Second-line anti-TB Drugs Research Articles

Extensively drug-resistant tuberculosis – first report of a case in Austria, May 2008

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Resistance to second-line injectables and treatment outcomes in multidrug-resistant and extensively drug-resistant tuberculosis cases

No information is currently available on the influence of injectable second-line drugs on treatment outcomes of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) patients. To investigate this issue, a large series of MDR- and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation (Archangels Oblast) between 1999 and 2006 were analysed. All study sites performed drug susceptibility testing for first- and second-line anti-TB drugs, laboratory quality assurance and treatment delivery according to World Health Organization recommendations. Out of 4,583 culture-confirmed cases, 240 MDR- and 48 XDR-TB cases had a definitive outcome recorded (treatment success, death, failure). Among MDR- and XDR-TB cases, capreomycin resistance yielded a higher proportion of failure and death than capreomycin-susceptible cases. Resistance to capreomycin was independently associated with unfavourable outcome (logistic regression analysis: odds ratio 3.51). In the treatment of patients with multidrug-resistant and extensively drug-resistant tuberculosis, resistance to the injectable drug capreomycin was an independent predictor for therapy failure in this cohort. As Mycobacterium tuberculosis drug resistance is increasing worldwide, there is an urgent need for novel interventions in the fight against tuberculosis.

Strategies of extensively drug-resistant TB risk management for health workers and other care givers

Extensive drug resistance in TB is not a new phenomenon. It is created when patients with multidrug-resistant TB (MDR-TB) are treated with second-line anti-TB drugs but fail to be cured. The first principle in managing the risk of extensively drug-resistant TB (XDR-TB) is ‘do not generate XDR-TB’. Once it is created, every effort must be made to prevent it from spreading. Health workers and care givers in long-term care facilities and prisons may have a considerable risk of exposure to TB, including XDR-TB. The principles in the control of TB transmission in healthcare settings, long-term care facilities and prisons include early identification and isolation of infectious TB patients, effective treatment of TB as soon as possible, environmental control with proper ventilation and personal protection of healthcare workers and others. Patients with the highest risk of developing XDR-TB are those MDR-TB patients who failed treatment using a second-line regimen and TB patients who have a history of contact with XDR-TB patients. The core principles in managing the risk of XDR-TB for health workers and care givers are reducing the risks of exposure to XDR-TB, becoming infected and developing XDR-TB. If TB has developed, the principles include promptly diagnosing XDR-TB and starting proper treatment.

Evidence of primary transmission of multidrug‐resistant tuberculosis in the Western Province of Papua New Guinea

To review patient outcomes and the molecular epidemiology of multidrug-resistant tuberculosis (MDR-TB) strains isolated from patients living in the Western Province of Papua New Guinea (PNG) seeking treatment in Australia. Review of all cases of MDR-TB among people living in the open border region between the Western Province of PNG and the Torres Strait Islands of Australia who presented to health clinics in the region between 2000 and 2006. All cases of suspected TB were bacteriologically confirmed at the time of presentation by the Mycobacterium Reference Laboratory in Brisbane. Drug resistance patterns; drug use and duration; molecular typing of TB strains; patient outcomes. Between 2000 and 2006, 60 patients from the Western Province of PNG were diagnosed with TB, of which 15 had MDR-TB. Mortality was high, although no patient who was able to maintain access to supervised therapy died. All 15 MDR-TB isolates were Beijing-family strains showing the same unique mycobacterial interspersed repetitive unit (MIRU) profile, with the exception of a single strain that differed by a single repeat at one locus. Restriction fragment length polymorphism (RFLP) typing on 10 of these strains further differentiated them into two distinct clusters. Transmission of MDR-TB is occurring in the Western Province of PNG. Additional resources are urgently needed to interrupt the ongoing transmission of MDR-TB from the Western Province of PNG to the Torres Strait Islands. Good supervision and management of patient treatment, which includes ensuring a regular supply of second-line anti-TB drugs, are essential elements of TB control.

