Outbreaks Of Multidrug-resistant Tuberculosis Research Articles

Frequency of Beijing family of Mycobacterium tuberculosis in Mashhad, Northeast of Iran

Background: Beijing family of Mycobacterium tuberculosis (M. tuberculosis) is widespread in Asia and has been involved in outbreaks of multidrug-resistant tuberculosis in various parts of the world. The aim of the current study was to evaluate the frequency of Beijing family of M. tuberculosis in patients with tuberculosis in Mashhad, Iran. Materials and Methods: Totally, 72 specimens of M. tuberculosis were collected from pulmonary samples of patients at Ghaem hospital in Mashhad (Iran) between April 2011 and May 2012. The authors used IS6110-based polymerase chain reaction (IS6110-based PCR) method to identify Beijing family of M. tuberculosis. Based on PCR results, strains belonging to Beijing and non-Beijing families were detected. Also, among members of Beijing family, ancient and modern subfamilies were distinguished. Results: Beijing genotype was observed in five (6.9%) of 72 culture positive samples. In the present study, no cases of modern subfamilies were detected. M. tuberculosis had a higher frequency in men (61.1%) compared to that of women (38.9%). Our data demonstrated that IS6110-based PCR can be used to distinguish Beijing family from non-Beijing family, with high specificity and sensitivity. Conclusion: The improvement of convenient and quick methods to detect and control Beijing family of M. tuberculosis in clinical samples is an interesting subject in areas where M. tuberculosis is prevalent. This method has the advantages of being quick, cost-effective, and requires comparatively less clinical laboratory equipment. K e y w o r ds: Mycobacterium tuberculosis; Beijing lineage; Polymerase chain reaction

Epidemiologic Correlates of Pyrazinamide-Resistant Mycobacterium tuberculosis in New York City.

Pyrazinamide (PZA) has important sterilizing activity in tuberculosis (TB) chemotherapy. We describe trends, risk factors, and molecular epidemiology associated with PZA-resistant (PZA(r)) Mycobacterium tuberculosis in New York City (NYC). From 2001 to 2008, all incident culture-positive TB cases reported by the NYC Department of Health and Mental Hygiene (DOHMH) were genotyped by IS6110-based restriction fragment length polymorphism and spoligotype. Multidrug-resistant (MDR) isolates underwent DNA sequencing of resistance-determining regions of pncA, rpoB, katG, and fabG1. Demographic and clinical information were extracted from the NYC DOHMH TB registry. During this period, PZA(r) doubled (1.6% to 3.6%) overall, accounting for 44% (70/159) of the MDR population and 1.4% (75/5511) of the non-MDR population. Molecular genotyping revealed strong microbial phylogenetic associations with PZA(r). Clustered isolates and those from acid-fast bacillus (AFB) smear-positive cases had 2.7 (95% confidence interval [CI] = 1.71 to 4.36) and 2.0 (95% CI = 1.19 to 3.43) times higher odds of being PZA(r), respectively, indicating a strong likelihood of recent transmission. Among the MDR population, PZA(r) was acquired somewhat more frequently via primary transmission than by independent pathways. Our molecular analysis also revealed that several historic M. tuberculosis strains responsible for MDR TB outbreaks in the early 1990s were continuing to circulate in NYC. We conclude that the increasing incidence of PZA(r), with clear microbial risk factors, underscores the importance of routine PZA drug susceptibility testing and M. tuberculosis genotyping for the identification, control, and prevention of increasingly resistant organisms.

Brote de tuberculosis multirresistente en dos colegios de educación secundaria

ObjectivesTo describe an outbreak of multidrug-resistant tuberculosis (MDR-TB) in two schools MethodsThis was a prospective, observational study of an outbreak of MDR-TB in 2 schools located in the towns of Onda and Nules, in the Spanish province of Castellon, from the moment of detection in November 2008 until November 2014, including patient follow-up and contact tracing. ResultsFive cases of MDR-TB were diagnosed. Overall attack rate was 0.9%, and among the contacts traced, 66 had latent tuberculous infection, with an infection rate of 14.4%. Molecular characterization of the 5M. tuberculosis isolates was performed by restriction fragment length polymorphism (RFLP) analysis of the IS6110 sequence. In all 5 patients, cultures were negative at 4-month follow-up, showing the efficacy of the treatment given. No recurrence has been reported to date. ConclusionsIn the context of globalization and the increased prevalence of MDR-TB, outbreaks such as the one presented here are only to be expected. Contact tracing, strict follow-up of confirmed cases, the availability of fast diagnostic techniques to avoid treatment delay, and chemoprophylaxis, together with the molecular characterization of strains, are still essential

