Multidrug-resistant Tuberculosis Therapy Research Articles

A Pilot Study of an mHealth Application for Healthcare Workers: Poor Uptake Despite High Reported Acceptability at a Rural South African Community-Based MDR-TB Treatment Program

IntroductionAs the South African province of KwaZulu-Natal addresses a growing multidrug-resistant tuberculosis (MDR-TB) epidemic by shifting care and treatment from trained specialty centers to community hospitals, delivering and monitoring MDR-TB therapy has presented new challenges. In particular, tracking and reporting adverse clinical events have been difficult for mobile healthcare workers (HCWs), trained health professionals who travel daily to patient homes to administer and monitor therapy. We designed and piloted a mobile phone application (Mobilize) for mobile HCWs that electronically standardized the recording and tracking of MDR-TB patients on low-cost, functional phones.ObjectiveWe assess the acceptability and feasibility of using Mobilize to record and submit adverse events forms weekly during the intensive phase of MDR-TB therapy and evaluate mobile HCW perceptions throughout the pilot period.MethodsAll five mobile HCWs at one site were trained and provided with phones. Utilizing a mixed-methods evaluation, mobile HCWs’ usage patterns were tracked electronically for seven months and analyzed. Qualitative focus groups and questionnaires were designed to understand the impact of mobile phone technology on the work environment.ResultsMobile HCWs submitted nine of 33 (27%) expected adverse events forms, conflicting with qualitative results in which mobile HCWs stated that Mobilize improved adverse events communication, helped their daily workflow, and could be successfully expanded to other health interventions. When presented with the conflict between their expressed views and actual practice, mobile HCWs cited forgetfulness and believed patients should take more responsibility for their own care.DiscussionThis pilot experience demonstrated poor uptake by HCWs despite positive responses to using mHealth. Though our results should be interpreted cautiously because of the small number of mobile HCWs and MDR-TB patients in this study, we recommend carefully exploring the motivations of HCWs and technologic enhancements prior to scaling new mHealth initiatives in resource poor settings.

Adverse Events in an Integrated Home-Based Treatment Program for MDR-TB and HIV in KwaZulu-Natal, South Africa

Most patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are HIV-infected, but the safety and tolerability of cotreatment are unknown. The authors reviewed all adverse events (AEs) for patients with MDR-TB in a home-based treatment program in rural KwaZulu-Natal. Of 91 MDR-TB patients, 74 (81%) were HIV-positive and receiving antiretroviral therapy. AEs were common, but most were mild and did not require therapy modification. The most common severe AEs were hypothyroidism (36%) and psychosis (5%). Patients receiving concurrent antiretroviral therapy did not experience AEs more frequently than those on MDR-TB therapy alone. Concurrent treatment for MDR-TB/HIV can be safely administered in a home-based care setting.

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

RationaleA 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.ObjectivesThis 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.MethodsThis 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 ResultsIn 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).ConclusionsThe 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.

The Conundrum of MDR-TB and Combination Therapy

Cases of multidrug-resistant tuberculosis (MDR-TB) are increasing. MDR complicates therapy and results in lower success rates and higher mortality, especially in HIV coinfected patients. This article discusses the conundrum of MDR-TB and combination therapy and ways to address it.

Survival in XDR TB: Shifting the Curve and Shifting the Paradigm

Survival in XDR TB: Shifting the Curve and Shifting the Paradigm

Adverse Effects of Multidrug-Resistant Tuberculosis Treatment With a Standardized Regimen: A Report From Iran

