WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin.

The decline in the high incidence of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer-type dementia among the Chamorro population of the western Pacific islands of Guam and Rota, coupled with the absence of demonstrable viral and hereditable factors in this disease, suggests the gradual disappearance of an environmental factor selectively associated with this culture. One candidate is seed of the neurotoxic plant Cycas circinalis L., a traditional source of food and medicine which has been used less with the Americanization of the Chamorro people after World War II. Macaques were fed the Cycas amino acid beta-N-methylamino-L-alanine, a low-potency convulsant that has excitotoxic activity in mouse brain, which is attenuated by N-methyl-D-aspartate receptor antagonists. These animals developed corticomoto-neuronal dysfunction, parkinsonian features, and behavioral anomalies, with chromatolytic and degenerative changes of motor neurons in cerebral cortex and spinal cord. In concert with existing epidemiological and animal data, these findings support the hypothesis that cycad exposure plays an important role in the etiology of the Guam disease.

Approaches to defining day-one competency: a framework for learning veterinary skills.

Competency at graduation, in a variety of physical and attitudinal skills, is an essential outcome measure for courses training veterinary surgeons. The approach adopted by the Royal Veterinary College, London, to identify and define the expected skill competencies required of our veterinary undergraduates by the time of graduation is described. In addition, we demonstrate how this skill set was built into a framework that was aligned with other student learning objectives. This two-year project resulted in the publication of a day-one skills handbook, which was introduced to the college staff and students in 2007.

Global monitoring of collaborative TB-HIV activities.

Tuberculosis (TB) and human immunodeficiency virus (HIV) programs are increasingly working together towards providing universal access to integrated TB and HIV prevention, treatment, care and support services. To monitor progress we need to measure the delivery and impact of these services; however, the lack of investment in monitoring and evaluation and the added complexity of sharing data between two vertical programs, makes monitoring and evaluation of collaborative TB-HIV activities especially challenging. We describe the global system to record, report and analyse data on collaborative TB-HIV activities and summarize results to date. Although the data suggest that there is a steady increase in collaborative TB-HIV activities in many high-burden countries over time, we are already falling behind the globally agreed implementation milestones. This is due to a combination of slow implementation and lack of necessary tools and systems for capturing activity data. In particular, data from HIV program monitoring of TB screening, TB preventive treatments and TB infection control for people living with HIV is lacking. Much remains to be done by both programs to improve the implementation, monitoring and evaluation of collaborative TB-HIV activities and to optimize prevention, treatment and care for people infected with both TB and HIV, especially in areas at high risk of drug-resistant TB.

Drug-resistant tuberculosis and HIV in Ukraine: a threatening convergence of two epidemics?

OBJECTIVE: To investigate anti-tuberculosis (TB) drug resistance rates in Donetsk Oblast, Ukraine, and to explore the association between the epidemics of human immunodeficiency virus (HIV) and multidrug-resistant TB (MDR-TB). METHODS: All consecutive newly diagnosed and previously treated patients with sputum smear-positive TB presenting to all TB units in Donetsk Oblast over 12 months were invited to take part in the study. A total of 1293 and 203 patients with TB were tested for HIV and MDR-TB in the civilian and penitentiary sectors, respectively. RESULTS: Of those enrolled for the study, 307 were HIV-positive, 379 had MDR-TB, and 97 had MDR-TB and HIV co-infection. MDR-TB rates in the civilian sector were respectively 15.5% (95%CI 13.1-17.8) and 41.5% (95%CI 36.4-46.5) in newly diagnosed and previously treated TB patients. Among prisoners, MDR-TB rates were 21.8% (95%CI 12.4-31.2) in new cases and 52.8% (95%CI 43.9-61.7) in previously treated TB cases. HIV status was significantly associated with MDR-TB (OR 1.7, 95%CI 1.3-2.3). CONCLUSIONS: High MDR-TB rates and a positive association between MDR-TB and HIV epidemics were found in Donetsk Oblast. Urgent measures to improve HIV prevention, control of drug-resistant TB and collaboration between HIV and TB control activities need to be implemented without further delay.

Comparison of intermittent ethambutol with rifampicin-based regimens in HIV-infected adults with PTB, Kampala.

