Large intestine dysbacteriosis and therapy efficacy in patients with respiratory tract tuberculosis in sanatoria]

Long-term chemotherapy of tuberculosis leads to dysbacteriosis of the large intestine, that significantly decreases tolerance of tuberculosis drugs, provokes persistence of tuberculosis intoxication and retards involution of tuberculosis process in the lungs. Recovery of the bifidoflora and lactoflora due to the use of an original sour-milk drink developed by the authors was stated in 65 and 55% of the patients respectively. Moreover, it promoted higher tolerance of the chemotherapeutics since its composition includes amino acids, vitamins B, C, D and E, enzymes and microelements. It should be indicated that the drink was used simultaneously with the chemotherapy and did not require its discontinuation. Therefore, it is recommended that the scheme of the treatment of patients with pulmonary tuberculosis in sanatoria should include corrigating agents and in particular probiotics containing live bifido- and lactobacteria having no contraindications and side effects, and providing elimination of intestinal dysbacteriosis.     

Dynamics of the shedding of bacterial and ultrafine forms of mycobacteria during the chemotherapy of patients with pulmonary tuberculosis

The specific features of bacterial excretion by patients with pulmonary tuberculosis in the process of chemotherapy, depending on the duration of treatment, have been studied, and the time-course of the excretion of ultramicro forms of mycobacteria by patients with and without caverns in the lungs in the process of chemotherapy has been followed. The results of the detection of M. tuberculosis ultramicro forms with the use of the biological and bacteriological methods indicate that both these methods are highly effective and informative. The method of the direct reversion of ultramicro forms into coccoid ones in Shkol'nikova's culture medium with 10% of plasma added has proved to be the simplest. The injection of sputum filtrates containing filter-passing (ultramicro) forms of mycobacteria into experimental animals induced the development of specific minor tuberculous inflammation of a productive character without the caseation of granulomas or progressing; such inflammation coursed as a latent lympho-hematogenous process.     

Management of extra-pulmonary tuberculosis (excluding miliary and meningeal) in south and west Wales (1976-8).

In a retrospective survey of the management of extrapulmonary tuberculosis lymph node and genitourinary tuberculosis were found more commonly than bone and joint or gynaecological disease. Only 29% of patients received 18 moths'' chemotherapy while 31% received nine to 12 months'' treatment with rifampicin and isoniazid regimens and 34% had short-course chemotherapy with other regimens. Five patients were not offered any chemotherapy after diagnosis, and in five patients the diagnosis was overlooked because of administrative errors. One patient died from tuberculosis (renal). Poor drug compliance appeared less of a problem than in pulmonary tuberculosis. Only 14% of patients had their disease managed solely by consultants who were not specialists in chest disease. Liaison with a chest consultant did not necessarily ensure chemotherapy for 18 moths.     

Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice

We investigated the protective role of immune-sera against reactivation of Mycobacterium tuberculosis infection in SCID mice and found that passive immunization with sera obtained from mice treated with detoxified M. tuberculosis extracts (delivered in liposomes in a composition known as RUTI) exerted significant protection. Our SCID mouse model consisted of aerosol infection by M. tuberculosis, followed by 3 to 8weeks of chemotherapy with isoniazid+rifampicin (INH+RIF) (25 and 10mg/kg, respectively). After infection and antibiotic administration, two groups of mice were treated for up to 10weeks with intraperitoneal passive immunization using hyperimmune serum (HS) obtained from mice infected with M. tuberculosis, treated with chemotherapy (INH+RIF) for 8weeks and inoculated with RUTI (HS group) or with normal serum (CT group). Significant differences were found between HS and CT groups in the number of bacilli in the lungs (3.68+/-2.02 vs. 5.72+/-1.41log(10) c.f.u.), extent of pulmonary granulomatomous infiltration (10.33+/-0.67 vs. 31.2+/-1.77%), and percentage of animals without pulmonary abscesses (16.7% vs. 45.5%). These data strongly suggest a protective role of specific antibodies against lung dissemination of M. tuberculosis infection.     

Case holding in patients with tuberculosis in Botswana.