Compared with the treatment of drug-sensitive tuberculosis, the treatment of multidrug-resistant tuberculosis (MDR-TB) is more difficult. This study was conducted at the national referral center of tuberculosis in Tehran, Iran, to evaluate adverse drug reactions of treatment of MDR-TB. From 2006 to 2009, all patients admitted into Masih Daneshvari Hospital in Tehran, Iran, for MDR-TB were considered for this study. The standard treatment for MDR-TB consisted of amikacin, prothionamide, ofloxacin, and cycloserine. Ethambutol and pyrazinamide were added to treatment if mycobacterium was sensitive to them. All adverse effects observed in patients were recorded in our registry. Eighty patients were considered in the study; of this cohort, 44 were male and 36 were female. The mean age of patients was 40.64 ± 17.53 years (range, 14-81 years). All patients received standardized therapy for MDR-TB. The major adverse effects included neurologic side effects (depression, convulsions, consciousness, psychosis, suicide; 7.5%), hepatitis (5%), rash (1.3%), renal toxicity (3.8%), and auditory toxicity (14.5%). Those with neurologic side effects had less favorable outcome (P value = 0.038) and risk of death was increased among them (odds ratio, 13.8; 95% confidence interval, 2.2-86.77). Other adverse effects did not show statistical significance in our analysis. A major adverse effect such as neurologic side effects (depression, convulsions, consciousness, and psychosis) can result in an increased chance of death among patients with MDR-TB.

Ambulatory-Based Standardized Therapy for Multi-Drug Resistant Tuberculosis: Experience from Nepal, 2005–2006

ObjectiveThe aim of this study was to describe treatment outcomes for multi-drug resistant tuberculosis (MDR-TB) outpatients on a standardized regimen in Nepal.MethodologyData on pulmonary MDR-TB patients enrolled for treatment in the Green Light Committee-approved National Programme between 15 September 2005 and 15 September 2006 were studied. Standardized regimen was used (8Z-Km-Ofx-Eto-Cs/16Z-Ofx-Eto-Cs) for a maximum of 32 months and follow-up was by smear and culture. Drug susceptibility testing (DST) results were not used to modify the treatment regimen. MDR-TB therapy was delivered in outpatient facilities for the whole course of treatment. Multivariable analysis was used to explain bacteriological cure as a function of sex, age, initial body weight, history of previous treatment and the region of report.Principal FindingsIn the first 12-months, 175 laboratory-confirmed MDR-TB cases (62% males) had outcomes reported. Most cases had failed a Category 2 first-line regimen (87%) or a Category 1 regimen (6%), 2% were previously untreated contacts of MDR-TB cases and 5% were unspecified. Cure was reported among 70% of patients (range 38%–93% by Region), 8% died, 5% failed treatment, and 17% defaulted. Unfavorable outcomes were not correlated to the number of resistant drugs at baseline DST. Cases who died had a lower mean body weight than those surviving (40.3 kg vs 47.2 kg, p<0.05). Default was significantly higher in two regions [Eastern OR = 6.2; 95%CL2.0-18.9; Far West OR = 5.0; 95%CL1.0-24.3]. At logistic regression, cure was inversely associated with body weight <36 kg [Adj.OR = 0.1; 95%CL0.0-0.3; ref. 55–75 kg] and treatment in the Eastern region [Adj.OR = 0.1; 95%CL0.0-0.4; ref. Central region].ConclusionsThe implementation of an ambulatory-based treatment programme for MDR-TB based on a fully standardized regimen can yield high cure rates even in resource-limited settings. The determinants of unfavorable outcome should be investigated thoroughly to maximize likelihood of successful treatment.

High Level of Cross-Resistance between Kanamycin, Amikacin, and Capreomycin among Mycobacterium tuberculosis Isolates from Georgia and a Close Relation with Mutations in the rrs Gene

