Adult Multidrug-resistant Tuberculosis Research Articles

Estimating the contribution of transmission in primary healthcare clinics to community-wide TB disease incidence, and the impact of infection prevention and control interventions, in KwaZulu-Natal, South Africa

BackgroundThere is a high risk of Mycobacterium tuberculosis (Mtb) transmission in healthcare facilities in high burden settings. WHO guidelines on tuberculosis (TB) infection prevention and control (IPC) recommend a range...

Treatment outcomes of pulmonary multidrug-resistant tuberculosis; 10 year follow up study

ABSTRACT Aim: Treatment rates of multidrug-resistant tuberculosis (MDR-TB) vary from clinic to clinic. In this study, the characteristics of MDR-TB patients followed in two clinics of our hospital and their relationship with treatment results were investigated. Material and Method: This observational retrospective cohort study performed in a government hospital which is one of the important reference center for management of tuberculosis in Turkey. Seventy-nine adult MDR-TB cases who'm diagnosed and treated between 2004-2014 were retrospectively enrolled into the study. Results: Of the patients with MDR-TB, 58 were male, 21 were female, mean age was 36.24 ± 13.75 and all of them were HIV (-). 64 patients completed treatment, 15 patients still under treatment. The average hospitalization time was 162.76. Radiologically, 11 patients had diffuse disease and 68 patients had limited disease. The mean number of patients who received second-line drugs were 5.18 ± 0.5 and drug-related side effects developed in 36 patients. Cure was achieved in 84.4% of the patients, 7.8% discontinued the treatment, 7.8% died during the treatment and there wasn’t any treatment failure. Conclusion: In our study, we think that the factors that increase the success of MDR-TB treatment are: young age, low resistance to second line medication, prolongation of hospitalization, good compliance with treatment, low rate of ofloxacin use in previous treatment, use of fluoroquinolones in new patients, surgery in selected patients.

Protocol for a case–control study of vitamin D status, adult multidrug-resistant tuberculosis disease and tuberculosis infection in Mumbai, India

IntroductionVitamin D status may be an important determinant of multidrug-resistant tuberculosis (MDR-TB) infection, progression to disease and treatment outcomes. Novel and potentially cost-effective therapies such as vitamin D supplementation are...

Treatment Outcomes and Adverse Drug Effects of Ethambutol, Cycloserine, and Terizidone for the Treatment of Multidrug-Resistant Tuberculosis in South Africa.

Treatment outcomes among multidrug-resistant tuberculosis (MDR-TB) patients receiving ethambutol, cycloserine, or terizidone as part of a standardized regimen were compared, determining occurrence of serious adverse drug events (SADEs). Newly diagnosed adult MDR-TB patients were enrolled between 2000 and 2004, receiving a standardized multidrug regimen for 18 to 24 months, including ethambutol, cycloserine, or terizidone. Cycloserine and terizidone were recorded individually. SADEs and factors associated with culture conversion and unfavorable treatment outcomes (default, death, treatment failure) were determined. Of 858 patients, 435 (51%) received ethambutol, 278 (32%) received cycloserine, and 145 (17%) received terizidone. Demographic and baseline clinical data were comparable. Successful treatment occurred in 56%, significantly more in patients receiving cycloserine (60%) and terizidone (62%) than in those receiving ethambutol (52% [P = 0.03]). Defaults rates were 30% in ethambutol patients versus 15% and 11% for cycloserine and terizidone patients, respectively. Terizidone was associated with fewer unfavorable outcomes (adjusted odds ratio [AOR], 0.4; P = 0.008; 95% confidence interval [CI], 0.2 to 0.8). Patients receiving cycloserine were more likely to achieve culture conversion than those receiving ethambutol or terizidone (AOR, 2.2; P = 0.02; 95% CI, 1.12 to 4.38). Failure to convert increased the odds of unfavorable outcomes (AOR, 23.7; P < 0.001; 95% CI, 13 to 44). SADEs were reported in two patients receiving ethambutol, seven patients receiving cycloserine, and three receiving terizidone (P = 0.05). Ethambutol was associated with high culture conversion and default rates. Cycloserine achieved higher culture conversion rates than terizidone. Fewer patients on terizidone experienced SADEs, with lower default rates. The differences that we observed between cycloserine and terizidone require further elucidation.

Meta-analysis on Effectiveness and Safety of Moxifloxacin in Treatment of Multidrug Resistant Tuberculosis in Adults.

