Molecular Epidemiology of Mycobacterium tuberculosis strains isolated from pulmonary tuberculosis patients in south Ethiopia.

INTRODUCTION: Understanding the epidemiology of tuberculosis is limited by lack of genotyping data. We sought to characterize the drug susceptibility testing patterns and genetic diversity of M. tuberculosis isolates in southern Ethiopia. METHODOLOGY: A cross-sectional study was conducted among newly diagnosed sputum smear positive patients with tuberculosis visiting nine health facilities in southern Ethiopia from June 2015 to May 2016. Three consecutive sputum samples (spot-morning-spot) per patient were examined using acid-fast bacilli smear microscopy with all smear positive specimens having acid-fast bacilli cultures performed. M. tuberculosis isolates had drug susceptibility testing performed using indirect proportion method and were genotyped with RD9 deletion analysis and spoligotyping. Mapping of strain was made using geographic information system. RESULTS: Among 250 newly diagnosed patients with tuberculosis, 4% were HIV co-infected. All 230 isolates tested were M. tuberculosis strains belonging to three lineages: Euro-American, 187 (81%), East-African-Indian, 31 (14%), and Lineage 7 (Ethiopian lineage), 8 (4%); categorized into 63 different spoligotype patterns, of which 85% fell into 28 clusters. M. tuberculosis strains were clustered by geographic localities. The dominant spoligotypes were SIT149 (21%) and SIT53 (19%). Drug susceptibility testing found that 14% of isolates tested were resistant to > 1 first line anti- tuberculosis drugs and 11% to INH. SIT 149 was dominant among drug resistant isolates. CONCLUSIONS: The study revealed several clusters and drug resistant strains of M. tuberculosis in the study area, suggesting recent transmission including of drug resistant tuberculosis. Wider monitoring of drug susceptibility testing and geospatial analysis of transmission trends is required to control tuberculosis in southern Ethiopia.

Genomic-based surveillance reveals high ongoing transmission of multi-drug-resistant Mycobacterium tuberculosis in Southern Brazil.

Genomic-based surveillance on the occurrence of drug resistance and its transmission dynamics has emerged as a powerful tool for the control of tuberculosis (TB). A whole-genome sequencing approach, phenotypic testing and clinical-epidemiological investigation were used to undertake a retrospective population-based study on drug-resistant (DR)-TB in Rio Grande do Sul, the largest state in Southern Brazil. The analysis included 305 resistant Mycobacterium tuberculosis strains sampled statewide from 2011 to 2014, and covered 75.7% of all DR-TB cases identified in this period. Lineage 4 was found to be predominant (99.3%), with high sublineage-level diversity composed mainly of 4.3.4.2 [Latin American and Mediterranean (LAM)/RD174], 4.3.3 (LAM/RD115) and 4.1.2.1 (Haarlem/RD182) sublineages. Genomic diversity was also reflected in resistance of the variants to first-line drugs. A large number of distinct resistance-conferring mutations, including variants that have not been reported previously in any other setting worldwide, and 22 isoniazid-monoresistant strains with mutations described as disputed in the rpoB gene but causing rifampicin resistance generally missed by automated phenotypic tests as BACTEC MGIT. Using a cut-off of five single nucleotide polymorphisms, the estimated recent transmission rate was 55.1%, with 168 strains grouped into 28 genomic clusters. The most worrying fact concerns multi-drug-resistant (MDR) strains, of which 73.4% were clustered. Different resistance profiles and acquisition of novel mutations intraclusters revealed important amplification of resistance in the region. This study described the diversity of M. tuberculosis strains, the basis of drug resistance, and ongoing transmission dynamics across the largest state in Southern Brazil, stressing the urgent need for MDR-TB transmission control state-wide.

A comparison of patient treatment pathways among multidrug-resistant and drug-sensitive TB cases in Delhi, India: A cross-sectional study.

