Resistant Urogenital Tuberculosis

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Resistant Urogenital Tuberculosis
Prof. Ekaterina Kulchavenya
urotub@yandex.ru

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Resistant Urogenital Tuberculosis

  1. 1. Resistant Urogenital Tuberculosis Prof. Ekaterina Kulchavenya urotub@yandex.ru
  2. 2. Although TB is very old disease (first cases are dated back to the times of pharaohs), it is not absolutely clear still now.
  3. 3. The World Health Organization recognized TB as a global problem and emphasized, that TB kills more young and adults than any other infectious disease; TB kills more women than any single cause of maternal mortality WHO report 2006
  4. 4. African region has the highest estimated incidence rate (356 per 100,000 habitants) but the absolutely highest number of TB patients lives in the most densely populated countries of Asia. Bangladesh, China, India, Indonesia and Pakistan together account for half of the new cases arising each year. The worldwide estimated incidence of new cases is 139 per 100,000 on average (9.2 million). WHO report 2008
  5. 5. 180 Isoniazid (H) 160 PASA 155 140 Streptomycin (S) Protionamyd 120 118 100 Pyrazinamid (Z) 80 Rifampicin (R) 91 88 86 83 83 84 83 83 84 72 Etambutol (E) 60 59 58 47 45 40 34 20 0 60 65 70 75 80 85 90 95 00 01 02 03 04 05 06 07 08 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 per 100,000 inhabitants
  6. 6. In countries with low incidence of TB lymphonodal TB predominates in structure of extrapulmonary TB. 6% 6% 17% CNS bone&joint UGT 50% lymponodal 21% abdominal Germany 5% 5% 11% 13% 2% 20% 18% 6% 13% 12% 41% 54% USA Macedonia
  7. 7. Structure of extrapulmonary TB Russian Federation 11% bone&joints 26% 8% UGT In countries with 17% lymph. nodes severe epidemic of eyes TB, Urogenital 38% others tuberculosis is the Tunis most common form 10% of extrapulmonary 9% 35% TB and the second 14% common form of TB as whole 14% 18%
  8. 8. Male Genital TB seems to be a rare disease. Nevertheless, 77% men died from tuberculosis of all localizations had prostate tuberculosis, mostly overlooked during life time. Actually, this means in Russia about 19000 men yearly. Kulchavenya E, 2007
  9. 9. Share of UGT among EPT in Siberia 1600 1400 1200 417 398 313 1000 340 286 299 313 800 600 973 865 820 854 863 400 753 871 200 0 1999 2003 2004 2005 2006 2007 2008 EPT UGT
  10. 10. Sex proportion in EPT patients 160 140 120 100 80 60 40 20 0 Bone&Joint UGT LN others male female Kulchavenya E, 2009
  11. 11. Age proportion in UGT patients 30 25 20 15 10 5 0 0-14 15-17 18-24 25-34 35-44 45-54 56-64 65 и ст male urol female urol Kulchavenya E, 2009
  12. 12. • TB is a disease caused by Mycobacterium tuberculosis, firstly revealed by Robert Koch
  13. 13. Diploma of Nobel laureate Robert Koch
  14. 14. Receipt of banquet
  15. 15. M. Tuberculosis complex M. t uber s culo sis M. bo v i M. microti M. canetti M. africanum
  16. 16. TYPES OF MYCOBACTERIA • M. tuberculosis human (M. tuberculosis) – causes disease in 80-85%. • M. tuberculosis bovis (M. bovis) – causes disease in 10-15%, mostly in contacted with infected animals. • M. tuberculosis avium (M. avium) – causes disease in 1-5%. • М. tuberculosis africanus (M. africanum) – causes disease in up to 90% in habitants of South Africa (initially resistant to tyoacetazon).
  17. 17. Atypical mycobacteria: M.kansasii, M.marinum, M.simiae M.scrofuloceum, M.xnopi, M.szulgal M.avium, M.intracellulare, M.paratuberculesis, M.heamophilus M.fortuitum, M.chelonae, M.abscessus М.leprae
  18. 18. Artificial-created Mycobacteria • M. tuberculosis BCG – from M. tuberculosis bovis (vaccine strain) • M. tuberculosis – resistant to antituberculous drugs
  19. 19. Identification of MBT in urine is very difficult task, because mycobacteriuria is inconstant and scanty, barely perceptible
  20. 20. Identification of MBT: 1. Microscopy ü Light microscopy (stain Ziehl – Neelsen) ü Fluorescent microscopy Detection of all acid – fast bacteria
  21. 21. Identification of MBT: 2. Culture diagnostic • At least three, but preferably five, consecutive early morning specimens of urine should be cultured, each onto at least two slants (Lowenstein - Jensen, Finn – II, Middlebrook 7H9-12) • a plain Löwenstein-Jensen culture medium to isolate M. tuberculosis • a pyruvic egg medium containing penicillin to identify M. bovis, which is partially anaerobic and grows below the surface of the culture medium
  22. 22. Standard technique is positive in 36-44% of UGT patients only. In study of Novikov (2004) bacteriological tests were performed 3 times in one day – at 8 o’clock, 11 and 13 o’clock. Positive cultures were on 15% higher
  23. 23. Very important is shortest time between collection of urine and its sowing, optimal time should be about 40 min.
