journalclub 22-2-11 (Resistance to 2nd line anti-TB injectable drugs)

Resistance to second-line injectables and treatment outcomes in MDR and XDR tuberculosis cases :

Resistance to second-line injectables and treatment outcomes in MDR and XDR tuberculosis cases Dr.Nadeem-Ur-Rasool DCH Trainee

Conducted By:

Conducted By G.B. Migliori , C . Lange, R. Centis , G . Sotgiu , R. Mu ¨ tterlein , H . Hoffmann, K . Kliiman , G . De Iaco , F.N . Lauria , M.D. Richardson, A . Spanevello , D.M. Cirillo and TBNET Study Group

Conducted At :

Conducted At (Bad Lippspringe Hospital , Bad Lippspringe, Germany ); ( Grossansdorf Hospital, Grossansdorf , Germany); ( Supranational Reference Laboratory, Borstel,Germany ); ( S. Raffaele Hospital, Milan, Italy); ( Milano University, Milan, Italy ); ( Villa Marelli Institute, Milan, Italy); ( University of Perugia, Perugia, Italy ); ( Brescia University, Brescia, Italy); ( Sondalo Hospital,Sondalo , Italy); (Supranational Reference Laboratory and Istituto Superiore di Sanita` , Rome , Italy ); ( INMI L. Spallanzani , Rome, Italy); ( National Tuberculosis Programme , Tartu, Estonia); ( Archangels University, Archangels, Russian Federation). (Fondazione S. Maugeri, Cassano delle Murge, Italy and Archangels University, Archangels, Russian Federation);

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From 1999 to 2006 PUBLISHED IN EUROPEAN RESPIRATORY JOURNAL VOLUME 31 NUMBER 6, 2008 Study Design Chort Study

Aim:

Aim To investigate the influence of injectable second-line drugs on treatment and outcomes of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) patients. To assess the drug susceptibility testing for first- and second-line anti-TB drugs. To assure laboratory quality and treatment delivery according to World Health Organization recommendations .

XDR and MDR:

XDR and MDR Extensively drug-resistant (XDR) tubercu­losis (TB) is defined as resistance to at least rifampicin and isoniazid , plus resistance to any fluoroquinolone and at least one of three injectable anti-TB drugs ( capreomycin , kanamycin , or amikacin ). Multidrug­resistant (MDR)-TB is defined as resistance to at least rifampicin and isoniazid .

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XDR-TB patients have a higher risk of death and failure than those with MDR-TB, two TuBerculosis Network (TBNET) studies showed that : 1 ) resistance to additional first-line drugs (other than isoniazid and rifampicin ) is a predictor of adverse out-comes ; and 2 ) resistance to fluoroquinolones contributes to increased risk of death and failure in these cases.

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Treatment success Resistant 9 (39) 72 (66) 15 (72) 4 (36) 22 (48) 8 (36) Susceptible 156 (72) 93 (71) 150 (69) 18(49) 0(0) 14(54) Died Resistant 5(22) 20(18) 3(14) 4 (36) 12 (26) 8 (36) Susceptible 38(17) 23(18) 40(18) 10 (27) 2 (100) 6 (23) Failure Resistant 9(39) 18(16) 3(14) 3 (28) 12 (26) 6 (28) Susceptible 23(11) 14(11) 29(13) 9 (24) 0 (0) 6 (23) Total 23(100) 110 (100) 21(100) 11(100) 46 (100) 22 (100) Resistant Susceptible 217 (100) 130 (100) 219 (100) 37(100) 2 (100) 26 (100 ) MDR-TB XDR-TB Capreomycin Kanamycin Amikacin Capreomycin Kanamycin Amikacin Outcomes of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) cases resistant and susceptible to injectable second-line drugs

METHODS :

METHODS 4,583 culture-confirmed diagnosed TB cases between 1999 and 2006 were selected. Drug resistance and treatment outcome data was reviewed for outcomes of MDR-TB and XDR- TBcases resistant and susceptible to injectable second-line drugs . Standard World Health Organization (WHO) definitions for MDR-TB, XDR-TB and treatment outcome (treatment success, died, failure, default and transferred out) were used .

