Drug development for tuberculosis: the missing ingredient.
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Biomedical subjects
Publications and source records attributed to A Fanning.
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BACKGROUND: The risk for and determinants of transmission of tuberculosis in hospitals caring for moderate numbers of patients with tuberculosis remain uncertain. OBJECTIVE: To study the association of tuberculin conversion among health care workers with ventilation of patient care areas. DESIGN: Cross-sectional observational survey. SETTING: 17 acute-care community or university hospitals. PARTICIPANTS: All personnel who worked at least 2 days per week in the respiratory and physiotherapy departments or in selected nursing units. MEASUREMENTS: Participating workers underwent tuberculin skin testing and completed self-administered questionnaires. Previous tuberculin tests and bacille Calmette-Guérin vaccinations were verified. Records of patients with tuberculosis who were hospitalized in the 3 years preceding the study were reviewed. Air exchanges per hour in patient care areas were measured by using a tracer gas technique. Multivariate proportional hazards regression was used to estimate the effect of occupational factors on documented tuberculin conversion, after adjustment for nonoccupational factors, among participants with at least one previous negative result on tuberculin skin testing. RESULTS: Tuberculin conversion was associated with ventilation of general or nonisolation patient rooms of less than 2 air exchanges per hour (adjusted hazard ratio, 3.4 [95% CI, 2.1 to 5.8]); with work in moderate- to high-risk hospitals (adjusted hazard ratio, 2.2 [CI, 1.3 to 3.5]); and with work in the nursing (adjusted hazard ratio, 4.3 [CI, 2.7 to 6.9]), respiratory therapy (adjusted hazard ratio, 6.1 [CI, 3.1 to 12.0]), and physiotherapy (adjusted hazard ratio, 3.3 [CI, 1.5 to 7.2]) departments or housekeeping (adjusted hazard ratio, 4.2 [CI, 2.3 to 7.6]). Conversion was not associated with inadequate ventilation of respiratory isolation rooms (adjusted hazard ratio, 1.0 [CI, 0.8 to 1.3]). CONCLUSION: Tuberculin conversion among health care workers was strongly associated with inadequate ventilation in general patient rooms and with type and duration of work, but not with ventilation of respiratory isolation rooms.
The lipoxygenase-derived eicosanoids leukotrienes and lipoxins are well defined regulators of hemeodynamics and leukocyte recruitment in inflammatory conditions. Here, we describe a novel bioaction of lipoxin A(4) (LXA(4)), namely inhibition of leukotriene D(4) (LTD(4))-induced human renal mesangial cell proliferation, and investigate the signal transduction mechanisms involved. LXA(4) blocked LTD(4)-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity in parallel to inhibition of LTD(4)-induced mesangial cell proliferation. Screening of a human mesangial cell cDNA library revealed expression of the recently described cys-leukotriene(1)/LTD(4) receptor. LTD(4)-induced mesangial cell proliferation required both extracellular-related signal regulated kinase (erk) and PI 3-kinase activation and may involve platelet-derived growth factor receptor transactivation. LTD(4)-stimulated the MAP kinases erk and p38 via a pertussis toxin (PTX)-sensitive pathway dependent on PI 3-kinase and protein kinase C activation. On screening a cDNA library, mesangial cells were found to express the previously described LXA(4) receptor. In contrast to LTD(4), LXA(4) showed differential activation of erk and p38. LXA(4) activation of erk was insensitive to PTX and PI 3-kinase inhibition, whereas LXA(4) activation of p38 was sensitive to PTX and could be blocked by the LTD(4) receptor antagonist SKF 104353. These data suggest that LXA(4) stimulation of the MAP kinase superfamily involves two distinct receptors: one shared with LTD(4) and coupled to a PTX-sensitive G protein (G(i)) and a second coupled via an alternative G protein, such as G(q) or G(12), to erk activation. These data expand on the spectrum of LXA(4) bioactions within an inflammatory milieu.
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Globally, the proportion of all cases of tuberculosis (TB) caused by drug-resistant strains is increasing. We report the case of a Canadian citizen who acquired a highly drug-resistant strain of Mycobacterium bovis while visiting a relative with AIDS-related tuberculosis in Spain. The origin of the strain was traced using spoligotyping, a polymerase chain reaction (PCR)-based fingerprint technology, and the European DNA database. The level of primary drug resistance-all five first-line drugs and 19 of 21 second-line drugs-in this case was unprecedented in Canada. Isolation of this strain from a Canadian citizen represents the first report of its appearance in this hemisphere. The infection was contained and combined medical-surgical treatment delivered.
