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

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

4. Although TB is
very old disease
(first cases are
dated back to the
times of pharaohs),
it is not absolutely
clear still now.

5. 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

6. 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

8. 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

9. 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

10. 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%

11. 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

12. 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

13. Sex proportion in EPT patients
160
140
120
100
80
60
40
20
0
Bone&Joint UGT LN others
male female
Kulchavenya E, 2009

14. 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

15. • TB is a disease caused by
Mycobacterium tuberculosis, firstly
revealed by Robert Koch

16. Diploma of Nobel laureate Robert Koch

17. Receipt of banquet

18. M. Tuberculosis complex
M. t
uber s
culo
sis M. bo v i
M. microti M. canetti
M. africanum

19. 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).

20. 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

21. Artificial-created
Mycobacteria
• M. tuberculosis BCG – from M.
tuberculosis bovis (vaccine strain)
• M. tuberculosis – resistant to
antituberculous drugs

22. Identification of MBT in urine
is very difficult task, because
mycobacteriuria is inconstant
and scanty, barely perceptible

23. Identification of MBT:
1. Microscopy
ü Light microscopy (stain Ziehl – Neelsen)
ü Fluorescent microscopy
Detection of all acid – fast bacteria

24. 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

25. 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

26. Very important is shortest time between
collection of urine and its sowing,
optimal time should be about 40 min.

27. Identification of MBT:
3. Drug susceptibility test
üAbsolute concentration
üMethod of proportions
üMethod resistance ratio

28. Identification of MBT:
• Automated system Bactec MGIT 960 –
Mycobacteria Growth Indicator Tube. This
tube has a fluorescent oxygen sensor.

29. Molecular diagnostics of TB
GENOME ANALYSIS
Polymerase chain reaction
PCR analysis

30. 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

31. 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

32. 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

33. • 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

34. ANTITUBERCULOUS DRUGS
The first-line antituberculous drugs are:
• isoniazid (H)
• rifampicin (R)
• pyrazinamide (Pz)
• streptomycin (S)
• ethambutol (E)

35. 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).

36. 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.

38. 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)

39. Chemotherapy for TB:
1965-th
Tomorrow?
Today

41. 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

42. 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

43. 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

44. 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

45. 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.

46. 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

47. 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

48. 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

49. In 2008, an estimated
up to 510 000 cases
of MDR-TB
emerged globally.
TDR is coming!

50. 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

51. MDR in Russia 2006 (% among all patients)
63,0
22,3
new-revealed pts chronic pts
M. Vladimirskiy et al. 2006

52. 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

53. Mostly drug-resistant mycobacteria are
revealed in pulmonary TB patients

54. Compared with PTB, EPTB is
negatively associated with multidrug
resistance
(OR 0.6)
Peto HM et al., 2009

55. 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

56. Among 98 patients
with PT + UGT 70.0% had
MDR in sputum, but all strains in urine
were susceptible
Nersesyan and Remrzova., 2008

57. There is no reasonable explanation of
this fact, we must take it
for what it is worth

58. There is a very few papers on drug
resistant urogenital tuberculosis

59. 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

60. 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

61. 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

62. 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.

63. 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

67. Fistulous uroTB obligatory accompanies with
drug resistant mycobacteria

68. 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.

69. 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

70. 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

71. Optimal antibacterial therapy for
non-specific UTI in regions with
severe epidemic situation

72. 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

73. 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

74. 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.

75. 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

76. Optimal therapy:
• Fosfomycin
• Amoxicillin / clavulanic acid
• Nitrofurantoin
• Gentamicin
• Cefalosporins

77. NON-optimal therapy:
• Rifampicin
• Amycacin, streptomycin,
kanamycin
• Fluorquinolons

78. 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

79. 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.

81. 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

82. Address drug delivery
liposomal forms;
mycobacteriophags;
lymphotropic therapy;
laser therapy

83. 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.

84. Chemotherapy for prostate TB
Fq
PAS
Z
R
H
0 2 4 6 8 10 12 14

85. Chemotherapy for complicated kidney TB
Fq
Cs
PAS
Z
R
H
0 2 4 6 8 10 12

86. 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

87. Drug resistance of MBT in UGT
occurs rarer than in PTB,
nevertheless
it may be up to 65%.

88. MBT from fistulas (both renal and
genital) by all means are resistant at
least to one antiTB drug.

89. Mono- and poly-drug resistance of
mycobacteria in UGT patients
predominates,
MDR and XDR are less frequent.

90. UroTB with MDR or XDR
mycobacteria requires individual
scheme of the therapy, using not less
than 6-7 drugs simultaneously,
fluorquinolons and reserve drugs.