BACKGROUND: The human immunodeficiency virus (HIV) is a key factor responsible for the high rates of tuberculosis (TB) in sub-Saharan Africa. Treatment of TB with rifampicin (R, RMP) containing short-course regimens is highly effective in HIV-infected adults. We conducted a study to compare the efficacy and safety of intermittent ethambutol (E, EMB) with two RMP-containing regimens to treat pulmonary TB in HIV-infected patients. SETTING: National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda. DESIGN: This was a prospective cohort compared to two non-randomised control groups. The study group and the two control arms were treated with 2 months of isoniazid (H), RMP, pyrazinamide (Z) and EMB followed by 6 E3H3 for the study group and 4HR or 6HR for controls. RESULTS: Between April 1993 and March 2000, 136 patients were enrolled in the 2EHRZ/E3H3 arm, 147 in the 2EHRZ/4HR arm and 266 in the 2EHRZ/6HR arm. The relapse rate was 18.2 per 100 person-years observation (PYO) for the study regimen compared to 9.7/100 PYO (P = 0.0063) and 4.8/100 PYO (P = 0.0001) in patients treated with 2 EHRZ/4HR or 2EHRZ/6HR, respectively. CONCLUSION: The 2EHRZ/6E3H3 regimen is safe and effective but has a significant risk of relapse.

Formation of glycine and aminoacetone from L-threonine by rat liver mitochondria.

Threonine is a precursor of glycine in the rat, but the metabolic pathway involved is unclear. To elucidate this pathway, the biosynthesis of glycine, and of aminoacetone, from L-threonine were studied in rat liver mitochondrial preparations of differing integrities. In the absence of added cofactors, intact mitochondria formed glycine and aminoacetone in approximately equal amounts from 20 mM L-threonine, but exogenous NAD+ decreased and CoA increased the ratio of glycine to aminoacetone formed. In intact and freeze-thawed mitochondria, the ratio of glycine to aminoacetone formed was markedly sensitive to the concentration of L-threonine, glycine being the major product at low L-threonine concentrations. Disruption of mitochondrial integrity by sonication (1 min) decreased the ratio of glycine to aminoacetone formed, and in 20000 X g supernatant fractions from sonicated (3 min) mitochondria, aminoacetone was the major product. The main non-nitogenous two-carbon compound detected when intact mitochondria catabolized L-threonine to glycine was acetate, which was probably derived from deacylation of acetyl-CoA. These results suggest that glycine formation from L-threonine in rat liver mitochondria occurred primarily by the coupled activities of threonine dehydrogenase and 2-amino-3-oxobutyrate CoA-ligase, the extent of coupling between the enzymes being dependent upon a close physical relationship and upon the flux through the dehydrogenase reaction. In vivo glycine synthesis would predominate, and aminoacetone would be a minor product.

Performance-related allowances within the Malawi National Tuberculosis Control Programme.

SETTING: National Tuberculosis (TB) Control Programme (NTP), Malawi. OBJECTIVES: To determine the feasibility and effectiveness of performance-related allowances for NTP personnel working at central and regional levels in Malawi. In particular, to determine 1) whether programme staff can complete 6-monthly self-assessment forms related to the tasks they are expected to perform during that period, and 2) whether the NTP can achieve four key programme targets related to case finding, treatment outcome and the sending of sputum specimens for drug resistance monitoring. DESIGN: A descriptive study. RESULTS: For January to June 2003, 25 personnel completed self-assessment forms, and in all cases individual performance was judged satisfactory. For July to December 2003, 21 personnel completed self-assessment forms, and in 20 cases individual performance was judged satisfactory. In the first quarter of 2003, only one target was achieved for the country, and NTP personnel were awarded one quarter of the performance payment. In the third quarter, two targets were achieved and NTP personnel were awarded one half of the performance payment. CONCLUSION: It is feasible to implement performance-related payments for NTP personnel. Ways to routinely introduce such a system for NTP and other staff in the health sector urgently need to be explored.

Can we get more HIV-positive tuberculosis patients on antiretroviral treatment in a rural district of Malawi?