Background:Moxifloxacin, a fourth generation fluoroquinolone, which has good antibacterial activity against both Gram-positive cocci and Gram-negative bacteria. To date, there are no meta-analysis to evaluate the efficacy and safety of moxifloxacin for multi-drug resistant tuberculosis (MDR-TB) treatment. This meta-analysis to explore the efficacy and safety of the moxifloxacin in treatment of MDR-TB in adults.Methods:Databases of PubMed, Embase, Embase, Ovid, and Google Scholar databases were investigated for eligible literatures from their establishments to August, 2019. Included studies were selected according to precise eligibility criteria: MDR-TB confirmed by the clinical diagnostic criteria (at least 2 or more first-line drugs resistant to isoniazid and rifampicin). Study design was limited to retrospective studies, randomized controlled trials, or prospective cohort studies; the control group was treated with other drugs or no moxifloxacin. Statistical analysis was performed by RevMan 5.3 software.Results:Eight studies with a total of 1447 patients were finally eligible for the final systematic review and meta-analysis. Moxifloxacin regimen was related to a significantly elevated treatment success rate compared with levofloxacin or conventional therapy regimen (OR = 1.94; 95% CI = 1.16–3.25, P = .01). No significant difference of sputum culture conversion rate (OR = 1.15; 95% CI = 0.82–1.60; P = 0.43) was found between 2 groups. In addition, there was no significant difference in the increased risks of gastrointestinal trouble (OR = 1.28; 95% CI = 0.98–1.68; P = .05), hepatotoxicity (OR = 0.91; 95% CI = 0.64–1.30; P = .6), dermatologic abnormalities (OR = 1.11; 95% CI = 0.74–1.67; P = .62), and vision change (OR = 1.47; 95% CI = 0.74–2.89; P = .27) between the moxifloxacin-containing regimens and control group.Conclusions:This meta-analysis revealed that the addition of moxifloxacin to the recommended regimen significantly improved the rate of treatment success in the treatment of MDR-TB, with no additional adverse moxifloxacin events.

The relevance of household contacts tracing among child contacts of patients with multidrug-resistant tuberculosis

BACKGROUND. The World Health Organization (WHO) reports an unknown contact history of pediatric tuberculosis (TB), especially in children younger than 5 years old. Tracing pediatric household contacts of patients with multidrug-resistant TB (MDR-TB) is considered to be a highly effective intervention for detection of new cases of chemoresistant TB in children and timely prevention of its transmission. OBJECTIVE. To study the nature of TB process manifestations and concordance of mycobacterium tuberculosis (MBT) drug resistance profiles in household child contacts of patients with MDR-TB. MATERIALS AND METHODS. The nature of TB process manifestations and concordance of MBT drug resistance profiles in 12 household child contacts of patients with MDR-TB in 6 households (6 adult MDR-TB index patients, IP) were studied. Adults and children were examined and treated in the Pulmonary Tuberculosis Department No 3 and in the Pediatric Department of the Clinical Base of the Department of Phthisiology and Pulmonology of Zaporizhzhia State Medical University at the Municipal Institution “Zaporizhzhia Regional Tuberculosis Clinical Dispensary”. RESULTS AND DISCUSSION. The tracing of children who were household contacts of the MDR-TB IP revealed the following features. The incidence of child TB was 2 times higher than that of contact adults (44 % vs. 20 %). Moreover, the incidence among children younger than 2 years of age was almost 3 times higher than in children across other age groups (54.5 % vs. 18.2 % in children younger than 5 years of age and 18.2 % in children aged 5 years and older). The children were non-BCG vaccinated in 63.6 % of cases. There was an alarmingly high rate of non-BCG vaccinated children, namely 83.3 % among individuals younger than 2 years of age and all of those younger than 5 years of age (100 %). The children mostly presented small clinical forms of non-destructive TB: intrathoracic lymph node TB (36.4 %), MBT complex (36.4 %) and focal TB (18.2 %). Most of the children (63.6 %) who developed TB were detected within the first year of IP with MDR-TB follow-up, and it is worthy of note that in the majority of cases (4 households; 66.6 %). With respect to the concordance of MBT drug resistance profiles between the children and MDR-TB IP in the households, diagnosis in children was microbiologically confirmed in only 3 cases (3 households) demonstrating the complete concordance of profiles in each one. At the same time, the complete concordance of MBT drug resistance profiles between adult household contacts and the MDR-TB IP was also recorded in 3 cases. As is evident, across the household contacts group aged between 0 and 18 years who were exposed to the MDR-TB IP, the most susceptible to develop TB were non-BCG vaccinated children younger than 2 years. More worryingly is that among 3 microbiologically conformed individuals of this age group, 2 children younger than 2 years were found to have their own drug resistant MTB isolates. CONCLUSIONS. Tracing household child contacts of MDR-TB IP is particularly effective for timely detection of active TB within the first year of MDR-TB IP follow-up. Non-BCG vaccinated children younger than 2 years of age are at the highest risk for MDR-TB followed by non-BCG vaccinated children younger than 5 years of age. The early detection and timely antimycobacterial therapy initiation based on drug susceptibility test results of a MDR-TB IP is a guarantee not only for an effective treatment but also for a reduction in the MDR-TB transmission to other persons.

