Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57-72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45-66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36-60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27-53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4-16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4-26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6-9.0 months duration and the total duration of treatment 20.1-25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens.

Microscopic-observation drug-susceptibility assay for the diagnosis of TB.

BACKGROUND: New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. Rapid, sensitive detection of tuberculosis and multidrug-resistant tuberculosis in sputum has been demonstrated in proof-of-principle studies of the microscopic-observation drug-susceptibility (MODS) assay, in which broth cultures are examined microscopically to detect characteristic growth. METHODS: In an operational setting in Peru, we investigated the performance of the MODS assay for culture and drug-susceptibility testing in three target groups: unselected patients with suspected tuberculosis, prescreened patients at high risk for tuberculosis or multidrug-resistant tuberculosis, and unselected hospitalized patients infected with the human immunodeficiency virus. We compared the MODS assay head-to-head with two reference methods: automated mycobacterial culture and culture on Löwenstein-Jensen medium with the proportion method. RESULTS: Of 3760 sputum samples, 401 (10.7%) yielded cultures positive for Mycobacterium tuberculosis. Sensitivity of detection was 97.8% for MODS culture, 89.0% for automated mycobacterial culture, and 84.0% for Löwenstein-Jensen culture (P<0.001); the median time to culture positivity was 7 days, 13 days, and 26 days, respectively (P<0.001), and the median time to the results of susceptibility tests was 7 days, 22 days, and 68 days, respectively. The incremental benefit of a second MODS culture was minimal, particularly in patients at high risk for tuberculosis or multidrug-resistant tuberculosis. Agreement between MODS and the reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, 99% for rifampin and isoniazid (combined results for multidrug resistance), 95% for ethambutol, and 92% for streptomycin (kappa values, 1.0, 0.89, 0.93, 0.71, and 0.72, respectively). CONCLUSIONS: A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used.

Lack of an adverse effect of Giardia intestinalis infection on the health of Peruvian children.

Giardia intestinalis is a common gastrointestinal protozoan worldwide, but its effects on childhood growth in developing countries are not clearly understood. The authors aimed to describe its effects on child growth. They followed 220 Peruvian children daily for diarrhea, weekly for stool samples, and monthly for anthropometry. The authors modeled the effect of nutritional status on the risk of Giardia infection and the risk of diarrhea attributable to Giardia using negative binomial regression. They modeled the effects of Giardia infection on growth using linear regression, with 85% of children becoming infected with Giardia and 87% of these becoming reinfected. In multivariable analysis, the risk of Giardia infection did not vary with weight for age (relative risk = 1.00, 95% confidence interval: 0.89, 1.12) or height for age (relative risk = 0.92, 95% confidence interval: 0.82, 1.04). Giardiasis did not affect growth at 1 or 2 months following the first infection at any age interval. The longitudinal prevalence of Giardia between 6 and 24 months of age was not associated with height gain in that interval (p = 0.981). Giardia was not associated with an increased risk of diarrhea at any age interval. Study results question the importance of Giardia as a childhood pathogen in developing countries where giardiasis is hyperendemic.

Infrequent MODS TB culture cross-contamination in a high-burden resource-poor setting.

One obstacle to wider use of rapid liquid culture-based tuberculosis diagnostics such as the microscopic observation drug susceptibility (MODS) assay is concern about cross-contamination. We investigated the rate of laboratory cross-contamination in MODS, automated MBBacT, and Lowenstein-Jensen (LJ) cultures performed in parallel, through triangulation of microbiologic (reculturing stored samples), molecular (spoligotype/RFLP), and clinical epidemiologic data. At least 1 culture was positive for Mycobacterium tuberculosis for 362 (11%) of 3416 samples; 53 were regarded as potential cross-contamination suspects. Cross-contamination accounted for 17 false-positive cultures from 14 samples representing 0.41% (14/3416) and 0.17% (17/10248) of samples and cultures, respectively. Positive predictive values for MODS, MBBacT (bioMérieux, Durham, NC), and LJ were 99.1%, 98.7%, and 99.7%, and specificity was 99.9% for all 3. Low rates of cross-contamination are achievable in mycobacterial laboratories in resource-poor settings even when a large proportion of samples are infectious and highly sensitive liquid culture-based diagnostics such as MODS are used.

Vitamin A supplements, routine immunization, and the subsequent risk of Plasmodium infection among children under 5 years in sub-Saharan Africa.

Recent studies, partly based on murine models, suggest childhood immunization and vitamin A supplements may confer protection against malaria infection, although strong evidence to support these theories in humans has so far been lacking. We analyzed national survey data from children aged 6-59 months in four sub-Saharan African countries over an 18-month time period, to determine the risk of Plasmodium spp. parasitemia (n=8390) and Plasmodium falciparum HRP-2 (PfHRP-2)-related antigenemia (n=6121) following vitamin A supplementation and standard vaccination. Bacille Calmette Guerin-vaccinated children were more likely to be PfHRP-2 positive (relative risk [RR]=4.06, 95% confidence interval [CI]=2.00-8.28). No association was identified with parasitemia. Measles and polio vaccination were not associated with malaria. Children receiving vitamin A were less likely to present with parasitemia (RR=0.46, 95% CI=0.39-0.54) and antigenemia (RR=0.23, 95% CI=0.17-0.29). Future studies focusing on climate seasonality, placental malaria and HIV are needed to characterize better the association between vitamin A and malaria infection in different settings.

