Multidrug-resistant tuberculosis in Central Asia.Multidrug-resistant tuberculosis (MDR-TB MDR-TB Multi-Drug Resistant Tuberculosis ) has emerged as a major threat to TB control, particularly in the former Soviet Union. To determine levels of drug resistance within a directly observed treatment Directly Observed Treatment (DOT) or Directly Observed Therapy is watching the patient take his/her medication to ensure medications are taken in the right combination and for the correct duration. strategy (DOTS) program supported by Medecins Sans Frontieres in two regions in Uzbekistan and Turkmenistan, Central Asia, we conducted a cross-sectional survey of smear-positive TB patients in selected districts of Karakalpakstan (Uzbekistan) and Dashoguz (Turkmenistan). High levels of MDR-TB were found in both regions. In Karakalpakstan, 14 (13%) of 106 new patients were infected with MDR-TB; 43 (40%) of 107 previously treated patients were similarly infected. The proportions for Dashoguz were 4% (4/105 patients) and 18% (18/98 patients), respectively. Overall, 27% of patients with positive smear results whose infections were treated through the DOTS program in Karakalpakstan and 11% of similar patients in Dashoguz were infected with multidrug-resistant strains of TB on admission. These results show the need for concerted action by the international community to contain transmission and reduce the effects of MDR-TB.
Tuberculosis (TB) has increased substantially in many parts of the former Soviet Union, particularly in those areas most affected by economic decline and failing health infrastructures (1). In addition to resurgent re·sur·gent
1. Experiencing or tending to bring about renewal or revival.
2. Sweeping or surging back again.
Adj. 1. TB, significant proportions of multidrug-resistant TB (MDR-TB) have been demonstrated in small pockets where drug -susceptibility surveys have been conducted, and these areas have been termed "hot spots hot spots
acute moist dermatitis. " (2,3). This article reports the results of a drug-susceptibility survey conducted by Medecins Sans Frontieres (MSF MSF Manufacturing, Science, and Finance (Union) ) in collaboration with local ministries of health, in northwestern Uzbekistan and northern Turkmenistan in Central Asia. These regions, in addition to experiencing a substantial economic crisis, are facing a severe water shortage and the desiccation des·ic·ca·tion
The process of being desiccated.
desic·ca of the Aral Sea Aral Sea (ăr`əl), salt lake, SW Kazakhstan and NW Uzbekistan, E of the Caspian Sea in an area of interior drainage. To the north and west are the edges of the arid Ustyurt Plateau; the Kyzyl Kum desert stretches to the southeast. (4).
A TB treatment program based on the directly observed treatment strategy (DOTS) (5) recommended by the World Health Organization was introduced progressively into three regions south of the Aral Sea by the humanitarian medical aid organization, Medecins Sans Frontieres. These regions, the Republic of Karakalpakstan, and Khorezm Oblast oblast (ō`bläst, ŏ`–, Rus. ô`bləstyə) [Rus.,=region], administrative and territorial division in Russia, Ukraine, Belarus, and the former USSR. in Uzbekistan and Dashoguz Velayat in Turkmenistan (Figure 1), have a total population of approximately 4 million people. Implementation of DOTS started in 1998 and was completed with full coverage by late 2003. In 2002, more than 8,000 patients were registered and treated under DOTS from the three regions. Facilities for culturing sputum sputum /spu·tum/ (spu´tum) [L.] expectoration; matter ejected from the trachea, bronchi, and lungs through the mouth.
sputum cruen´tum bloody sputum. and drug susceptibility testing susceptibility test Antimicrobial susceptibility test, see there were not available in the area at the time of the survey.
[FIGURE 1 OMITTED]
From the start of DOTS implementation, >10% of those treated remained smear-positive. This finding, combined with a dearth of information on drug resistance in Central Asia, prompted the initiation of a drug-susceptibility survey with the aim of determining levels of resistance to both first- and second-line anti-TB drugs and, in particular, the levels of MDR-TB.
The current survey was conducted in two of the regions covered by DOTS, the Republic of Karakalpakstan in Uzbekistan and Dashoguz Velayat in Turkmenistan. Although adjacent, these regions are separated by an international border. Key characteristics of these regions and countries are given in Table 1; the two regions differ in terms of total case reporting rate and in economic status.
The survey was designed on the basis of recommendations given in the World Health Organization/International Union Against Tuberculosis and Lung Disease lung disease Pulmonary disease Pulmonology Any condition causing or indicating impaired lung function Types of LD Obstructive lung disease–↓ in air flow caused by a narrowing or blockage of airways–eg, asthma, emphysema, chronic bronchitis; (WHO/IUATLD) guidelines for surveillance of drug-resistant TB (8). It was designed to be a cross-sectional survey of smear-positive pulmonary TB pulmonary TB Pulmonary tuberculosis, see there patients in whom DOTS TB treatment had been initiated in four districts in the Autonomous Republic A significant number of autonomous republics can be found within the successor states of the Soviet Union, but the majority are located within Russia. Many of these republics were established during the Soviet period as Autonomous Soviet Socialist Republics, or ASSRs. of Karakalpakstan in Uzbekistan and four districts in Dashoguz Velayat in Turkmenistan. Three of the districts in each region were selected because they had the longest running DOTS programs in the region. The fourth district in each region was selected as the newest district implementing DOTS before initiation of the survey. When the survey was initiated, 7 of the 17 districts in Karakalpakstan were implementing DOTS TB treatment, as were 7 of the 9 districts in Dashoguz. Although selection of districts in which to conduct the survey was not random, all smear-positive patients whose TB was diagnosed in DOTS laboratories (regardless of previous TB treatment status) from July 2001 in the selected districts were sequentially requested to participate in the survey. Patients were excluded if they refused to undergo DOTS treatment or if they did not reside in one of the districts chosen in the study. Patients defined as "chronic," that is, patients whose TB was not resolved after at least two courses of DOTS treatment, were not eligible to be included in the study. Smear positivity was defined as at least one sputum sample reading >10 bacilli/100 fields in a sputum smear Noun 1. sputum smear - any of several cytologic smears obtained from different parts of the lower respiratory tract; used for cytologic study of cancer and other diseases of the lungs
bronchoscopic smear, lower respiratory tract smear by direct microscopy microscopy /mi·cros·co·py/ (mi-kros´kah-pe) examination under or observation by means of the microscope.