BACKGROUND: The delay in the diagnosis and treatment initiation of patients with MDR-TB worsens individual prognosis and increases the risk of disease transmission in the community. These delays have been attributed to delay in treatment-seeking by the patient and shifting to multiple healthcare facilities before being tested and diagnosed through India's National Tuberculosis Elimination Program (NTEP). OBJECTIVE: to identify treatment pathways in patients with MDR-TB from the time of onset of symptoms and treatment seeking until diagnosis at a PMDT site and subsequent treatment initiation. We also compared these characteristics with those of patients with DS-TB. METHODS: We recruited a total of 168 patients with MDR-TB and DS-TB each, in Delhi. Data were analyzed using IBM SPSS Version 25. RESULTS: The mean (SD) patient delay for initial treatment-seeking was 20.9 (15.9) days in patients with MDR-TB, and 16.1 (17.1) days in patients with DS-TB (p < 0.001). The median time from visit to the first healthcare facility (HCF) until confirmation of MDR-TB diagnosis was 78.5 days, and until treatment initiation was 102.5 days. Among patients with DS-TB, the time interval from a visit to the first HCF until the initiation of ATT-DOTS was 61.5 days.. Patients diagnosed with DS-TB, whose first source of treatment was a private facility (n = 49), reported a significant delay in the initiation of ATT-DOTS (p < 0.001). CONCLUSIONS: Despite the introduction of universal drug sensitivity testing in individuals having presumptive MDR-TB, a significant delay in the diagnosis and initiation of effective MDR-TB treatment persists as a major public health challenge in India.

Whole genome sequencing of drug resistant Mycobacterium tuberculosis isolates from a high burden tuberculosis region of North West Pakistan.

Tuberculosis (TB), caused by Mycobacterium tuberculosis bacteria, is a leading infectious cause of mortality worldwide, including in Pakistan. Drug resistant M. tuberculosis is an emerging threat for TB control, making it important to detect the underlying genetic mutations, and thereby inform treatment decision making and prevent transmission. Whole genome sequencing has emerged as the new diagnostic to reliably predict drug resistance within a clinically relevant time frame, and its deployment will have the greatest impact on TB control in highly endemic regions. To evaluate the mutations leading to drug resistance and to assess for evidence of the transmission of resistant strains, 81 M. tuberculosis samples from Khyber Pakhtunkhwa province (North West Pakistan) were subjected to whole genome sequencing and standard drug susceptibility testing for eleven anti-TB drugs. We found the majority of M. tuberculosis isolates were the CAS/Delhi strain-type (lineage 3; n = 57; 70.4%) and multi-drug resistant (MDR; n = 62; 76.5%). The most frequent resistance mutations were observed in the katG and rpoB genes, conferring resistance to isoniazid and rifampicin respectively. Mutations were also observed in genes conferring resistance to other first and second-line drugs, including in pncA (pyrazinamide), embB (ethambutol), gyrA (fluoroquinolones), rrs (aminoglycosides), rpsL, rrs and giB (streptomycin) loci. Whilst the majority of mutations have been reported in global datasets, we describe unreported putative resistance markers in katG, ethA (ethionamide), gyrA and gyrB (fluoroquinolones), and pncA. Analysis of the mutations revealed that acquisition of rifampicin resistance often preceded isoniazid in our isolates. We also observed a high proportion (17.6%) of pre-MDR isolates with fluoroquinolone resistance markers, potentially due to unregulated anti-TB drug use. Our isolates were compared to previously sequenced strains from Pakistan in a combined phylogenetic tree analysis. The presence of lineage 2 was only observed in our isolates. Using a cut-off of less than ten genome-wide mutation differences between isolates, a transmission analysis revealed 18 M. tuberculosis isolates clustering within eight networks, thereby providing evidence of drug-resistant TB transmission in the Khyber Pakhtunkhwa province. Overall, we have demonstrated that drug-resistant TB isolates are circulating and transmitted in North West Pakistan. Further, we have shown the usefulness of whole genome sequencing as a diagnostic tool for characterizing M. tuberculosis isolates, which will assist future epidemiological studies and disease control activities in Pakistan.