The World Health Organization (WHO) has set a target of treating 3 million people with antiretroviral treatment (ART) by 2005. In sub-Saharan Africa, HIV-positive tuberculosis (TB) patients could significantly contribute to this target. ART (stavudine/lamivudine/nevirapine) was initiated in Thyolo district, Malawi, in April 2003, and all HIV-positive TB patients were considered eligible and offered ART. Despite this, only 44 (13%) of 352 TB patients were eventually started on ART by the end of November 2003. Most TB patients leave hospital after 2 weeks to complete the initial phase of anti-tuberculosis treatment (rifampicin-based) in the community, and ART is offered to HIV-positive TB patients after they have started the continuation phase of treatment (isoniazid/ ethambutol). ART is only offered at hospital, while the majority of TB patients take their continuation phase of anti-tuberculosis treatment from health centres. HIV-positive TB patients therefore find it difficult to access ART. In this paper, we discuss a series of options to increase the uptake of ART among HIV-positive TB patients. The main options are: 1) to hospitalise HIV-positive TB patients with a view to starting ART in the continuation phase in hospital; 2) to decentralise ART delivery so ART can be delivered at health centres; 3) to replace nevirapine with efavirenz so ART can be started earlier in the initial phase of anti-tuberculosis treatment. Decentralisation of ART from hospitals to health centres would greatly improve ART access.

WHO clinical staging of HIV infection and disease, tuberculosis and eligibility for antiretroviral treatment: relationship to CD4 lymphocyte counts.

SETTING: Thyolo district, Malawi. OBJECTIVES: To determine in HIV-positive individuals aged over 13 years CD4 lymphocyte counts in patients classified as WHO Clinical Stage III and IV and patients with active and previous tuberculosis (TB). DESIGN: Cross-sectional study. METHODS: CD4 lymphocyte counts were determined in all consecutive HIV-positive individuals presenting to the antiretroviral clinic in WHO Stage III and IV. RESULTS: A CD4 lymphocyte count of < or = 350 cells/microl was found in 413 (90%) of 457 individuals in WHO Stage III and IV, 96% of 77 individuals with active TB, 92% of 65 individuals with a history of pulmonary TB (PTB) in the last year, 91% of 89 individuals with a previous history of PTB beyond 1 year, 81% of 32 individuals with a previous history of extra-pulmonary TB, 93% of 107 individuals with active or past TB with another HIV-related disease and 89% of 158 individuals with active or past TB without another HIV-related disease. CONCLUSIONS: In our setting, nine of 10 HIV-positive individuals presenting in WHO Stage III and IV and with active or previous TB have CD4 counts of < or = 350 cells/microl. It would thus be reasonable, in this or similar settings where CD4 counts are unavailable for clinical management, for all such patients to be considered eligible for antiretroviral therapy.

Tuberculosis and HIV: current status in Africa.

PIP: Having radically and permanently altered the face of tuberculosis (TB) in Africa, HIV/AIDS is the major threat to TB control programs in Africa. As HIV prevalence rises, so will TB rates. TB rates will plateau once HIV infection does. The control of TB therefore partly depends upon the control of HIV transmission. The current epidemiological situation is described with regard to TB case notification, incidence estimates, and projections; TB and HIV co-infection; and evidence of the interaction between TB and HIV. The impact of HIV upon the clinical management of TB with regard to diagnostic obstacles and treatment complications is considered, followed by an examination of the threats and opportunities for National Tuberculosis Program activities in Africa in the context of HIV/AIDS. Community-based TB care approaches and the role of isoniazid preventive therapy in HIV-infected people are also considered.^ieng

Infection and morbidity in patients with tuberculosis in Nairobi, Kenya.

OBJECTIVE: To examine the role of acute infection as a cause of morbidity in patients with tuberculosis. DESIGN: Cross-sectional documentation of predefined acute morbid events. SETTING: Infectious Diseases Hospital, Nairobi, Kenya. PATIENTS: Adults (> or = 15 years), inpatients and outpatients with a diagnosis of tuberculosis presenting with one or more of a series of clinical features. A new event was defined as one occurring at least 1 week after the initial event. INTERVENTIONS: Patients' treatment was modified depending on the results of laboratory investigations. MAIN OUTCOME MEASURES: There were 642 events from 398 patients, 235 HIV-positive patients had 438 events and 163 HIV-negative patients had 204 events (P < 0.0001). Forty-two out of the 235 (18%) HIV-positive patients were bacteraemic compared with nine out of the 163 (6%) HIV-negative patients (P = 0.0003). The most common isolates from blood were Salmonella typhimurium and Streptococcus pneumoniae. RESULTS: Faecal specimens were obtained more commonly from HIV-positive patients (P < 0.001), and often contained bacterial pathogens. CONCLUSIONS: Many of the causes of morbidity in patients with tuberculosis and HIV are not due to tuberculosis or antituberculous therapy, and will not be identified without microbiological investigation.