1. The study of microscopes.
The objectives of the study were described to each patient, and written informed consent was obtained before an additional sputum sample was collected for the study. All patients were informed that the results would not be available to either themselves or their treating physician and would not affect their treatment. At the time of the survey, no opportunity was available for patients to be treated with second-line drugs second-line drug Any therapeutic agent that is not the drug of choice, or the 1st normally used to treat a particular condition; in rheumatoid arthritis, 2nd under DOTS-Plus. To ensure patient confidentiality patient confidentiality Medical practice A Pt's right to privacy and freedom from public dissemination of information that the Pt regards as being of a personal nature. See HIPAA, Medical privacy. , sputum samples and clinical information forms were encoded with a unique survey identification number.
MDR-TB is defined as resistance to at least isoniazid isoniazid (ī'sōnī`əzĭd), drug used to treat tuberculosis. Also known as isonicotinic acid hydrazide, isoniazid is the most effective antituberculosis drug currently available. and rifampin rifampin (rĭfăm`pĭn), antibiotic used in the treatment of tuberculosis. It is also used to eliminate the meningococcus microorganism from carriers and to treat leprosy, or Hansen's disease. . On the basis of estimated levels of 10% and 20% MDR-TB for new and retreatment cases, sample sizes were calculated to be 81 for new cases (10% [+ or -] 6%, 95% confidence limit [CL]) and 100 for re-treatment cases (20% [+ or -] 7%, 95% CL). Because approximately 50% of patients with positive smears have been previously treated, a sample size of 100 was chosen for each category in both regions, for a total of 400 patients. Recruitment continued until the desired sample size was reached or surpassed in both categories and in both regions.
Demographic and Clinical Information
Each patient who consented to participate in the survey was interviewed by the admitting doctor in each TB facility. A clinical information form was developed, based on recommendations by the WHO and IUATLD IUATLD International Union Against Tuberculosis and Lung Disease (8), to collect basic demographic, socioeconomic, and medical information. Particular attention was paid to questions that would clarify previous TB treatment for each patient. Questions were included about previous hospitalization hospitalization /hos·pi·tal·iza·tion/ (hos?pi-t'l-i-za´shun)
1. the placing of a patient in a hospital for treatment.
2. the term of confinement in a hospital. and about which anti-TB drugs the patient may have taken. Previous TB treatment assessed by the interview was then compared to the patient's previous TB treatment status as determined through the functioning DOTS program. Any discrepancies were then investigated and clarified by reinterviewing the patients and physicians who treated their condition. In addition, for patients from Karakalpakstan only, medical records from the previous Soviet system of TB treatment were checked for previous TB treatment.
New patients were defined as those who had received no or <1 month of antituberculosis drug antituberculosis drug Infectious disease Any drug–eg, isoniazid, rifampin, ethambutol, streptomycin, pyrazinamide, ethionamide, para-aminosalicylic acid, kanamycin, cycloserine, capreomycin, ciprofloxacin, amikacin, used to manage TB; multidrug-resistant treatment before diagnosis. Retreatment patients were all those previously treated with TB drugs for [greater than or equal to] 1 month. Data on the HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. status of patients with TB are not available in this area.
Transport of Sputum Samples and Laboratory Testing
Because no local capability for culture and drug-sensitivity testing exists, sputum samples were transported directly to a supranational Supranational
An international organization, or union, whereby member states transcend national boundaries
or interests to share in the decision-making and vote on issues pertaining to the wider grouping. reference laboratory (SRL 1. SRL - Bharat Jayaraman.
["Towards a Broader Basis for Logic Programming", B. Jayaraman, TR CS Dept, SUNY Buffalo, 1990].
2. SRL - Schema Representation language.
3. SRL - Structured Robot Language.
C. Blume & W. Jacob, U Karlsruhe. ) in Europe. Sputum specimens were shipped from both regions separately either weekly or biweekly bi·week·ly
1. Happening every two weeks.
2. Happening twice a week; semiweekly.
n. pl. bi·week·lies
A publication issued every two weeks.
1. Every two weeks. throughout the survey. Samples were first transported to the regional laboratories in each region by car. They were then flown to the capital cities in Uzbekistan This is a list of cities in Uzbekistan. The names of many places have been changed during the last century, sometimes more than once. Wherever possible, the old names have been included and linked to the new ones. and Turkmenistan; they were then transported as international air cargo air cargo: see aviation. to Frankfurt, Germany, and on to Hamburg Hamburg, city, Germany
Hamburg (häm`brkh), officially Freie und Hansestadt Hamburg (Free and Hanseatic City of Hamburg), city (1994 pop. and the SRL in Borstel, Germany. All international regulations pertaining per·tain
intr.v. per·tained, per·tain·ing, per·tains
1. To have reference; relate: evidence that pertains to the accident.
2. to the transport of infectious material were followed.