The aminoglycosides kanamycin and amikacin and the macrocyclic peptide capreomycin are key drugs for the treatment of multidrug-resistant tuberculosis (MDR-TB). The increasing rates of resistance to these drugs and the possible cross-resistance between them are concerns for MDR-TB therapy. Mutations in the 16S rRNA gene (rrs) have been associated with resistance to each of the drugs, and mutations of the tlyA gene, which encodes a putative rRNA methyltransferase, are thought to confer capreomycin resistance in Mycobacterium tuberculosis bacteria. Studies of possible cross-resistance have shown variable results. In this study, the MICs of these drugs for 145 clinical isolates from Georgia and the sequences of the rrs and tlyA genes of the isolates were determined. Of 78 kanamycin-resistant strains, 9 (11.5%) were susceptible to amikacin and 16 (20.5%) were susceptible to capreomycin. Four strains were resistant to capreomycin but were susceptible to the other drugs, whereas all amikacin-resistant isolates were resistant to kanamycin. Sequencing revealed six types of mutations in the rrs gene (A514C, C517T, A1401G, C1402T, C1443G, T1521C) but no mutations in the tlyA gene. The A514C, C517T, C1443G, and T1521C mutations showed no association with resistance to any of the drugs. The A1401G and C1402T mutations were observed in 65 kanamycin-resistant isolates and the 4 capreomycin-resistant isolates, respectively, whereas none of the susceptible isolates showed either of those mutations. The four mutants with the C1402T mutations showed high levels of resistance to capreomycin but no resistance to kanamycin and amikacin. Detection of the A1401G mutation appeared to be 100% specific for the detection of resistance to kanamycin and amikacin, while the sensitivities reached 85.9% and 94.2%, respectively.

Oversight Without Obstruction: The Challenge for High-Containment Labs

A cross the nation, government agencies, industries, and academic institutions are building high-containment biological laboratories to research hazardous pathogens that might accidentally or intentionally be introduced to the United States. Experts agree that the knowledge gained from such labs is a boon to public health—these are the places where the diagnostic test for Ebola virus, antitoxins for botulism, and therapies for multidrug-resistant tuberculosis were developed. But many of these same experts also point to the need for strict oversight of high-containment labs, and some worry that unchecked proliferation of such facilities increases the odds that study pathogens will make their way into the environment. The challenge for governing agencies is to provide researchers the flexibility to do their work while ensuring public safety. In 2003, the Senate Committee on Governmental Affairs convened a hearing on the potential vulnerabilities of the U.S. food supply and agricultural sector to deliberate contamination. Two years earlier, the United Kingdom had experienced an epidemic of foot-and-mouth disease (FMD) that devastated the British livestock industry. The disease was not introduced intentionally, but many found the timing disquieting, given the subsequent events of 9/11 and deaths later that fall from anthrax sent through the mail. The U.S. agricultural sector accounts for 13% of the gross domestic product and is vulnerable to both intentional and accidental introduction of infectious disease, according to Lawrence Dyckman, director of natural resources and environment for the U.S. Government Accountability Office (GAO). In testimony at the 2003 hearing, Dyckman identified more than 40 contagious foreign animal diseases as threats to the U.S. agricultural economy. This vulnerability prompted President George W. Bush to issue Homeland Security Presidential Directive 9 in 2004. Among other provisions, the directive called for the secretaries of the U.S. Department of Agriculture (USDA) and Department of Homeland Security (DHS) to develop secure, state-of-the-art biocontainment laboratories to research and develop diagnostic capabilities for exotic animal diseases, including “zoonotic” diseases that can be transmitted to humans. Three years later, the House Energy and Commerce Subcommittee on Oversight and Investigations held a hearing on the proliferation and oversight of high-containment labs. In testimony before the subcommittee, Gigi Kwik Gronvall, a senior associate with the Center for Biosecurity of the University of Pittsburgh Medical Center, said, “Protecting the nation against destabilizing large-scale epidemics, whether natural or man-made, is an urgent priority. . . . [N]ew high-containment laboratories are necessary if we are to produce the scientific advances needed to develop medical countermeasures against bioweapons and emerging diseases.” At the same time, said Gronvall and other witnesses, the need for rigorous oversight and training of personnel is paramount.