Survival of patients with multidrug-resistant tuberculosis in Central China: a retrospective cohort study.

The aim of this study was to evaluate long-term survival and risk factors associated with multidrug-resistant tuberculosis (MDR-TB) patient survival in Central China. Between December 2006 and June 2011, incident and retreatment adult MDR-TB patients were enrolled in the present study. Cox proportional hazard regression analysis was used to evaluate the risk factors affecting survival. The total follow-up period was 270 person-years (PY) for 356 MDR-TB cases in Wuhan. Of the 356 cases, 103 patients died, yielding an average case fatality rate of 381.2 per 1000 TB patients per year. Using adjusted Cox regression analysis, older age (adjusted hazard ratio (aHR) >3.0 starting from 30 years) and low education level (primary and middle school; aHR 1.67 (95% CI 1.01-2.77)) were independently associated with lower survival. Diabetes mellitus profoundly affected the survival of MDR-TB patients (aHR 1.95 (95% CI 1.30-2.93)). Our data demonstrate that coexistent diabetes significantly and negatively impacted MDR-TB patient survival. In addition, MDR-TB patients aged 60 years or older exhibited a greater risk of mortality during follow-up. Our findings emphasise that MDR-TB patients with comorbidities that increase their risk of death require additional medical interventions to reduce mortality.

Feasibility of Identifying Household Contacts of Rifampin-and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.

We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.

HIV testing uptake among the household contacts of multidrug-resistant tuberculosis index cases in eight countries.

The household contacts (HHCs) of multidrug-resistant tuberculosis (MDR-TB) index cases are at high risk of tuberculous infection and disease progression, particularly if infected with the human immunodeficiency virus (HIV). HIV testing is important for risk assessment and clinical management. This was a cross-sectional, multi-country study of adult MDR-TB index cases and HHCs. All adult and child HHCs were offered HIV testing if never tested or if HIV-negative >1 year previously when last tested. We measured HIV testing uptake and used logistic regression to evaluate predictors. A total of 1007 HHCs of 284 index cases were enrolled in eight countries. HIV status was known at enrolment for 226 (22%) HHCs; 39 (4%) were HIV-positive. HIV testing was offered to 769 (98%) of the 781 remaining HHCs; 544 (71%) agreed to testing. Of 535 who were actually tested, 26 (5%) were HIV-infected. HIV testing uptake varied by site (median 86%, range 0-100%; P < 0.0001), and was lower in children aged <18 years than in adults (59% vs. 78%; adjusted for site P < 0.0001). HIV testing of HHCs of MDR-TB index cases is feasible and high-yield, with 5% testing positive. Reasons for low test uptake among children and at specific sites-including sites with high HIV prevalence-require further study to ensure all persons at risk for HIV are aware of their status.

Delay in diagnosis and treatment among adult multidrug resistant tuberculosis patients in Yangon Regional Tuberculosis Center, Myanmar: a cross-sectional study