Whole genome sequence analysis of multidrug-resistant Mycobacterium tuberculosis Beijing isolates from an outbreak in Thailand

The Mycobacterium tuberculosis Beijing family is often associated with multidrug resistance and large outbreaks. Conventional genotyping study of a community outbreak of multidrug-resistant tuberculosis (MDR-TB) that occurred in Kanchanaburi Province, Thailand was carried out. The study revealed that the outbreak was clonal and the strain was identified as a member of Beijing family. Although, the outbreak isolates showed identical spoligotyping and mycobacterial interspersed repetitive units-variable number tandem repeats patterns, a discrepancy regarding ethambutol resistance was observed. In-depth characterization of the isolates through whole genome sequencing of the first and the last three isolates from our culture collection showed them to belong to principal genetic group 1, single nucleotide polymorphism (SNP) cluster group 2, sequence type 10. Compared with the M. tuberculosis H37Rv reference genome, 1242 SNPs were commonly found in all isolates. The genomes of these isolates were shown to be clonal and highly stable over a 5-year period and two or three unique SNPs were identified in each of the last three isolates. Genes known to be associated with drug resistance and their promoter regions, where applicable, were analyzed. The presence of low or no fitness cost mutations for drug resistance and an additional L731P SNP in the rpoB gene was observed in all isolates. These findings might account for the successful transmission of this MDR-TB strain.

Outbreak of multidrug-resistant tuberculosis in an aboriginal family in eastern Taiwan

Spread of multidrug-resistant tuberculosis (MDR-TB) strains in the general population presents a serious threat to public health and severely threatens existing control efforts. Techniques such as spoligotyping and Mycobacterium interspersed repetitive units—variable-number tandem-repeat typing of mycobacterial isolates have been employed to confirm familial outbreaks of MDR-TB. We diagnosed and traced four MDR-TB cases in a family via genotyping. Despite aggressive treatment, the index case remained culture positive, but the other patients were cured. This is the first documentation of a familial MDR-TB outbreak affecting human immunodeficiency virus-seronegative patients in eastern Taiwan. Molecular techniques are important in the identification of sources of MDR-TB infections. The adult index case in our study developed MDR-TB due to poor compliance with the drug regimen (acquired resistance), followed by transmission of MDR-TB to his children in close household contact. This emphasizes the importance of an effective drug delivery program, such as directly observed treatment, to improve drug compliance and prevent the emergence of drug-resistant cases.

Whole-Genome Sequence of a Multidrug-Resistant Mycobacterium tuberculosis Beijing Sequence Type 10 Isolate from an Outbreak in Thailand.

Infections with the Beijing family of Mycobacterium tuberculosis occur worldwide and are endemic in Asian countries. We present the draft genome sequence of DS6701, a multidrug-resistant M. tuberculosis Beijing strain of sequence type 10. The isolate is a representative of strains isolated from a multidrug-resistant tuberculosis outbreak in Thailand.

Two genetically-related multidrug-resistant Mycobacterium tuberculosis strains induce divergent outcomes of infection in two human macrophage models

Mycobacterium tuberculosis has a considerable degree of genetic variability resulting in different epidemiology and disease outcomes. We evaluated the pathogen-host cell interaction of two genetically closely-related multidrug-resistant M. tuberculosis strains of the Haarlem family, namely the strain M, responsible for an extensive multidrug-resistant tuberculosis outbreak, and its kin strain 410 which caused a single case in two decades. Intracellular growth and cytokine responses were evaluated in human monocyte-derived macrophages and dU937 macrophage-like cells. In monocyte-derived macrophages, strain M grew more slowly and induced lower levels of TNF-α and IL-10 than 410, contrasting with previous studies with other strains, where a direct correlation was observed between increased intracellular growth and epidemiological success. On the other hand, in dU937 cells, no difference in growth was observed between both strains, and strain M induced significantly higher TNF-α levels than strain 410. We found that both cell models differed critically in the expression of receptors for M. tuberculosis entry, which might explain the different infection outcomes. Our results in monocyte-derived macrophages suggest that strain M relies on a modest replication rate and cytokine induction, keeping a state of quiescence and remaining rather unnoticed by the host. Collectively, our results underscore the impact of M. tuberculosis intra-species variations on the outcome of host cell infection and show that results can differ depending on the in vitro infection model.

