capreomycin for 211 days (range 68-649) (numbers based on the 84 episodes)
Evolution and final outcome
Among the 84 episodes, 41 MDR-TB and 1 XDR-TB episodes reached treatment completion, 3 MDR-TB and 2 XDRTB failed treatment, 1 MDR-TB patient died from stroke while still on therapy, 16 MDR-TB were lost to follow up. At the time of analysis 12 MDR-TB and 8 XDR-TB were still on therapy. As sputum collection is generally difficult to obtain when the evolution is favourable, no patient reached the WHO definition of cure in our series. Median time to sputum culture conversion was 69 days (range 37-116 days) for MDR-TB episodes and 97 days (range 85-188) for XDR-TB. This difference was statistically significant (Wilcoxon sum of square test, p = 0, 0391). Median time of hospitalisation was 105 days (range 61-149) for MDR-TB and 288 days (range 262-305) for a XDR-TB. Median time of treatment duration after sputum culture conversion reached 406 days (range 288-589). Among the six subjects who presented more than one MDR-TB episode, 1 reached treatment completion, 3 defaulted and 2 ended up in treatment failure. We recorded severe hepatotoxicity in 20% of the episodes (17/84). 7% of nephrotoxicity (6/83) and 29% of ototoxicity (24/83) with capreomycin or amikacin use, 32% of polyneuropathy (10/31) and 26% haematological side effects (8/31) with linezolid use and 9% of hypothyroidism (6/70) with prothionamide use. Most patients complained of gastro-intestinal disturbances but data on suspected drugs are generally not available. All of the above required treatment adaptation (interruption or dose reduction of the suspected drugs).
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MDR-TB IN A BELGIAN INFECTIOUS DISEASES UNIT
DISCUSSION This retrospective study started in 1996 reviewed 84 episodes of MDR/XDR-TB that occurred in 78 subjects over 15 years in St Pierre University Hospital, Brussels with a growing number of recorded cases per year and an increasing proportion of XDR cases. Our findings are in accordance with other observations(1, 9). Most cases came from low income countries. Transmission of MDR TB in the Belgian population is limited with only 4 Belgian cases in this study. Ninety-five % of our cases were immigrants with a majority coming from Eastern Europe, Asia and Africa. The pattern of resistance differed according to the patients’ demographic origin. This is explained by the heterogeneous availability and use of anti-tuberculous agents around the world. All of our XDR-TB cases came either from Eastern Europe or Asia where second-line agents are readily available and often mismanaged leading to the selection of drug resistant mutants. Extensively resistant cases were found when second-line therapy has been used previously for more than a month (1, 9-13). We have observed one case resistant to Linezolid in a patient previously exposed to this drug. Linezolid has only been used since a few years in the treatment of TB with promising efficacy despite occurrence of side effects (14). This underlines once again the importance of adequate use of second-line drugs for MDR-TB (15). WHO’s guidelines about MDR-TB treatment remain difficult to comply with. In our cohort the recommended number of drugs was respected but not the duration of therapy (406 days after culture conversion compared with the 540 days after sputum culture conversion recommended by WHO in order to prevent relapse (2)). This illustrates the gap between recommandations and “real life”. The guidelines are issued from observational retrospectives studies which suggest that 18 to 24 month of therapy is associated with better outcome. In clinical practice, side effects and loss to follow up are barriers to this long treatment duration. Management of side effects and compliance are problematic especially with drugs like amikacine, capreomycin, linezolid or prothionamide (4). As our results show, these drugs induce a high percentage of side effects leading to treatment interruption or reconsideration. In our experience, total treatment interruption because of side effects has not occurred. Compliance to treatment was particularly difficult to ensure after discharge from the hospital as the vast majority of our patients were immigrants, illegal aliens or asylum seekers facing a lot of psycho-social problems. Financial issues were not a barrier since therapy was paid by the Belgian health care system. Considering the unfavourable outcome that remains associated with XDR-TB cases new therapeutic options have been looked at for the most resistant strains (12, 16). As in vitro efficacy of the combination of meropenem-clavulanate against susceptible as well as resistant M.tuberculosis strains has been demonstrated, we have used this compound in association with the remaining active drugs, in 6 XDR patients for whom no suitable active treatment could be found (3 or less active drugs shown by the antibiogram) (17, 18, 19). One case is now considered as cured after 19 month of this therapy. Four out of five additional cases are evolving favourably. One patient deceased from TB.
Acta Clinica Belgica, 2013; 68-5
In conclusion, we have observed a growing number of MDR-TB cases in St Pierre University Hospital since 1996. Eighty-four episodes were recorded, including 11 XDR-TB episodes over 15 years. This represents 1-2% of all TB cases being handled in our institution. MDR-TB cases are mostly found in immigrants usually in precarious social situations. Worst case figures came from Eastern Europe and Asia (all of our XDR cases) but we have also found 4 Belgian cases, including 2 health care workers. This means that resistant TB has to be suspected in all patients with risk factors whatever their demographic origin. Most of these cases are still treatable but at the price of enhanced complications and treatment toxicity. Despite the fact that new therapeutic options are hopefully to be expected in the future, early diagnosis and adequate management following WHO recommendations are cornerstone to struggle the MDR-TB epidemic.
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