The Impact of Anti-Retroviral Therapy on Tuberculosis Detection at the National Level in South Africa.

Human immunodeficiency virus/tuberculosis (HIV/TB) coinfection is particularly prevalent in South Africa, where TB has been the leading cause of death for more than a decade. The 2004-2008 national rollout of antiretroviral therapy (ART) provides a unique opportunity to examine the population-level impact of ART on the TB epidemic. We performed longitudinal regression analysis to follow the evolution of TB outcomes before and after the introduction of ART using a large data set from the National Health Laboratory Service. This is the first study to produce estimates of the impact of the ART rollout by exploiting staggered timing and geographic variation in the rollout. After ART became available in a health facility, 3.7% (P < 0.0001) more patients were tested for TB and 3.2% (P < 0.0001) more received repeat testing; however, there was a steep rise in testing before the introduction of ART. Although the number of TB-positive patients increased by 4.3% (P = 0.0002) in the first year post-ART, the TB rate among tested patients fell by 2 percentage points (8%, P = 0.001) after 2 years. Sputum smear testing declined relative to more technologically advanced diagnostics post-ART. Antiretroviral therapy availability increased the attention to TB screening and drew new patients into the health-care system. Small increases in the numbers of repeat patients are indicative of retention in care. The decline in TB rates post-ART suggests that the reduction in TB risk due to improved immune functioning and health-care contact likely outweighed the increased TB risk because of the longer lifespan of ART initiators.

Evolution of Phenotypic and Molecular Drug Susceptibility Testing.

Drug Resistant Tuberculosis (DRTB) is an emerging problem world-wide. In order to control the disease and decrease the number of cases overtime a prompt diagnosis followed by an appropriate treatment should be provided to patients. Phenotypic DST based on liquid automated culture has greatly reduced the time needed to generate reliable data but has the drawback to be expensive and prone to contamination in the absence of appropriate infrastructures. In the past 10 years molecular biology tools have been developed. Those tools target the main mutations responsible for DRTB and are now globally accessible in term of cost and infrastructures needed for the implementation. The dissemination of the Xpert MTB/rif has radically increased the capacity to perform the detection of rifampicin resistant TB cases. One of the main challenges for the large scale implementation of molecular based tests is the emergence of conflicting results between phenotypic and genotypic tests. This mines the confidence of clinicians in the molecular tests and delays the initiation of an appropriate treatment. A new technique is revolutionizing the genotypic approach to DST: the WGS by Next-Generation Sequencing technologies. This methodology promises to become the solution for a rapid access to universal DST, able indeed to overcome the limitations of the current phenotypic and genotypic assays. Today the use of the generated information is still challenging in decentralized facilities due to the lack of automation for sample processing and standardization in the analysis.The growing knowledge of the molecular mechanisms at the basis of drug resistance and the introduction of high-performing user-friendly tools at peripheral level should allow the very much needed accurate diagnosis of DRTB in the near future.

Transmission of multi-drug resistant tuberculosis in Mongolia is driven by Beijing strains of Mycobacterium tuberculosis resistant to all first-line drugs.