Nosocomial transmission of extensively drug-resistant tuberculosis in a rural hospital in South Africa.

Extensively drug-resistant tuberculosis (XDR-tuberculosis) is a global public health threat, but few data exist elucidating factors driving this epidemic. The initial XDR-tuberculosis report from South Africa suggested transmission is an important factor, but detailed epidemiologic and molecular analyses were not available for further characterization. We performed a retrospective, observational study among XDR-tuberculosis patients to identify hospital-associated epidemiologic links. We used spoligotyping, IS6110-based restriction fragment-length polymorphism analysis, and sequencing of resistance-determining regions to identify clusters. Social network analysis was used to construct transmission networks among genotypically clustered patients. Among 148 XDR-tuberculosis patients, 98% were infected with human immunodeficiency virus (HIV), and 59% had smear-positive tuberculosis. Nearly all (93%) were hospitalized while infectious with XDR-tuberculosis (median duration, 15 days; interquartile range: 10-25 days). Genotyping identified a predominant cluster comprising 96% of isolates. Epidemiologic links were identified for 82% of patients; social network analysis demonstrated multiple generations of transmission across a highly interconnected network. The XDR-tuberculosis epidemic in Tugela Ferry, South Africa, has been highly clonal. However, the epidemic is not the result of a point-source outbreak; rather, a high degree of interconnectedness allowed multiple generations of nosocomial transmission. Similar to the outbreaks of multidrug-resistant tuberculosis in the 1990s, poor infection control, delayed diagnosis, and a high HIV prevalence facilitated transmission. Important lessons from those outbreaks must be applied to stem further expansion of this epidemic.

Protecting health care workers from tuberculosis in China: a review of policy and practice in China and the United States

Tuberculosis causes >1.7 million deaths worldwide each year and is frequently transmitted in hospitals. Outbreaks of multidrug-resistant tuberculosis have led to illness and death among health care workers (HCWs) in many countries. Some countries, such as the United States, implemented occupational health policies that substantially reduced tuberculosis rates among HCWs. Inadequate tuberculosis infection control in China may contribute to its high burden of tuberculosis and multidrug-resistant tuberculosis, which are both the second highest worldwide. Occupational health policies in China for tuberculosis control can be strengthened. We reviewed the development and content of tuberculosis infection control policies in the United States and China. Sources included published academic literature, Chinese Ministry of Health policies, US government agency reports, legal databases, personal observations of hospitals, review of internet discussion sites, and discussions with HCWs and health care and law experts. In the United States, slow acceptance of the tuberculosis problem in HCWs resulted in decades of inaction. Tuberculosis infection control policies, based mostly on expert opinion, were implemented only after tuberculosis resurged in the 1980s. Effective evidence-based policies were developed only after multiple cycles of policy implementation, evaluation and revision. These policies have now substantially reduced occupational tuberculosis. In China, tuberculosis has not been formally recognized as an occupational disease, and data regarding the burden in HCWs are sparse. Vagueness of current labour laws and suboptimal alignment of infection control authority and expertise result in varied and sometimes absent protection of HCWs against tuberculosis. Formal evaluations of occupational tuberculosis policies have not been reported. By collecting data on its current HCW tuberculosis burden and infection control practices, refining policies, continually evaluating its policies based on accumulated evidence and rapidly identifying unsuspected tuberculosis cases, China can develop a more comprehensive strategy to ensure the health of HCWs and reduce transmission of tuberculosis and multidrug-resistant tuberculosis.

Low-level rifampicin-resistant <I>Mycobacterium tuberculosis</I> strains raise a new therapeutic challenge [Short communication

In an outbreak of multidrug-resistant tuberculosis, the outbreak strain had an Asp516Tyr rpoB gene mutation. Phenotypically, low-level rifampicin (RMP) resistance (minimum inhibitory concentration [MIC] 1-2 mg/l) was observed. Based on drug susceptibility test results, three patients were treated with 12-15 month rifabutin-based regimens and one with a 12-month RMP-based regimen. We retrospectively performed pharmacokinetic calculations to assess the potential for RMP treatment, from which we conclude that MICs for RMP up to 1 μg/ml may be safely overcome by applying 20 mg/kg RMP doses in treatment regimens.