Sputum samples were cultured, and drug-sensitivity testing was performed by the German SRL in Borstel. Strains were tested for drug sensitivity to the five first-line drugs used in the DOTS program in the Aral Sea area, namely, isoniazid, rifampin, pyrazinamide, ethambutol ethambutol /etham·bu·tol/ (e-tham´bu-tol) an antibacterial, specifically effective against Mycobacterium; used with one or more other antituberculous drugs in the treatment of pulmonary tuberculosis, administered as the , and streptomycin streptomycin (strĕp'tōmī`sĭn), antibiotic produced by soil bacteria of the genus Streptomyces and active against both gram-positive and gram-negative bacteria (see Gram's stain), including species resistant to other . In addition, drug-susceptibility testing for three second-line drugs was performed; susceptibility to prothionamide was tested on all strains, whereas susceptibility to capreomycin capreomycin /cap·reo·my·cin/ (kap?re-o-mi´sin) a polypeptide antibiotic produced by Streptomyces capreolus, which is active against human strains of Mycobacterium tuberculosis ; used as the disulfate salt. and ofloxacin was tested on all strains, excluding the first 45 sent from both countries (24 from Uzbekistan and 21 from Turkmenistan, 11% of strains). Strains from a small, randomly drawn sample of patients with MDR-TB (20 isolates) and patients whose strains were susceptible to antimicrobial antimicrobial /an·ti·mi·cro·bi·al/ (-mi-kro´be-al)
1. killing microorganisms or suppressing their multiplication or growth.
2. an agent with such effects. drugs (10 isolates) were later tested for resistance to kanamycin kanamycin /kan·a·my·cin/ (kan?ah-mi´sin) an aminoglycoside antibiotic derived from Streptomyces kanamyceticus, effective against aerobic gram-negative bacilli and some gram-positive bacteria, including mycobacteria; used as the .
Primary isolation and culture of mycobacterial mycobacterial
emanating from or pertaining to mycobacterium.
may be caused by Mycobacterium tuberculosis (see cutaneous tuberculosis), M. isolates followed standard recommendations, where specimens were decontaminated by NALC-NaOH and added to two solid media; Lowenstein-Jensen and Stonebrink ad MGIT MGIT Mahatma Gandhi Institute of Technology (India)
MGIT Maritime Group Inport Training 960TB (Becton-Dickinson Microbiology microbiology: see biology.
Scientific study of microorganisms, a diverse group of simple life-forms including protozoans, algae, molds, bacteria, and viruses. Systems, Cockeysville, MD) (9). For all strains, drug-susceptibility testing was performed on Lowenstein-Jensen media by the proportion method. If growth was insufficient, drug-susceptibility testing was performed by using the modified proportion method in BACTEC 460TB (Becton-Dickinson). The SRL participates in annual quality control programs within Germany and within the WHO and Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. (CDC See Control Data, century date change and Back Orifice.
CDC - Control Data Corporation ) SRL network. In addition, an internal quality control system for all techniques and media was used.
All clinical and laboratory data were entered into a database by using EpiInfo (6.04, CDC, Atlanta, GA). Chi-square analysis was used for comparisons of proportions. Logistic regression In statistics, logistic regression is a regression model for binomially distributed response/dependent variables. It is useful for modeling the probability of an event occurring as a function of other factors. analysis was performed to identify variables independently associated with MDR-TB (SPSS A statistical package from SPSS, Inc., Chicago (www.spss.com) that runs on PCs, most mainframes and minis and is used extensively in marketing research. It provides over 50 statistical processes, including regression analysis, correlation and analysis of variance. version 10.0, SPSS Inc., Chicago, IL). Cluster sampling Cluster sampling is a sampling technique used when "natural" groupings are evident in a statistical population. It is often used in marketing research. In this technique, the total population is divided into these groups (or clusters) and a sample of the groups is selected. was taken into account through use of the Fleiss quadratic quadratic, mathematical expression of the second degree in one or more unknowns (see polynomial). The general quadratic in one unknown has the form ax2+bx+c, where a, b, and c are constants and x is the variable. approximation approximation /ap·prox·i·ma·tion/ (ah-prok?si-ma´shun)
1. the act or process of bringing into proximity or apposition.
2. a numerical value of limited accuracy. in calculating 95% CL for the proportions of MDR-TB in the sample. Separate design effects were calculated for each region.
Recruitment of Patients
Patient recruitment began in July 2001 in both regions and was completed by the end of January 2002 in Karakalpakstan and March 2002 in Dashoguz. In total, 441 patients were enrolled in the study, 213 from Dashoguz and 228 from Karakalpakstan. Overall, 76% of eligible patients were recruited in Dashoguz and 68% in Karakalpakstan. The main reasons patients were not enrolled were the following: refusal to participate (13% in Karakalpakstan and 3% in Dashoguz), patient default before treatment (8% in both Karakalpakstan and Dashoguz), and logistic constraints in the timely collection and transport of sputum samples (9% in Karakalpakstan and 2% in Dashoguz). Other reasons for nonparticipation in the study included the following: unable to produce an additional adequate sputum sample (5% in Dashoguz), patient imprisonment Imprisonment
See also Isolation.
former federal maximum security penitentiary, near San Francisco; “escapeproof.” [Am. Hist.: Flexner, 218]
German prison ship in World War II. [Br. Hist. after diagnosis (3% in Dashoguz), and patient transfer out of the program after diagnosis. The relative biases introduced by these reasons for nonparticipation are unknown; however, the high rate of refusal to participate in Karakalpakstan was mostly due to inadequate patient communication in the early stages of the survey and is therefore unlikely to have affected the representativeness of the sample.