BACKGROUND: Mongolia has high and rising rates of multi-drug resistant tuberculosis (MDR-TB). Spatio-temporal and programmatic evidence suggests a major contribution from MDR-TB transmission, but genotypic evidence has not been assessed. METHODS: All MDR-TB cases identified during 2012 were examined. Demographic and bacteriological data were obtained from the National Tuberculosis Reference Laboratory. Isolates of Mycobacterium tuberculosis from culture-confirmed category 1 treatment failures were genotyped using 24-loci mycobacterium interspersed repetitive unit (MIRU-24) analysis. RESULTS: Of the 210 MDR-TB cases identified, 115 (54.8%) were treatment failures (34.8% category 1; 20.0% category 2). Streptomycin resistance was present in 156 (74.3%) cases; including 55/73 (75.3%) category 1 treatment failures who had never been exposed to streptomycin. Among category 1 treatment failures, Beijing lineage strains predominated (88.0%; 59/67 of genotyped isolates). MIRU-24 clustering was documented in 62.7% (42/67) of strains; 55.2% (37/67) remained clustered when drug susceptibility test results were considered. In total 59.5% (25/42) of clustered strains were Beijing lineage and demonstrated in-vitro resistance to all first-line drugs tested. CONCLUSION: The MDR-TB epidemic in Mongolia appears to be driven by primary transmission of Beijing lineage strains resistant to all first-line drugs. Enhanced infection control strategies together with early MDR-TB case detection and appropriate treatment are necessary to limit escalation of the MDR-TB epidemic.

Prevalence and transmission of pyrazinamide resistant Mycobacterium tuberculosis in China.

Pyrazinamide (PZA) is an important first-line anti-tuberculosis drug, however, there are relatively few available data on PZA resistant (PZA-R) rate in China. From June 2009 to June 2012, we selected 493 isolates from five field settings in China to investigate PZA-R by pncA gene sequencing. The result showed that PZA-R rate was 1.0% (2/196) among pan-susceptible isolates, 3.1% (4/130) among isoniazid (INH) mono-resistant isolates, 14.0% (6/43) among rifampin (RIF) mono-resistant isolates and 43.5% (54/124) among multidrug resistant (MDR) isolates. MDR tuberculosis (TB), RIF mono-resistance, and retreatment were found to be risk factors for PZA-R. Newly diagnosed PZA-R TB patients and clustered isolates with identical pncA mutations indicate that transmission of PZA-R isolates plays an important role in emergence of PZA-R TB. The results suggest that, it is necessary to conduct PZA susceptibility test among MDR isolates and modify the treatment regimens accordingly.

The fourth national anti-tuberculosis drug resistance survey in Viet Nam.

SETTING: Viet Nam's Fourth National Anti-Tuberculosis Drug Resistance Survey was conducted in 2011. OBJECTIVE: To determine the prevalence of resistance to the four main first-line anti-tuberculosis drugs in Viet Nam. METHODS: Eighty clusters were selected using a probability proportion to size approach. Drug susceptibility testing (DST) against the four main first-line anti-tuberculosis drugs was performed. RESULTS: A total of 1629 smear-positive tuberculosis (TB) patients were eligible for culture. Of these, DST results were available for 1312 patients, including 1105 new TB cases, 195 previously treated TB cases and 12 cases with an unknown treatment history. The proportion of cases with resistance to any drug was 32.7% (95%CI 29.1-36.5) among new cases and 54.2% (95%CI 44.3-63.7) among previously treated cases. The proportion of multidrug-resistant TB (MDR-TB) cases was 4.0% (95%CI 2.5-5.4) in new cases and 23.3 (95%CI 16.7-29.9) in previously treated cases. CONCLUSIONS: The fourth drug resistance survey in Viet Nam found that the proportion of MDR-TB among new and previously treated cases was not significantly different from that in the 2005 survey. The National TB Programme should prioritise the detection and treatment of MDR-TB to reduce transmission of MDR-TB in the community.

Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis.