Retrospective analysis of multi-drug resistant tuberculosis outbreak during a flight using computational fluid dynamics and infection risk assessment

Air travel brings convenience to humans but also hastens the global spread of infectious diseases. Not only transporting infectious individuals from one place to another, air travel also provides a chance for infectious diseases transmission during the flight, especially if the disease can be transmitted via the airborne route. A number of documented outbreaks of airborne transmissible diseases were associated with disease transmission during the air travel. This study performed retrospective analysis on an infamous multi-drug resistant Tuberculosis (MDR-TB) outbreak on a commercial flight, where 6 people were infected with the multi-drug resistant disease during the 8.75 h flight. Airflow pattern and the infectious particle dispersion in the aircraft cabin were simulated using computational fluid dynamics (CFD). Infection risks of the passengers under a range of infectious source strength values were then assessed using the dose-response model. Based on the risk data, the infectious source strength of the index case passenger was estimated by likelihood analysis. A concept of mix-ratio was introduced to estimate the impact of human movement and cough behavior on the disease transmission. From the maximum likelihood estimation, the index case passenger may have generated 17.2 millions of viable bacilli/hr during the flight. Spatial pattern of the infection case and the spatial variation of infection risk were reflected in this estimation. The findings of this study provide additional understanding of infectious disease transmission during air travel. The infectious source strength of MDR-TB estimated from this study can be used in further risk assessment on the disease.

Islands of Hope: Building Local Capacity to Manage an Outbreak of Multidrug-Resistant Tuberculosis in the Pacific

A single case of multidrug-resistant tuberculosis (MDR-TB) can overwhelm the technical and financial capacity of small TB programs. In May 2008, the island state of Chuuk requested assistance for their first cases of MDR-TB. Second-line drugs and isolation rooms were unavailable, lab capacity was limited, and clinicians lacked experience. Delayed response caused prolonged transmission among household contacts. Several agencies responded with technical assistance and resources. Subsequent evaluations identified 16 additional MDR-TB cases and 124 infected contacts. Within six months, the local TB program gained remarkable capacity to manage MDR-TB cases and contacts, and greatly improve care for all TB patients. The Chuuk outbreak demonstrates the importance of establishing MDR-TB readiness in smaller jurisdictions and maintaining an essential TB control infrastructure.

Re‐emergence of the Progenitors of a Multidrug‐Resistant Outbreak Strain ofMycobacterium tuberculosisamong the Post‐Outbreak Case Patients

BACKGROUND. The progenitors of multidrug-resistant tuberculosis (MDR-TB) outbreak strains might evolve into new outbreak strains. We hypothesized that these strains could re-emerge among post-outbreak patients with TB and must thus be tracked. METHODS. To identify the progenitors of the outbreak strain, we first determined the precise IS6110 genomic insertion locations of a Haarlem3 strain that caused a severe MDR-TB outbreak in Tunisia. Next, we searched by polymerase chain reaction for these outbreak-specific IS6110 transposition sites in all the Haarlem3 post-outbreak isolates recovered in the epidemic region. RESULTS. By analyzing the distribution of the outbreak-specific IS6110 transposition sites, we were able to trap, among isolates recovered from post-outbreak new patients, drug-susceptible and drug-resistant isolates that are likely to represent the very close progenitors of the outbreak strain. Mycobacterial interspersed repetitive units-variable number of tandem repeats typing and sequential accumulation of rifampicin resistance-associated rpoB mutations further confirmed the identity of the outbreak's progenitor strains. CONCLUSIONS. The data of the current study show that the progenitors of an MDR-TB outbreak strain could re-emerge among post-outbreak TB cases. We provide an IS6110 insertion site-based approach to better trace back the events preceding the emergence of MDR-TB outbreaks, irrespective of the availability of a pre-outbreak strain collection.

Tuberculosis, a re-emergent disease

Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. In Western Europe, regions with a high incidence of TB usually also have a high incidence of HIV infection; TB and HIV co-infection have increased over the past decade and among HIV infected patients, nearly half also develop TB. In settings where HIV is prevalent, TB drug resistance has also increased and several reports of TB and multi-drug resistant TB outbreaks, especially in health care settings, raise serious concerns about nosocomial transmission. Further research and new developments into more rapid diagnostic methods and sensitivity testing as well as the development of new anti-TB drugs are important to fight the disease. In addition, public health infrastructures have to be strengthened in order to increase adherence to TB treatment, where directly observed treatment strategy is the cornerstone for a successful outcome.

