Low body mass index as a predictor of sputum culture conversion and treatment outcomes among patients receiving treatment for multidrug-resistant tuberculosis in Lesotho.

BACKGROUND: A low body mass index (BMI) at the start of treatment for rifampicin- or multidrug-resistant tuberculosis (MDR/RR-TB) is associated with poor treatment outcomes and may contribute to delayed sputum culture conversion, thereby prolonging the period of potential transmission to others. Whether the relative importance of low BMI in predicting treatment outcomes differs by HIV status is unclear. OBJECTIVES: We evaluated the association between low BMI and two dependent variables, sputum culture conversion and end-of-treatment outcome, among patients receiving treatment for MDR/RR-TB in Lesotho, a setting with a high prevalence of HIV infection. METHODS: Secondary data from a prospective cohort of patients initiating a longer (18-20 months) treatment containing bedaquiline and/or delamanid under routine programmatic conditions in Lesotho were analysed. Risk ratios and differences were adjusted for potential confounders using multivariable logistic regression, and estimates were stratified by HIV status. RESULTS: Of 264 patients, 105 and 250 were eligible for culture conversion and end-of-treatment analyses, respectively. Seventy-one per cent of patients (74/105) experienced culture conversion within six months, while 74% (184/250) experienced a favourable end-of-treatment outcome. Low BMI was associated with a lower frequency of culture conversion at six months among those who were not living with HIV (relative risk [RR]: 0.50 [95% CI: 0.21, 0.79]); this association was attenuated among those living with HIV (RR: 0.88 [95% CI: 0.68, 1.23]). A low BMI was moderately associated with a lower frequency of treatment success (RR = 0.89 [95% CI: 0.77, 1.03]), regardless of HIV status. CONCLUSIONS: Low BMI was common and associated with the frequency of six-month culture conversion and end-of-treatment outcomes. The association with culture conversion was more pronounced among those not living with HIV. Addressing the myriad factors that drive low BMI in this setting could hasten culture conversion and improve end-of-treatment outcomes. This will require a multipronged approach focused on alleviating food insecurity and enabling prompt diagnosis and treatment of HIV and TB.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

Community-Based Outbreak Investigation And Response: Enhancing Preparedness, Public Health Capacity, And Equity.

Throughout the COVID-19 pandemic, the US has struggled with many aspects of the public health response, from determining where transmission is occurring to building trust with communities and implementing interventions. Three factors have contributed to these challenges: insufficient local public health capacity, siloed interventions, and underuse of a cluster-based approach to outbreak response. In this article we introduce Community-based Outbreak Investigation and Response (COIR), a local public health strategy developed during the COVID-19 pandemic that addresses these shortcomings. COIR can help local public health entities conduct disease surveillance more effectively, take a more proactive and efficient approach to mitigating transmission, coordinate response efforts, build community trust, and advance equity. We offer a practitioner's lens, informed through on-the-ground experience and engagement with policy makers, to highlight the financing, workforce, data system, and information-sharing policy changes needed to scale up COIR throughout the country. COIR can enable the US public health system to develop effective solutions to many of today's public health challenges and improve the nation's preparedness for public health crises in the years to come.

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB.

BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Introducing new and repurposed TB drugs: the endTB experience.

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015-2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

Setting up pharmacovigilance based on available endTB Project data for bedaquiline.

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the 'advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

Salvage therapy for multidrug-resistant tuberculosis.

Treatment of multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis resistant to both isoniazid and rifampicin, is challenging under the best of circumstances, and particularly in resource-limited settings. For patients who remain persistently sputum-culture-positive despite therapy with second-line TB drugs, treatment options are limited, especially if disease is too advanced for resective surgery. Salvage therapy refers to the design of a regimen combining new and previously used drugs in a final effort to attain sputum conversion before declaring treatment to have failed. We retrospectively evaluated the outcomes of salvage therapy in 213 Peruvian patients. Salvage regimens included a median of two new drugs (range 1-6) and nine (range 5-13) total (new plus previously used) drugs. The most frequently used new drug was moxifloxacin, followed by capreomycin, amoxicillin-clavulanate, kanamycin and clarithromycin. Culture conversion occurred in 65 (30.5%) patients. Salvage regimens that included moxifloxacin were significantly more likely to be followed by culture conversion (OR 2.2; p 0.02). Later-generation fluoroquinolones such as moxifloxacin should be used in salvage therapy but also in the initial treatment of MDR-TB, if the best clinical strategy is to use the most effective drugs when the patient has the best chance for cure. New TB drugs are most likely to be initially used in salvage patients, in conditions similar to those described here. Close bacteriological monitoring of these patients will be essential, as useful information about the best way to use these new drugs can be gained from analysis of salvage therapy cohorts.