BACKGROUND: Effective treatment for drug-susceptible tuberculosis (TB) rapidly renders patients non-infectious, long before conversion of sputum acid-fast smear or culture to negative. Multidrug-resistant TB (MDR-TB) patients on treatment are currently assumed to remain infectious for months. While the resources required for prolonged hospitalization are a barrier to the scale-up of MDR-TB treatment, the safety of community treatment is clear. OBJECTIVES: To estimate the impact of treatment on infectiousness among MDR-TB patients. METHODS: A series of five human-to-guinea pig TB transmission studies was conducted to test various interventions for infection control. Guinea pigs in adjacent chambers were exposed to exhaust air from a hospital ward occupied by mostly sputum smear- and culture-positive MDR-TB patients. The guinea pigs then underwent tuberculin skin testing for infection. Only the control groups of guinea pigs from each study (no interventions used) provide the data for this analysis. The number of guinea pigs infected in each study is reported and correlated with Mycobacterium tuberculosis drug susceptibility relative to treatment. RESULTS: Despite exposure to presumably infectious MDR-TB patients, infection percentages among guinea pigs ranged from 1% to 77% in the five experiments conducted. In one experiment in which guinea pigs were exposed to 27 MDR-TB patients newly started on effective treatment for 3 months, there was minimal transmission. In four other experiments with greater transmission, guinea pigs had been exposed to patients with unsuspected extensively drug-resistant tuberculosis who were not on effective treatment. CONCLUSIONS: In this model, effective treatment appears to render MDR-TB patients rapidly non-infectious. Further prospective studies on this subject are needed.

Primary drug resistance among pulmonary treatment-naïve tuberculosis patients in Amazonas State, Brazil.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is the main indicator of previous treatment in tuberculosis (TB) patients. MDR-TB among treatment-naïve patients indicates infection with drug-resistant Mycobacterium tuberculosis strains, and such cases are considered primary drug-resistant cases. OBJECTIVE: To estimate the prevalence of drug resistance in pulmonary TB (PTB) treatment-naïve patients and to identify the socio-demographic and clinical characteristics of the resistant population. METHODS: A total of 205 treatment-naïve PTB patients from Manaus, Amazonas State, Brazil, were enrolled. Drug susceptibility testing (DST) was performed on all positive mycobacterial cultures using the 1% proportion method. RESULTS: Positive M. tuberculosis cultures were obtained from only 175 patients for DST. The prevalence of primary MDR-TB was 1.7% (3/175); 14.3% (25/175) of the cultures presented resistance to at least one of the drugs. Resistance to streptomycin, isoniazid, rifampicin and ethambutol was respectively 8.6%, 6.9%, 3.4% and 2.3%. An association between TB patients with resistance to more than one drug and known previous household contact with a TB patient was observed (P= 0.008, OR 6.7, 95%CI 1.2-67.3). CONCLUSIONS: Although the prevalence of primary MDR-TB currently is relatively low, it may become a major public health problem if tailored treatment is not provided, as resistance to more than one drug is significantly associated with household contact.

Decline in rates of acquired multidrug-resistant tuberculosis after implementation of the directly observed therapy, short course (DOTS) and DOTS-Plus programmes in Taiwan.

OBJECTIVES: To investigate the impact of the directly observed therapy, short course (DOTS) and DOTS-Plus strategies on changes in resistance profiles among Mycobacterium tuberculosis (MTB). METHODS: We performed a retrospective analysis of resistance profiles among isolates of MTB obtained from 2160 consecutive patients with culture-confirmed pulmonary tuberculosis (TB) between 2005 and 2011 at a referral centre in southern Taiwan. RESULTS: Of the 2160 patients, 70 (3.2%) had primary multidrug-resistant (MDR)-TB, 178 (8.2%) had acquired MDR-TB, 10 (0.5%) had primary extensively drug-resistant (XDR)-TB, 23 (1.1%) had acquired XDR-TB and 5 (0.2%) had totally drug-resistant (TDR)-TB. Trend analysis revealed that the rates of acquired MDR-TB were significantly lower after implementation of the DOTS and DOTS-Plus programmes (P < 0.01). There was a significant negative correlation between the coverage rates of the DOTS and DOTS-Plus programmes and the rates of acquired MDR-TB (r = -0.84, P = 0.02 and r = -0.92, P = 0.03, respectively). The rates of resistance to rifampicin, isoniazid, ofloxacin, moxifloxacin, levofloxacin and para-aminosalicylic acid also decreased significantly during the study period. However, the rates of primary MDR-TB remained stable (P = 0.11). Multivariate logistic regression analysis showed that age ranging from 45 to 64 years, positive acid-fast stain results at the initiation of treatment and treatment without DOTS were independent risk factors associated with acquired MDR-TB. In addition, previous treatment for TB (100% versus 19% for TDR-TB and non-TDR-TB, P < 0.01) and treatment without DOTS (80% versus 44% for TDR-TB and non-TDR-TB, P = 0.18) were risk factors for TDR-TB. CONCLUSIONS: DOTS and DOTS-Plus are both effective at preventing the acquisition of MDR-TB in Taiwan.