Inclusion criteria:

Inclusion criteria 288 cases with laboratory-confirmed MDR- or XDR-TB for whom a definitive treatment end-point was recorded (treatment success, treatment failure or death) .

Exclusive criteria:

Exclusive criteria Cases were excluded :- if they did not meet the definition of confirmed MDR- or XDR-TB, if they were confirmed MDR-or XDR-TB cases but did not have a definitive treatment outcome recorded. Thus, MDR- and XDR-TB cases without a definitive outcome were excluded from the analysis; including 77 (18%) cases still undergoing treatment, 57 (13%) who defaulted and three (0.7%) who transferred out.

Drug susceptibility testing (DST):

Drug susceptibility testing (DST) On first-line anti-TB drugs and second-line anti-TB drugs was performed according to WHO recommendations by quality-assured laboratories and re-tested at the WHO Supranational Reference Laboratories. At all sites, regimens to treat MDR- and XDR-TB cases were tailored to the DST results according to WHO recommendations. Each of the locations had access to all categories of second-line drugs ( injectable & oral agents )during the study period . Third-line agents (amoxicillin/ clavulanic acid, clarithromycin , clofazimine ) were available in all locations except Archangels Oblast

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The prevalence of resistance to injectable second-line drugs ( capreomycin , kanamycin or amikacin ) was analysed . Logistic regression analysis was performed. The variables included in the statistical analysis were: country, sex, age at the time of diagnosis, immigrant status, DST results , treatment outcomes and MDR- or XDR-TB status

RESULTS :

RESULTS 69,633 pts. Were screened,out of which 4,583 were culture-confirmed cases. Among these,361 (7.9%) were MDR-TB and 64 (1.4%) were XDR-TB cases. Of these, 240 (66.5%) MDR-TB cases and 48 (75%) XDR-TB cases had a definitive outcome recorded and were included in the analysis (tables 1 and 2). In the final sample of 288 cases for analysis, 124 (43%) cases were resistant to one or more of the second-line injectables. In total, 43 (15%) cases were resistant to amikacin , 34 (12%) to capreomycin and 156 (54%) to kanamycin . 52 were resistant to more than one injectable .

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TABLE 2 Outcomes of extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant tuberculosis (MDR-TB) cases susceptible and resistant to one or more injectable second-line drug in Estonia, Germany, Italy and Russian Federation (Archangels Oblast) MDR-TB Treatment success Died Failure Total Crude OR (95%CI) # Adjusted Or (95%CI) Susceptible 89 (72) 23 (18) 12 (10) 124 (100) 1 1 Resistant to 1 drug 62(71) 14(16) 11(13) 87 (100) 1.02 (0.55–1.88) 1.01 (0.09–11.94) Resistant to 2 drugs 8 (40) 4 (20) 8 (40) 20 (100) 1.95 (1.19–3.18) 1.02(0.42–2.47) Resistant to 3 drugs 6 (67) 2 (22) 1 (11) 9 (100) 1.08 (0.67–1.75) 0.92 (0.56–1.51) XDR-TB + Resistant to 1 drug 13 (52) 7 (28) 5 (20) 25 (100) Resistant to 2 drugs 6 (40) 4 (27) 5 (33) 15 (100) Resistant to 3 drugs 3 (37.5) 3 (37.5) 2 (25) 8 (100) Overall sample Susceptible 89 (72) 23 (18) 12 (10) 124 (100) 1 1 Resistant to 1 drug 75 (67) 21(19) 16 (14) 112 (100) 1.25 (0.72–2.18) 2.23 (0.37–1 3.41) Resistant to 2 drugs 14 (40) 8 (23) 13 (37) 35 (100) 1.95 (1.32–2.88) 1.2 (0.56–2.59) Resistant to 3 drugs 9 (53) 5 (29) 3 (18) 17 (100) 1.31(0.93–1.84) 0.92 (0.56–1.51) Data are presented as n (%), unless otherwise stated. OR: odds ratio; CI: confidence interval. #: number of injectables the patient is resistant to versus susceptible

