Novel pediatric delivery systems for second-line anti-tuberculosis medications: a case study

Tens of thousands of children are sick with multidrugresistant forms of tuberculosis (MDR-TB), but there are limited child-friendly delivery systems for second-line medications. This case study presents the devel opment of a granular dosing spoon pediatric delivery system for para-aminosalicylic acid. This product is the first of its kind for MDR-TB and could serve as a model for the development of other urgently needed pediatric delivery systems for second-line anti-tuberculosis drugs

Novel pediatric delivery systems for second-line anti-tuberculosis medications: a case study

Tens of thousands of children are sick with multidrugresistant forms of tuberculosis (MDR-TB), but there are limited child-friendly delivery systems for second-line medications. This case study presents the devel opment of a granular dosing spoon pediatric delivery system for para-aminosalicylic acid. This product is the first of its kind for MDR-TB and could serve as a model for the development of other urgently needed pediatric delivery systems for second-line anti-tuberculosis drugs

Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru.

BACKGROUND: Despite the prevalence of multidrug-resistant tuberculosis in nearly all low-income countries surveyed, effective therapy has been deemed too expensive and considered not to be feasible outside referral centers. We evaluated the results of community-based therapy for multidrug-resistant tuberculosis in a poor section of Lima, Peru. METHODS: We describe the first 75 patients to receive ambulatory treatment with individualized regimens for chronic multidrug-resistant tuberculosis in northern Lima. We conducted a retrospective review of the charts of all patients enrolled in the program between August 1, 1996, and February 1, 1999, and identified predictors of poor outcomes. RESULTS: The infecting strains of Mycobacterium tuberculosis were resistant to a median of six drugs. Among the 66 patients who completed four or more months of therapy, 83 percent (55) were probably cured at the completion of treatment. Five of these 66 patients (8 percent) died while receiving therapy. Only one patient continued to have positive cultures after six months of treatment. All patients in whom treatment failed or who died had extensive bilateral pulmonary disease. In a multiple Cox proportional-hazards regression model, the predictors of the time to treatment failure or death were a low hematocrit (hazard ratio, 4.09; 95 percent confidence interval, 1.35 to 12.36) and a low body-mass index (hazard ratio, 3.23; 95 percent confidence interval, 0.90 to 11.53). Inclusion of pyrazinamide and ethambutol in the regimen (when susceptibility was confirmed) was associated with a favorable outcome (hazard ratio for treatment failure or death, 0.30; 95 percent confidence interval, 0.11 to 0.83). CONCLUSIONS: Community-based outpatient treatment of multidrug-resistant tuberculosis can yield high cure rates even in resource-poor settings. Early initiation of appropriate therapy can preserve susceptibility to first-line drugs and improve treatment outcomes

Time to Culture Conversion and Regimen Composition in Multidrug-Resistant Tuberculosis Treatment

Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31–92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs

The Impact of Tuberculosis on the Well-Being of Adolescents and Young Adults.

The health needs of adolescents and young adults (AYAs) have been neglected in tuberculosis (TB) care, control, and research. AYAs, who are distinct from younger children and older adults, undergo dynamic physical, psychological, emotional, cognitive, and social development. Five domains of adolescent well-being are crucial to a successful transition between childhood and adulthood: (1) Good health; (2) connectedness and contribution to society; (3) safety and a supportive environment; (4) learning, competence, education, skills, and employability; and (5) agency and resilience. This review summarizes the evidence of the impact of TB disease and treatment on these five domains of AYA well-being

Aggressive Regimens for Multidrug-Resistant Tuberculosis Reduce Recurrence

Background. Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatmentrelated factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. Methods. We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. Results. Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2-53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17-0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17-50.60]; P = .004). Conclusions. Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease

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/microl (range 5-824 cells/microl). 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

Implementing a Substance-Use Screening and Intervention Program for People Living with Rifampicin-Resistant Tuberculosis: Pragmatic Experience from Khayelitsha, South Africa

Substance use (SU) is associated with poor rifampicin-resistant tuberculosis (RR-TB) treatment outcomes. In 2017, a SBIRT (SU screening-brief intervention-referral to treatment) was integrated into routine RR-TB care in Khayelitsha, South Africa. This was a retrospective study of persons with RR-TB who were screened for SU between 1 July 2018 and 30 September 2020 using the ASSIST (Alcohol, Smoking and Substance Involvement Screening Test). Here we describe outcomes from this program. Persons scoring moderate/high risk received a brief intervention and referral to treatment. Overall, 333 persons were initiated on RR-TB treatment; 38% (n = 128) were screened for SU. Of those, 88% (n = 113/128) reported SU; 65% (n = 83/128) had moderate/high risk SU. Eighty percent (n = 103/128) reported alcohol use, of whom 52% (n = 54/103) reported moderate/high risk alcohol use. Seventy-seven persons were screened for SU within ≤2 months of RR-TB treatment initiation, of whom 69%, 12%, and 12% had outcomes of treatment success, loss to follow-up and death, respectively. Outcomes did not differ between persons with no/low risk and moderate/high risk SU or based on the receipt of naltrexone (p > 0.05). SU was common among persons with RR-TB; there is a need for interventions to address this co-morbidity as part of “person-centered care”. Integrated, holistic care is needed at the community level to address unique challenges of persons with RR-TB and SU

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