Anna Starshinova in TB seminar 18-19.9.2017 St Petersburg - Nordic Russian Health Programme

1. А. Starshinova
MD, DMedSci, PhD
St.-Petersburg, September 18-19, 2017
Personified approaches to the
treatment of tuberculosis depending on
pathogen drug sensitivity
Seminar on Tuberculosis in St. Petersburg
St-Petersburg Research Institute of Phthisiopulmonology

2. Tuberculosis in the World
WHO Global Tuberculosis report, 2016
Tuberculosis - is
one of the most
contagious
diseases!
About a third of the world's population is
infected by Mycobacteria tuberculosis;
Number of new cases of tuberculosis from
2012 to 2015 is increased from 8.7 to 10.4
million;
In 2015 480 000 new cases of tuberculosis with
MDR –TB were detected. 45% annually occurs
in India, China and in Russian Federation;
In 2015 1.4 million people died of tuberculosis
and 0.4 died (390 000) from a combination of
tuberculosis and HIV infection

3. WHO European Region has fastest decline of
TB incidence in the world
TB notification trend reflects true reduction in spread of the disease
and is strongly influenced by improvements in high-priority countries.
Source: European Centre for Disease Prevention and Control / WHO Regional Office for Europe.
Tuberculosis surveillance and monitoring in Europe 2016.
Stockholm: European Centre for Disease Prevention and Control; 2016
WHO European Region, 1980-2014
Notification (18 High-
priority countries)
Estimated incidence (53
Member States)
Notification rate (53
Member States)
Notification (European
Union/European Economic
Area (EU/EEA))
30,5
37
58,9
12,2
0
10
20
30
40
50
60
70
80
90
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014
Rateper100000population

4. Tuberculosis in Russia
Tuberculosis in In Russian Federation (analytical review), 2015
Morbidity of tuberculosis was decreased by half
(from 90.7 in 2000 to 57.7 in 2015 per 100 000
population);
Mortality of tuberculosis was decreased threefold
(from 20.0 in 2000 to 8.3 in 2015 per 100 000
population);
Increase of MDR-TB index (from 15.9 in 2005 to 25.5
in 2015 per 100 000 population);
Increase of TB with HIV-infection (from 6.5 in 2006
to 17.3 in 2015 per 100 000 population);
Vasilieva I, 2016; Nechaeva O., 2016; Aksenova V., 2016

5. Main directions in struggle against TB (WHO)
Early diagnosis of
tuberculosis
including
universal drug-
susceptibility
testing
Collaborative
tuberculosis/HIV
activities; and
management of
comorbidities
Treatment of
all people with
tuberculosis
including drug-
resistant
tuberculosis;
and patient
support
Preventive
therapy and
vaccination
against
tuberculosis
A DRAFT OF GLOBAL STRATEGY AND PURPOSES IN THE FIELD OF PREVENTION, TREATMENT
AND FIGHT AGAINST TB FOR THE PERIOD 2015 (14 th March 2014 )
In 2035: to eliminate tuberculosis as a problem of public
healthcare (no more than 1 case per 1 million population)

6. Three stages of the fight against tuberculosis
in Russia
In 1902 in Berlin, Russia was
one of the first countries to
join the Tuberculosis Control
League
The royal family begins the season in
the Livadia Palace in the Crimea
The pre-revolutionary
period 1902-1917
The Soviet period
1917 - 1991
In 1922 year the state program of struggle
against tuberculosis was adopted:
- early detection ( the use of Mantu test
and X-ray);
- isolation and rehabilitation in sanatoria;
- prophylaxis (BCG vaccination)
Period after
restructuring
1991 until now
Creation of new
programs and
technologies
In comparison with 1913 in 1941 mortality from
TB in USSR was decreased by
60% - 80:100 000
Not exact statistic data, but
1/3 of the population died of
tuberculosis
Expected Result –
reduction of morbidity
and mortality rates
three folds
Sanatoriums were
organized and collection
of money was conducted
for treatment of TB
patients.
In 2014 a new program
of the Government of
the Russian
Federation No. 294
was adopted
Morbidity of TB in Russia in period for
1965 to 1992

7. Dynamic of morbidity and mortality rates of
tuberculosis in Russia from 1970 to 2016
(in 100 000 of population)
Data of TB monitoring Federal Center (form №8), 2017