  24. 24. Identification of MBT: 3. Drug susceptibility test üAbsolute concentration üMethod of proportions üMethod resistance ratio
  25. 25. Identification of MBT: • Automated system Bactec MGIT 960 – Mycobacteria Growth Indicator Tube. This tube has a fluorescent oxygen sensor.
  26. 26. Molecular diagnostics of TB GENOME ANALYSIS Polymerase chain reaction PCR analysis
  27. 27. Biochip technology in EIMB: Manufacturing by photo- induced copolymerization plate with light robot probes pin Gel pads with immobilized probes 50-500 μm gel pad
  28. 28. Identification of M. tuberculosis strains with biochips Strain sensitive to rifampicin treatment Strain with mutation in 531 nucleotide resistant to rifampicin treatment Ser531 → Leu POX
  29. 29. The concept of the efficiency of bactericidal therapy for TB 30 25 MIC (mkg/ml) 20 15 10 5 0 Strains of MBT with different resistance
  30. 30. • The cornerstone of antituberculous therapy is multidrug treatment to decrease the duration of therapy and to diminish the likelihood that drug-resistant organisms will develop
  31. 31. ANTITUBERCULOUS DRUGS The first-line antituberculous drugs are: • isoniazid (H) • rifampicin (R) • pyrazinamide (Pz) • streptomycin (S) • ethambutol (E)
  32. 32. ANTITUBERCULOUS DRUGS The second-line antituberculous drugs are: • protionamyd (Pt) / etionamyd (Et) • kanamycin (K) • amycacin (A) • capreomycin (Cap), • cycloserin (Cs), • rifabutin (Rb), • PASA (PAS), • fluorquinolons (Fq).
  33. 33. Ranking of TB Drugs 1st-Line Injections Fluoro- Oral 2nd- “3rd line” quinolones line 1. RIF 5. STM 6. MOXI 9. ETA 13. CLO 5. KAN 6. GATI 9. PTA 5. AMK 7. LEVO 2. INH 5. CAP 10. PAS 14. AMXCLV 8. OFLO 14. IMIPEN 8. CIPRO 3. PZA 11. CYS 15. LNZ 11. TRZ 4. EMB 12. THIA 16. CLARI Drugs within a table cell are cross-resistant with the other drugs in that cell. Drugs with the same number are approximately equivalent in efficacy.
  34. 34. Rifacomb plus (R+H+Z) Mayrin (E+H+R) Rifinag (R+H) Rifater (R+H+Z) Mayrin P (E+H+R+Z) Rifacomb (R+H+ В6)
  35. 35. Chemotherapy for TB: 1965-th Tomorrow? Today
  36. 36. DRUG RESISTANCE OF MICROORGANISMS •The natural or acquired ability of a microorganism to maintain vital functions under the action of drugs in the so-called critical or higher concentrations. S. Borisov, 2009
  37. 37. DRUG RESISTANCE OF MICROORGANISMS •Characteristic of all microorganisms • Is a clinical problem in surgery, obstetrics and gynecology, and many sections of Internal Medicine • In TB has become a worldwide medical and political problem S. Borisov, 2009
  38. 38. REASONS FOR DEVELOPMENT OF DRUG RESICTANT M.tuberculosis • Insufficient volume / duration of chemotherapy • Peculiarities of TB process • Condition of the patient and/or comorbidity • Non-optimal therapy • Drug deficiency • Behavior of the patient
  39. 39. Drug-resistance: - mono – to one of any antituberculous drugs; - poly – to more than one of any drugs used for the treatment of the disease, excluding isoniazid and rifampicin simultaneously; - multi-drug resistance (MDR) - MBT are resistant to at least isoniazid and rifampicin
  40. 40. Multidrug-resistant TB is associated both with a higher incidence of treatment failures and of disease recurrence, as well as with higher mortality than forms of TB sensitive to first-line drugs.
