José Sifuentes-Osornio

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Epidemiology of Candidemia in Latin America: A Laboratory-Based Survey

Background The epidemiology of candidemia varies depending on the geographic region. Little is known about the epidemiology of candidemia in Latin America. Methods We conducted a 24-month laboratory-based survey of candidemia in 20 centers of seven Latin American countries. Incidence rates were calculated and the epidemiology of candidemia was characterized. Results Among 672 episodes of candidemia, 297 (44.2%) occurred in children (23.7% younger than 1 year), 36.2% in adults between 19 and 60 years old and 19.6% in elderly patients. The overall incidence was 1.18 cases per 1,000 admissions, and varied across countries, with the highest incidence in Colombia and the lowest in Chile. Candida albicans (37.6%), C. parapsilosis (26.5%) and C. tropicalis (17.6%) were the leading agents, with great variability in species distribution in the different countries. Most isolates were highly susceptible to fluconazole, voriconazole, amphotericin B and anidulafungin. Fluconazole was the most frequent agent used as primary treatment (65.8%), and the overall 30-day survival was 59.3%. Conclusions This first large epidemiologic study of candidemia in Latin America showed a high incidence of candidemia, high percentage of children, typical species distribution, with C. albicans, C. parapsilosis and C. tropicalis accounting for the majority of episodes, and low resistance rates.

Association of diabetes and tuberculosis: impact on treatment and post-treatment outcomes

Objective To determine the clinical consequences of pulmonary tuberculosis (TB) among patients with diabetes mellitus (DM). Methods We conducted a prospective study of patients with TB in Southern Mexico. From 1995 to 2010, patients with acid-fast bacilli or Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and microbiological evaluation. Annual follow-ups were performed to ascertain treatment outcome, recurrence, relapse and reinfection. Results The prevalence of DM among 1262 patients with pulmonary TB was 29.63% (n=374). Patients with DM and pulmonary TB had more severe clinical manifestations (cavities of any size on the chest x-ray, adjusted OR (aOR) 1.80, 95% CI 1.35 to 2.41), delayed sputum conversion (aOR 1.51, 95% CI 1.09 to 2.10), a higher probability of treatment failure (aOR 2.93, 95% CI 1.18 to 7.23), recurrence (adjusted HR (aHR) 1.76, 95% CI 1.11 to 2.79) and relapse (aHR 1.83, 95% CI 1.04 to 3.23). Most of the second episodes among patients with DM were caused by bacteria with the same genotype but, in 5/26 instances (19.23%), reinfection with a different strain occurred. Conclusions Given the growing epidemic of DM worldwide, it is necessary to add DM prevention and control strategies to TB control programmes and vice versa and to evaluate their effectiveness. The concurrence of both diseases potentially carries a risk of global spreading, with serious implications for TB control and the achievement of the United Nations Millennium Development Goals.

Does DOTS work in populations with drug-resistant tuberculosis?

BACKGROUND Directly observed therapy (DOTS) is the main strategy for prevention and control of tuberculosis worldwide. However, its effect on tuberculosis transmission in populations with moderate rates of drug-resistant disease is not known. METHODS This population-based prospective study in southern Mexico between March, 1995, and February, 2000, was based on passive case finding and detection of acid-fast bacilli in sputum samples to diagnose pulmonary tuberculosis. We also used cultures, drug-susceptibility testing, bacterial genotyping, and monitoring of treatment outcomes. FINDINGS We enrolled 436 patients; the HIV seroprevalence rate was 2%. We used three indicators to monitor continuing tuberculosis transmission: the incidence rate of pulmonary tuberculosis, which decreased by 54.4% between 1995 and 2000, from 42.1 to 19.2 per 10(5) population (p=0.00048); the percentage of clustered pulmonary tuberculosis cases, which decreased by 62.6% from 22% to 8% (p=0.02); and the rate of primary drug resistance, which decreased by 84.0% from 9.4 to 1.5 per 10(5) population (p=0.004). Rates of multidrug-resistant (MDR) tuberculosis also decreased (p<0.0001). The case-fatality ratio was 12% for MDR tuberculosis (five of 41), 7% for strains resistant to at least one drug after exclusion of MDR (four of 55), and 3% for pansusceptible strains (nine of 272). There were 13 treatment failures (11%) in 1995 and one (2%) in 2000 (p=0.012). INTERPRETATION Even in settings with moderate rates of MDR tuberculosis, DOTS can rapidly reduce the transmission and incidence of both drug-susceptible and drug-resistant tuberculosis. However, further interventions, such as drug-susceptibility testing and standardised or individualised treatment regimens, are needed to reduce mortality rates for MDR tuberculosis.

