Jennifer Furin

Comprehensive Treatment of Extensively Drug-Resistant Tuberculosis

BACKGROUND Extensively drug-resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. We describe the management of extensively drug-resistant tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. METHODS A total of 810 patients were referred for free individualized therapy, including drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively drug-resistant tuberculosis and developed regimens that included five or more drugs to which the infecting isolate was not resistant. RESULTS Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [+/-SD] number of regimens, 4.2+/-1.9 vs. 3.2+/-1.6; P<0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4+/-1.1 vs. 5.3+/-1.5; P<0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3+/-1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P=0.36). CONCLUSIONS Extensively drug-resistant tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for tuberculosis.

Programmes and principles in treatment of multidrug-resistant tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) presents an increasing threat to global tuberculosis control. Many crucial management issues in MDR-TB treatment remain unanswered. We reviewed the existing scientific research on MDR-TB treatment, which consists entirely of retrospective cohort studies. Although direct comparisons of these studies are impossible, some insights can be gained: MDR-TB can and should be addressed therapeutically in resource-poor settings; starting of treatment early is crucial; aggressive treatment regimens and high-end dosing are recommended given the lower potency of second-line antituberculosis drugs; and strategies to improve treatment adherence, such as directly observed therapy, should be used. Opportunities to treat MDR-TB in developing countries are now possible through the Global Fund to Fight AIDS, TB, and Malaria, and the Green Light Committee for Access to Second-line Anti-tuberculosis Drugs. As treatment of MDR-TB becomes increasingly available in resource-poor areas, where it is needed most, further clinical and operational research is urgently needed to guide clinicians in the management of this disease.

Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study

BACKGROUND Mycobacterium tuberculosis strains that cause untreatable drug-resistant disease are a threat worldwide. We describe the treatment, management, and outcomes of patients with extensively drug-resistant tuberculosis in Tomsk, Russia. METHODS We undertook a retrospective cohort study of 608 patients with multidrug resistant tuberculosis who had treatment in civilian or prison services, between Sept 10, 2000, and Nov 1, 2004, according to the treatment strategy recommended by WHO. Clinical characteristics, management practices, and treatment outcomes of patients with extensively drug-resistant (XDR) tuberculosis and non-extensively drug-resistant (non-XDR) tuberculosis are described. The main outcome was the frequency of poor and favourable outcomes at the end of treatment. FINDINGS Of 608 patients with multidrug resistant tuberculosis, 29 (4.8%) patients had baseline XDR tuberculosis. Treatment failure was more common in patients with XDR tuberculosis than in those with non-XDR tuberculosis (31%vs 8.5%, p=0.0008). 48.3% of patients with XDR tuberculosis and 66.7% of patients with non-XDR tuberculosis had treatment cure or completion (p=0.04). The frequency and management of adverse events did not differ between patients with XDR and non-XDR tuberculosis. INTERPRETATION The chronic features of tuberculosis in these patients suggest that extensively drug-resistant tuberculosis may be acquired through previous treatments that include second-line drugs. Aggressive management of this infectious disease is feasible and can prevent high mortality rates and further transmission of drug-resistant strains of Mycobacterium tuberculosis.

Early Outcomes of MDR-TB Treatment in a High HIV-Prevalence Setting in Southern Africa

Background Little is known about treatment of multidrug-resistant tuberculosis (MDR-TB) in high HIV-prevalence settings such as sub-Saharan Africa. Methodology/Principal Findings We did a retrospective analysis of early outcomes of the first cohort of patients registered in the Lesotho national MDR-TB program between July 21, 2007 and April 21, 2008. Seventy-six patients were included for analysis. Patient follow-up ended when an outcome was recorded, or on October 21, 2008 for those still on treatment. Fifty-six patients (74%) were infected with HIV; the median CD4 cell count was 184 cells/μl (range 5–824 cells/μl). By the end of the follow-up period, study patients had been followed for a median of 252 days (range 12–451 days). Twenty-two patients (29%) had died, and 52 patients (68%) were alive and in treatment. In patients who did not die, culture conversion was documented in 52/54 patients (96%). One patient had defaulted, and one patient had transferred out. Death occurred after a median of 66 days in treatment (range 12–374 days). Conclusions/Significance In a region where clinicians and program managers are increasingly confronted by drug-resistant tuberculosis, this report provides sobering evidence of the difficulty of MDR-TB treatment in high HIV-prevalence settings. In Lesotho, an innovative community-based treatment model that involved social and nutritional support, twice-daily directly observed treatment and early empiric use of second-line TB drugs was successful in reducing mortality of MDR-TB patients. Further research is urgently needed to improve MDR-TB treatment outcomes in high HIV-prevalence settings.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Community-based therapy for children with multidrug-resistant tuberculosis