Bayesian estimation of mixture models with prespecified elements to compare drug resistance in treatment-naïve and experienced tuberculosis cases.

We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years.

Drug-resistant tuberculosis: a worldwide epidemic poses a new challenge.

BACKGROUND: Although the incidence of tuberculosis (TB) in Germany is now declining, the world as a whole faces the threat of a catastrophe that will also affect the industrialized nations. The main reason, aside from TB/HIV co-infection, is the increase of resistant TB strains. The situation is already serious because of the spread of multidrug-resistant TB, i.e., TB that is resistant to the two most important antituberculous drugs, and is being further aggravated by resistance to second-line drugs as well. METHOD: Selective review of the literature. RESULTS: There are an estimated half a million cases of multidrug-resistant TB worldwide, and so-called extensively resistant TB (XDR-TB), with additional resistance to defined second-line drugs, is now prevalent in more than 45 countries. An accurate assessment of the situation is hampered by a widespread lack of laboratory capacity and/or proper surveillance. The problem is mainly due to inappropriate treatment, which may have many causes, but is theoretically avoidable. Aside from programmatic weaknesses, a lack of diagnostic and therapeutic tools causes difficulties in many countries. DISCUSSION: Only rapid and internationally concerted action, combined with intensified research efforts and the support of the affected nations, will be able to prevent the development of a situation that will no longer be manageable even with 21(st)-century technology.

Cost-effectiveness of treating multidrug-resistant tuberculosis.

BACKGROUND: Despite the existence of effective drug treatments, tuberculosis (TB) causes 2 million deaths annually worldwide. Effective treatment is complicated by multidrug-resistant TB (MDR TB) strains that respond only to second-line drugs. We projected the health benefits and cost-effectiveness of using drug susceptibility testing and second-line drugs in a lower-middle-income setting with high levels of MDR TB. METHODS AND FINDINGS: We developed a dynamic state-transition model of TB. In a base case analysis, the model was calibrated to approximate the TB epidemic in Peru, a setting with a smear-positive TB incidence of 120 per 100,000 and 4.5% MDR TB among prevalent cases. Secondary analyses considered other settings. The following strategies were evaluated: first-line drugs administered under directly observed therapy (DOTS), locally standardized second-line drugs for previously treated cases (STR1), locally standardized second-line drugs for previously treated cases with test-confirmed MDR TB (STR2), comprehensive drug susceptibility testing and individualized treatment for previously treated cases (ITR1), and comprehensive drug susceptibility testing and individualized treatment for all cases (ITR2). Outcomes were costs per TB death averted and costs per quality-adjusted life year (QALY) gained. We found that strategies incorporating the use of second-line drug regimens following first-line treatment failure were highly cost-effective compared to strategies using first-line drugs only. In our base case, standardized second-line treatment for confirmed MDR TB cases (STR2) had an incremental cost-effectiveness ratio of 720 dollars per QALY (8,700 dollars per averted death) compared to DOTS. Individualized second-line drug treatment for MDR TB following first-line failure (ITR1) provided more benefit at an incremental cost of 990 dollars per QALY (12,000 dollars per averted death) compared to STR2. A more aggressive version of the individualized treatment strategy (ITR2), in which both new and previously treated cases are tested for MDR TB, had an incremental cost-effectiveness ratio of 11,000 dollars per QALY (160,000 dollars per averted death) compared to ITR1. The STR2 and ITR1 strategies remained cost-effective under a wide range of alternative assumptions about treatment costs, effectiveness, MDR TB prevalence, and transmission. CONCLUSIONS: Treatment of MDR TB using second-line drugs is highly cost-effective in Peru. In other settings, the attractiveness of strategies using second-line drugs will depend on TB incidence, MDR burden, and the available budget, but simulation results suggest that individualized regimens would be cost-effective in a wide range of situations.