Extensively Drug-Resistant Tuberculosis in South Korea: Risk Factors and Treatment Outcomes among Patients at a Tertiary Referral Hospital

Extensively drug-resistant (XDR) tuberculosis (TB) is a major public health threat in South Korea. We analyzed baseline epidemiological data for 250 patients enrolled in an ongoing prospective observational study of TB at a large tertiary referral hospital in South Korea. Twenty-six subjects with XDR TB were identified; all were patients who had previously received TB therapy. Cumulative previous treatment duration (range, 18-34 months; odds ratio [OR], 5.6; 95% confidence interval [CI], 1.0-59), number of previously received second-line anti-TB drugs (OR, 1.3; 95% CI, 1.1-1.5), and female sex (OR, 3.2; 95% CI, 1.1-8.3) were significantly associated with XDR TB in crude analyses. After controlling for other factors in a multivariable model, cumulative previous treatment duration remained significantly associated with XDR TB (OR, 5.8; 95% CI, 1.0-61). Subjects with XDR TB were more likely to produce culture-positive sputum at 6 months, compared with patients with non-multidrug resistant TB (risk ratio, 13; 95% CI, 5.1-53). Kanamycin resistance was found to be predictive of 6-month culture positivity after adjustment for ofloxacin and streptomycin resistance (risk ratio, 3.9; 95% CI, 1.9-11). XDR TB was found to be associated with the cumulative duration of previous treatment with second-line TB drugs among subjects in a tertiary care TB hospital. Patients with XDR TB were more likely to not respond to therapy, and successful conversion of sputum culture results to negative was correlated with initial susceptibility to both fluoroquinolones and kanamycin but not to streptomycin.

Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis: epidemiology and control

The emergence of multidrug-resistant (MDR)-TB and, more recently, of extensively drug-resistant (XDR)-TB is a real threat to achieve TB control and elimination. Over 400,000 new cases of MDR-TB occur each year and, although their number is currently unknown, XDR cases are recognized in every setting where there has been the capacity to detect them. The long-term vision for the full control of MDR-TB requires the scaling-up of culture and drug-susceptibility testing capacity, which is very limited in disease-endemic countries, and the expanded use of high-technology assays for rapid determination of resistance. MDR cases are treatable and well designed regimens, largely based on second-line anti-TB drugs, can considerably improve cure rates. However, treatment regimens need to be markedly improved through the introduction of less toxic and more powerful drugs, thus reducing duration of treatment and tolerability. This is of utmost importance for XDR-TB cases. The prevalence of MDR-TB and XDR-TB are inversely correlated with the quality of TB control and the proper use of second-line anti-TB drugs. Adherence to proper standards of care and control is imperative and a top priority of all TB control efforts. However, the risk of an uncontrollable epidemic of MDR- and XDR-TB is real considering current levels of financing and commitment to care.

Extensively Drug-ResistantMycobacterium tuberculosis, India

Extensively Drug-Resistant<i>Mycobacterium tuberculosis</i>, India

Tuberculosis mutirresistente en la edad pediátrica

To study the clinical and epidemiological features in eight pediatric patients with multidrug-resistant tuberculosis (MDR-TB) diagnosed from 1994 to 2005 in three hospitals in Madrid (Spain).A retrospective study was performed in patients aged less than 15 years old with positive culture for multidrug-resistant Mycobacterium tuberculosis and patients with negative cultures diagnosed after contact with MDR-TB.Pulmonary tuberculosis was diagnosed in seven patients and arthritis in one. Fifty percent of the patients were immigrants and an adult source case was found in four (50%). M. tuberculosis was isolated in gastric juice in four patients and in synovial biopsy in one. In three patients cultures were negative but these patients had previously been in contact with MDR-TB. Two strains were resistant to isoniazid and rifampicin, four were resistant to isoniazid, rifampicin and streptomycin, one was resistant to isoniazid, rifampicin, streptomycin and pyrazinamide, and one was resistant to 11 drugs. Six patients initially received conventional treatment without improvement. Patients received therapy for 15 months (range: 12 to 18) with 3 to 5 drugs according to the sensitivity study. The following adverse effects were observed: creatine phosphokinase increase (one patient), tendinitis (one patient), alteration of visual evoked responses (one patient) and transitory psychosis (one patient). One patient required pulmonary lobectomy. All patients responded satisfactorily to medical treatment.MDR-TB should be suspected in patients not responding to TB treatment, especially those from countries with high resistance rates. In patients with negative cultures, treatment should rely on the results of a sensitivity study in the adult source case. MDR-TB requires the use of second-line anti-TB drugs for prolonged periods with possible toxic effects.

Clinical and operational value of the extensively drug-resistant tuberculosis definition

Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance.