8. Morbidity of TB in St.-Petersburg
(per 100 000 population)
43.0
51.7
46.7
41.1 40.7
35.0 33.5
32.4 31.8 30.7
27.7
24.0 22.7 22.9
0
10
20
30
40
50
60
2010 2011 2012 2013 2014 2015 2016
Заболеваемость территориальная (ф-8)
Заболеваемость постоянных жителей (ф-33)
Morbidity of TB in territory (form -8)
1761
1203
Morbidity of TB in local people (form - 33)

9. 2008 2009 2010 2011 2012 2013 2014 2015 2016
10,8 10,2
7,4 8,3 8,1
6,5
5,3 5,2
3,5
6,6
5,2
4,3 4,1 3,7 3,5 3
1,9 1,3
территориальнаясмертность
смертность среди постоянногонаселения
Mortality of TB in period
of 2008-2016 in St. - Petersburg
(per 100 000 population)
Mortality of TB in territory (form -8)
Mortality of TB in in local people (form - 33)

10. Problem of drug resistance of MBT to anti-TB drugs is
a consequence of chemotherapy itself ...
Grow yourselves!
Laserson K. F. et al. Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis
//The International Journal of Tuberculosis and Lung Disease. – 2005. – Т. 9. – №. 6. – С. 640-645.

11. WHO/HTM/TB/2016.13
MDR and RR TB is a global problem

12. Treatment of MDR and XDR TB is a global problem
(Global report WHO, 2016)
According to WHO in 2015 there were
480 000 new TB cases with MDR mycobacteria
and 210 000 (20%) died
TB with extended drug resistance observed in 92
countries
Treatment efficacy of MDR TB (worldwide) - 52%.
XDR TB (worldwide) - 28%
34 out of 107 countries reached treatment efficacy of MDR TB 75%
due to introduction of new drugs
In 2015 in 9.5% cases of MDR TB and XDR TB were
diagnosed

13. Transmission of MDR-TB in European Region
Source: European Centre for Disease Prevention and Control/WHO Regional Office for Europe.
Tuberculosis surveillance and monitoring in Europe 2016.
Stockholm: European Centre for Disease Prevention and Control; 2016.

14. MDR-TB in the Europe in period of 2005 - 2014 years
Armenia Austria Azerbaijan Belarus
Belgium Bulgaria Denmark Estonia
Finland Gemany Italy Lithuania
Tuberculosis surveillance and monitoring in Europe 2016 (WHO, 2016)
33 009 MDR-TB cases was diagnosed in 2014 in
Europe, it is 45.2% cases in all TB patients in
European region
Azerbaijan

15. Treatment success rate of new pulmonary culture-
positive MDR TB cases in the Europe
Tuberculosis surveillance and monitoring in Europe 2016 (WHO, 2016)
48.7% is efficacy of MDR-TB
treatment in European in 2014

16. HIV co-infection among TB patients continues
to rise in the WHO European Region
HIV and TB create a deadly
synergy
Between 2006 and 2014
HIV-TB co-infection
increased from 2.8% to
8.0% with annual average
increase of 13%
Source: European Centre for Disease Prevention and Control/WHO Regional Office for Europe.
Tuberculosis surveillance and monitoring in Europe 2016.
Stockholm: European Centre for Disease Prevention and Control; 2016.
Proportion of HIV co-infection among TB
patients in
WHO European Region, 2006-2014
2,8 2,8
3,4
4,8
6,0
6,3 6,1
7,8 8,0
0
1
2
3
4
5
6
7
8
9
2006 2007 2008 2009 2010 2011 2012 2013 2014
%HIVamongTBcases

17. Cases of tuberculosis and HIV infection in countries with a
high burden of tuberculosis
Steady increase of new cases with
HIV and TB is registered in the
countries with high TB insides
HIV and TB
Source: European Centre for Disease Prevention and Control/WHO Regional Office for Europe.
Tuberculosis surveillance and monitoring in Europe 2016.
Stockholm: European Centre for Disease Prevention and Control; 2016.
Armenia Armenia Belarus
Russia
Estonia Georgia
UzbekistanUkraine
KyrgyzstanKazakhstan
RomaniaMoldova
Tajikistan Turkey
Bulgaria
LithuaniaLatvia