OBJECTIVE--To evaluate the effectiveness of daily supervised short course chemotherapy in a national tuberculosis programme. DESIGN--Observation of programme during 1984-90. In October 1986 short course chemotherapy was introduced with patients receiving treatment daily from staff in their nearest health facility. SETTING--Botswana national tuberculosis programme. SUBJECTS--All patients with tuberculosis. MAIN OUTCOME MEASURES--Proportions of patients complying with and defaulting from treatment (missing > or = 43 days'' treatment). RESULTS--2938 cases of tuberculosis were recorded in 1990, 1528 of which were of sputum positive pulmonary disease. 2711 (92.3%) patients complied with treatment and 227 (7.7%) defaulted. Before introduction of short course chemotherapy compliance was about 60% compared with over 90% in 1987-90. CONCLUSIONS--A programme using daily supervised short course chemotherapy integrated into the primary health care system is an effective method of treating tuberculosis. The costs of the programme need to be evaluated.     

The dependence of the inflammatory reaction on the properties of Mycobacterium tuberculosis and the course of specific pulmonary process

The systemic analysis of the inflammatory process in untreated patients with newly diagnosed infiltrative-destructive tuberculosis has been performed in the context of host mycobacterium interaction. Variability of acute phase proteins (APP) reflecting mobilization of nonspecific protective systems of the body did not depend on cytotoxicity of Mycobacterium tuberculosis (MBT). In 87.5% of patients the dependence between effectiveness of antituberculous chemotherapy (for three months) and combination of MBT characteristics and initial APP levels was found. Patients with effectiveness of therapy, which was inadequate to MBT cytotoxicity, were characterized by its dependence on the APP level and MBT sensitivity to antituberculous agents. Results of multifactorial analysis of parameters reflecting intensity of the inflammatory response, pathological process in the lungs, and characteristics of MBT suggest that the overall result of the host-pathogen interactions primarily depends on adequateness of protective systems of the host organism.     

Diagnostic Value of the Amplicor PCR Assay for Initial Diagnosis and Assessment of Treatment Response for Pulmonary Tuberculosis

We evaluated the Amplicor PCR assay as an initial diagnostic tool on the basis of clinical diagnosis, and assessed this assay as a follow-up test for patients with pulmonary tuberculosis during chemotherapy. Of the 208 specimens from 155 patients who were bacteriologically and/or clinically diagnosed with active tuberculosis before chemotherapy, 144 were Amplicor PCR-positive (sensitivity, 69.2%), which was equal to the results of culturing. Among 89 specimens which showed positive results by smear and culturing, the Amplicor PCR assay detected 87 (97.8%), whereas among 55 specimens which showed smear-negative but culture-positive results, the Amplicor PCR assay detected 46 (83.6%)(P = 0.003). No false positive results were found in the two systems (specificity, 100%, 120/120). The Amplicor PCR assay was also evaluated as a follow-up test using 926 specimens from 207 patients receiving active tuberculosis chemotherapy. Among 433 specimens which showed Amplicor-PCR positive, 222 (51.3%) were culture-negative. On the other hand, among 233 culture-positive specimens, only 12 (5.2%) were Amplicor PCR-negative. Therefore, this assay is useful for the rapid diagnosis of tuberculosis. The duration of Amplicor PCR-positive after culture-negative conversion was significantly associated with the presence of cavitary lesion, smear-positive specimens before treatment, and smear-positive specimens with negative cultures during chemotherapy.     

Evaluation of the nonspecific reactivity of the body in pulmonary tuberculosis by means of a "skin window"]

Cell reaction of the interstitial tissue in the aseptic inflammation areas was studied to determine the nonspecific reactivity of the organism in patients with infiltrative tuberculosis of the lungs. Rebuck's "skin window" method modified by Shurenkova was used. Results of investigations conducted in 15 patients and 10 healthy individuals indicated the absence in them of any significant difference in the character of the inflammatory exudate. Consequently, infiltrative tuberculosis of the lungs coursed against the background of unchanged nonspecific reactivity of the organism.     

Suboptimal activation of antigen-specific CD4+ effector cells enables persistence of M. tuberculosis in vivo