Extensively Drug-resistant Tuberculosis, Italy and Germany

To the Editor: Twenty-three countries have reported >1 case of extensively drug-resistant tuberculosis (XDR TB) (1); however, information about XDR TB is still incomplete. In particular, the response of XDR TB to treatment in countries with low incidence is not known. We compared mortality rates from XDR TB with those from multidrug-resistant (MDR) TB. We analyzed data from all culture-confirmed TB cases diagnosed during 2003–2006 by the TB clinical reference centers in Italy (Sondalo, Milan, Rome) and Germany (Borstel, Grosshansdorf, Bad-Lippspringe) and reviewed original clinical records. Drug susceptibility testing for first- and second-line anti-TB drugs was performed according to World Health Organization (WHO) recommendations by quality-assured laboratories and retested at WHO Supranational Reference Laboratories (Rome/Milan; Borstel) (2–4). XDR TB was defined as resistance to at least rifampin and isoniazid (MDR TB definition) in addition to any fluoroquinolone and >1 of 3 injectable anti-TB drugs (capreomycin, kanamycin, amikacin) (3). Characteristics of MDR TB and XDR TB cases were compared by χ2 test (categorical variables), Student t test (admission days), and Kaplan-Maier curve (sputum smear, culture conversion), where appropriate. Of 2,888 culture-positive TB cases analyzed (Italy 2,140, Germany 748), 126 (4.4%) were MDR (Italy 83, Germany 43) and 11 (0.4%) were XDR (Italy 8, Germany 3). We estimate that the TB cases analyzed represent 24% of culture-positive cases reported in Italy (69.7% of MDR) and 4.2% of those reported in Germany (12.6% of MDR). XDR TB was diagnosed in each year of the study. All 11 XDR TB patients were receiving retreatment, and of the 126 MDR TB patients, 74 (58.7%) were receiving retreatment. All XDR TB patients were HIV seronegative; and of 109 MDR TB patients tested for HIV, 10 (9.2%) were HIV seropositive. Details about previous treatment regimens, drug resistance, and duration of treatment of XDR TB patients are summarized in the Appendix Table. XDR TB patients were significantly more likely than MDR TB patients to be resistant to all first-line drugs (8/11 vs. 36/126, p<0.005); 2 of these patients were resistant to all tested drugs (Appendix Table). In Germany, nonnationals accounted for 95.3% (41/43) of MDR-TB cases and 100% (3 of 3) of XDR TB cases (all from the former Soviet Union); in Italy, they accounted for 72.3% (60/83) and 50% (4/8), respectively (p 45 years of age (64% [7/11] and 23% [29/126], respectively, p<0.01). Radiologic patterns of the thorax did not differ between XDR TB and MDR TB patients. In the overall sample, the only variable significantly associated with death (other than XDR TB status) was immigrant status (p<0.01). The association between XDR TB status and risk for death remained significant after stratification by immigrant status (p<0.05). Our findings suggest that mismanagement of TB cases plays a major role in emergence of the problem in Europe (along with suboptimal infection control in congregate settings) (5), while in high HIV-prevalence settings (e.g., South Africa) XDR TB was mainly observed in patients never treated previously (6). Mortality rates among MDR TB patients treated in reference centers (6.3%) were lower than the rate observed in a previous study in general hospitals in Italy (8.7%) (5), although a proportion of our MDR TB patients are still completing treatment. This difference in rates is probably due to better management of MDR in the reference centers. Because of the high proportion of XDR TB patients still receiving treatment, further follow-up is necessary to assess potential for cure. The clinical relevance of resistance to all first-line drugs or other factors (e.g., delayed or inadequate treatment, suboptimal observation of drug intake) as major determinants of death needs further evaluation. The appearance of XDR TB in western Europe confirms that poor management and poor infection control in congregate settings exist and that new rapid diagnostic tests and new drugs are urgently needed.

The Philippines case study

Most TB patients in the Philippines are treated by private practitioners who do not conform to the international standard of TB care.1 We established a private-public mix DOTS (PPMD) centre to engage private physicians in the DOTS strategy.2 The cure rate in new cases was 83.9% and failure was 0.01%, with corresponding rates in previously treated cases of 58.6% and 39.7%, respectively. All isolates from the treatment failures were MDR-TB, indicating failure of previous TB treatment outside DOTS. As a DOTS-Plus pilot project, the Green Light Committee (GLC) of the working group on multidrug-resistant TB provided this PPMD access to second-line anti-TB drugs (SLDs) and technical assistance. Our experience illustrates the challenges in MDR-TB management.