High risk of drug-resistant tuberculosis when first-line therapy fails in a high HIV prevalence setting.

SETTING: Lesotho national multidrug-resistant tuberculosis (MDR-TB) program. OBJECTIVE: To determine the prevalence of drug-resistant TB (DR-TB) among patients registered for MDR-TB treatment after failure or suspected failure of the standard 6-month regimen for new TB patients (Category I). DESIGN: We conducted a retrospective cohort study of patients registered for MDR-TB treatment following failure or suspected failure of Category I. RESULTS: A total of 76 patients were included in the analysis, including 51 Category I treatment failures and 25 suspected Category I treatment failures. The prevalence of resistance to any drug was 92% among the treatment failures and 72% among the suspected failures. The proportion of MDR-TB was respectively 78% and 28% among the treatment failures and suspected failures. Among the subgroup of human immunodeficiency virus (HIV) positive patients, the proportion of MDR-TB was 84% among failures and 23% among suspected failures. CONCLUSION: DR-TB and MDR-TB were common among patients in whom Category I failed. Early initiation of empiric second-line anti-tuberculosis treatment while awaiting culture and drug susceptibility testing (DST) results should be considered for HIV-negative and -positive patients who have failed first-line anti-tuberculosis treatment; patients suspected to be failing a first-line regimen should undergo DST at the end of the intensive phase.

Distribution of adult respiratory illnesses at a primary health centre in Lesotho.

SETTING: Primary health centre in the highlands of Lesotho. BACKGROUND: There is limited information about the relative frequencies of common respiratory illnesses in resource-limited settings, particularly in sub-Saharan Africa. OBJECTIVE: To examine whether the distribution of respiratory illnesses in this region is unique due to the high prevalence of human immunodeficiency virus infection. DESIGN: In a prospective, cross-sectional study of adults and adolescents with cough or difficulty breathing recruited from the waiting areas of the health centre, the primary outcome was the respiratory diagnosis for each participant, which was based on history, physical examination, response to antibiotics and the results of chest radiography (CXR) and sputum examinations. RESULTS: Acute respiratory infections accounted for 65% of all diagnoses among 696 patients who were evaluated by a clinician and CXR. Pneumonia accounted for 10% of all diagnoses, and confirmed or probable tuberculosis (TB) accounted for 13%. Chronic respiratory conditions, including asthma, chronic obstructive pulmonary disease, silicosis and old TB, accounted for 14% of all diagnoses. Excluding 61 patients with an uninterpretable CXR, 36% (228) of the participants had significant pathology on CXR. CONCLUSION: A high proportion of patients presenting to a primary health centre in Lesotho with routine respiratory complaints have serious respiratory illnesses.

High rate of hypothyroidism among patients treated for multidrug-resistant tuberculosis in Lesotho.

BACKGROUND: Hypothyroidism is a known side effect of treatment for multidrug-resistant tuberculosis (MDR-TB), but it is considered to be rare. Hypothyroidism has vague and non-specific symptoms, and can be easily missed by clinicians. OBJECTIVE: To report the high rate of hypothyroidism in a cohort of MDR-TB patients in Lesotho and to describe our approach to diagnosis and management. DESIGN: A retrospective study of 212 patients who initiated treatment for MDR-TB in Lesotho between 27 July 2007 and 24 March 2009 was performed. RESULTS: Among 186 patients screened, 129 (69%) had hypothyroidism, defined as at least one documented thyroid-stimulating hormone (TSH) result > 10.0 mIU/l; 100 (54%) patients had a maximum TSH > 20.0 mIU/l. At 93 days after starting MDR-TB treatment, half of the patients had developed hypothyroidism. CONCLUSION: Hypothyroidism may be more common during MDR-TB treatment than previously recognized. Screening all patients, even those without symptoms, for hypothyroidism within 2-3 months of starting MDR-TB treatment should be considered until prospective studies can inform screening guidelines.