Treatment Outcomes for HIV‐Uninfected Patients with Multidrug‐Resistant and Extensively Drug‐Resistant Tuberculosis

Multidrug-resistant (MDR) tuberculosis (TB) is more difficult to treat than is drug-susceptible TB. To elucidate the optimal therapy for MDR TB, we assessed the treatment outcomes and prognostic factors for patients with MDR TB. This study included patients who received an individualized treatment regimen for MDR TB at Samsung Medical Center, a tertiary referral hospital in Seoul, Korea, from January 1995 through December 2004. To identify the prognostic factors related to favorable treatment outcomes, univariate comparison and multiple logistic regression were performed. Of 155 patients, 18 (12%) had newly diagnosed MDR TB, 81 (52%) had previously received treatment with first-line drugs, and 56 (36%) had received treatment with second-line drugs. The isolated strains were resistant to a median of 5 drugs. Twenty-seven patients (17%) had extensively drug-resistant (XDR) TB at the start of treatment. Outcome assessment revealed that 102 patients (66%) were cured or completed therapy. The treatment success rates did not differ significantly between patients with non-XDR MDR TB and those with XDR TB (66% vs. 67%). Surgical resection was performed more frequently for patients with XDR TB than for those with non-XDR MDR TB (48% vs. 17%). Combined surgical resection, body mass index >/=18.5 (calculated as the weight in kilograms divided by the square of the height in meters), use of >4 effective drugs, and a negative sputum smear result were independent predictors of a favorable outcome. Early aggressive treatment comprising at least 4 effective drugs and surgical resection, when indicated, may improve the outcome for patients with MDR TB or XDR TB.

Risk Factors and Mortality Associated with Default from Multidrug‐Resistant Tuberculosis Treatment

Completing treatment for multidrug-resistant (MDR) tuberculosis (TB) may be more challenging than completing first-line TB therapy, especially in resource-poor settings. The objectives of this study were to (1) identify risk factors for default from MDR TB therapy (defined as prolonged treatment interruption), (2) quantify mortality among patients who default from treatment, and (3) identify risk factors for death after default from treatment. We performed a retrospective chart review to identify risk factors for default from MDR TB therapy and conducted home visits to assess mortality among patients who defaulted from such therapy. Sixty-seven (10.0%) of 671 patients defaulted from MDR TB therapy. The median time to treatment default was 438 days (interquartile range, 152-710 days), and 27 (40.3%) of the 67 patients who defaulted from treatment had culture-positive sputum at the time of default. Substance use (hazard ratio, 2.96; 95% confidence interval, 1.56-5.62; P = .001), substandard housing conditions (hazard ratio, 1.83; 95% confidence interval, 1.07-3.11; P = .03), later year of enrollment (hazard ratio, 1.62, 95% confidence interval, 1.09-2.41; P = .02), and health district (P = .02) predicted default from therapy in a multivariable analysis. Severe adverse events did not predict default from therapy. Forty-seven (70.1%) of 67 patients who defaulted from therapy were successfully traced; of these, 25 (53.2%) had died. Poor bacteriologic response, <1 year of treatment at the time of default, low education level, and diagnosis with a psychiatric disorder significantly predicted death after default in a multivariable analysis. The proportion of patients who defaulted from MDR TB treatment was relatively low. The large proportion of patients who had culture-positive sputum at the time of treatment default underscores the public health importance of minimizing treatment default. Prognosis for patients who defaulted from therapy was poor. Interventions aimed at preventing treatment default may reduce TB-related mortality.

Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)—a report of ten cases

Multidrug resistant tuberculosis (MDR-TB) is an increasing problem in many parts of the world and in Norway the increase has been substantial since 1998. New therapies for MDR-TB have not been introduced since the fluoroquinolones in the 1970s. The cure rate of this disease has been reported to be lower than for non-drug resistant TB, and the use of new experimental drugs in combination therapy is warranted. Ten consecutive patients with culture proven MDR-TB were treated with the novel antibiotic drug linezolid in combination regimens for 6-40 (median 17) weeks and followed up 11-50 (median 24) months after end of treatment. All strains were sensitive to linezolid with MIC<4 mg/l. Treatment was given as direct observed therapy (DOT) and sputum cultures, blood chemistry and neurologic examination were undertaken on a regular basis. Nine patients were cured, one patient with poor adherence to treatment and advanced AIDS died. Seven of 10 patients experienced serious adverse events, which led to withdrawal of linezolid in all seven. Six patients developed peripheral neuropathy and five patients bone marrow depression, blood transfusions were given to three patients and in all five patients bone marrow function normalized after cessation of linezolid. Peripheral neuropathy was not fully reversed in all patients. Linezolid seems highly active in combination treatment of MDR-TB. Cultures became negative 10-37 days after the introduction of the drug. However, peripheral neuropathy and bone marrow depression led to linezolid withdrawal in seven patients, and neuropathy may not be fully reversible in all patients.

Which agents should we use for the treatment of multidrug-resistant Mycobacterium tuberculosis?

The inappropriate treatment of drug-susceptible tuberculosis can lead to the selection and transmission of multidrug-resistant tuberculosis (MDR-TB), indicating resistance to at least isoniazid and rifampicin. In the treatment of MDR-TB, residual first-line drugs, such as ethambutol, pyrazinamide and streptomycin must be appropriately combined with additional second-line drugs, guided by individual susceptibility patterns. The clinical pharmacology of these second-line antituberculous drugs is reviewed. Fluoroquinolones represent the only substantial therapeutic advance in the last 20 years. Many factors potentially affect the outcome of MDR-TB. Treatment adherence, prior exposure to antituberculous drugs, the number of drugs to which the infection is still susceptible and the time since the first diagnosis of tuberculosis are the most relevant. The management of MDR-TB requires considerable expertise. When initiating or revising therapy for MDR-TB, the process of selecting drugs should rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence. In making drug selection, we propose to follow a hierarchy based on the intrinsic activity against Mycobacterium tuberculosis and the clinical evidence of efficacy of the available active compounds.

Hypokalemia Among Patients Receiving Treatment for Multidrug-Resistant Tuberculosis

Between January 1999 and December 2000, 125 patients in Lima, Peru were enrolled in individualized treatment for multidrug-resistant tuberculosis (MDR-TB). Hypokalemia was observed to be an important adverse effect encountered in this cohort. To identify risk factors associated with the development and persistence of hypokalemia during MDR-TB therapy, and to review the incidence and management of hypokalemia in patients receiving MDR-TB therapy. A retrospective case series of 125 patients who received individualized therapy for MDR-TB between January 1, 1999, and December 31, 2000. Among 115 patients who were screened for electrolyte abnormalities, 31.3% had hypokalemia, defined as a potassium level of < 3.5 mEq/L. Mean serum potassium at time of diagnosis was 2.85 mEq/L. Diagnosis of low serum potassium occurred, on average, after 5.1 months of individualized therapy. Multivariate analysis of risk factors for this adverse reaction identified two causes: administration of capreomycin, and low initial body weight. Normalization of potassium levels was achieved in 86% of patients. Electrolyte disturbance was frequently encountered in our cohort of patients with MDR-TB. Successful screening and management of hypokalemia was facilitated by training the health-care team in the use of a standardized algorithm. Morbidity from hypokalemia can be significant; however, effective management of this side effect is possible without sacrificing MDR-TB treatment efficacy.

Infectious disease in Haiti. HIV/AIDS, tuberculosis and social inequalities.