Worldwide Emergence of Extensively Drug-resistant Tuberculosis

Mycobacterium tuberculosis strains that are resistant to an increasing number of second-line drugs used to treat multidrug-resistant tuberculosis (MDR TB) are becoming a threat to public health worldwide. We surveyed the Network of Supranational Reference Laboratories for M. tuberculosis isolates that were resistant to second-line anti-TB drugs during 2000-2004. We defined extensively drug-resistant TB (XDR TB) as MDR TB with further resistance to > or = 3 of the 6 classes of second-line drugs. Of 23 eligible laboratories, 14 (61%) contributed data on 17,690 isolates, which reflected drug susceptibility results from 48 countries. Of 3,520 (19.9%) MDR TB isolates, 347 (9.9%) met criteria for XDR TB. Further investigation of population-based trends and expanded efforts to prevent drug resistance and effectively treat patients with MDR TB are crucial for protection of public health and control of TB.

Editorial: The treatment of multi‐drug resistant tuberculosis – a return to the pre‐antibiotic era?

When Magdalena was 15 years old she was diagnosed with smear-positive pulmonary tuberculosis (TB). She lived with her mother, a stepfather and 13 siblings in a very humble dwelling in an Andean country. Her stepfather would often beat her because she was unable to perform her assigned domestic chores. As a result, she would flee and abandon her treatment. She was prescribed several regimens which she took erratically. Three years later she was still smear-positive; the chest X-ray showed multiple cavities in both apices and drug susceptibility testing confirmed resistance to isoniacid (H), rifampicin (R), ethambutol (E) and streptomycin (S). The following year she became pregnant and died of respiratory insufficiency 6 months later. Peter is a 45-year-old primary school teacher in an Eastern African country; he lives with his wife and several children. In September 2000, he was diagnosed with smear-positive TB and was given the category I regimen (2HRZE/6HE; Z 1⁄4 pyrazinamide); at the completion of treatment he was still smear-positive. Despite taking the category II regimen (2HRZES/1HRZE/5HRE) twice, he remained smear-positive. He saw a consultant in the capital who prescribed the entire gamut of secondline TB medications. The only drug which Peter was able to find was ciprofloxacin, which he took for several months. His latest drug susceptibility tests have demonstrated resistance to H, R, E, S and ciprofloxacin; the chest X-ray shows multiple cavities, especially in the left lung. He remains weak, emaciated, dyspnoeic and smear-positive. These two patients from different continents had two characteristics in common: first, they suffered from a very serious form of TB; and secondly, they could not be treated adequately for lack of medication. Let us briefly examine the reasons underlying their clinical condition and lack of effective treatment.

Cost of treatment for multidrug‐resistant tuberculosis in South Korea

Costs associated with multidrug-resistant tuberculosis (MDR-TB) are higher than those associated with drug-susceptible TB because of the higher prices of second-line anti-TB drugs, the prolonged duration of treatment, greater productivity loss and higher mortality. The aim of this study was to estimate the cost of treatment for MDR-TB according to the treatment strategy and prognosis in South Korea. We estimated the direct (medical and non-medical) and indirect cost for the treatment of MDR-TB according to the treatment strategies and prognosis: in medically treated, surgically treated and deceased patients groups. The same analyses were undertaken for drug-susceptible TB for comparison. The patients with MDR-TB or drug-susceptible TB were randomly selected from the TB cohort of Seoul National University Hospital, Seoul, South Korea. Direct costs per person were US$4000 (US$2527-4841) in the medically treated group, US$17,457 (US$10,133-26,418) in the surgically treated group and US$33,362 (US$25 386-40 338) in the deceased group. Total costs per person were US$15,856 (US$10,752-38,421), US$47,159 (US$20,587-77,622) and US$478,357 (US$257,377-777,778), respectively. For the patients with drug-susceptible TB, the total cost ranged from US$1680 to US$7637 (median US$2166). The cost for the treatment of MDR-TB is seven to 22 times that of managing the drug-susceptible TB in South Korea. Considering the high cost, transmissibility and considerable fatality of MDR-TB, there is a need to provide specific separate funding for multidrug-resistant tuberculosis.