Determination of critical concentrations of second-line anti-tuberculosis drugs with clinical and microbiological relevance.

BACKGROUND: Reliable DST against second-line anti-tuberculosis drugs (SLDs) is crucial for the management of the increasing burden of patients affected by multidrug- and extensively drug-resistant TB. METHODS: This study utilizes 252 clinical isolates of Mycobacterium tuberculosis from five countries (Hong Kong Special Administrative Region, Korea, Latvia, Peru, Philippines) with documented treatment histories to establish clinically and microbiologically relevant critical concentrations (CCs) of six SLDs for three routine testing methods: the absolute concentration method using Löwenstein-Jensen (LJ) medium, the 1% proportion method using Middlebrook 7H10 agar medium, and the radiometric BACTEC 460 system. FINDINGS: In LJ medium, CCs of capreomycin, ethionamide, kanamycin, ofloxacin, rho-aminosalicylic acid and cycloserine (CS) were respectively 40.0, 40.0, 30.0, 3.0, 1.0 and 30.0 mg/l. In 7H10 agar medium, the respective CCs for the first five antibiotics (except CS) were 8.0, 2.0-3.0, 3.0-5.0, 1.0-1.5 and 0.5-1.0 mg/l. In BACTEC 460 broth, the respective CCs were 1.5-2.0, 1.0-1.5, 2.0-3.0, 0.5-1.0 and 0.5-1.0 mg/l. Precautions in DST interpretation was also discussed. INTERPRETATION: By adopting this set of CCs as a global standard to define second-line drug susceptibility and resistance, as well as precautions in result interpretation, the screening, diagnosis and management of patients with drug-resistant TB can be greatly improved.

Improved case detection of active tuberculosis associated with an antiretroviral treatment program in Lesotho.

Tuberculosis (TB) remains the leading infectious killer of adults with human immunodeficiency virus (HIV) globally. Lesotho has the third highest prevalence of HIV and the fourth highest prevalence of TB worldwide, and the majority of TB patients are co-infected with HIV. This paper describes an antiretroviral treatment (ART) program instituted in a health center in a mountain region of Lesotho. Although the main goal of the program was to increase HIV detection and initiate ART for patients, the program also resulted in a ten-fold increase in the detection of TB among patients with and without HIV.

Representative drug susceptibility patterns for guiding design of retreatment regimens for MDR-TB.

BACKGROUND: There is no gold standard on how national tuberculosis programs should design retreatment regimens. Often drug susceptibility testing (DST) is not available for all patients, and representative DST patterns in patient populations are used to guide therapy. OBJECTIVES: To examine DST patterns in different patient populations based on previous treatment and to estimate the number of effective anti-tuberculosis agents in several retreatment regimens. METHODS: We reviewed DST results from patients treated with individualized regimens in Peru between January 1998 and July 2004. We stratified patients into four groups based on previous treatment exposure from Group 1 who had failed only one regimen to Group 4 who had failed three regimens. We compared resistance frequencies across the four groups. In Groups 1 and 3, the number of likely effective agents under six possible retreatment regimen scenarios was estimated. RESULTS: Resistance to second-line drugs was significantly higher in groups with more previous courses of treatment. A few retreatment regimens could be identified that would allow at least 80% of patients to receive at least four likely effective drugs. CONCLUSION: Because it is associated with resistance frequencies, previous treatment exposure can serve to guide the design of non-individualized MDR-TB regimens.

Acquisition of drug resistance in multidrug-resistant Mycobacterium tuberculosis during directly observed empiric retreatment with standardized regimens.