Laboratory Culture Results
All 441 sputum samples were sent to SRL in Borstel, Germany. Mycobacterium tuberculosis Mycobacterium tuberculosis
Mycobacterium tuberculosis was cultured from 416 samples (213 from Karakalpakstan and 203 from Dashoguz). Overall, 12 (2.7%) of the 441 samples were found to be contaminated contaminated,
v 1. made radioactive by the addition of small quantities of radioactive material.
2. made contaminated by adding infective or radiographic materials.
3. an infective surface or object. , and an additional 11 (2.5%) could not be cultured. Other than M. tuberculosis M. tuberculosis,
n the bacterium responsible for tuberculosis, generally a respiratory infection in man; nonrespiratory tuberculosis is considered an indicator disease for AIDS. See also tuberculosis. , two other strains of Mycobacterium mycobacterium
Any of the rod-shaped bacteria that make up the genus Mycobacterium. The two most important species cause tuberculosis and leprosy in humans; another species causes tuberculosis in both cattle and humans. (one M. bovis and one M. fortuitum) were grown.
Demographics of the Study Population
For the purposes of analysis, only patients for whom a valid culture for M. tuberculosis was obtained were included. The final sample consisted of 106 new patients and 107 retreatment patients in Karakalpakstan and 105 new cases and 98 retreatment cases in Dashoguz. Patients ranged in age from 11 years to 77 years, with a mean of 34 years and a median of 31 years. The mean age was slightly but nonsignificantly higher in retreatment patients. Overall, 60% of the patients in the study sample were male, with more men among retreatment cases than new cases (65% vs. 55%). Overall 53% of all patients with positive smears registered in the DOTS program in the year 2002 in Karakalpakstan and Dashoguz were male.
Considerably more single men than single women lived in both regions; overall, 19% of women and 40% of men were single. Approximately 70% of all patients, both men and women in both countries, reported at least 10 years of education. No women reported previous imprisonment, whereas 25% of men in Dashoguz and 36% of men in Karakalpakstan reported being in prison at some stage during their lives.
First-line Anti-TB Drug Resistance
Results on resistance to the five first-line drugs tested are given in Tables 2 and 3. In Karakalpakstan, the strains of 52% of new patients and 20% of retreatment patients were fully sensitive to all five first-line drugs. In Dashoguz, strains from 70% of new patients and 38% of retreatment patients were sensitive to the five first-line drugs. The most notable monoresistance (resistance to just one first-line drug) was seen for streptomycin in both regions (in 11% of all Karakalpakstan patients and in 14% of Dashoguz patients). Similarly, streptomycin showed the highest levels of drug resistance overall; strains from 58% of all patients in Karakalpakstan and from 37% of patients in Dashoguz were resistant to streptomycin. Major resistance to isoniazid also occurred, with 53% of all patients in Karakalpakstan and 31% in Dashoguz infected with resistant strains. Resistance to rifampin was closely correlated to multidrug resistance multidrug resistance,
n the adaptation of tumor cells or infectious agents to resist chemotherapeutic agents. ; only one patient had a strain that was resistant to rifampin without also being resistant to isoniazid.
Levels of MDR-TB were high; overall, 27% (95% CL 15% to 42%) of all positive smears from patients starting DOTS treatment were infected with MDR-TB strains in Karakalpakstan and 11% (95% CL 7% to 17%) in Dashoguz. The proportion of MDR-TB was higher in Karakalpakstan than in Dashoguz for both new and retreatment cases; 13% (95% CL 4% to 35%) versus 4% (95% CL 1% to 11%) for new cases and 40% (95% CL 21% to 62%) versus 18% (95% CL 11% to 28%) for retreatment cases.
Second-line Anti-TB Drug Resistance
Resistance results to the three second-line drugs first tested are shown in Table 4. Of these three drugs tested on most strains, clinically significant resistance was shown only to prothionamide, with 16% resistance among MDR-TB cases in Karakalpakstan and 9% in Dashoguz. Kanamycin was tested on a randomly drawn sample of 20 previously identified MDR-TB isolates and 10 non-MDR-TB isolates from two districts in Karakalpakstan. Two of the MDR-TB isolates showed resistance to kanamycin (10%), whereas none of the 10 non-MDR-TB strains showed resistance.
Factors Associated with MDR-TB
To investigate factors associated with the high rates of MDR-TB, a multivariable logistic regression analysis was conducted with MDR-TB as the dependent variable. The following factors were entered into the model: sex, previous TB treatment, previous imprisonment, unemployment, alcohol use, and region. Factors significantly predicting MDR-TB in the model were previous TB treatment, region, and female sex (Table 5). Although a large proportion of male patients reported previous imprisonment, this factor was not significant on either univariate or multivariable analysis.
Since previous TB treatment is the strongest factor associated with MDR-TB, the logistic regression was repeated, including only new patients from both regions. Both female gender (OR 7.8, 95% CL 1.7 to 36.3) and region (OR 3.8, 95% CL 1.2 to 12.4) remained significant predictors of MDR-TB.
Clearly, the most notable factor predicting MDR-TB is previous TB treatment. Most retreatment patients in both regions reported only one previous episode of treatment, 60% in Karakalpakstan and 66% in Dashoguz. In addition, most retreatment patients were not previously treated under DOTS, 83% in Karakalpakstan and 75% in Dashoguz. Of those that received previous DOTS treatment, 50% were new patients before their previous DOTS treatment. These patients had levels of MDR-TB similar to retreatment patients overall (Karakalpakstan, 3/8, 38%; Dashoguz, 2/15, 13%). Those that received DOTS treatment in addition to previous non-DOTS TB treatment had higher rates of MDR-TB (Karakalpakstan, 6/8, 75%; Dashoguz, 7/14, 50%).