18. Each list contains 30 countries, defined as the top 20 in terms of absolute numbers of
cases plus the additional 10 countries with the most severe burden in terms of case
rates per capita that do not already appear in the “top 20” and that meet a minimum
threshold in terms of absolute numbers of cases (10 000 per year for TB, and 1000
per year for TB/HIV and MDR-TB). Each list accounts for 83–90% of the global
burden.
Countries with most severe burden of TB
in 2016-2020

19. Russia is among 22 countries with high burden of TB
Brazil, China, India, Russia and South Africa contribute
almost 50% of all TB cases in the World
MDR Tuberculosis in Russia
0
500000
1000000
1500000
2000000
2500000
Индия
Китай
ЮжнаяАфрика
Индонезия
Пакистан
Бангладеш
Филипины
Эфиопия
ДРКонго
Нигерия
Вьетнам
Мьянма
РоссийскаяФедерация
Мозамбик
Кения
Таиланд
Бразилия
Зимбабве
Танзания
Уганда
Камбоджа
Афганистан
Числоновыхслучаев
22 страны
с высоким бременем
ТБ
Другие страны
80%

20. ( форма №33 на 100 000 населения)
Level of MDR-TB in patient with bacterial excretion in Russia
(per 100 000 population)
In 52,1% diagnosed 18890 patients
with XDR-TB in 2015- in 32,5% MDR-TB diagnosed in children
Number of patients with MDR TB in
Russia
Vasilieva I, 2016; Nechaeva O., 2016; Aksenova V., 2016
9,3% - newly diagnosed cases
10,6% - among relapsed
19,7% - among repeatedly treated

21. TB and HIV case in Russia in period of 2009-2016
(per 100 000 population)
Center of TB monitoring in Moscow, O. Nechaeva, 2016. (form -33)
http://mednet.ru/ru/czentr-monitoringa-tuberkuleza.html
58.4 – 43.2% TB and HIV with MDR (Panteleev A., 2014)

22. MDR TB in new cases of TB in St.-Petersburg (%)
2010 2011 2012 2013 2014 2015 2016
15.2
20.7
23.3 23.5
20.5 20.9
25.0
44.8 44.7
50.6
% МЛУ от ВВБ % МЛУ от контингентовin new case of MDR TB in new case of MDR TB in patients with
relapses

23. 2010 2011 2012 2013 2014 2015 2016
204
248 262 266 268
225
301
977
923 917
абсолютное число впервые выявленных пациентов с ТБ+ВИЧ
абсолютное число активных пациентов с ТБ+ВИЧ
Absolute number of TB + HIV patients
(form 33)
Absolute number in new TB and HIV cases
Absolute number in active TB and HIV cases

24. Modern technologies for evaluation of drug sensitivity
M.tuberculosis in Russia
Fluorescent
microscopy
BACTEC MGIT 960
Microbiological technology
Molecular genetic
technologies
PCR-Рb, cartridges,
Hybridization on chip,
Hybridization on stripes,
Sequencing

25. Laboratory facilities in Russia
64 specialized laboratories
in Russia, 3 reference
laboratories

26. Studies of the molecular-genetic
structure of mycobacteria’s
Genome M. avium hominissuis
Genotype М. Beijing
1500 genomes of
the genotype
Beijing in NCBI
Clade A
B0/W148
Clade C
40 genomes from the St. Petersburg Research
Institute of Phthisiopulmonology
Cole S. T., Brosch R., Parkhill J. et al. //
Nature. – 1998. –V. 393.

27. Сollection of more than 5,000 strains of
Mycobacterium tuberculosis
• Currently, the collection contains more than 5,000 strains of Mycobacterium
tuberculosis from patients from 57 different regions of Russia. Whole
genome sequencing was performed on clinical isolates of Mycobacterium
tuberculosis from 31 regions of Russia.

28. • 150 clinical izolates of M. tuberculosis from 45
regions Russian Federation
Russian Federation:
69 MDR
• 19 XDR
• 88 extrapulmonary TB
• 72 lung TB
Beijing
lUra
LAM
T
Haarlem
6%
5%
4%
5%
4%
76%
Ural
Haarlem
LAM
T
Others
Beijing
7%
7%
16%
2%
1%
67%
Extrapulmonary TB
Mokrousov I, Chernyaeva E, Vyazovaya A, Sinkov V, Zhuravlev V, Narvskaya O. 2016. Next-generation sequencing of
Mycobacterium tuberculosis. Emerg. Infect. Dis. 22 (6): 1127-1129.
Whole - genome sequencing M. tuberculosis in Russia
Lung TB