PIP: Tuberculosis (TB) is a common complication of HIV in Africa. A 1988-89 study further confirmed that considerable morbidity and mortality from acute bacterial infection occurred in HIV patients. It has also been found that anti-TB therapy seems to be as effective in HIV-positive as in HIV-negative TB patients. This paper reports on the level and nature of infectious morbidity suffered by HIV-positive patients receiving treatment for TB. The assessment is based upon a sample of inpatients and outpatients at the Infectious Diseases Hospital in Nairobi. Patients were aged 15 years and older, with a TB diagnosis presenting with 1 or more of a series of clinical features. 642 morbid events were seen in 398 patients: 235 HIV-positive patients had 438 event and 163 HIV-negative patients had 204 events. 18% of the HIV-positive patients versus 6% of the HIV-negative patients were bacteremic. Salmonella typhimurium and Streptococcus pneumoniae were most commonly isolated from sera, while fecal specimens were obtained more commonly from HIV-positive patients and often contained bacterial pathogens. The authors conclude that many causes of morbidity in patients with TB and HIV are not due to TB or anti-TB therapy and will not be identified without microbiological investigation. These results suggest that even with effective anti-TB chemotherapy HIV-positive patients will remain or become unwell.

The impact of HIV on infectiousness of pulmonary tuberculosis: a community study in Zambia.

OBJECTIVE: To examine the impact of HIV on infectiousness of pulmonary tuberculosis (TB). DESIGN: A cross-sectional tuberculin survey carried out among household contacts of HIV-1-positive and negative patients with bacteriologically confirmed pulmonary TB. Contacts were also examined for active TB. SETTING: Index cases were recruited from patients attending the University Teaching Hospital in Lusaka, Zambia and household contacts were examined during visits to their homes within Lusaka. PATIENTS, PARTICIPANTS: A total of 207 contacts of 43 HIV-positive patients, and 141 contacts of 28 HIV-negative patients with pulmonary TB were examined. MAIN OUTCOME MEASURES: Proportion of contacts of HIV-positive and negative index cases with a positive tuberculin response (diameter of induration > or = 5 mm to a dose of 2 tuberculin units). RESULTS: Fifty-two per cent of contacts of HIV-positive pulmonary TB patients had a positive tuberculin response compared with 71% of contacts of HIV-negative patients (odds ratio, 0.43; 95% CI, 0.26-0.72; P < 0.001). This difference persisted after allowing for between-household variations in the tuberculin response. Tuberculin response in the contact was related to age of contact, intimacy with the index case and crowding in the household. However, the effect of HIV status of the index case was not confounded by these variables. Tuberculin response in the contact was also related to the number of bacilli seen in the sputum smear of the index case which partially explained the effect of HIV status of the index case. Active TB was diagnosed in 4% of contacts of HIV-positive and 3% of contacts of HIV-negative cases, respectively (P = 0.8). CONCLUSIONS: HIV-positive patients with pulmonary TB may be less infectious than their HIV-negative counterparts and this may partly be explained by lower bacillary load in the sputum.