  41. 41. Global epidemiology of MDR-TB and the role of WHO in fighting MDR-TB Prioritized Areas of TB Control in Modern Social and Epidemiological Environment 28 November - 1 December 2006 Yekaterinburg, Russia
  42. 42. Background 458,000 MDR-TB cases emerge every year Without treatment MDR-TB continues to spread leading to additional suffering for patient and communities With inadequate treatment or treatment with poor quality drugs incurable TB strains can develop and spread
  43. 43. XDR-TB: extensively drug-resistant MBT XDR: MDR-TB plus resistance to any fluoroquinolone and, at least, 1 of 3 injectables (ami, kana or capreo) Of 17,690 isolates from 49 countries during 2000-2004 20% were MDR; 2% XDR XDR found in: USA: 4% of MDR Latvia: 19% of MDR S Korea: 15% of MDR XDR found in Southern Africa associated with HIV
  44. 44. In 2008, an estimated up to 510 000 cases of MDR-TB emerged globally. TDR is coming!
  45. 45. MDR is in the whole world, but mostly – in 3 countries 458,000 700 000 600 000 310,000 500 000 400 000 300 000 161,000 115,000 200 000 34,000 100 000 - Total China + China India Russia India + Russia
  46. 46. MDR in Russia 2006 (% among all patients) 63,0 22,3 new-revealed pts chronic pts M. Vladimirskiy et al. 2006
  47. 47. Drug resistant MBT in prisons in 2008 (%) whole 90 80,1 resistance 80 MDR 69,4 70 ХDR 60 51 48,2 50 37,6 40 30 18,6 20 6,6 8,4 10 2,8 0 whole primary secondary resistance resistance resistance
  48. 48. Mostly drug-resistant mycobacteria are revealed in pulmonary TB patients
  49. 49. Compared with PTB, EPTB is negatively associated with multidrug resistance (OR 0.6) Peto HM et al., 2009
  50. 50. Mono-, poly and multi-drug resistant MBT to the basic antituberculous drugs were found in up to 52.2% in extrapulmonary TB patients and up to 78.7% in pulmonary TB patients in Moscow in 2006 Vishnevskyi V et al., 2008
  51. 51. Among 98 patients with PT + UGT 70.0% had MDR in sputum, but all strains in urine were susceptible Nersesyan and Remrzova., 2008
  52. 52. There is no reasonable explanation of this fact, we must take it for what it is worth
  53. 53. There is a very few papers on drug resistant urogenital tuberculosis
  54. 54. Overall drug resistance in UGT was 8.3% (7.4% non-AIDS/11.5% AIDS) in a tertiary hospital, Valencia during the years 1993-1996. Cremades Romero et al., 1998
  55. 55. Of 12 MBT isolates in UGT, eight (66.7%) were found susceptible to all of the antituberculous agents, while one was found resistant to isoniazid and ethambutol, one was resistant to isoniazid and rifampicin, and two were resistant to only isoniazid. Aslan G. et al., 2007
  56. 56. Among 83 strains of MBT in UGT patients 17 (20.5%) were resistant: 70 60 rifampicin 64,7 64,7 50 streptomycin ethambutol 40 isoniazid kanamycin 30 MDR (R+H) 20 Polyresistance 20,5 10 17 11,8 5,9 11,8 0 Nersesyan and Remrzova., 2008
  57. 57. How can we prevent drug resistance? • Early diagnostic. • Complex intensive therapy with 4-5 antituberculous drugs for 2-4 months follow 2-3 drugs for 5-10 months. • Using pathogenetic therapy.
  58. 58. Diagnosis • Poor knowledge of the doctors and the population, absence of the pathognomonic symptoms, non-optimal antibacterial therapy for non-specific UTI resulted in late diagnosis of urogenital tuberculosis with polycavernous complicated forms
  59. 59. Fistulous uroTB obligatory accompanies with drug resistant mycobacteria
  60. 60. Diagnosis • For a correct diagnosis a careful investigation of the epidemiological history (contact with tuberculous infection, TB in history, especially in childhood) • and special diagnostic algorithms, including provocative tests, are necessary.