29. Drug resistance and lineage
0%
20%
40%
60%
80%
100%
Beijin
g
Bj all
N=193
non-Bj
N=71
XDR
MDR
DR
pan-S
B0/W1
48
Haarle
m
LAM Ural Euro-
Americ
an
A. Vyazovaya, I. Mokrousov, V. Zhuravlev, N. Solovieva, T. Otten, B. Vishnevsky, O. Narvskaya Dominance of the Beijing
genotype among XDR Mycobacterium tuberculosis strains in Russia. International Journal of Mycobacteriology.2015 Vol. 4,
Suppl. 1, Pages 84–85

30. Rv1269c
Rv2405
B0/W148
Beijing / Lineage 2
Ural / 4.2.1
Ancient Beijing
Modern Beijing
LAM / 4.3.3
T / 4.1.2.1
T / 4.8
Mycobacterium canettii
Lineage 4
kdpD
Rv1995
mmr
Rv0073
TB27.3
Rv0654
pks9
Rv1928c
Rv2275
arsB1
Rv3047c
mce1R
Rv0420c
Rv0976c
Rv1045
Rv1258c
mcr11
Rv1775
ctpF
Rv2084
Rv2437
Rv2709
Rv2885c
Rv2923c
dxs2
Rv3776
Rv3830c
Rv3847
Insertions and deletions associated with genetic
groups
pks7
Rv1739c
fadE18
moeW
Rv3190A
Rv0025
Rv0461
vapB26
mce2D
Rv1199c
cyp128
Rv2280
mmpL9
Rv2561
Rv2665
Rv2850c
espG2
E.Chernyaeva 2017

31. The first database of genomic variations based on
the full genomic sequencing of M. tuberculosis
Genome-based Mycobacterium Tuberculosis Variation (GMTV) Database
http://mtb.dobzhanskycenter.org
The first database of genomic variations (SNPs and InDels), obtained from the
results of full genome sequencing of M. tuberculosis, including information on
clinical, epidemiological and microbiological data.
Contains information on the genomes of M. tuberculosis, which are sequenced
worldwide
• 1836 strains MTB
• 630 - MDR
• 224 - PZA-resistant
• 84 - XDR
Chernyaeva et al., BMC Genomics 2014 15:308.

32. The possibility of assigning an individual approach chemotherapy
regimen when using molecular genetic methods of diagnosis
Results of molecular genetic methods application in diagnostic
of M. tuberculosis drug resistance:
- Gene/Xpert RIF/Mbt and (only in RIF – more 95%);
- PCR real time (sensitivity of different drugs)
- HAIN test (detection mutations in genes of M. tuberculosis is
responsible for resistance to different drugs (INH (katG, inhA)
более 95%; RIF (rpoB); FQ (gyrA) более 90%; Am (rrs), Km (eis);
Cm (tlyA) more then 70-90%; E (embB), PZA (pncA) (Helpful table DR
mutations: Survival Guide v3 pages 46-47).
Using of drugs in individual
approach

33. Treatment efficacy in patients with MDR TB
• Efficacy of TB treatment – not less than 85%*
• Efficacy of MDR TB treatment – 75%*
*Global strategy and targets for tuberculosis prevention, care and control after 2015, WHO, 2013
Treatment efficacy in MDR TB –
36,9%;
Treatment efficacy in newly
diagnosed MDR TB – 53,8%
( Russia, 2015 )
Treatment failure – 18,3%;
Died from TB – 12,2%;
Prematurely discontinued
treatment – 14,6%
( Russia, 2015 )
WHO recommendations for
treatment efficacy

34. Key reasons of low efficiency TB therapy
Increasing TB bacteria`s drug
resistance
Low diagnosis quality Disease agent (MBT) is not identified
Full spectrum of MBT drug resistance
was not revealed while detecting
disease agent
Growing patient`s comorbidity
Increasing number of adverse drug
reactions
Lack of new TB drugs
Lack of chemotherapy control
Patient compliance
Contact with MDR TB patient
The use of early surgical
treatmentSurgical treatment

35. Development of new drugs and treatment
technologies
How to treat in Century
of MDR/XDR
tuberculosis ?
How to deliver the drug
directly to the source of
inflammation?