This survey has shown extremely high rates of MDR-TB in regions of two countries in Central Asia, although the confidence intervals confidence interval,
n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. are large because of the small sample size and cluster sampling. These findings, along with similar data from other regions, suggest that the former Soviet Union is one large hot spot for MDR-TB.
Because of logistic constraints, sampling was restricted to four districts implementing DOTS in each of the two regions. These districts were not randomly selected. However, as sampling was sequential, the final sample is representative of patients with positive smears whose cases were diagnosed in these districts. The DOTS strategy was implemented in the Aral Sea area, starting in the districts most affected by the environmental degradation Environmental degradation is the deterioration of the environment through depletion of resources such as air, water and soil; the destruction of ecosystems and the extinction of wildlife. . These districts are more economically deprived and therefore may have higher rates of TB incidence. However, we have no reason to suspect that the prevalence of drug resistance is different in neighboring neigh·bor
1. One who lives near or next to another.
2. A person, place, or thing adjacent to or located near another.
3. A fellow human.
4. Used as a form of familiar address.
v. districts. Drug resistance may well increase as patients are increasingly able to purchase drugs privately and use them sporadically. In addition, patients who refused DOTS treatment and those defined as having chronic TB were not included in the survey. These patients are more likely to have had previous erratic TB treatment and therefore may be more likely to harbor drug-resistant strains. If this were the case, then the figures presented here are an underestimate of the situation.
In this survey, careful attention was paid to the differentiation of new and retreatment patients. A retrospective review retrospective review,
a posttreatment assessment of services on a case-by-case or aggregate basis after the services have been performed. of pre-DOTS medical records in Karakalpakstan showed only one misclassified patient, among the 213 included. As well, in the Aral Sea area DOTS program, all patients in whom active TB is diagnosed have the opportunity to receive DOTS treatment, regardless of previous treatment status. Thus, no motivation or incentive exists for patients or doctors to misrepresent mis·rep·re·sent
tr.v. mis·rep·re·sent·ed, mis·rep·re·sent·ing, mis·rep·re·sents
1. To give an incorrect or misleading representation of.
2. their previous TB treatment status, as has been suggested elsewhere (10). Nevertheless, some misclassification is possible but is not expected to greatly alter the high proportions of MDR-TB seen among new patients, particularly in Karakalpakstan. These levels of MDR-TB indicate the likely transmission of multidrug-resistant strains.
Testing showed some second-line drug resistance, particularly for prothionamide, among MDR-TB strains. The regions in our study are poorer and more isolated than other parts of both countries and other areas in the former Soviet Union, which possibly spares them from the high rates of second-line drug resistance seen in other areas (11). Although not all strains were tested for second-line resistance, the sample is still representative because only the first 11% of strains (Karakalpakstan and Dashoguz, respectively) from patients sequentially recruited into the survey were not tested for capreomycin and ofloxacin, and no systematic differences were found between the strains from first patients and strains from latter patients.
The difference in levels of TB drug resistance between the two regions that are geographically adjacent but separated by a national border provides clues regarding the emergence of drug resistance. Since gaining independence from the former Soviet Union, most Central Asian states have experienced a substantial decline in healthcare services (12). In Uzbekistan, during the 1990s, the gross domestic product (GDP GDP (guanosine diphosphate): see guanine. ) declined considerably as has the percentage of GDP spent on health (13). Turkmenistan fared somewhat better financially because of its considerable oil and gas wealth; it has a per capita [Latin, By the heads or polls.] A term used in the Descent and Distribution of the estate of one who dies without a will. It means to share and share alike according to the number of individuals. GDP almost double that of Uzbekistan (6), with a relatively stable percentage spent on health (14).
These declines in healthcare spending in both countries have resulted in intermittent shortages of most first-line anti-TB drugs. Local TB physicians in Karakalpakstan (Uzbekistan) estimate that before the DOTS program started, nearly 50% of patients had their treatment interrupted because of problems with drug supply. Additionally, because of the lack of drugs, patients were often requested to purchase drugs themselves after they left the hospital for the continuation phase at home. Many patients likely could not afford all drugs and therefore purchased what they could, resulting again in treatment interruptions. High streptomycin resistance attests to the widespread use of this popular injectable in·ject·a·ble
Capable of being injected. Used of a drug.
A drug or medicine that can be injected. antimicrobial agent, often as a short monotherapy monotherapy /mono·ther·a·py/ (-ther´ah-pe) treatment of a condition by means of a single drug.
Treatment of a disorder with a single drug. course. Although drug shortages have been reported over the last decade in Turkmenistan, they likely affected an overall lower percentage of patients, which explains the lower rate of drug resistance seen in Dashoguz.
The extent to which drug resistance existed before the collapse of the Soviet Union is unknown. The Soviet system hospitalized TB patients for long periods, with consequently high levels of interruption and default. In addition, treatment regimens using combinations of all first-line and some second-line drugs were not standardized standardized
pertaining to data that have been submitted to standardization procedures.
standardized morbidity rate
see morbidity rate.
standardized mortality rate
see mortality rate. (1). These conditions may have contributed to a baseline level of resistance from which the notable level of MDR-TB shown here has emerged. Most retreatment patients were not previously treated under DOTS; thus, our results cannot be attributed to the implementation of DOTS.