BackgroundDelays in diagnosis and treatment initiation may allow the emergence of new cases by transmission to the community, and is one of the challenges facing programme management of drug resistance in Myanmar. This study aimed to explore delays in diagnosis and treatment initiation, and associated factors among patients with multidrug-resistant tuberculosis.MethodsA cross-sectional study was conducted at Yangon Regional Tuberculosis Centre, Myanmar. Data were collected by face-to-face interviews and treatment-card reviews of all adult patients who had registered and started treatment with the standard regimen from May to November, 2017. Delay time was categorized by using median cut-off and analyzed using SPSS version 23.0. Logistic regression analysis was performed to assess the relative impact of predictor variables on diagnosis and treatment delays.ResultsA total of 210 patients participated in this study. The median diagnosis delay was 9 days, IQR 3 (8–11) and 58.6% of the patients experienced a long diagnosis delay. Below middle school education (adjusted odds ratio [AOR] = 2.75, 95% CI = 1.22–6.21), non-permanent salaried employment (AOR = 3.03, 95% CI = 1.32–6.95), co-existing diabetes mellitus (AOR = 5.06, 95% CI = 1.97–13.01) and poor awareness (AOR = 2.99, 95% CI = 1.29–6.92) were independent predictors of long diagnosis delay. The median treatment delay was 13 days, IQR 9 (8–17) and 51% of the patients experienced long treatment delay. Age 31–50 years (AOR = 4.50, 95% CI = 1.47–13.97) and age > 50 years (AOR = 9.40, 95% CI = 2.55–34.83), history with MDR-TB patient (AOR = 3.16, 95% CI = 1.29–7.69), > 20 km away from a Regional TB Centre (AOR = 14.33, 95% CI = 1.91–107.64) and poor awareness (AOR = 4.62, 95% CI = 1.56–13.67) were independent predictors of long treatment delay.ConclusionsStrengthening comprehensive health education, enhancing treatment adherence counseling, providing more Xpert MTB/RIF machines, expanding decentralized MDR-TB treatment centers, ensuring timely sputum transportation, provision of a patient support package immediately after confirmation, and strengthening contact-tracing for all household contacts with MDR-TB patients and active tuberculosis screening were the most effective ways to shorten delays in MDR-TB diagnosis and treatment initiation.

Resource utilization for multidrug-resistant tuberculosis household contact investigations (A5300/I2003).

Current guidelines recommend evaluation of the household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB); however, implementation of this policy is challenging. To describe the resource utilization and operational challenges encountered when identifying and characterizing adult MDR-TB index cases and their HHCs. Cross-sectional study of adult MDR-TB index cases and HHCs at 16 clinical research sites in eight countries. Site-level resource utilization was assessed with surveys. Between October 2015 and April 2016, 308 index cases and 1018 HHCs were enrolled. Of 280 index cases with sputum collected, 94 were smear-positive (34%, 95%CI 28-39), and of 201 with chest X-rays, 87 had cavitary disease (43%, 95%CI 37-50) after a mean duration of treatment of 8 weeks. Staff required 512 attempts to evaluate the 308 households, with a median time per attempt of 4 h; 77% (95%CI 73-80) of HHCs were at increased risk for TB: 13% were aged <5 years, 8% were infected with the human immunodeficiency virus, and 79% were positive on the tuberculin skin test/interferon-gamma release assay. One hundred and twenty-one previously undiagnosed TB cases were identified. Issues identified by site staff included the complexity of personnel and participant transportation, infection control, personnel safety and management of stigma. HHC investigations can be high yield, but are labor-intensive.

The burden of multidrug-resistant tuberculosis in children.

Childhood tuberculosis (TB) has historically been neglected, although in recent years there has been increased focus on this problem. In particular, there have been two efforts to estimate the burden of pediatric multidrug-resistant TB (MDR-TB). We review current estimates of the global incidence of pediatric MDR-TB disease. We then combine pediatric MDR-TB treatment data from the World Health Organization and recently published case fatality ratio estimates for children with TB to produce mortality estimates for children with MDR-TB. Finally, we combine treatment data and estimates of household size and disease risk to estimate how many children could be treated for probable or confirmed MDR-TB by carrying out household contact investigations around adult MDR-TB patients. Between 25 000 and 32 000 children develop MDR-TB disease annually, accounting for around 3% of all pediatric TB cases. Only 3-4% of these children are likely to receive MDR-TB treatment. We estimate that around 21% of children who develop MDR-TB disease will die. Carrying out household contact investigations around adult MDR-TB patients could find an estimated 12 times as many pediatric MDR-TB cases as are currently being identified. The diagnosis and treatment of children with MDR-TB needs to be prioritized by TB programs.

Burden of tuberculosis among household children of adult multi drug resistant patients and their response to first line anti tubercular drugs