Acute lower respiratory infection among Bacille Calmette-Guérin (BCG)-vaccinated children.

OBJECTIVE: To determine whether Bacille Calmette-Guerin (BCG) vaccination is linked to the risk of acute lower respiratory infection (ALRI) among children <5 years of age. METHODS: Data from Macro International Demographic and Health Surveys and United Nations Children's Fund Multiple Indicator Cluster Surveys were used to identify a primary cohort of 58,021 children in 19 countries (2005-2010) and a secondary cohort of 93,301 children in 18 countries (2000-2007). Information was collected by trained interviewers during home visits using standardized questionnaires, review of vaccination health cards, and measurement of health indicators. RESULTS: BCG vaccination was associated with a 17% to 37% risk reduction for suspected ALRI in both cohorts. The only vaccine or vitamin supplement to modify the effect of BCG was diphtheria-tetanus-pertussis (DTP; P < .001). The order in which the vaccines were first received was central to this phenomena (BCG before DTP, adjusted/propensity score-weighted relative risk [apRR]: 0.79, 95% confidence interval [CI]: 0.70-0.89; BCG with DTP, apRR: 0.82, 95% CI: 0.71-0.94; and BCG after DTP, apRR: 1.00, 95% CI: 0.87-1.13) but not number of DTP doses received. Other modifiers included vaccine strain used in immunization programs, chlorinating drinking water, using wood-burning fuel cook stoves, and owning livestock. CONCLUSIONS: Children vaccinated with BCG had a significantly lower risk of suspected ALRI. Clarification is needed as to whether this is due to reductions in the underlying risk of tuberculosis or ALRI per se.

Molecular epidemiology of tuberculosis transmission: Contextualizing the evidence through social network theory.

Despite a long-standing recognition that factors such as age, gender, and socioeconomic status play a fundamental role in tuberculosis transmission and susceptibility, few molecular epidemiological studies have fully elucidated the etiological mechanisms by which each of these social factors may influence transmission of the disease. In this paper, we propose that in order to achieve this goal, molecular epidemiology must move towards a more holistic approach for disease transmission, thus enabling social theory to be integrated into molecular epidemiological studies on tuberculosis. We then present a social network model to illustrate how molecular and social epidemiology can be combined to study disease transmission patterns, and provide preliminary molecular epidemiological evidence to support the role of social networks in tuberculosis transmission.

Invasive group A streptococcal infections, clinical manifestations and their predictors, Montreal, 1995-2001.

We identified 306 invasive group A streptococcal infections (IGASI) by passive population-based surveillance in Montreal, Canada, from 1995 to 2001. The average yearly reported incidence was 2.4 per 100,000 persons, with a 14% death rate. Among clinical manifestations, incidence of pneumonia increased from 0.06 per 100,000 in 1995 to 0.50 per 100,000 in 2000. Over a span of 7 years, the odds of developing pneumonia increased (odds ratio [OR] = 1.21, 95% confidence interval [CI] 1.0-1.5), while they decreased for soft-tissue infections (OR = 0.86, 95% CI 0.7-1.0). Serotypes M1 and M3 accounted for 30% of IGASI. However, neither serotype was significantly associated with specific clinical manifestations, which suggests that manifestation development among IGASI might be attributable to host or environmental factors rather than the pathogen. In our study, these factors included age, gender, underlying medical conditions, and living environment, yet none explained temporal changes in risk for pneumonia and soft-tissue infections.

Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis suitable for use in resource-poor settings.

There is an urgent need for new tools to improve our ability to diagnose tuberculosis (TB) and multidrug-resistant TB (MDR-TB) in resource-poor settings. In a retrospective analysis undertaken in a region with a high incidence of TB, we evaluated the performance of the microscopic observation drug susceptibility assay (MODS), a novel assay developed in Perú which uses an inverted light microscope and culture in Middlebrook 7H9 broth to detect mycobacterial growth. MODS detected 94.0% of 1,908 positive sputum cultures, whereas Lowenstein-Jensen (LJ) culture detected only 86.9% (P < 0.001). The median time to culture positivity was 8 days (compared to 16 days for the same 208 samples by LJ culture; P < 0.001, Wilcoxon signed rank test). The results obtained by direct susceptibility testing using MODS demonstrated excellent concordance for isoniazid and rifampin and the detection of multidrug resistance with those obtained by indirect colorimetric methods: the microplate Alamar Blue assay (MABA) and the tetrazolium microplate assay (TEMA) (agreement, 95, 98, and 94%; kappa values, 0.8, 0.7, and 0.7, respectively). The concordance of the susceptibility testing results for ethambutol and streptomycin was poor. MODS is a novel assay which can detect the organisms responsible for TB and MDR-TB directly from sputum inexpensively, rapidly, and effectively. A comprehensive prospective evaluation of MODS is under way in Perú, and independent validation in nonresearch laboratories should be undertaken at the earliest opportunity.