Adaptive immunity to Mycobacterium tuberculosis controls progressive bacterial growth and disease but does not eradicate infection. Among CD4+ T cells in the lungs of M. tuberculosis-infected mice, we observed that few produced IFN-γ without ex vivo restimulation. Therefore, we hypothesized that one mechanism whereby M. tuberculosis avoids elimination is by limiting activation of CD4+ effector T cells at the site of infection in the lungs. To test this hypothesis, we adoptively transferred Th1-polarized CD4+ effector T cells specific for M. tuberculosis Ag85B peptide 25 (P25TCRTh1 cells), which trafficked to the lungs of infected mice and exhibited antigen-dependent IFN-γ production. During the early phase of infection, ～10% of P25TCRTh1 cells produced IFN-γ in vivo; this declined to <1% as infection progressed to chronic phase. Bacterial downregulation of fbpB (encoding Ag85B) contributed to the decrease in effector T cell activation in the lungs, as a strain of M. tuberculosis engineered to express fbpB in the chronic phase stimulated P25TCRTh1 effector cells at higher frequencies in vivo, and this resulted in CD4+ T cell-dependent reduction of lung bacterial burdens and prolonged survival of mice. Administration of synthetic peptide 25 alone also increased activation of endogenous antigen-specific effector cells and reduced the bacterial burden in the lungs without apparent host toxicity. These results indicate that CD4+ effector T cells are activated at suboptimal frequencies in tuberculosis, and that increasing effector T cell activation in the lungs by providing one or more epitope peptides may be a successful strategy for TB therapy.     

Efficacy of cow's kumiss in the treatment of large intestine dysbacteriosis and its impact on tolerability of antituberculosis agents in patients with respiratory tract tuberculosis]

Dysbacteriosis of the large intestine is one of severe complications of long-term use of antituberculosis agents in the treatment of respiratory tract tuberculosis that results in a significant decrease of tolerability of antituberculosis agents, persistence of tuberculosis intoxication and slower involution of the tuberculosis process in the lungs. When the complex treatment with antituberculosis agents was accompanied by the use of cow's kumiss for correction of the large intestine dysbacteriosis, the intoxication signs disappeared in 12% of the patients in the main group, while in the patients of the control group the level of the intoxication syndrome increased twice. The rate of the tuberculosis lesions regression evident from the lung roentgenograms was 2.7-fold higher in the main group vs. the control (62 and 23% respectively). The indices of the lung functional capacity recovery in the patients of the main group vs. the control were also higher (41 and 33% respectively). Hepatic toxic reactions in the patients not given cow's kumiss for correction of dysbacteriosis were 8 times more frequent vs. the control. The results of the study made it possible to develop recommendations for phthisiologists in the use of cow's kumiss as one of the methods of pathogenetic therapy in complex treatment of patients with respiratory tract tuberculosis in sanatoria.     

Restoration of mycobacterial antigen-induced proliferation and interferon-gamma responses in peripheral blood mononuclear cells of tuberculosis patients upon effective chemotherapy

Peripheral blood mononuclear cells (PBMC) were obtained from culture-proven tuberculosis (TB) patients before and after 2 and 6 months of chemotherapy with a multi-drug regimen. PBMC were tested for cellular responses in antigen-induced proliferation and interferon-gamma (IFN-gamma) assays in response to complex mycobacterial antigens (whole cell Mycobacterium bovis BCG and M. tuberculosis, cell walls and short-term culture filtrate [ST-CF] of M. tuberculosis), fractionated ST-CF antigens (fractions F1-F10) and ESAT-6. The responses in TB patients before anti-TB treatment were low (median stimulation index (SI)=1-7, median delta IFN-gamma=0-12 U ml(-1), and percent responders=13-67%) to all the antigenic preparations. Following the administration of anti-TB chemotherapy for 2 months, there were significant (P<0.05) improvements in the cellular responses (median SI=9-76, median delta IFN-gamma=3-70 U ml(-1), and percent responders=33-100%) to most of the antigenic preparations tested. However, concanavalin A-induced proliferation responses of PBMC from the same patients before and after 2 months of chemotherapy were high and comparable (median SI=101 and 114, respectively, P>0.05, 100% responders). A further increase in IFN-gamma responses (median delta IFN-gamma=14-250 U ml(-1) and percent responders=43-100%) to mycobacterial antigens was observed in patients receiving chemotherapy for 6 months. Among the ST-CF fractions, F1 and F2 containing low molecular mass proteins resulted in the highest responses, whereas ESAT-6 showed responses comparable to these fractions only in a minority of the patients. HLA-DR typing of these patients showed heterogeneity in the expression of molecules encoded by HLA-DRB genes. These results show that effective chemotherapy restores cellular responses of TB patients to a large number of M. tuberculosis antigens, which could be useful in monitoring the efficacy of anti-TB treatment.     