More than 50 years after the introduction of chemotherapy for the treatment of tuberculosis (TB), the disease is far from being under control. Among curable infectious diseases, TB remains the number‐one killer—each year, 2 million people still die of the disease and 8.4 million more fall ill (World Health Organization (WHO), 2002a). And future projections are grim. Fewer than half of all TB cases are diagnosed, and of those that are, fewer than 30% have access to the care recommended by the WHO (WHO, 2002a). The increase in TB worldwide is due, in part, to the expansion of the HIV/AIDS pandemic (WHO, 2001): at least one‐third of people with HIV die of TB (WHO, 2002a). HIV/AIDS now causes more than 3 million deaths per year (UNAIDS, 2002). More than 90% of HIV/AIDS deaths and new infections occur in poor countries where less than 5% of those who need antiretroviral treatment have access to these therapies (WHO, 2002b). If we consider that, on average, 10% of people with HIV need antiretroviral treatment, the 5% figure comes down to less than 1% in sub‐Saharan Africa, the region most affected by the pandemic. > The social contexts in which our patients became infected are an integral part of their stories Large‐scale social forces, such as racism, sexism, political violence, poverty and other social inequalities, are rooted in historical and economic processes and sculpt the distribution and outcome of HIV/AIDS and TB. We refer to these social forces as ‘structural violence’ (Castro & Farmer, 2002, 2003a,b; Farmer, 2003), which predisposes the human body to pathogenic vulnerability by shaping the risk of infection and subsequent disease reactivation. After infection, structural violence also determines who has access to diagnostics and effective therapy. Drugs that could stop or slow down these epidemics, such as …

RhulL-2 adjunctive therapy in multidrug resistant tuberculosis: A comparison of two treatment regimens and placebo

Setting: Low-dose recombinant human interleukin 2 (rhulL-2) adjunctive immunotherapy in multidrug resistant tuberculosis (MDR-TB) patients. Objective: Evaluation of the effects of daily versus pulse-administered rhulL-2 compared to placebo. Design: MDR-TB patients on best available antituberculous chemotherapy received rhulL-2 for 30 consecutive days (daily therapy), or for 5 days followed by a 9-day ‘rest’, for three cycles (pulse therapy). Placebo control patients received diluent. The cumulative total dose of rhulL-2 given to each patient in either rhulL-2 treatment group was the same. Patient immunologic, microbiologic, and radiologic responses were compared. Results: The three treatment schedules induced different results. Immune activation was documented in patients receiving daily rhulL-2 therapy. Numbers of CD25 + and CD56 + cells in the peripheral blood were increased in these patients, but not in patients receiving pulse rhulL-2 or placebo. In addition, 5 8 (62%) patients receiving daily rhulL-2 demonstrated reduced or cleared sputum bacterial load while only 2 7 (28%) pulse rhulL-2 treated and 2 8 (25%) controls showed bacillary clearance. Chest radiographs of 7 12 (58%) patients receiving daily rhulL-2 indicated significant improvement over 6 weeks. Only 2 9 (22%) pulse rhulL-2-treated patients and 5 12 (42%) placebo controls showed radiologic improvement. Conclusion: Daily low dose rhulL-2 adjunctive treatment stimulates immune activation and may enhance the antimicrobial response in MDR-TB.

Therapy of multidrug-resistant tuberculosis: lessons from studies with mice.

The activities of antituberculosis agents were evaluated in a murine tuberculosis model using a drug-resistant isolate. A multidrug-resistant clinical isolate from a recent outbreak of tuberculosis in the New York State correctional system was used for infection. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 49967 (strain CNL) organisms were given intravenously to 4-week-old female outbred mice. Treatment was started 1 day after infection and given for 4 weeks. Spleens and lungs were homogenized, and viable cell counts were determined. Statistical analysis indicated that ethionamide, sparfloxacin, ofloxacin, capreomycin, clarithromycin, and clofazimine are active in the murine test system with this multidrug-resistant tuberculosis isolate. Sparfloxacin is the most active quinolone. Despite in vitro resistance, isoniazid has moderate activity. In vitro susceptibility data coupled with evaluation of agents against drug-resistant isolates in the murine system should provide information necessary to design clinical trials for treatment of infections with these organisms.