Study of M.

tuberculosis resistance to antitubercular drugs in some Kosovo regions

(Prishtina, Ferizaj and Gjilan) during 2003-2014

Rukije Mehmeti1, Gazmend Zhuri1,, Zoja Bujupi1,Drita Zajmi2,3. Hasan Hafizi4

1. UCC-Hospital for Lung Diseases

2. National Institute of Public Health of Kosova

3 Medical Faculty, University of Prishtina, Kosova,

4.University Clinical Center-Tirana,Albania

Correspondence to:

Hasan Hafizi

University Clinical Center-Tirana,Albania

Mother Theresa Street NN.

10.000 Prishtina, KOSOVA

+381 38 551 431 ext.1037

Mob. +37744238135

e-mail:
Introduction

Kosovo is a landlocked country situated in Southeastern Europe in center of Balkan Peninsula.

Kosovo has 10980 km2,Population 1,859,203, Density: 159/km2 /km2. Pop:52.7% < 20 year,

Capital is Prishtina, 7 Regions, 38 municipalities, Employment: Unemployment: 60% ,

Extreme poverty: 12%

The DOTS implementation started in Kosovo in 2000 and was progressively implemented
following internationally recommended TB control strategies (4-11). Implementation was greatly
supported until 2005 by different donors (USAID, SI
DA, EAR, US Federal Bureau for Immigration) through NGOs Doctors of the World, Mercy
Corps, under WHO technical supervision.The Global Fund (GF) continues to greatly support the
development process of a national
programme in Kosovo. DOTS strategy started implementation in the year 2000, Republic of
Kosovo is being challenged by the transition and social, political, institutional and cultural
development. Tuberculosis as a disease has been for decades and still is a problem for Kosovar
environment, which by health international institutions as WHO-(World Health Organization)
is qualified as a major threat for public health in Kosovo. Every year in Kosovo one thousand TB
cases in avera
ge are registered, and such cases mainly involve the productive age groups (15-45 years) of both
genders. Also TB multi-drug resistant cases are an additional problem of this epidemic.
After the conflict the action plans 2000-2004 and 2005-2009 were developed. And thanks to
donations and foreign technical assistance and withcooperation between MoH, TB Office and TB
Technical Committee many changes were made where
by the epidemics of tuberculosis was put under the control and TB cases were reduced int o half,
from 1674 TB cases in the year 2001 to 834 cases in the year 2014. So it was an impressive
success.

Anti-tubercular drug resistance poses a major health problem in the developed as well as
developing countries. The resistance develops as a result of inadequate treatment regimes from
the patient as well as from the health workers. A greater number of patients with tuberculosis,
especially with drug-resistant tuberculosis is found in those countries where the tuberculosis
program control is weak.
The patient with active resistant tuberculosis poses a risk for transmission of resistant
tuberculosis to others. According to WHO there are about 9 million patients with all forms of
tuberculosis, of which 1.1 million end with death. In 1.1 million patients with TB / HIV
coincidence about 360,000 cases end with death, whereas with multi-drug resistance 480 000
cases of which 210 000 deaths.

Aim of the study:

The purpose of this study has been to investigate the frequency of mono-resistant, multi-resistant
and poli-resistant strains as well as the frequency of resistant strains in general during the period
2003-2014;

To describe phenotypes of resistance and present the differences between the patients who were
not treated previously and those previously treated with anti-tuberculars.

Materials and methods:

In this study are used the data collected from the registry books in the dispensary of lung
diseases and tuberculosis as well as the culture results from the National Institute of Public
Health of Kosovo-Microbiological Laboratory / Reference Laboratory.
The collected data are presented in the form of graphs and tables.

Results and discussion

In this study were included 2112 cases with positive culture of complex M. tuberculosis isolated
in the National Reference Laboratory for TB in NIPHK during 2013-2014.

Drug sensitivity testing of first line drug was realised with proportion method(Canetti et
al.,1963,1969;Vestal,1975) in Lowenstein Jensen tarrain (16,17).Critic proportion of
antituberculotic drugs and critic proportion of for sensitivity used in this study are gathered in
tab nr.1:

Concentratio Critic
Antituberculotics n proportion
Izoniazid 0.2 g/ml 1%
Rifampicin 40.0 g/ml 1%
Streptomicin 4.0 g/ml 1%
Ethambutol 2.0 g/ml 1%

Statement1. Antituberculotic drugs and critic proportion testing

All the positive cultures included in the study belongs to the samples taken before starting
treatment.(or within month of started treatment).2112 included cases were classified in 2 groups:
a)new cases (patient that have not taken never antituberculotic drugs or have taken less than one
month);
b)old cases(patient treated earlier for one or more treatment cycles completed or not).