A case of Transverse Myelitis due to Multidrug-Resistant Tuberculosis

Acute transverse myelitis (TM) is a neurological syndrome caused by inflammation of the spinal cord. TM is rare but is frequently caused by viral or bacterial infections. TM caused by tuberculosis (TB) is extremely rare and there are no reports of TM caused by multidrug-resistant TB (MDR-TB). We report a case of acute TM due to MDR-TB in a 40-year-old man. The patient had been diagnosed with pulmonary TB and was started on the first-line anti-TB treatment. However, the chest radiographic findings were aggravated and neurological symptoms such as weakness in both lower extremities, sensory changes, and voiding difficulty were newly developed. The T2-weighted magnetic resonance image of the spine showed diffusely increased signal intensity in the spinal cord, particularly at the lower cervical and upper thoracic levels, without any definite evidence of myeloradicular compression, which is consistent with a diagnosis of TM. A drug susceptibility test revealed MDR and second-line anti-TB drugs were prescribed. The chest radiographic findings showed improvement after treatment, the mycobacterial culture converted to negative, the MRI findings improved, and there was partial improvement in the low extremity weakness. The patient has been prescribing second-line anti-TB medications for 14 months. (Tuberc Respir Dis 2006; 60: 353-356)

Mycobacterium tuberculosisDrug Resistance, Abkhazia

To the Editor: Drug-resistant tuberculosis (TB) has been identified as a major problem in the former Soviet Union, and was recently surveyed in the Aral Sea regions of Dashoguz (Turkmenistan) and Karakalpakstan (Uzbekistan) (1). However, few data are available for the Caucasian region and published reports have focused mainly on prisons (2,3). We report a drug resistance survey for first- and second-line anti-TB drugs conducted in Abkhazia, a Caucasian region of 8,600 km2 with approximately 250,000 inhabitants, at the western end of Georgia on the Black Sea. The collapse of the Soviet Union lead to disruption of TB control activities in all Eastern bloc regions (4). In Abkhazia, the shortage and poor quality of drugs, self-medication, and poor adherence to the therapy became even more evident during the war with Georgia in 1993 and the international embargo that followed. A TB program based on the World Health Organization/International Union against Tuberculosis and Lung Disease (WHO/IUATLD) recommendations was initiated in Abkhazia with the support of Medecins Sans Frontieres (MSF) in 1999. In 2000, monitoring of drug resistance was started for new cases and previously treated case-patients. The study was performed in collaboration with the Guliripchi TB Hospital, MSF, and the Istituto Superiore di Sanita (ISS), a WHO/IUATLD Supranational Reference Laboratory for anti-TB drug resistance. Sputa were collected from all patients attending Guliripchi TB Hospital in Sukhumi, the capital of Abkhazia, from September 2000 to April 2004. Patients were either referred by their practitioners or came spontaneously because TB was suspected. Diagnosis, treatment, and hospitalization were provided free. Samples were treated as previously described (5). Of 489 sputa collected from individual patients, 447 were culture positive (246 from new case-patients and 201 from previously treated case-patients) and 42 were culture negative; of these, >90% showed a negative, doubtful, or 1+ smear result. Susceptibility to first-line (streptomycin, isoniazid, rifampin, and ethambutol) and second-line (kanamycin, ethionamide, capreomycin, cycloserine, p-aminosalicylic acid, and ofloxacin) drugs was determined by the proportion method on Middlebrook 7H10 agar. The critical concentrations used were streptomycin, 2 µg/mL; isoniazid, 0.2 µg/mL; rifampin, 1 µg/mL; ethambutol, 5 µg/mL; kanamycin, 5 µg/mL; ethionamide, 5 µg/mL; capreomycin, 10 µg/mL; p-aminosalicylic acid, 2 µg/mL; and ofloxacin, 2 µg/mL (6–8). Cycloserine was used at a concentration of 30 µg/mL (9). If a strain was resistant to >1 first-line drugs, the susceptibility to all second-line drugs was determined. Data on resistance to the first- and second-line drugs are given in the Table. The strains isolated from 35.8% of the new cases and 57.2% of the previously treated case-patients were resistant to >1 first-line drugs. The highest monoresistance was seen for isoniazid and streptomycin in both new and previously treated case-patients, while monoresistance to rifampin and ethambutol was low ( 1 second-line drugs. Table First-line and second line antituberculosis drug resistance in 447 Mycobacterium tuberculosis strains collected in Abkhazia from September 2000 to April 2004* Few data have been reported on drug resistance to first- and second-line drugs in the former Soviet Union and in the Caucasian region (1–4). Overall, in Abkhazia, monoresistance to isoniazid was higher than in Karakalpakstan and Dashoguz (1), while monoresistance to streptomycin was lower. MDR-TB in new and previously treated case-patients showed levels intermediate between these 2 regions. Resistance to kanamycin and ethionamide was 14.3% and 12.8%, respectively, while resistance to ofloxacin was low (1.5%). Fluoroquinolones have not been commonly used in Abkhazia and former regions of the Soviet Union. Currently, regimens for the treatment of MDR-TB in Abkhazia combine an intensive phase for a minimum of 6 months with at least 4 drugs to which the MTB strain is susceptible, including 1 parenteral agent and 1 fluoroquinolone (ofloxacin), followed by a continuation phase of at least 15 months with >3 drugs. This is the first survey reporting drug susceptibility data for MTB within the Caucasus. It indicates that the prevalence of MDR strains is similar to that in other central Asia regions (1). Our results are representative of the present situation in Abkhazia since sampling systematically covered all TB cases for the period examined. The Guliripchi TB Hospital of Sukhumi is the only TB treatment center in the region, and all cases were included in the study. Overall, our data show that second-line drug resistance is present in Abkhazia, particularly among cases with MDR, and suggest the adoption of strategies for access and correct use of second-line drugs (10).