乌体林斯联合化疗治疗耐多药肺结核疗效观察

目的探讨乌体林斯联合化疗治疗耐多药肺结核（MDR-TB）疗效。方法将146例耐多药肺结核患者随机分为乌体林斯加化疗的治疔组（76例）和仅用化疗的对照组（70例）。治疗组采用左氧氟沙星＋吡嗪酰胺＋乙胺丁醇＋利福喷丁＋异烟肼及乌体林斯1.72μg/m l深部肌注,每周2次;对照组单纯用左氧氟沙星＋吡嗪酰胺＋乙胺丁醇＋利福喷丁＋异烟肼方案治疗,疗程均为18个月。结果治疗6个月、12个月、18个月后,治疗组涂阳阴转率分别为67%、82%、92%,对照组涂阳阴转率分别为34%、44%、51%,痰菌阴转率治疗组显著高于对照组（P〈0.05）组。治疗组病灶吸收显著高于对照组。结论乌体林斯能增加肺结核患者的痰菌阴转率,促进病灶吸收好转,可以作为耐药性肺结核的辅助治疗。     

Corynebacterium pseudodiphtheriticum isolated from relevant clinical sites of infection: a human pathogen overlooked in emerging countries

Aims:  To examine the occurrence of and to determine the antimicrobial susceptibility of Corynebacterium pseudodiphtheriticum among patients with bacterial infections at a teaching hospital.
Methods and Results:  A total of 113 Coryne. pseudodiphtheriticum strains identified by conventional biochemical methods and API-Coryne System were recovered from patients from different age groups: 65·48% adults (18 to ≤59 years old), 9·73% aged (≥60 years old); 14·15% infants (<18 years old); 4·42% newborns (0–7 days). Micro-organisms were mostly related to infections in the urinary (29·2%) and respiratory tracts (27·45%) and intravenous sites (18·6%). Clinical samples were obtained only from 32·7% patients (26 adults, four aged, four infants and three newborns) presenting at least one of the predisposing conditions: end-stage renal disease; renal transplant; AIDS and Mycobacterium tuberculosis infection; cancer, hepatic cirrhosis; haemodialysis and catheter use. Antimicrobial susceptibility tests identified multiresistant phenotypes. Most strains (>50%) were resistant to oxacillin, erythromycin and clindamycin.
Conclusions:  Despite significant differences in age and functional status of patients Coryne. pseudodiphtheriticum may be implicated as a cause of respiratory and nonrespiratory human infections.
Significance and Impact of the Study:  Data are valuable for practitioners indicating the occurrence of multiresistant phenotypes and the possibility of severe infections due to Coryne. pseudodiphtheriticum , a pathogen usually overlooked in emerging countries.     

纤维支气管镜局部注药治疗耐药支气管内膜结核

目的:探讨和评价经纤维支气管镜局部注药对耐药肺结核合并支气管内膜结核患者的可行性和疗效.方法:对120例确诊为耐药肺结核合并支气管内膜结核患者,在进行全身抗结核治疗的同时依据患者志愿,随机分为两组,一组即单纯化疗者,另一组化疗+支气管镜注药组.比较两组病人在临床症状、痰菌阴转、影像学及纤维支气管镜下的疗效差异.结果:耐药肺结核合并支气管内膜结核经全身抗结核治疗辅以支气管镜局部给药,疗效显著优于单纯全身抗结核治疗.结论:使用支气管镜治疗耐药支气管内膜结核,可明显提高疗效、缩短病程,值得在临床上广泛应用.     

Survey of pulmonary tuberculosis in south and west Wales (1976-8).

In routine clinical practice 20% of patients with pulmonary tuberculosis were treated with the regimen recommended by the British Thoracic Association after the British trial of short-course chemotherapy. Despite the use of several regimens that could be considered inadequate, no patients from the survey within south and west Wales appears to have relapsed yet. Deaths from pulmonary tuberculosis continue at the same rate as 10 years ago. Patient default remains a difficult problem even with modern, less toxic, short-course regimens.     

Does the onset of tuberculosis in AIDS predict shorter survival? Results of a cohort study in 17 European countries over 13 years. AIDS in Europe Study Group.

OBJECTIVE--To assess the impact of tuberculosis on mortality in patients with AIDS. DESIGN--Community based cohort study. SETTING--52 centres in 17 countries (AIDS in Europe study). SUBJECTS--5249 patients who were alive and free of tuberculosis one month after the diagnosis of AIDS, enrolled between 1979 and 1989, and followed up until 1992. MAIN OUTCOME MEASURES--Onset of clinically active tuberculosis or death, or both. RESULTS--During a mean follow up period of 15 months 201 (4%) patients developed tuberculosis and 3889 (74%) died. Patients who developed tuberculosis survived significantly longer (median 22 months) than those who did not (median 16 months). This apparent survival advantage was due to patients who survived longer having more opportunity to develop tuberculosis (or any other disease). In models that took into account the time at which tuberculosis was diagnosed, the onset of tuberculosis was associated with a significant increase in mortality (adjusted relative hazard of death 1.34; 95% confidence interval 1.12 to 1.60). CONCLUSIONS--The onset of tuberculosis in patients with AIDS predicts a substantial increase in mortality. Whether this increased mortality is directly attributable to the tuberculosis remains uncertain. If the association is causal preventive chemotherapy and aggressive treatment of tuberculosis could improve survival in AIDS.     