PIP: Between April and December 1989, the chest clinic of the University Teaching Hospital in Lusaka, Zambia, confirmed pulmonary tuberculosis (TB) in 141 adults, 95 (67%) of whom were HIV-1 seropositive. Health workers made home visits to 71 of the index cases (43 HIV-1 positive and 28 HIV-1 negative) to learn whether the 348 household members would also develop TB, thus allowing researchers to determine the effect of HIV on infectiousness of TB. Contacts of HIV-1 positive patients developed TB at a lower rate than did those of HIV-1 negative patients (52% vs. 71%; odds ratio [OR] = 0.43; p .001). This difference continued even after controlling for between-household variations, indicating that confounding variables did not account for the difference. Age of contact, intimacy with the index case, and crowding in the household were associated with the tuberculin response in the contact, but they did not confound the effect of HIV status. Tuberculin response in the contact was associated with the number of bacilli in the sputum smear (crude OR = 3.13; p = .013, and adjusted OR =1.84; p = .28), suggesting that the number of bacilli somewhat explained the difference in infectiousness between HIV-1 positive and HIV-1 negative patients. 12 contacts (8 of HIV-positive cases and 4 of HIV-negative cases) developed active TB after the TB diagnosis in the index case. These findings clearly demonstrated that infection with Mycobacterium tuberculosis was less likely in household members of HIV-1 positive cases than in those of HIV-1 negative cases. The lower bacillary load in the sputum in HIV- 1 cases may have accounted somewhat for the lower infectiousness of pulmonary TB.

Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial.

OBJECTIVES: To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV-1-infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV-1-infected adults. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial in Nairobi, Kenya. SUBJECTS: Six hundred and eighty-four HIV-1-infected adults. MAIN OUTCOME MEASURES: Development of tuberculosis and death. RESULTS: Three hundred and forty-two subjects received isoniazid and 342 received placebo. The median CD4 lymphocyte counts at enrolment were 322 and 346 x 10(6)/l in the isoniazid and placebo groups, respectively. The overall median follow-up from enrolment was 1.83 years (range, 0-3.4 years). The incidence of tuberculosis in the isoniazid group was 4.29 per 100 person-years (PY) of observation [95% confidence interval (CI) 2.78-6.33] and 3.86 per 100 PY of observation (95% CI, 2.45-5.79) in the placebo group, giving an adjusted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49-1.71). The adjusted rate ratio for tuberculosis for isoniazid versus placebo for tuberculin skin test (TST)-positive subjects was 0.60 (95% CI, 0.23-1.60) and for the TST-negative subjects, 1.23 (95% CI, 0.55-2.76). The overall adjusted mortality rate ratio for isoniazid versus placebo was 1.18 (95% CI, 0.79-1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST-positive of 0.33 (95% CI, 0.09-1.23) and for TST-negative subjects, 1.39 (95% CI, 0.90-2.12). CONCLUSIONS: Overall there was no statistically significant protective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST-positive subjects, where reactivation is likely to be the more important pathogenetic mechanism, there was some protection and some reduction in mortality, although this was not statistically significant. The small number of individuals in this subgroup made the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rapid progression to disease or insufficient duration of isoniazid in subjects with relatively advanced immunosuppression. The rate of drug resistance observed in subjects who received isoniazid and subsequently developed tuberculosis was low.

The interaction of beta-N-methylamino-L-alanine with bicarbonate: an 1H-NMR study.

The mode of action of the neurotoxic, non-protein amino acid beta-N-methylamino-L-alanine (L-BMAA) is unknown. We have shown, using 1H-NMR spectroscopy, that L-BMAA forms a stable adduct with bicarbonate (probably a carbamate). The properties of this adduct may explain the observation that L-BMAA and N-methyl-D-aspartic acid appear to act at the same central nervous system receptors.

Resistance to trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. Implication of folinic acid.

Pneumocystis carinii pneumonia is a well-known complication of immunosuppression in renal transplant recipients. Treatment is generally with trimethoprim-sulfamethoxazole (TMP-SMZ). A case of Pneumocystis pneumonia failed to respond to TMP-SMZ until concomitant administration of folinic acid was stopped. Physicians should be alerted to the possibility that folinic acid may impair the efficacy of TMP-SMZ in Pneumocystis carinii infection.

The neurolathyrogen, beta-N-oxalyl-L-alpha,beta-diaminopropionic acid, is a potent agonist at 'glutamate preferring' receptors in the frog spinal cord.

A neurotoxic amino acid, beta-N-oxalyl-L-alpha,beta-diaminopropionate (beta-ODAP), found in seeds of Lathyrus sativus and a possible causative agent of neurolathyrism, was equipotent with kainate as a depolarizing agent of frog spinal cord ventral roots. beta-ODAP and kainate appeared to act on a common receptor, as their actions could not be differentiated pharmacologically. These results could explain some of the symptoms of neurolathyrism.