Multiple drug resistance: a threat for tuberculosis control

Drug-resistant tuberculosis (TB) was reported soon after the introduction of streptomycin, although it did not receive major attention until recently. It was not considered a major issue in the industrialized world until outbreaks of multidrug-resistant TB (MDR-TB) were reported among HIV infected people. Administration of standard short-course chemotherapy (SSCC) with first-line drugs under directly observed therapy (DOT) is the cornerstone of modern TB control. Unfortunately, data available on the treatment outcome of MDR-TB cases under routine programmatic conditions suggest that patients with MDR-TB respond poorly to SSCC with first-line drugs. Since 1994, the World Health Organization and the International Union Against Tuberculosis and Lung Disease (IU-ATLD) have conducted anti-TB drug resistance surveys through a network of subregional laboratories and researchers. Drug resistance was present in almost all settings surveyed, and prevalence varied widely across regions. High prevalence of MDR-TB is widespread in the Russian Federation and areas of the former Soviet Union (Estonia, Kazakhstan, Latvia, and Lithuania) as well as Israel, Liaoning and Henan Provinces in China, and Ecuador. The Global Project has surveyed areas representing over one third of notified TB cases. However, enormous gaps still exist in the most crucial areas. The most effective strategy to prevent the emergence of drug resistance is through implementation of the directly observed treatment short (DOTS) strategy. Effective implementation of the DOTS strategy saves lives through decreased TB transmission, decreased risk of emergence of drug-resistance, and decreased risk for individual TB patients of treatment failure, TB relapse, and death. The World Bank recognizes the DOTS strategy as one of the most cost-effective health interventions, and recommends that effective TB treatment be a part of the essential clinical services package available in primary health care settings. Governments are responsible for ensuring the provision of effective TB control through the DOTS strategy. WHO and its international partners have formed the DOTS-Plus Working Group, which is attempting to determine the best possible strategy to manage MDR-TB. One of the goals of DOTS-Plus is to increase access to expensive second-line anti-TB drugs for WHO-approved TB control programmes in low- and middle-income countries.

Multicenter laboratory validation of susceptibility testing of Mycobacterium tuberculosis against classical second-line and newer antimicrobial drugs by using the radiometric BACTEC 460 technique and the proportion method with solid media.

In a large multicenter study involving six major study sites in the United States, Canada, and Europe, the susceptibilities of 272 Mycobacterium tuberculosis strains to classical second-line antituberculosis (anti-TB) drugs (capreomycin, cycloserine, ethionamide, and kanamycin) and newer compounds (amikacin, clofazimine, ofloxacin, and rifabutin) were determined by the radiometric BACTEC 460 procedure and the conventional proportion method on Middlebrook 7H10 agar. Previously established critical concentrations for classical second-line anti-TB drugs were compared with several concentrations in liquid medium to establish equivalence. MICs of newer compounds determined in liquid medium were either the same or up to four times lower than those determined in agar medium. After establishing critical concentrations (breakpoints) in the extended testing of clinical isolates, we obtained an excellent overall correlation between the two systems, with no errors with amikacin, kanamycin, and ofloxacin and very few major or very major errors with the other drugs; however, for cycloserine, no breakpoint concentration could be recommended due to repeatedly inconsistent results by both methods. Based on these data we conclude that the BACTEC 460 procedure is a simple and rapid method requiring 4 to 8 days on average to generate accurate antimicrobial susceptibility testing (AST) results for eight anti-TB drugs other than those considered primary ones. These data not only fill a major gap of knowledge regarding the critical test concentrations of secondary anti-TB drugs but also provide a baseline for future evaluations of M. tuberculosis AST with the more recently developed, nonradiometric broth-based culture systems.