Development and estimation of nanosomal rifampicin]

A lab-scale method for preparation of rifampicin-loaded polybutylcyanoacrylate nanoparticles (nanosames) was developed. The biodistribution of the nanosome-entrapped rifampicin after its intravenous administration was studied on healthy mice. The nanoparticles provided significant liver and spleen accumulation of rifampicin. Modification of the nanoparticles surface with poloxamer 407 or poloxamine 908 led to optimization of the biodistribution: the concentrations of rifampicin in the lungs and plasma increased, whereas the liver accumulation decreased vs. the unmodified nanoparticles. The increased lung accumulation of rifampicin enhanced bacterial clearance in the lungs of the mice infected with M. tuberculosis. The results showed that the use of the nanoparticles for optimization of the drug biodistribution was effective for increasing the efficacy of antiinfective chemotherapy.     

Attitudes about Tuberculosis Prevention in the Elimination Phase: A Survey among Physicians in Germany

Background

Targeted and stringent measures of tuberculosis prevention are necessary to achieve the goal of tuberculosis elimination in countries of low tuberculosis incidence.

Methods

We ascertained the knowledge about tuberculosis risk factors and stringency of tuberculosis prevention measures by a standardized questionnaire among physicians in Germany involved in the care of individuals from classical risk groups for tuberculosis.

Results

510 physicians responded to the online survey. Among 16 risk factors immunosuppressive therapy, HIV-infection and treatment with TNF-antagonist were thought to be the most important risk factors for the development of tuberculosis in Germany. Exposure to a patient with tuberculosis ranked on the 10^th position. In the event of a positive tuberculin-skin-test or interferon-γ release assay only 50%, 40%, 36% and 25% of physicians found that preventive chemotherapy was indicated for individuals undergoing tumor necrosis factor-antagonist therapy, close contacts of tuberculosis patients, HIV-infected individuals and migrants, respectively.

Conclusions

A remarkably low proportion of individuals with latent infection with Mycobacterium tuberculosis belonging to classical risk groups for tuberculosis are considered candidates for preventive chemotherapy in Germany. Better knowledge about the risk for tuberculosis in different groups and more stringent and targeted preventive interventions will probably be necessary to achieve tuberculosis elimination in Germany.     

Attempted immunotherapy for Mycobacterium tuberculosis with viral and protein vaccines based on Ag85B-ESAT6 in a mouse model

The increasing threat of drug-resistant strains of Mycobacterium tuberculosis (M. tb) and co-infection with human immunodeficiency virus (HIV) has worsened the international public health crisis and challenged conventional chemotherapy. Therapeutic vaccines, which possess the capacity to stimulate the immune system and affect the disease progression, deserve reconsideration to aid chemotherapy. Vaccines based on Ag85B-ESAT6 fusion protein were tested as potential immunotherapeutic vaccines against ongoing intravenous infection in a mouse model. Therapeutic efficacy was evaluated by enumeration of bacilli in infected tissues and by histological examination of the lungs. Ag85B-ESAT6 with the adjuvant dimethyl dioctadecylammonium bromide (DDA) - monophosphoryl lipid A (MPL) did not reduce bacterial load, however induced a sharp weight loss and worsened pathology. Recombinant virus-based vaccines failed to protect mice against tuberculosis either. More efforts should be taken to search for protective candidates and elucidate the mechanism for immunotherapy.     

The antilysozyme activity of Mycobacterium tuberculosis L forms

The method for the detection of antilysozyme activity (ALA) in M. tuberculosis L forms was developed. The level of ALA in M. tuberculosis L forms isolated from patients with different clinical forms of the disease varied within 1-5 micrograms. M. tuberculosis L forms with the ALA level > 4 micrograms were isolated from patients with the progressing course of the disease. The method for the prognostication of the course of the tuberculous process in the lungs by the results of the antilysozyme test was proposed.