36. Steps to create new anti-TB drugs
Development of
active substance Proving its viability
Evidence presentation to
community

38. 1943 – Streptomycin (S)
1948 – PAS
1952 – Isoniazid (H)
1954 – Pyrazinamide (Z)
1957 – Kanamycin
1960 – Ethionamide
1961 – Ethambutol (E)
1962 – Gatifloxacin
1963 – Capreomycin (Cm)
1963 – Rifampicin (R)
Clinical studies of new TB-drugs
1993 – Perchlozon (Phx) (RU Reg 2013)
1996 – Moxifloxacin (Mfl) ( Reg XXX)
2000 – RA-824 (nitroimidazo-
ozazine-oxazine sub-class)
2005 –TMS-207 (Bedaqulin)
2006 – OPC-67683 (Delamanid)
Streptomycin /
PAS/ Isoniazid
24
months
Streptomycin
/ Isoniazid /
Ethambutol
18
months
Streptomycin
/ Isoniazid /
Ethambutol /
Rifampicin
6-12
months
-Reducing the duration of
therapy
-Increase efficacy of therapy
Adapted from Ma Z et al. Lancet (2010);
Pipeline Report, June 2013.
Anti-TB drugs evolution

39. New anti-TB drugs in Russia
 PBTZ 169 – benzothiazinon (II phase )
 Pretomanid - (PA-824 – nitroimidazopyran) III phase
 Bedaquiline - III phase
 Thioureidoiminomethylpyridinii perchloras (Tpp)
Perchlozon® - IV phase
The global aim is development of new
scheme, individualized chemotherapy
and short courses of treatment

40. In 1993 in Irkutsk Institute of Chemistry synthesized
PERCHLOZONE ®
A new chemical class of anti-TB drugs of
thiosemicarbazone
In 1978 – 1988 in St. Petersburg Scientific Research Institute of
Phthisiopulmonology more than 1,000 compounds with anti-TB activity were
screened
("Perchlozon" - a new compound with high antituberculosis activity / Vinogradova T. et all// Chemistry
of drugs. - St. Petersburg, 1994. - P.94-95.)
HN CH N NH C NH2
S
ClO4
Thioureidoiminomethylpyridinii perchloras (Tpp)
Perchlozon®

41. Phases of clinical trails in development of
Thioureidoiminomethylpyridinii perchloras
Screening of chemical compounds (around 1000)
with anti-TB activity 1978 – 1988
Preclinical trails (GLP)
Phase I clinical trials
“Open comparative prospective study of safety, tolerability, and
pharmacokinetics after oral administration of Perchlozon® in
healthy subjects"
II – III Phase clinical trials
"Multicenter randomized trial of efficacy and safety of Perchlozon ®
in treatment of patients with pulmonary tuberculosis"
1990 – 2006
IV Phase clinical trials
“Multicentre, randomized, double-blind, placebo controlled parallel-
group study of efficacy and safety of Perhlozon® in complex
therapy of pulmonary tuberculosis with multiple drug resistance
including patients with HIV infection”
Stated in 2014
2009
2010 -2012

42. HN CH N NH C
S
NH2
CLO4
Patent № 1621449 (1993)
Patent № 2423977 (2011 )
Thioureidoiminomethylpyridinii perchloras
(Tpp) is registered and recommended for use
Registration certificate ЛП-001899
dated 09.11.2012

43. New thiosemicarbazone
- Perchlozon is shifting from prodrug to active form by monooxygenase
and affects on TB bacteria by interrupting synthesis of cell wall of microorganism
(bacteriostatic effect)
Int J Antimicrob Agents. 2015 Feb 3. pii: S0924-8579(15)00049-7. doi: 10.1016/j.ijantimicag. The new
tuberculosis drug Perchlozone® shows cross-resistance with thiacetazone. Gopal P, Dick T.

44. Dynamic of abacillation in
comparison groups
%
*р<0,05- reliable differences
between groups
I. Chernokchaeva and all (ERS International Congress/ 2016)
Radiologic dynamic in comparison groups
(decreasing infiltration, partial diffusion of
focus,decreasing destruction)
Efficacy of therapy with using Tpp
Tpp+ 5-6 drugs with Tpp group I (n=37)
5-6 drugs without Tpp group II
(n=35, comparison group)

45. Bedaquiline (Sirturo®)
Marketing number: ЛП-002281
(Janssen Pharmaceuticals, Inc.)
Bedaquiline passed III phase of
clinical trials and was recommended
for treatment of MDR tuberculosis.
No data is available on the use of
Bedaquiline in presence of
concomitant infections and HIV.
Recommended:
400 mg daily during two first weeks,
then - 200 mg 3 times in a week (total weekly dose
600 mg).
Overall duration of treatment course – 24 weeks.