The risk of acquiring additional drug resistance in strains of multidrug-resistant tuberculosis (MDR-TB) during failure of empiric standardized retreatment regimens is poorly defined. We sought to estimate this risk by comparing drug susceptibility profiles and RFLP patterns of paired MDR-TB isolates collected from 27 patients before and after retreatment failure. Among 23 patients with paired isolates with concordant RFLP patterns, 19 (83%) had become resistant to at least one additional drug after failed retreatment. In this limited group of MDR-TB patients, acquisition of resistance was common during failure of empiric drug regimens. Further study is needed to confirm these findings.

Self-administered, standardized regimens for multidrug-resistant tuberculosis in South Korea.

SETTING: National Masan Tuberculosis Hospital, Masan, South Korea, a 430-bed tertiary referral hospital specializing in tuberculosis. OBJECTIVE: To evaluate the treatment outcomes of standardized, empiric regimens for multidrug-resistant tuberculosis (MDR-TB). DESIGN: A retrospective analysis of the hospital records of 142 patients with MDR-TB who had failed short-course chemotherapy. Between 1 January 1998 and 30 June 2000, patients were started on one of two standardized, empiric regimens based on previous treatment history. Drug susceptibility testing of the infecting strain was not used to modify the treatment regimen. Treatment was continued for at least 18 months after conversion to a negative culture. RESULTS: Sixty-three patients (44.1%) were cured and discharged from treatment after at least 18 months of negative cultures; 18 (12.7%) failed treatment, 41 (28.9%) defaulted, four died (2.8%), and 15 (10.6%) were transferred to another institution. One patient is still on treatment. Resistance to ofloxacin was the only risk factor related to poor outcome (death or failure) in univariate or multiple logistic regression analysis. CONCLUSIONS: High levels of resistance to second-line drugs are likely a cause of poor outcome of MDR-TB therapy in Korea. Directly observed therapy and other methods to increase patient compliance should be considered nationwide, as they may improve MDR-TB treatment outcomes.

The treatment of tuberculosis in South Korea.

South Korea's complex system of tuberculosis control has never been fully described. The prevalence of tuberculosis has dropped dramatically since 1965, partly because of farsighted governmental policy that provided low-cost, accessible tuberculosis treatment to the entire population. Within the tuberculosis control system, public and private sector entities provide a wide variety of treatment options. The National Tuberculosis Program focuses on improving cure rates for new cases, while the private sector has taken more of a role in the treatment of drug-resistant tuberculosis and other types of complicated cases. There has been a decrease in drug-resistant tuberculosis since 1980 for multiple reasons, including increased cure rates from the introduction of rifampin-based regimens, improved nutrition and living standards, and the treatment of drug-resistant cases in the private sector. Multidrug-resistant tuberculosis, however, still poses a significant threat to public health. The limited outcomes data that exist in South Korea for multidrug-resistant tuberculosis treatment suggest that cure rates are low and failure and abandonment rates are high. New public health measures are needed to improve the control of multidrug-resistant tuberculosis.

Clinical and programmatic considerations in the treatment of MDR-TB in children: a series of 16 patients from Lima, Peru.

SETTING: Since 2000, the directly observed treatment, short-course (DOTS) strategy has been expanded in several countries to include treatment of multidrug-resistant tuberculosis (MDR-TB). This strategy is known as DOTS-Plus. Tuberculosis is a common cause of morbidity and mortality for children throughout the developing world. Children may also be infected with MDR-TB, yet most developing countries do not specifically address pediatric MDR-TB. OBJECTIVE: To present the intermediate outcomes of the first 16 children enrolled in the Peruvian DOTS-Plus program and to demonstrate the tolerability of second-line anti-tuberculosis drugs. RESULTS: Three children completed therapy and are cured, one child had bacteriologic and clinical failure after 12 months of therapy and died of respiratory insufficiency, and 12 have intermediate outcomes demonstrating favorable clinical, bacteriologic, and radiographic evidence of improvement after 9-19 months of therapy. CONCLUSIONS: Of the 16 pediatric DOTS-Plus patients, 15 have tolerated therapy well and have had favorable clinical evolution. However, the diagnosis of pediatric MDR-TB is often extremely delayed due to reliance on the adult case definition and should be changed to prevent progressive, chronic illness in such children. Programmatic changes could facilitate earlier diagnosis and treatment of pediatric MDR-TB in Peru and in other DOTS-Plus programs.