Gender differentials of pulmonary tuberculosis transmission and reactivation in an endemic area

Background: In most low income countries there are twice as many cases of tuberculosis (TB) reported among men than among women, a difference commonly attributed to biological and epidemiological characteristics as well as socioeconomic and cultural barriers in access to health care. The World Health Organization has encouraged gender specific comparisons in TB rates to determine whether women with TB are less likely than men with TB to be diagnosed, reported, and treated. A study was undertaken to identify gender based differences in patients with pulmonary TB and to use this information to improve TB control efforts. Methods: Individuals with a cough for more than 2 weeks in southern Mexico were screened from March 1995 to April 2003. Clinical and mycobacteriological information (isolation, identification, drug susceptibility testing and IS6110 based genotyping, and spoligotyping) was collected from those with bacteriologically confirmed pulmonary TB. Patients were treated in accordance with official norms and followed to ascertain treatment outcome, retreatment, and vital status. Results: 623 patients with pulmonary TB were enrolled. The male:female incidence rate ratio for overall, reactivated, and recently transmitted disease was 1.58 (95% CI 1.34 to 1.86), 1.64 (95% CI 1.36 to 1.98), and 1.41 (95% CI 1.01 to 1.96), respectively. Men were more likely than women to default from treatment (adjusted OR 3.30, 95% CI 1.46 to 7.43), to be retreated (hazard ratio (HR) 3.15, 95% CI 1.38 to 7.22), and to die from TB (HR 2.23, 95% CI 1.25 to 3.99). Conclusions: Higher rates of transmitted and reactivated disease and poorer treatment outcomes among men are indicators of gender differentials in the diagnosis and treatment of pulmonary TB, and suggest specific strategies in endemic settings.

Epidemiology of Invasive Fungal Infections in Latin America.

The pathogenic role of invasive fungal infections (IFIs) has increased during the past two decades in Latin America and worldwide, and the number of patients at risk has risen dramatically. Working habits and leisure activities have also been a focus of attention by public health officials, as endemic mycoses have provoked a number of outbreaks. An extensive search of medical literature from Latin America suggests that the incidence of IFIs from both endemic and opportunistic fungi has increased. The increase in endemic mycoses is probably related to population changes (migration, tourism, and increased population growth), whereas the increase in opportunistic mycoses may be associated with the greater number of people at risk. In both cases, the early and appropriate use of diagnostic procedures has improved diagnosis and outcome.

Nested Polymerase Chain Reaction for Mycobacterium tuberculosis DNA Detection in Aqueous and Vitreous of Patients with Uveitis