46. Bedaquiline safety
Prospective blind non-randomized single-site study
70 patients
TB Bacteria (+) MDR
Newly diagnosed TB
21,4%
Previously treated TB patients
78,6%
91,4% (64)
Concomitant
pathology+
Smear conversion
87% (61 patients)
Bedaquiline
+ 4-6 drugs
S. Borisov and all (Moscow) (ERS International Congress/ 2016)

47. Efficacy and safety of Bedaquiline and Linezolid including
treatment in XDR TB
Prospected non-randomized multicenter study
Respiratory TB
+ MDR
32 patients
Bazhenov A. et all (Russia, Ekaterinburg) (ERS International Congress/ 2016)
Newly diagnosed disease
12,5%
After ineffective ATT
87,5%
6 Months:
4 drugs *
+Bedaquiline
+Linezolid
83,9%
Smear conversion
77,4%
Positive Rg- dynamics
43,7%
Cavitation closure
Adverse drug reactions
1patient
(QT interval elongation up to 520 sec.)
Duration of the
disease
*Combination of drugs
in accordance with
resistogramm

48. Dynamics of bacterial excretion and X-ray in Bedaquiline and
Linezolid treatment in MDR-TB(%)
n=20
Beliaeva E., Starshinova A., St.-Petersburg, 2016
5 (11,6%) – adverse drug reactions:
2 – allergic reaction (bronchospasm) within 1st week of treatment;
3 – QT interval elongation with clinical signs (shortness of breath, heartbeat, general
weakness).

49. Drugs for treatment of MDR TB
• Alternative drugs – injection aminoglycosides: kanamycin (Km)
and amikacin (Am); polypeptide (kapreomycin - Cm); II
generation fluroquinolones – ofloxacin (Ofx), III generation –
levofloxacin (Lfx), sparfloxacinum (Sfx), IV generation -
moxifloxacinum (Mfx), prothionamidum (Pto), aethionamidum
(Eto), cycloserinum (Cs)/terizidonum (Trd), para-aminosalicylic
acid (PAS), clofazimine (not registered in Russia).
• New drugs: Bedaquiline (Bdq),
Thioureidoiminomethylpyridinii perchloras (Tpp),
Delamanid (not registered in Russia).
• Antibiotics with wide spectrum (not primarily anti-TB)
demonstrate bactericidal or bacteriostatic effect on MBT in vitro
– Linezolid (Lzd), amoxicillin + clavulanic acid (Amx/Сlv),
emipinem (Imp)/cilastatin (Cln), meropenem (Mpm).

50. Impact of new anti-TB drugs
(WHO, 2014)
Companion handbook to the WHO guidelines for the programmatic management
of drug-resistant tuberculosis/ World Health Organization; 2014.- с.448.
The 5th Group of drugs with limited data on efficacy and or long-term
safety in treatment of drug-resistant forms of tuberculosis (in this group
new anti-tuberculosis drugs – Bedaquiline and Delamanid are included)

51. New capabilities of chemotherapy
Introduction of new drugs
Researching of interaction
between drugs
Development of individualized
chemotherapy regimens
Monitoring of new side effects
By variety of drug resistance
By tolerance to drugs
combination
Development of drug resistance for new
drugs

52. Clinical case of patient’s treatment with XDR-MBT pulmonary
tuberculosis with the use of a new therapy regimen
Rg 18.01.17 и 02.02.17
Patient (25 years old) with lung TB and for the first time XDR-TB
in the resistance MBT with S,H,R,E,Z,Eth,A,Ofx,Cm,Mfx (0,5), Lfx, K

53. Treatment – chemotherapy 6 drugs in 29.03.17.
- Tpp 0,6;
- Linezolid (Lzd), 0,6;
- Meropenem (Mpm) 1,0 в/в капельно;
- Bedaquiline (Bdq);
- Para-aminosalicylic acid (PAS) 12,0;
- Amoxicillin + clavulanic acid (Amx/Сlv), 1,2;
Adverse events:
1) Secondary convulsive syndrome;
2) in 4 months - diffusely non-toxic goiter, subclinical hypothyroidism.
After 1 Month