  61. 61. Diagnosis Mantoux test is positive in more than 90% of patients, but it has no value in regions with severe epidemic situation (China, Russia, India, Africa), where all adults are infected with MBT and thus all immunocompetent inhabitants have positive skin tuberculin test
  62. 62. Diagnosis New Diascintest is more effective as it allows to differentiate a reaction after BCG vaccination and latent tuberculous infection Infected with MTB Suffer from TB
  63. 63. Optimal antibacterial therapy for non-specific UTI in regions with severe epidemic situation
  64. 64. Susceptibility of E.Coli in out-patient with UTI in UTIAP–2 Study (n=258) in Russia 100 89,5 89,9 90,7 92,6 93,8 % s u scep tib le str ain s 80 73,3 56,2 60 40 20 8,1 0 nitroxolin ampicillin co-trimoxazol nalidixic acid pipemidic acid norfloxacin ciprofloxacin gentamicin nitrofurantoin
  65. 65. Susceptibility of E.coli (%) in Russia on ARESC - Study Antibiotic (n=301) 1.Fosfomycin 99.3 2. Mecillinam 97.3 3. Nitrofurantoin 94.7 4. Ciprofloxacin 87.4 5. Nalidixic acid 82.7 6. Amoxi/clav 83.0 7. Cefuroxime 83.4 8. TMP-SMX 69.4 9. Ampicillin 42.0 Naber et al 2008 Eur Urol 54: 1164-1178
  66. 66. XI National Russian Urological Congress approved a resolution, that all cases of UTI should be suspected for TB, and first line therapy should exclude antibacterials affecting MBT (fluorquinolons, rifampicin, streptomycin or amycacin). All patients with UTI primary should be investigated for TB by culture and/or microscopy. Only after TB is excluded, they may be treated with fluorquinolons.
  67. 67. 11 – 6,6% 167 pts Acute debute 156 – 93,4% Chronic disease 59 – 37,8% 4,8months 27,3 months 97 – 62,2% papillitis cavernas 47 – 79,7% 24 – 24,7% optimal optimal 12 – 20,3% nonoptimal 73 – 75,3% nonoptimal
  68. 68. Optimal therapy: • Fosfomycin • Amoxicillin / clavulanic acid • Nitrofurantoin • Gentamicin • Cefalosporins
  69. 69. NON-optimal therapy: • Rifampicin • Amycacin, streptomycin, kanamycin • Fluorquinolons
  70. 70. Table 1. WHO Standard schemes of a chemotherapy Essential drug Recommended dosage (abbreviation) (dosage range) in mg.kg Daily 3 times weekly isoniazide (H) 5 (4-6) 10 (8-12) rifampicin (R) 10 (8-12) 10 (8-12) Pyrazinamide (Z) 25 (25-30) 35 (30-40) streptomycin (S) 15 (12-18) 15 (12-18) ethambutol (E) 15 (15-20) 30 (25-35) thioacetazone (T) 2.5 Not applicable
  71. 71. Table 3. Russian Standard schemes of a chemotherapy Regime Phase Intensive Continuation phase I 2HRZE/S 6 H R / 6 H3 R3 II-a 2HRZES+1HRZE 5 H R E / 5 H3 R3 E3 II-б 3 H R Z E [Pt] [Cap] / [K] [Fq] According to sensitivity of MBT III 2HRZE 4 H R / 4 H3 R3 6HE IV Not less then 5 drugs Not less then 3 drugs [Z E Pt Cap / K Fq] [E Pt Fq] [Rb] [Cs] [PAS] [Rb] [Cs] [PAS] Length not less then 6 mo. Length not less then 12 mo.
  72. 72. Disadvantages of DOTS • Is aimed on destructive pulmonary TB •Doesn't take in account the features of UGT •Etambutol is contraindicated in hematuria •Streptomycin is contraindicated in stricture of ureter or urethra, microcystis • Resulted in a lot of relapses and drug resistance
  73. 73. Address drug delivery liposomal forms; mycobacteriophags; lymphotropic therapy; laser therapy
  74. 74. One of such antibiotics is levofloxacin. Its concentration in prostate tissue is 4 times higher than in plasma, and concentration in the macrophages – in 8-12 times higher.
  75. 75. Chemotherapy for prostate TB Fq PAS Z R H 0 2 4 6 8 10 12 14
  76. 76. Chemotherapy for complicated kidney TB Fq Cs PAS Z R H 0 2 4 6 8 10 12
  77. 77. Treatment of MDR TB Groups Of Drugs How to Use Them 1. Oral first line drugs As many as possible 2. Injectable drugs One best AG 3. Fluorquinolons One best FQ 4. Traditional oral As many as needed second line drugs 5. Third line drugs Only if necessary
  78. 78. Drug resistance of MBT in UGT occurs rarer than in PTB, nevertheless it may be up to 65%.
  79. 79. MBT from fistulas (both renal and genital) by all means are resistant at least to one antiTB drug.
  80. 80. Mono- and poly-drug resistance of mycobacteria in UGT patients predominates, MDR and XDR are less frequent.
  81. 81. UroTB with MDR or XDR mycobacteria requires individual scheme of the therapy, using not less than 6-7 drugs simultaneously, fluorquinolons and reserve drugs.

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