ObjectiveThe objective of the study was to find the prevalence and incidence of tuberculosis among household contacts of adult Multi Drug Resistant-tuberculosis (MDR-TB) patients and to evaluate their response to first line anti-tubercular drugs. Materials and methodsThis prospective observational study was conducted from January 2014 to August 2015 at a tertiary care center in India. We included child contacts of ≤14year age of recently diagnosed adult MDR-TB patients. Detailed demographic, socio-economic and treatment history including previous treatment, MDR suspect criterion, and HIV status of the index case was collected. Enrolled children were screened for tuberculosis at initial screening as well as during each follow up visit. Extra-pulmonary or sputum negative pulmonary cases were treated in category I. Sputum positive patients were treated as per sensitivity report. All children were followed up for a period of 1year. ResultsEighty contacts of 21 index cases were enrolled. Disease prevalence at initial screening was 11.3% (n-9) and incidence on follow up was 1.4% (n-1). Prevalence of latent infection was 23.8% with incidence of 15.4% on follow up. Two patients were found to be sputum positive both sensitive to first line drugs. Failure rate of initial treatment was 10% (n-1). This child was initially sputum positive and sensitive to first line drug, but was later found to have MDR-TB. ConclusionMild disease in child contacts of MDR-TB can still show good respond to first line treatment especially in areas with high disease burden.

Bedaquiline versus placebo for management of multiple drug-resistant tuberculosis: A systematic review.

Background:Multidrug-resistant tuberculosis (MDR-TB) is associated with significant morbidity and mortality. Bedaquiline is the first drug approved for treating MDR-TB.Objectives:We performed a systematic review and meta-analysis to summarize the totality of all available evidence on the efficacy of bedaquiline for the management of MDR-TB.Materials and Methods:We searched the following PubMed and Cochrane Registry of Clinical Trials. Randomized controlled trials (RCTs) with a parallel design comparing bedaquiline versus any treatment for the management of MDR-TB in adults were eligible for inclusion. Data were pooled under a random effects model.Results:Two trials published as three manuscripts with a total of 207 patients were included. As per the Cochrane risk of bias tool, majority of parameter were labeled as high or unclear risk of bias. Bedaquiline compared with placebo was associated with a statistically significant decrease in time to conversion of positive sputum culture to negative at 8 and 24 weeks with a significant increase in mortality on long-term follow-up. There was no difference in completion rates between bedaquiline and placebo.Conclusion:Bedaquiline is an effective treatment modality for MDR-TB but needs to be balanced against significant mortality. Future Phase 3 RCTs are needed to make a conclusive recommendation.

BEDAQUILINE: A long but much fruitful wait since seventies

Tuberculosis (TB) is a major health problem in developing countries one of the leading cause of deaths due to infectious disease in the world. Drug treatment had being successful with anti-tubercular drugs available, but Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are serious forms of TB which have emerged as real concern. Bedaquiline (TMC-207 or R207910), is a new anti TB agent been approved as a part of drug regimen therapy in pulmonary MDR-TB. Bedaquiline acts on energy metabolism of the bacteria. It acts as a bactericidal drug. There are two important black box warnings for this drug, firstly prolongation of QT interval and secondly increased risk of death with bedaquiline as compared to placebo treatment. Fast track approval for bedaquiline was based on two phase 2 trials. The FDA has approved bedaquiline on Dec 2012, for the treatment of MDR-TB in adults (&gt;18 years) as part of combination therapy under the fast track designation, priority review and orphan-product designation based on two Phase II trials. Careful use of this drug along with monitoring of the potential adverse effects and drug interactions becomes very important, as this new anti-tubercular drug has being approved after forty years, since last anti tubercular drug was approved.doi: http://dx.doi.org/10.3126/mjsbh.v13i1.13000

Map the gap: missing children with drug-resistant tuberculosis.

The lack of published information about children with multidrug-resistant tuberculosis (MDR-TB) is an obstacle to efforts to advocate for better diagnostics and treatment. To describe the lack of recognition in the published literature of MDR-TB and extensively drug-resistant TB (XDR-TB) in children. We conducted a systematic search of the literature published in countries that reported any MDR- or XDR-TB case by 2012 to identify MDR- or XDR-TB cases in adults and in children. Of 184 countries and territories that reported any case of MDR-TB during 2005-2012, we identified adult MDR-TB cases in the published literature in 143 (78%) countries and pediatric MDR-TB cases in 78 (42%) countries. Of the 92 countries that reported any case of XDR-TB, we identified adult XDR-TB cases in the published literature in 55 (60%) countries and pediatric XDR-TB cases for 9 (10%) countries. The absence of publications documenting child MDR- and XDR-TB cases in settings where MDR- and XDR-TB in adults have been reported indicates both exclusion of childhood disease from the public discourse on drug-resistant TB and likely underdetection of sick children. Our results highlight a large-scale lack of awareness about children with MDR- and XDR-TB.