OBJECTIVES. The goals were to describe the management of multidrug-resistant tuberculosis among children, to examine the tolerability of second-line antituberculosis agents among children, and to report the outcomes of children treated for multidrug-resistant tuberculosis in poor urban communities in Lima, Peru, a city with high tuberculosis prevalence. METHODS. A retrospective analysis of data for 38 children <15 years of age with multidrug-resistant tuberculosis, either documented with drug sensitivity testing of the childs tuberculosis isolate or suspected on the basis of the presence of clinical symptoms for a child with a household contact with documented multidrug-resistant tuberculosis, was performed. All 38 children initiated a supervised individualized treatment regimen for multidrug-resistant tuberculosis between July 1999 and July 2003. Each child received 18 to 24 months of therapy with ≥5 first- or second-line drugs to which their Mycobacterium tuberculosis strain was presumed to be sensitive. RESULTS. Forty-five percent of the children had malnutrition or anemia at the time of diagnosis, 29% had severe radiographic findings (defined as bilateral or cavitary disease), and 13% had extrapulmonary disease. Forty-five percent of the children were hospitalized initially because of the severity of illness. Adverse events were observed for 42% of the children, but no events required suspension of therapy for >5 days. Ninety-five percent of the children (36 of 38 children) achieved cures or probable cures, 1 child (2.5%) died, and 1 child (2.5%) defaulted from therapy. CONCLUSIONS. Multidrug-resistant tuberculosis disease among children can be treated successfully in resource-poor settings. Treatment is well tolerated by children, and severe adverse events with second-line agents are rare.

Surgery for patients with drug-resistant tuberculosis: report of 121 cases receiving community-based treatment in Lima, Peru

Background: While most patients with tuberculosis (TB) can be successfully treated using short-course medical chemotherapy, thoracic surgery is an important adjunctive strategy for many patients with drug-resistant disease. The need for physical, technical and financial resources presents a potential challenge to implementing surgery as a component of treatment for multidrug-resistant TB (MDR-TB) in resource-poor settings. However, a cohort of patients with severe MDR-TB in Lima, Peru underwent surgery as part of their treatment. Methods: 121 patients underwent pulmonary surgery for drug-resistant tuberculosis between May 1999 and January 2004. Surgery was performed by a team of thoracic surgeons under the Ministry of Health. Patient demographic data, clinical characteristics, surgical procedures and surgical outcomes were studied. Results: Most of the patients had failed multiple TB regimens and were resistant to a median of seven drugs. The median time of follow-up after surgery was 33 months. 79.3% of patients were culture-positive before surgery, and sustained culture-negative status among survivors was achieved in 74.8% of patients. 63% of those followed up for at least 6 months after surgery were either cured or probably cured. Postoperative complications, observed in 22.6% of patients, were associated with preoperative haemoptysis, vital capacity <50% and low forced expiratory volume in 1 s. Conclusions: This is one of the largest cohorts with MDR-TB to be treated with surgery, and the first from a resource-poor country. Although surgery is not often considered an option for patients in resource-poor settings, the findings of this study support the argument that adjunctive surgery should be considered an integral component of MDR-TB treatment programmes, even in poor countries such as Peru.

Treatment of Multidrug-Resistant Tuberculosis during Pregnancy: A Report of 7 Cases

Multidrug-resistant tuberculosis (MDR-TB) is a global public health problem affecting women of childbearing age. Little is known, however, about the safety of the drugs used to treat MDR-TB during pregnancy. We describe 7 patients who were treated for MDR-TB during pregnancy. These patients had chronic tuberculosis that had caused extensive parenchymal damage and had high-grade resistance to antituberculous drugs. All patients received individualized antituberculous therapy prior to delivery of healthy term infants. Neither obstetrical complications nor perinatal transmission of MDB-TB was observed. One patient experienced treatment failure, and another abandoned therapy. The other 5 patients are currently cured or in treatment and have culture-negative status. In each of these 7 cases, excellent treatment outcomes were obtained for the women and their children. Under certain circumstances, MDR-TB can be successfully treated during pregnancy.

Treating multidrug-resistant tuberculosis in Tomsk, Russia: developing programs that address the linkage between poverty and disease.

Tuberculosis (TB) and multidrug‐resistant TB (MDR‐TB) are diseases of poverty. Because Mycobacterium tuberculosis exists predominantly in a social space often defined by poverty and its comorbidities—overcrowded or congregate living conditions, substance dependence or abuse, and lack of access to proper health services, to name a few—the biology of this organism and of TB drug resistance is intimately linked to the social world in which patients live. This association is demonstrated in Russia, where political changes in the 1990s resulted in increased socioeconomic inequality and a breakdown in health services. The effect on TB and MDR‐TB is reflected both in terms of a rise in TB and MDR‐TB incidence and increased morbidity and mortality associated with the disease. We present the case example of Tomsk Oblast to delineate how poverty contributed to a growing MDR‐TB epidemic and increasing socioeconomic barriers to successful care, even when available. The MDR‐TB pilot project implemented in Tomsk addressed both programmatic and socioeconomic factors associated with unfavorable outcomes. The result has been a strengthening of the overall TB control program in the region and improved case‐holding for the most vulnerable patients. The model of MDR‐TB care in Tomsk is applicable for other resource‐poor settings facing challenges to TB and MDR‐TB control.

Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause Mortality

Rationale A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort. Methods This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.