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
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
19. TYPES OF
MYCOBACTERIA
โข M. tuberculosis human (M. tuberculosis) โ
causes disease in 80-85%.
โข M. tuberculosis bovis (M. bovis) โ causes
disease in 10-15%, mostly in contacted with
infected animals.
โข M. tuberculosis avium (M. avium) โ causes
disease in 1-5%.
โข ะ. tuberculosis africanus (M. africanum) โ
causes disease in up to 90% in habitants of
South Africa (initially resistant to tyoacetazon).
21. Artificial-created
Mycobacteria
โข M. tuberculosis BCG โ from M.
tuberculosis bovis (vaccine strain)
โข M. tuberculosis โ 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
รผ Light microscopy (stain Ziehl โ Neelsen)
รผ Fluorescent microscopy
Detection of all acid โ fast bacteria
24. Identification of MBT:
2. Culture diagnostic
โข At least three, but preferably five, consecutive
early morning specimens of urine should be
cultured, each onto at least two slants
(Lowenstein - Jensen, Finn โ II, Middlebrook
7H9-12)
โข a plain Lรถwenstein-Jensen culture medium to
isolate M. tuberculosis
โข 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 โ
at 8 oโclock, 11 and 13 oโclock.
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
รผAbsolute concentration
รผMethod of proportions
รผMethod resistance ratio
28. Identification of MBT:
โข Automated system Bactec MGIT 960 โ
Mycobacteria Growth Indicator Tube. This
tube has a fluorescent oxygen sensor.
30. Biochip technology in EIMB:
Manufacturing by photo-
induced copolymerization
plate
with
light robot probes
pin
Gel pads with immobilized probes
50-500 ฮผm
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 โ 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. โข 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
36. Ranking of TB Drugs
1st-Line Injections Fluoro- Oral 2nd- โ3rd lineโ
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.
37.
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+ ะ6)
41. DRUG RESISTANCE OF
MICROORGANISMS
โขThe 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
โขCharacteristic of all microorganisms
โข Is a clinical problem in surgery,
obstetrics and gynecology, and many
sections of Internal Medicine
โข In TB has become a worldwide
medical and political problem
S. Borisov, 2009
43. REASONS FOR DEVELOPMENT OF DRUG
RESICTANT M.tuberculosis
โข Insufficient volume / duration of
chemotherapy
โข Peculiarities of TB process
โข Condition of the patient and/or
comorbidity
โข Non-optimal therapy
โข Drug deficiency
โข Behavior of the patient
44. Drug-resistance:
- mono โ to one of any antituberculous drugs;
- poly โ 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 โ 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
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?
โข Early diagnostic.
โข Complex intensive therapy with 4-5
antituberculous drugs for 2-4 months
follow 2-3 drugs for 5-10 months.
โข Using pathogenetic therapy.
63. Diagnosis
โข 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
68. Diagnosis
โข For a correct diagnosis a careful
investigation of the epidemiological history
(contact with tuberculous infection, TB in
history, especially in childhood)
โข 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
72. Susceptibility of E.Coli in out-patient with UTI
in UTIAPโ2 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.
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-ะฑ 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.
80.
81. Disadvantages of DOTS
โข Is aimed on destructive pulmonary
TB
โขDoesn't take in account the
features of UGT
โขEtambutol is contraindicated in
hematuria
โขStreptomycin is contraindicated in
stricture of ureter or urethra,
microcystis
โข Resulted in a lot of relapses and
drug resistance
83. One of such antibiotics is
levofloxacin.
Its concentration in prostate
tissue is 4 times higher than in
plasma, and concentration in
the macrophages โ in 8-12
times higher.
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.