Elsewhere in the former Soviet Union, high rates of MDR-TB have been seen among prisoner populations (15). Although a high proportion of patients in our study reported previous imprisonment, no greater level of MDR-TB was seen among these patients. This finding suggests that MDR-TB is not confined con·fine
v. con·fined, con·fin·ing, con·fines
1. To keep within bounds; restrict: Please confine your remarks to the issues at hand. See Synonyms at limit. to specific sectors of the population, such as prisoners, but is a problem affecting the general community. Of particular concern in this area is the high rate of out-migration attributable to worsening wors·en
tr. & intr.v. wors·ened, wors·en·ing, wors·ens
To make or become worse.
Noun 1. worsening - process of changing to an inferior state
decline in quality, deterioration, declension environmental and socioeconomic conditions (16; unpub. data, Medecins Sans Frontieres, 2002), which can lead to international transmission of MDR-TB.
The finding of a greater risk for MDR-TB among women, independent of previous TB treatment status, is important and confirms similar findings in Archangels Oblast in Russia (17) and Estonia (18). In the Aral Sea area, women make up slightly less than 50% of all patients with positive smears registered in the DOTS program. This statistic suggests a greater susceptibility to drug-resistant TB and warrants further research.
Clearly, such high rates of MDR-TB as seen in both Karakalpakstan, Uzbekistan, and Dashoguz, Turkmenistan, are a substantial threat to TB control. Standardized treatment with first-line, through drugs implementing the DOTS strategy, would be expected to result in poor outcomes for more than one fourth of patients with positive smears in Karakalpakstan (19) and would render the WHO target of 85% success unattainable. These patients will remain infectious for long periods, with the resultant risk of transmitting drug-resistant strains. WHO suggests that high levels of MDR-TB (>3% among new cases) warrant the direct management of MDR-TB to contain transmission and reduce the high incidence and costs of this disease (20).
DOTS treatment on its own may well stop the production of more MDR-TB, but it is unlikely to reduce high levels of existing drug resistance (21). Effective treatment of all cases of TB is required to prevent transmission. MDR-TB treatment is expensive and lengthy, and the pool of those with expertise treating MDR-TB is limited. A simpler, more affordable, and more effective treatment strategy is required; however, until this exists, patients require treatment with existing strategies. As a result of this survey, Medecins Sans Frontieres has decided to launch a pilot DOTS-Plus MDR-TB treatment project in Karakalpakstan because the cost of inaction in·ac·tion
Lack or absence of action.
lack of action; inertia
Noun 1. will be high.
Table 1. Key characteristics of the two regions and countries included in the survey (a) Uzbekistan Turkmenistan Population (6) 25,256,000 4,834,000 GDP per capita (6) U.S.$ 2,333 U.S.$ 5,269 Health expenditure U.S.$ 86 U.S.$ 286 per capita (6) Estimated TB incidence 92/100,000/y 84/100,000/y rate (all cases) (7) Estimated smear-positive 44% 68% case detection (7) Karakalpakstan Dashoguz Population (2001 1,549,761 1,041,372 estimated) (b) DOTS implementation 1998 (pilot 2000 (pilot districts)-2003 districts)-2002 (full coverage) (full coverage) DOTS case notification 482/100,000/y 213/100,000/y rate (all cases) DOTS case notification 192/100,000/year 89/100,000/year rate (smear-positive cases) % of smear-positive cases 55 53 previously treated (2002) Success rate (new smear- 68% 82% positive cases registered in 2001) (a) GDP, gross domestic product; TB, tuberculosis; DOTS, directly observed treatment strategy. (b) Source: ministries of health in each region. Table 2. First-line anti-tuberculosis drug resistance results, Karakalpakstan, Uzbekistan (a) No. new No. retreatment cases (%) cases (%) Total no. (%) Total tested 106 107 213 Any resistance 51 (48.1) 86 (80.4) 137 (64.3) Monoresistance H only 3 (2.8) 7 (6.5) 10 (4.7) R only 0 0 0 E only 0 0 0 S only 12 (11.3) 11 (10.3) 23 (10.8) Z only 0 1 (0.9) 1 (0.5) H and R resistance MDR 14 (13.2) 43 (40.2) 57 (26.8) HR only 0 1 (0.9) 1 (0.5) HRE only 0 0 0 HRS only 4 (3.8) 10 (9.3) 14 (6.6) HRZ only 0 0 0 HRES only 6 (5.7) 19 (17.8) 25 (11.7) HREZ only 0 0 0 HRSZ only 1 (0.9) 0 1 (0.5) HRESZ 3 (2.8) 13 (12.1) 16 (7.5) H + other resistance HE only 0 0 0 HS only 13 (12.3) 15 (14.0) 28 (13.1) HZ only 1 (0.9) 1 2 (0.9) HES only 2 (1.9) 4 (3.7) 6 (2.8) HEZ only 0 0 0 HSZ only 1 (.9) 3 (2.8) 4 (1.9) HESZ only 5 (4.7) 1 (0.9) 6 (2.8) R + other resistance RE only 0 0 0 RS only 0 0 0 RZ only 0 0 0 RES only 0 0 0 RESZ only 0 0 0 Any drug resistance Any H resistance 39 (36.8) 74 (69.2) 113 (53.1) Any R resistance 14 (13.2) 43 (40.2) 57 (26.8) Any E resistance 16 (15.1) 37 (34.6) 53 (24.9) Any S resistance 47 (44.3) 76 (71.0) 123 (57.7) Any Z resistance 11 (10.4) 19 (17.8) 30 (14.1) (a) H, isoniazid; R, rifampin; E, ethambutol; S, streptomycin; Z, pyrizinamide. Table 3. First-line anti-tuberculosis drug resistance results, Dashoguz, Turkmenistan (a) No. new No. retreatment cases (%) cases(%) Total no. (%) Total tested 105 98 203 Any resistance 32 (30.5) 61 (62.2) 93 (45.8) Monoresistance H only 6 (5.7) 8 (8.2) 14 (6.9) R only 0 1 (1.0) 1 (0.5) E only 0 0 0 S only 16 (15.2) 13 (13.3) 29 (14.3) Z only 0 0 0 H and R resistance MDR 4 (3.8) 18 (18.4) 22 (10.8) HR only 0 0 0 HRE only 0 0 0 HRS only 3 (2.9) 7 (7.1) 10 (4.9) HRZ only 0 0 0 HRES only 1 6 (6.1) 7 (3.4) HREZ only 0 0 0 HRSZ only 0 3 (3.1) 3 (1.5) HRESZ 0 2 (2.0) 2 (1.0) H + other resistance HE only 0 1 (1.0) 1 (0.5) HS only 5 (4.8) 10 (10.2) 15 (7.4) HZ only 0 1 (1.0) 1 (0.5) HES only 1 (1.0) 6 (6.1) 7 (3.4) HEZ only 0 0 0 HSZ only 0 3 (3.1) 3 HESZ only 0 0 0 R + other resistance RE only 0 0 0 RS only 0 0 0 RZ only 0 0 RES only 0 0 0 RESZ only 0 0 0 Any drug resistance Any H resistance 16 (15.2) 47 (48.0) 63 Any R resistance 4 (3.8) 19 (19.4) 23 Any E resistance 2 (1.9) 15 (15.3) 17 Any S resistance 26 (24.8) 50 (51.0) 76 Any Z resistance 0 9 (9.2) 9 (a) H, isoniazid; R, rifampin; E, ethambutol; S, streptomycin; Z, pyrizinamide. Table 4. Second-line drug resistance results (a) New Retreatment Total Resistant (%) Total Resistant (%) Karakalpakstan (Uzbekistan) Prothionamide 106 7 (7) 107 11 (10) Capreomycin 88 1 (1) 101 1 (1) Ofloxacin 88 2 (2) 101 4 (4) Dashoguz (Turkmenistan) Prothionamide 105 1 (1) 98 4 (4) Capreomycin 89 0 93 0 Ofloxacin 89 0 93 0 MDR-TB (b) Total Resistant (%) Karakalpakstan (Uzbekistan) Prothionamide 57 9 (16) Capreomycin 56 1 (2) Ofloxacin 56 1 (2) Dashoguz (Turkmenistan) Prothionamide 22 2 (9) Capreomycin 21 0 Ofloxacin 21 0 (a) All strains were tested for prothionamide; a representative subset of these were tested for both capreomycin and ofloxacin. (b) MDR-TB, multidrug-resistant tuberculosis. Table 5. Factors associated with MDR-TB in univariate and multivariable logistic regression analysis (a) Odds ratios (95% confidence limits) Factor Univariate analysis Logistic regression Previous TB treatment 4.5 (2.6 to 8.0) 5.1 (2.8 to 9.3) Region (Karakalpakstan) 3.0 (1.8 to 5.1) 3.6 (2.0 to 6.4) Female gender 1.3 (0.8 to 2.2) 2.0 (1.1 to 3.7) Unemployment 2.3 (1.1 to 5.1) 2.1 (0.9 to 4.8) Previous imprisonment 1.7 (0.9 to 3.0) 1.3 (0.6 to 2.8) Alcohol use 0.9 (0.4 to 2.3) 0.7 (0.3 to 1.9) (a) MDR-TB, multidrug-resistant tuberculosis.
We thank the following persons and organizations for their assistance during this survey: the patients; the medical, nursing, and laboratory staffs from the eight districts; the ministries of health in Dashoguz Velayat and the Republic of Karakalpakstan; medical and logistics staff of Medecins Sans Frontieres; staff of the National Reference Centre for Mycobacteria mycobacteria
members of the genus Mycobacterium.
see opportunist (atypical) mycobacteria (below).
see opportunist (atypical) mycobacteria (below). , Borstel, Germany; and the airlines and customs organizations who facilitated the shipment of sputum samples.
Financial support for this study was provided by the World Health Organization.
(1.) Farmer PE, Kononets AS, Borisov SE, Goldfarb A, Healing T, McKee M. Recrudescent re·cru·desce
intr.v. re·cru·desced, re·cru·desc·ing, re·cru·desc·es
To break out anew or come into renewed activity, as after a period of quiescence. tuberculosis in the Russian Federation Russian Federation: see Russia. . In: Farmer P. Kim J, editors. The global impact of drug-resistant tuberculosis. Boston: Harvard Medical School Harvard Medical School (HMS) is one of the graduate schools of Harvard University. It is a prestigious American medical school located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts. and the Open Society Institute; 1999.
(2.) Espinal MA, Laszlo A, Simonsen L, Boulahbal F, Kim SJ, Reniero A, et al. Global trends in resistance to anti-tuberculosis drugs. N Engl J Med 2001;344:1294-303.
(3.) World Health Organization. Anti-tuberculosis drug resistance in the world: the WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance. WHO/TB/97.229. Geneva Geneva, canton and city, Switzerland
Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. : The Organization; 1997.
(4.) Small I, van der Meer Van der Meer is a Dutch surname that simply means the phrase 'from the lake' in English. Many years ago, descendants would have lived from a lake in the Netherlands which is how the name first originated. J, Upshur REG. Acting on an environmental disaster: the case of the Aral Sea. Environ Health Persp 2001;109:547-49.