BACKGROUND Tuberculosis may be a lethal disease. Its ocular manifestations are commonly associated with severe difficulties in diagnosis and therapy; furthermore, it may cause blindness. DNA amplification methods may allow early detection of small amounts of Mycobacterium tuberculosis DNA to afford the possibility of prompt diagnosis. We evaluated a nested polymerase chain reaction (nPCR) assay for detection of Mycobacterium tuberculosis DNA in aqueous and vitreous. METHODS In a case-control study, 22 cases of diagnosed TB uveitis (three HIV-infected patients) and 38 controls (18 HIV-infected patients) with other types of uveitis (syphilis, nine; cytomegalovirus, seven; toxoplasmosis, five; herpes simplex, one; autoimmune vasculitis, eight; Vogt-Koyanagi-Harada, four; pars planitis, one; serpinginous choroiditis, one; Wegener granulomatosis, one; and Fuchs iridocyclitis, one studied). Samples from aqueous or vitreous were cultured and analyzed by nPCR for presence of M. tuberculosis nucleic acids. We used two sets of primers corresponding to IS6110 region coding for 219 bp and 123 bp DNA sequences. RESULTS Results were confirmed by Southern blot. All samples were tested by PCR simultaneously for Herpes simplex I, Herpes zoster, cytomegalovirus (CMV) and Toxoplasma gondii. nPCR was positive in 17 cases (77.2%) and only in three controls (8.8%) p = 0.022. All cultures were negative. Southern blot confirmed all positive nPCR tests. According to our definition of cases, there were five false negative results: two in patients with pulmonary tuberculosis; two in patients with tuberculous lymphadenitis, and one with positive skin test and hematuria. There were three cases considered false positives for nPCR: one with autoimmune vasculitis, and two with toxoplasmic uveitis. CONCLUSIONS nPCR for TB in ocular fluids was positive in the majority of cases of ocular TB. This method is useful in early confirmation of ocular tuberculosis.

Virulence, immunopathology and transmissibility of selected strains of Mycobacterium tuberculosis in a murine model

After encounter with Mycobacterium tuberculosis, a series of non‐uniform immune responses are triggered that define the course of the infection. Eight M. tuberculosis strains were selected from a prospective population‐based study of pulmonary tuberculosis patients (1995–2003) based on relevant clinical/epidemiological patterns and tested in a well‐characterized BALB/c mouse model of progressive pulmonary tuberculosis. In addition, a new mouse model of transmissibility consisting of prolonged cohousing (up to 60 days) of infected and naïve animals was tested. Four phenotypes were defined based on strain virulence (mouse survival, lung bacillary load and tissue damage), immunology response (cytokine expression determined by real‐time polymerase chain reaction) and transmissibility (lung bacillary loads and cutaneous delayed‐type hypersensitivity in naïve animals).We identified four clearly defined strain phenotypes: (1) hypervirulent strain with non‐protective immune response and highly transmissible; (2) virulent strain, associated with high expression of proinflammatory cytokines (tumour necrosis factor and interferon) and very low anti‐inflammatory cytokine expression (interleukins 4 and 10), which induced accelerated death by immunopathology; (3) strain inducing efficient protective immunity with lower virulence, and (4) strain demonstrating strong and early macrophage activation (innate immunity) with delayed participation of acquired immunity (interferon expression). We were able to correlate virulent and transmissible phenotypes in the mouse model and markers of community transmission such as tuberculin reactivity among contacts, rapid progression to disease and cluster status. However, we were not able to find correlation with the other two phenotypes. Our new transmission model supported the hypothesis that among these strains increased virulence was linked to increased transmission.

Tuberculosis-Related Deaths within a Well-Functioning DOTS Control Program

To describe the molecular epidemiology of tuberculosis (TB)-related deaths in a well-managed program in a low-HIV area, we analyzed data from a cohort of 454 pulmonary TB patients recruited between March 1995 and October 2000 in southern Mexico. Patients who were sputum acid-fast bacillus smear positive underwent clinical and mycobacteriologic evaluation (isolation, identification, drug-susceptibility testing, and IS6110-based genotyping and spoligotyping) and received treatment from the local directly observed treatment strategy (DOTS) program. After an average of 2.3 years of follow-up, death was higher for clustered cases (28.6 vs. 7%, p=0.01). Cox analysis revealed that TB-related mortality hazard ratios included treatment default (8.9), multidrug resistance (5.7), recently transmitted TB (4.1), weight loss (3.9), and having less than 6 years of formal education (2). In this community, TB is associated with high mortality rates.