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Out of the 240 MDR-TB cases with a definitive outcome reported, the proportion of cases resistant to capreomycin , kanamycin and amikacin was 9.6% , 45.8% and 8.7% , respectively, and among the 48 XDR-TB cases it was 22.9% , 95.8% and 45.8% respectively. The proportion of HIV- seropositive patients was low in the sample of 288 cases: 10 (4.2%) out of 240 in MDR-TB and one (2.1%) out of 48 in XDR-TB cases. No significant differences in outcomes were noted for HIV-infected patients.

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Capreomycin -resistant MDR-TB cases yielded a higher proportion of failure and death than capreomycin -susceptible ones (14 (60.9%) out of 23 versus 61 (28.1%) out of 217). patients who were resistant to more than one injectable drug were more likely to achieve an unfavourable outcome.

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In MDR-TB cases, adverse outcomes appeared in 25 (28.7%) out of 87 single- injectable resistant cases versus 15 (51.7%) out of 29 multi- injectable resistant cases , and for XDR-TB in 12 (48%) out of 25 versus 14 (60.8%) out of 23 cases . A logistic regression analysis was used to compare outcomes for cases susceptible versus resistance to each of the injectable agents.

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A comparison of outcomes between cases susceptible to all three injectables versus cases resistant to one, two and three injectable drugs was performed (table 2). In this analysis, treatment outcomes did not appear to be poorer as the number of drugs to which a case was resistant increased.

DISCUSSION :

DISCUSSION The results suggest that resistance to capreomycin , in particular, significantly increases the risk of death and treatment failure in MDR- and XDR-TB cases, while resistance to either kanamycin or amikacin alone does not appear to be as important an indicator of poor prognosis. While the study did not show that resistance to more than one injectable leads to significantly poorer outcomes, a larger sample would help to clarify whether there is indeed a tendency toward poorer outcomes in cases with additional resistance. Outcomes for XDR-TB cases already resistant to fluoroquinolones seemed to be less affected by loss of multiple second-line injectable drugs.

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The strengths of the study include : large sample size, high quality of laboratory. Additionally limitations of the study include : 1 ) the inability to assess additional factors, including variability of provider treatment practices and existence of additional comorbid conditions (other than HIV) that may confound the results; 2) in spite of the large cohort, numbers are small when stratification per individual injectable drug is performed.

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At present, caution should always be used when interpreting data related to XDR-TB cases. In fact, universally accepted standardised approaches to testing drug concentrations and methods which correlate clinically with disease as well as quality assurance systems, including proficiency testing for second-line drugs, do not yet exist . A comparative analysis of the role played by the XDR-TB-defining drugs will further contribute to clarifying their relative importance in influencing treatment outcomes.

conclusion:

conclusion the present study is the first to assess the contribution of second-line injectable anti-TB drugs to treatment outcomes in MDR- and XDR-TB cases. The findings suggest that in the countries surveyed, resistance to second-line injectable drugs is, in general, widespread among drug-resistant cases. In the present study, the loss of capreomycin as an effective treatment agent appears to be an important predictor of poor treatment outcomes. The implications of this finding for clinical management need to be explored in more detail before any recommendations can be considered; the chances of treatment success are increased with early and effective intervention.

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Two parallel actions are critical at the programme level : 1) Strengthening existing tuberculosis control activities to prevent new cases of multidrug-resistant and extensively drug-resistant tuberculosis; 2) Improving national capacity to diagnose and treat existing drug-resistant cases effectively. At the global level: 1)The rational use of existing compounds must be urgently promoted to preserve their utility in treating the most difficult tuberculosis cases. 2)Intensify efforts to develop novel interventions (including new drugs and vaccines) to fight tuberculosis more effectively.