54. Clinical case After 4 months

55. Aim is to reach better ratio of medicinal effect to toxic effect by precise
drugs’ delivery.
New ways of drugs’ delivery to focus of
inflammation
New ways of drugs’ delivery
to focus of inflammation

56. Precise drug delivery of biocompatible nanoparticles with
drugs based on phagocytes as transporters and mini anti
substance as opsonines and addressed molecules.
Nanomedicine, October, 2015
Delivery drug of biocompatible nanoparticles

57. Possibility of directional transport of
antituberculosis agent in the focus of infection
In this study, we showed the possibility of directional transport of
antituberculosis agent in the focus of infection in various organs,
including brain, from the abdominal cavity. The presence of particles
with the drug, especially when there are antibodies on them, significantly
improved the survival of animals.

58. WHO Task Force Group
http://www.euro.who.int/en/health-topics/communicable-diseases/tuberculosis/publications/2014/the-role-of-surgery-in-
the-treatment-of-pulmonary-tb-and-multidrug-and-extensively-drug-resistant-tb0

59. Indication for surgical treatment of MDR TB
Surgical treatment is justified, safe and highly efficient,
including patients with HIV
• The most common indications:
a) failure of conservative treatment with persistence of constant
bacterial excretion in sputum;
b) patients with cessation of bacterial excretion in sputum, but with
persistence of cavities or bronchiectasis;
c) high risk of relapse, based on profile of drug resistance;
d) local lesions of lungs.
Surgical Treatment of Complications of Pulmonary Tuberculosis, including Drug-Resistant Tuberculosis
Rajhmun Madansein [et al.]/ International Journal of Infectious Diseases, 2015-03-01, Volume 32, Pages 61-67.
Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis/
World Health Organization; 2014.- 448p.
Surgical treatment of pulmonary tuberculosis. European Respiratory Society Monograph. Yablonski P. [et al.] -
2013. - Vol. 61, №1. - Chapter 3. – Р. 20-36.

60. Main principles of surgical treatment of MDR TB
• Complex chemotherapy is based on results of drug resistance’s
assessment.
• Regimen of chemotherapy should be continuous and intensified up-front
surgery.
• During post-surgery period intensive phase of treatment should be
continued or re-started.
Time lines for surgery treatment:
- after 4 months of controlled chemotherapy in case of drug sensitive tuberculosis
and cessation of bacterial excretion;
- in case of tuberculosis with drug resistance after 6-8 months of controlled
chemotherapy.

61. Criteria of adequate MDR TB treatment
Provision of conditions for therapy control
Individual approach in administration of
chemotherapy depending on drug sensitivity
(intensive phase and maintenance phase)
Accounting of somatic and psychological
status of patients
Timely performed surgical treatment of
MDR/XDR TB

62. Cooperation
Enhancement of staff
qualification
Participation in
symposiums and
conferences
Exchange of data and
new technologies
New scientific
projects
National association of
phthisiatrists

63. Our goal is to cure a patient, that means to
prevent further spread of infection…

64. Welcome to cooperation!
Our researchers team
Prof. A. Mushkin - Chief of
Pediatric Surgery and
Orthopedic Clinic,
Coordinator of "Non-
pulmonary TB" direction
www.spbniif.ru
DMedSci, MD A. Starshinova -
Leading Researcher
PhD V. Zhuravlev - Coordinator
of “Laboratory diagnostic"
direction
PhD А. Avetisian - Chief of
thoracic surgery department
PhD P. Gavrilov - Chief of
radiation department
Prof., DMedSci, MD, I. Dovgaluk -
Coordinator of "TB in Children"
Prof., DMedSci, MD, M. Pavlova -
Coordinator of
“Phthisiopulmonology"
Piotr Yablonskiy
Prof., DMedSci, MD,
chief of St.-Petersburg Research
Phthisiopulmonology Institute

65. Viam supervadet vadens….
Be healthy and happy !
Луций Анней Сенека

66. WELCOME TO
VI-TH NATIONAL ASSOCIATION
OF PHTHISIOPULMONOLOGYS
CONGRESS
OCTOBER 2017, 23 – 25
ST. PETERSBURG, RUSSIA WWW.NASPH.RU