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SETTING: In efforts to promote the use of fixed-dose combinations (FDCs) for the treatment of tuberculosis (TB), the World Health Organization (WHO) and partners address the issue of quality assurance. OBJECTIVE: To provide guidance for the development of strategies for quality assurance of FDCs. DESIGN: This review examines the WHO strategies for and experience with quality assurance and supply of vaccines. RESULTS: Several elements in the strategies for quality assurance and supply of vaccines may be applicable for FDCs. At national level, the important strategies are to strengthen National Regulatory Authorities (NRA) and procurement systems and develop planning activities. Stressing quality assurance of FDCs in training activities for regulatory personnel and recommending that aid agencies require adherence to quality assurance policies as conditions for support would promote the implementation of quality assurance of FDCs at country level. At the global level, pre-qualification of manufacturers of FDCs should be explored as a mechanism to assure quality. The pre-qualification process should include evaluation of product files, initial testing for compliance and consistency of specifications, and site visits to producers and NRAs. The vaccine model defines criteria for reassessment that can be used for FDCs.
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A recent resurgence of interest in tuberculosis as a global health problem has accompanied the resurgence of tuberculosis in both industrialised and developing countries. It has also been demonstrated recently that tuberculosis treatment and control is one of the most cost effective of all medical interventions. The human immunodeficiency virus (HIV) epidemic and increasing resistance to antituberculous drugs complicate our response to the problem of tuberculosis. Chemotherapy with currently available agents is highly effective, not only in pulmonary tuberculosis in adults, but also in extrapulmonary disease, and in disease in children and even patients with concomitant HIV infection. Short course chemotherapy and intermittent therapy are as effective as older regimens. Measures, including directly observed therapy, to maximise compliance with therapy, are of utmost importance. An efficient programme which assures compliance with effective antituberculosis chemotherapy should be a priority for health spending even in those countries with fewest resources.
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Strain identification of Mycobacterium tuberculosis would prove whether transmission had occurred between individuals. A method to characterize strains of M. tuberculosis has been developed utilizing polymerase chain reaction (PCR). Purified chromosomal DNA of cultured clinical samples of M. tuberculosis were subjected to PCR using short (10-12 nucleotide) oligonucleotide primers. PCR products visualized after agarose gel electrophoresis and ethidium bromide staining demonstrated that different strains of M. tuberculosis give different banding patterns. This technique was used to confirm the relationship between cases of tuberculosis in several clusters, prove the lack of relationship between 2 isolates with the same antibiotic-resistance pattern, confirm a suspected mislabeling event, and suggest the source of infection in a case of tuberculous meningitis. This method is rapid and simple and does not require radioactive probes.
Atypical species of mycobacteria (AMB) are now the most common cause of granulomatous lymphadenopathy. It is important for pediatric surgeons to be aware of this disease, because excision is the mainstay of therapy. We have reviewed the experience with this disease in Alberta by reviewing the records of the Provincial Laboratory of Public Health from 1979 to 1990. This facility reviews all tuberculosis cultures for the province. A total of 74 cases of infection caused by AMB were identified in patients under the age of 15. Complete records were available for 53 of these cases. These infections were characterized by a short history (11.2 weeks) of remarkably nontender regional lymphadenopathy (usually cervicofacial, 45/50) in young (average age, 13.6 months), caucasian (48/53) children. Attempts to treat these lesions by incision and drainage or drug therapy were unsuccessful (12/12 failed), whereas primary excision was successful in 33 of 37 cases. Secondary excisions were also successful in 16 of 16 cases where required. The annual rate of AMB over the study period was 1.21 cases per 100,000 children; the rate of M tuberculosis lymphadenopathy was 0.3 per 100,000. In the absence of specific risk factors for human tuberculosis (family history, native Indian or Asian ethnic origin) AMB is the most likely cause of prolonged painless lymphadenopathy and should be treated early by complete excision.
Human infection with Mycobacterium bovis is rare in developed countries because of milk pasteurisation and the slaughter of infected cattle. An epizootic of M bovis infection in domesticated elk (Cervus elaphus) in Alberta, Canada, which started in April, 1990, prompted us to seek human contacts of elk herds. There were 446 identified contacts, in 394 of whom tuberculin skin tests were done. Of 81 contacts who were skin-test positive, 50 had been in contact with culture-positive animals. 6 of 106 subjects tested a second time became tuberculin positive. 1 case of active M bovis infection was diagnosed by sputum culture. The mode of transmission of M bovis from these farm animals to man is likely to be aerosolisation of infected particles. Because of the apparent susceptibility of farmed Cervidae (deer) to M bovis infection, and the evidence of spread to man, control measures to prevent human infection should be developed.
The evidence of zoonotic transmission of M. bovis infection in the 1 veterinarian is confirmed by growth of the organism from his sputum 6 months after animal contact. The high rate of initial tuberculin reactivity and the skin test conversions of 6 persons in contact with culture-positive animals strongly suggest that further human infection has taken place. However, the lack of baseline testing on 48/81 test-positive individuals and the relatively high proportion of immigrants in some occupational groups makes it impossible to determine the extent of reactivity and infection that can be attributed to handling diseased elk. The method of spread is likely by aerosolization of infected particles produced from the cough of live animals, or by the housing of infected material in the rendering plant or postmortem laboratory. Although isoniazid prophylaxis has not been demonstrated to be protective against M. bovis reactivation disease, it seems reasonable to offer the drug to those contacts who are newly infected. Follow-up of human contacts of animal tuberculosis must be carried out.