(5.) World Health Organization. Managing tuberculosis at district level. A training course. Geneva: The Organization; 1994.
(6.) World Health Organization. Country profiles for Uzbekistan and Turkmenistan. [accessed 18 Nov 2003]. Available from: http://www.who.int/country/uzb/en/
(7.) World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2003. Geneva: The Organization: 2003. WHO/CDS/TB/2003.316 Reprint reprint An individually bound copy of an article in a journal or science communication . Available from: www.who.int/gtb/publications/globrep/index.html
(8.) World Health Organization and the International Union Against Tuberculosis and Lung Disease. Guidelines for the surveillance in drug-resistant tuberculosis. Geneva: The Organization;1997. WHO/TB/96.216.
(9.) Kent PT, Kubica GP. Public health mycobacteriology. A guide for the level III laboratory. Atlanta: Centers for Disease Control; 1985.
(10.) Tsogt G, Naranabt N, Buyankhisig B, Batkhuyag B, Fujiki A, Mori T. The nationwide tuberculosis drug resistance survey in Mongolia, 1999. Int J Tuberc Lung Dis 2002; 6:289-94.
(11.) Results from DOTS-Plus pilot program. Data presented at the WHO DOTS-Plus Working Group Meeting, Paris, October 2003.
(12.) McKee M, Figueras J, Chenet L. Health sector reform in the former soviet republics of central Asia. Int J Health Plann Manage 1998;13;131-47.
(13.) The Economist Intelligence Unit The Economist Intelligence Unit (EIU) is part of The Economist Group. It is a research and advisory company providing country, industry and management analysis worldwide and incorporates the former Business International Corporation, a U.S. . Country Report .Uzbekistan; 2002.
(14.) The European Observatory on Health Care Systems. In: Health care in Central Asia. McKee M, Healy J, Falkingham J, editors. Buckingham, UK: Open University Press; 2002. p. 179-93.
(15.) Kimerling ME, Kluge (jargon) kluge - /klooj/, /kluhj/ (From German "klug" /kloog/ - clever and Scottish "kludge") 1. A Rube Goldberg (or Heath Robinson) device, whether in hardware or software. H, Vezhnina N, Iacovazzi T, Demeulenaere T, Portaels F, et al. Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 1999;3:451-3.
(16.) United Nations High Commissioner for Refugees Headquartered in Geneva, Switzerland, the Office of the UN High Commissioner for Refugees (UNHCR) (established December 14, 1950) protects and supports refugees at the request of a government or the United Nations and assists in their return or resettlement. . Central Asia on the move. Refugees Magazine 1996 May. Available from: http://www.unhcr.ch/cgi-bin/texis/vtx/
(17.) Toungoussova OS, Caugant DA, Sandven P, Mariandyshev AO, Bjune G. Drug resistance of Mycobacterinm tuberculosis strains isolated from patients with pulmonary tuberculosis pulmonary tuberculosis
Tuberculosis of the lungs.
pulmonary tuberculosis Infectious disease Infection by Mycobacterium tuberculosis in Archangels, Russia. Int J Tuberc Lung Dis. 2002;6:406-14.
(18.) Lockman S Lock´man
n. 1. A public executioner.
Noun 1. lockman - a worker in charge of a lock (on a canal)
lockkeeper, lockmaster , Kruuner A, Binkin J, Levina K, Wang YC, Danilovitsch M, et al. Clinical outcomes of Estonian patients with multi-drug resistant versus drug-susceptible tuberculosis. Clin Infect Dis 2001;32:373-80.
(19.) Espinal, MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, Migliori GB, et al. Standard short-course chemotherapy for drug-resistant tuberculosis, treatment outcomes in 6 countries. JAMA JAMA
Journal of the American Medical Association 2000;283:2537-45.
(20.) Raviglione MC, Gupta R, Dye CM, Espinal MA. The burden of drug-resistant tuberculosis and mechanisms for its control. Ann NY Acad Sci 2001:953:88-97.
(21.) Farmer P, Bayona J, Becerra J, Furin J, Henry C, Hiatt H, et al. The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis 1998;2:869-76.
Ms. Cox is an epidemiologist with Medecins Sans Frontieres in the Aral Sea Area Tuberculosis Program, where she is pursuing research towards a doctoral degree in tuberculosis epidemiology. She previously worked with Medecins Sans Frontieres in Nigeria.
Address for correspondence: Helen S Helen, in Greek mythology, the most beautiful of women; daughter of Leda and Zeus, and sister of Castor and Pollux and Clytemnestra. While still a young girl Helen was abducted to Attica by Theseus and Polydeuces, but Castor and Pollux rescued her. . Cox, c/o Medecins Sans Frontieres, Uzbekistan, P.O. Box 333, 700000 Tashkent, Uzbekistan; fax: 998-71-120-7072; email: firstname.lastname@example.org
Helen Suzanne Cox Suzanne Cox is an English aerobic instructor. She was at one point a gladiator in the UK television show Gladiators. She went by the name Vogue. Videos
A reference mark () used in printing and writing. Also called diesis.
Noun 1. ]) Yared Kebede, ([section]) and Mohammed Aziz ([paragraph])
* Medecins Sans Frontieres Aral Sea Area Programme, Uzbekistan and Turkmenistan, Tashkent, Uzbekistan; ([dagger]) National Reference Centre for Mycobacteria, Borstel, Germany ([double dagger]) Ministry of Health, Nukus, Karakalpakstan, Uzbekistan; ([section]) Medecins Sans Frontieres, Amsterdam, the Netherlands; and ([paragraph]) World Health Organization, Geneva, Switzerland