Application of molecular genetic methods in macrolide, lincosamide and streptogramin resistance diagnostics and in detection of drug‐resistant Mycobacterium tuberculosis

Antimicrobial susceptibility testing has traditionally been based on measurements of minimal inhibitory concentrations of antimicrobials. Molecular genetic studies on antimicrobial resistance have produced a great deal of genetic information which can be used for diagnosis of antimicrobial resistance determinants. Bacteria can acquire resistance to macrolides, lincosamides and streptogramin antibiotics by modification of the target site of the drugs, by active efflux of the drugs, and by inactivation of the drugs. The genetic backgrounds of these resistance mechanisms are well known and several molecular methods for detection of resistance determinants have been developed. Outbreaks of multidrug-resistant tuberculosis have focused international attention on the emergence of Mycobacterium tuberculosis strains that are resistant to antimycobacterial agents. Knowledge of the antimycobacterial resistance genetics and progress in molecular methods has made it possible to develop rapid molecular methods for susceptibility testing. This review presents the genetic background of drug resistance and introduces some methods for genotypic susceptibility testing.

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.

Mycobacterium tuberculosis, Beijing genotype strains not associated with radiological presentation of pulmonary tuberculosis

Mycobacterium tuberculosis strains of the Beijing genotype have been involved in various outbreaks of multidrug-resistant tuberculosis. Some studies suggest that the infection with the Beijing genotype is associated with a different host immune response. Since this might also lead to a different chest X-ray (CXR) presentation, we compared CXRs of patients with pulmonary tuberculosis, 33 of whom were infected with the Beijing genotype and 76 with other genotypes. No significant differences were detected. We conclude that the Beijing genotype is not associated with a different CXR presentation.

Tuberculosis drug resistance: a global threat.

Resistance to antituberculosis drugs has been a problem since the era of chemotherapy began. After dramatic outbreaks of multidrug-resistant tuberculosis (MDR-TB) in the early 1990s, resistance became recognized as a global problem. MDR-TB now threatens the inhabitants of countries in Europe, Asia, Africa, and the Americas. An understanding of the molecular basis of drug resistance may contribute to the development of new drugs. Management of MDR-TB relies on prompt recognition and treatment with at least 3 drugs to which an isolate is susceptible.

Molecular Epidemiology of Multidrug-Resistant Tuberculosis, New York City, 1995–1997

From January 1, 1995, to December 31, 1997, we reviewed records of all New York City patients who had multidrug-resistant tuberculosis (MDRTB); we performed insertion sequence (IS) 6110-based DNA genotyping on the isolates. Secondary genotyping was performed for low IS6110 copy band strains. Patients with identical DNA pattern strains were considered clustered. From 1995 through 1997, MDRTB was diagnosed in 241 patients; 217 (90%) had no prior treatment history, and 166 (68.9%) were born in the United States or Puerto Rico. Compared with non-MDRTB patients, MDRTB patients were more likely to be born in the United States, have HIV infection, and work in health care. Genotyping results were available for 234 patients; 153 (65.4%) were clustered, 126 (82.3%) of them in eight clusters of >4 patients. Epidemiologic links were identified for 30 (12.8%) patients; most had been exposed to patients diagnosed before the study period. These strains were likely transmitted in the early 1990s when MDRTB outbreaks and tuberculosis transmission were widespread in New York.

New Challenges in the Clinical Management of Drug-Resistant Tuberculosis

Strains of Mycobacterium tuberculosis are multidrug-resistant when isoniazid and rifampin, the two most powerful antituberculous agents, do not inhibit their growth. Only a decade ago, outbreaks of multidrug-resistant tuberculosis (MDR-TB) occurred in New York, California, and Florida. In each setting, early detection by physicians decreased both transmission of and deaths caused by these strains. Working in Haiti, Peru, and Russia, our team has treated over 1,000 patients sick with MDR-TB. Most infecting strains were resistant to all first-line drugs. Because no new antituberculous drugs have been developed in decades, therapeutic options for such patients are limited. Our own experience suggests, however, that prompt detection and effective therapy can cure the great majority of cases of active MDR-TB. We review below the principles of MDR-TB treatment: 18–24 months of therapy with multidrug regimens, designed with use of drug susceptibility testing, and close attention to the management of adverse effects. We also discuss the treatment of MDR-TB in children, during pregnancy, and in the presence of HIV coinfection. Controversies in the management of MDR-TB are reviewed, including the use of resective surgery, the relative efficacy of different fluoroquinolones, and postexposure prophylaxis for close contacts of patients with pulmonary MDR-TB.