Familial outbreak of disseminated multidrug-resistant tuberculosis and meningitis.

Rapidly progressive multidrug-resistant tuberculosis (MDR-TB) is well documented in human immunodeficiency virus (HIV) positive subjects, but it is not fully recognised in HIV-negative subjects in the familial environment. We report three cases of MDR-TB in three young HIV-negative subjects from the same family. All the patients showed signs of meningitis during the course of their disease, and in two cases a resistant strain of Mycobacterium tuberculosis was isolated in cerebrospinal fluid. Two of the three subjects died from neurological complications; the other was successful treated utilising both systemic and intrathecal therapy for tuberculous meningitis. By a retrospective analysis of DNA obtained from Lowenstein-Jensen cultures, the strains were confirmed as M. tuberculosis resistant to rifampicin and isoniazid, and were closely related in the two cases where specimens were available for analysis. The resistance was acquired in two patients initially infected with a susceptible strain; in the other patient, the resistance was present on the first sensitivity test for which results were available. This report demonstrates the high risk of fatality from MDR-TB for HIV-negative subjects in the absence of reliable early diagnostic and preventive tools. It also reinforces the concept that genetic susceptibility to M. tuberculosis may be an important factor in the clinical presentation and outcome of MDR-TB.

[Incidence of resistance and risk factors for resistance in Mycobacterium tuberculosis. A retrospective study of 1,055 patients of a specialty hospital 1984 to 1993]. / Resistenzhäufigkeit und Risikofaktoren für Resistenz bei Mycobacterium tuberculosis. Eine retrospektive Untersuchung von 1055 Patienten eines Fachkrankenhauses von 1984 bis 1993.

For the past decade, there have been no data on the time course of drug-resistant tuberculosis and on risk factors for drug resistance in former West Germany. We reviewed the medical records of all patients with positive cultures for Mycobacterium tuberculosis from 1984 until 1993 in a hospital near Hamburg. Drug-susceptibility testing was performed for isoniazid, rifampicin, ethambutol, and streptomycin, using the modified proportion method. Of 1,055 patient, 9.6% had isolates resistant to one or more drugs. Of the isolates, 5.8% showed resistance to isoniazid or rifampicin and 1.8% to both isoniazid and rifampicin. There was no significant change of the resistance rate during the study period. Twenty six percent of 89 patients from South America, Africa or Asia had isolates resistant to one or more drugs, compared with 7.6% of 799 patients born in Germany (odds ratio (OR) 4.2; 95% confidence interval (95% CI) 2.5-7.3). Among patients born in Germany, 32% of 101 patients with a history of prior antituberculosis drug therapy had resistant organisms, versus 4.2% of 698 patients without prior therapy (OR 10.7; 95% CI 6.1-18.7). Resistance orates for 35 patients, who had been treated within the last 5 yrs, and for 65 patients, who had been treated more than 5 yrs ago, were 57 and 17%, respectively (OR 6.6; 95% CI 2.9-16.6). Our results suggest that there is no increase in the proportion of drug-resistant tuberculosis in our hospital, and that patients with a recent history of antituberculosis drug therapy and patients from South America, Africa, or Asia are at high risk for drug resistance.