Management of emerging multidrug-resistant tuberculosis in a low-prevalence setting

Multidrug-resistant (MDR) tuberculosis (TB) is an emerging concern in communities with a low TB prevalence and a high standard of public health. Twenty-three consecutive adult MDR TB patients who were treated at our institution between 2007 and 2013 were reviewed for demographic characteristics and anti-TB treatment management, which included surgical procedures and long-term patient follow-up. This report of our experience emphasizes the need for an individualized approach as MDR TB brings mycobacterial disease management to a higher level of expertise, and for a balance to be found between international current guidelines and patient-tailored treatment strategies.

Dose Regimen of Para-Aminosalicylic Acid Gastro-Resistant Formulation (PAS-GR) in Multidrug-Resistant Tuberculosis

Resurgence of multidrug-resistant tuberculosis (MDR-TB) has raised a renewed interest in para-aminosalicylic acid (PAS) and other efficacious drugs. A gastro-resistant granule formulation (PAS-GR) was designed to be better tolerated than earlier forms of PAS, with fewer adverse effects from reduced production of meta-aminophenol. PAS release from PAS-GR granules is slower than with earlier formulations. Pharmacokinetic data are, however, limited and only a few studies have assisted in defining the best PAS-GR dose regimen. Interest in refining the latter continues and recent data contributed in better defining the optimal PAS-GR dose regimen in adults and children. The present paper draws on these recent studies, synthesizes pharmacokinetic results from different population groups, and draws comparisons with in vitro data and the results of earlier pharmacokinetic studies in order to discuss the most appropriate dosing regimen for PAS-GR. A comparative in vitro dissolution study was carried out with a 1 g acid PAS equivalent of various formulations of PAS and PAS-GR and in vitro-in vivo correlations. Retrospective comparisons between recent and earlier clinical studies were also gathered to clarify the dose regimen of PAS-GR in adults and children. Exposure after a 4 g twice- or three times daily dose regimen in adult MDR-TB patients confirmed that both dose regimens can be used. The twice-daily dose regimen does not, however, confer any safety margin over the potentiality of "too" high plasma concentrations after a three times daily dose regimen and may lead to under-dosage when a dose is missed, as compliance often decreases over time. Based on available data and practical considerations, a 4 g three times daily dose regimen of PAS-GR should be the preferred dose in hospital settings, where it remains the best regimen to cover the around-the-clock suppression of mycobacteria based on the minimal inhibitory concentration for PAS. In MDR-TB adults and in hospital settings, there is no safety advantage in administering a regimen of 4 g twice daily. As compliance is critical to the effectiveness of the treatment, a 4 g three times daily dose regimen may be more forgiving if the patient misses a dose.

Multidrug-resistant tuberculosis in children: evidence from global surveillance

Multidrug-resistant tuberculosis (MDR-TB) can affect persons of any age, but it remains unknown whether children are more or less likely than adults to have MDR-TB.Representative drug resistance surveillance data reported to the World Health Organization between 1994 and 2011 were analysed to test the association between MDR-TB and age group (children aged <15 years versus adults aged ≥15 years), using odds ratios derived by logistic regression with robust standard errors.Of 85 countries with data from nationwide surveys or surveillance systems, 35 reported at least one paediatric MDR-TB case. Aggregated data on age and drug susceptibility testing for 323 046 tuberculosis cases notified in these 35 countries were analysed. Odds ratios for MDR-TB in children compared to adults varied widely between countries. In Germany, Namibia, South Africa, the UK and the USA, MDR-TB was positively associated with age <15 years. In the remaining countries no association was established.Despite the limitations intrinsic to the use of surveillance data and to the challenges of diagnosing childhood tuberculosis, our analysis suggests that proportions of MDR-TB in children and adults are similar in many settings. Of particular concern is the association found between age <15 years and MDR-TB in southern African countries with high HIV prevalence.

Epidemiology and management of childhood multidrug-resistant tuberculosis

SUMMARY: Multidrug-resistant tuberculosis (TB) in children is mainly caused by transmission of drug-resistant strains causing infection and disease (i.e., primary drug-resistant TB) and, therefore, follows adult multidrug-resistant TB trends. Diagnosis is made by culture and phenotypic or genotypic drug susceptibility testing, either from the child’s or the adult source case’s Mycobacterium tuberculosis isolate. Treatment is mainly with second-line anti-TB drugs, building a regimen with four effective drugs; the principles of management are the same as for adults. Monitoring for adverse events is important as second-line drugs are more toxic than first-line treatment. With early diagnosis and treatment, outcome is better than in adults. New drugs and drug combinations are in development and should also be evaluated in children.