From 2112 tested cases,1924 (91%)were no treated before and 188 (9%) cases were treated
before.
From 1924 cases not treated before, in 1456 (75.6%) cases after testing didn`t show resistance in
any antituberculotic drugs, 468(24,4%) cases has shown resistance in different combination of
antituberculotic drugs
From 188 treated cases before,in 114(60.6%) didn`t show resistancy,and 74 cases or 39.4% has
shown resistance in different antituberculotic drugs.

Results::
Results of different antituberculosis drugs are shown in table no 2 regarding treatment status-
treated or not treated before:

Table no. 2. Drug sensitivity in different antituberculosis drugs

N-TA TB TOTAL
N % N % N %
Patients testet
in any TB
drugC 1924 188
I .Only H 8 1 9
Only R 38 6 44
Only E 45 13 58
Only S 292 33 325
Tot.
monoresistenc
e 383 53 436
II.H+R 3 4 7
H+R+E 3 3 6
H+R+S 5 0 5
H+R+E+S 2 5 7
Multi
rezist.MDRD 13 12 25
III.H+E 2 1 3
H+S 1 1 2
H+E+S 3 0 3
R+E 12 3 15
R+S 33 2 35
R+E+S 0 0 0
E+S 21 2 23
Total
PolirezistenceE 72 9 81
IV, All kind H 27 15 42
 All kind R 96 23 119
All kind E 88 27 115
Al kind S 357 43 400

(A)
Patient not treated before with antituberculosis drugs or treated less than 1 month.
(B)
Patent treated before with antituberculosis drugs for 1 or more months, except patents that has
before undergone chemoprophylaxis.
(C)
Total number of case tested for DST for 1-st lineof antituberculosis drugs (H+R+E+S)
(D)
Resistance in H and R with or without other TB drugs resistance.
(E)
Resistance in 2 or more TB drugs other than MDR(H&R).
(F)
Resistance for all kind of H,R,E and SPr secilin medikament numri total I rasteve rezistente

From 2215 cases tested with culture in any kind of H ,resistance showed 27 cases or 1.4%,
In any kind of R 96 cases or 5.0 %,
In any kind of E 88 cases or 4.6% and in
Any kind of S 357 cases or 18.6%
From 1924 (91%) cases not treated before 18.6% has shown resistance in S, 1.4 % in H, 5.0%
in R, and 4,6 % in Et. From 188 (9.0%) cases treated before :
8.0 % showed resistance in H
12.2 % in R,
22.9% in S and
14,4 % in E (fig.1).

Fig,no.1 Treated patients and Resistance in any kind of TB drugs

Regarding monoresistance at NC:

15,2% showed resistance in S,
0.4% in H,
2.0 % in R and
2,3% in E. and
Retreated cases:
17,6% showed resistance in S,
0,5 % in H,
3.2% in R and
6.9 % in E (fig.2).

Fig,2guranr.2 Monoresistance in iny kind of TB drug

MDR TB in NC was at 0.7% and 6.4% of cses treated before(fig.3)

Fig, 3 Multidrug resistance at untreated and retreated patients

Polyresistance was seen in 3.7% of NC,amn them mostly combination (R+S) and 4.8% of
treated cases mostly seen combination of (R+E) (fig.4).
Figura nr.4 Polirezistenca te rastet e trajtuara dhe te patrajtuara me pare

From 2112 tested cases, 91% were cases with no history for previous treatment.

Among patients with no prior treatment:

15.2% were resistant to Streptomycin,
2.3% to Ethambutol,
0,2% to Rifampin and
0.4% to Isoniasid

While on the patient with prior treatment resistant to:

17.7 % showed resistance to streptomycin
6.9 % to Ethambutol
3,3% to Rifampin and
0.5% to Isoniasid

The prevalence of primary multidrug resistance was 0.2% and among them prior treated 2.1%.
The overall resistance for single drug was 19.9% at the patient with no prior treatment and
28.8% at the patients with history for prior treatment
Multidrug resistance was 0.7% at the patient with no prior treatment and
6.4% at the patient with prior treatment
Resistance was associated with a history for of previous treatment,

Conclusions: Resistance to Streptomycin and Ethambutol was most common. The overall
prevalence of MDR-TB is low.