wIRA: hyperthermia as a treatment option for intracellular bacteria, with special focus on Chlamydiae and Mycobacteria.

The emergence of antibiotic-resistant bacteria in the last century is alarming and calls for alternative, nonchemical treatment strategies. Thermal medicine uses heat for the treatment of infectious diseases but its use in facultative and obligate intracellular bacteria remains poorly studied. In this review, we summarize previous research on reducing the infectious burden of Mycobacterium ulcerans and Chlamydia trachomatis by using water-filtered infrared A-radiation (wIRA), a special form of heat radiation with high tissue penetration and low thermal load on the skin surface. Mycobacterium ulcerans is a thermosensitive bacterium causing chronic necrotizing skin disease. Therefore, previous data on wIRA-induced improvement of wound healing and reduction of wound infections is summarized first. Then, pathogenesis and treatment of infections with M. ulcerans causing Buruli ulcer and of those with C. trachomatis infecting the ocular conjunctiva and resulting in blinding trachoma are discussed. Both bacteria cause neglected tropical diseases and have similar geographical distributions. Results of previous in vitro and in vivo studies using wIRA on M. ulcerans and C. trachomatis infections are presented. Finally, technical aspects of using wIRA in patients are critically reviewed and open questions driving future research are highlighted. In conclusion, wIRA is a promising tool for reducing infectious burden due to intracellular bacteria such as M. ulcerans and C. trachomatis.

Protective immune mechanisms of Yifei Tongluo, a Chinese herb formulation, in the treatment of mycobacterial infection.

Yifei Tongluo (YFTL) is a traditional Chinese medicine (TCM) formulation which has been shown clinical efficacy in treatment of patients with multidrug-resistant tuberculosis in China. However, the underlying mechanisms of the effects of YFTL are lacking. This study investigated the effects of YFTL on immune regulation with a mouse lung infection model with Bacille Calmette-Guérin (BCG). We found that compared with untreated mice, the lung mycobacterial load in YFTL-treated mice was significantly reduced, accompanied by alleviated pulmonary inflammation with reduction of pro-inflammatory cytokines and increase of prostaglandin E2 (PGE2). Flow cytometry analyses showed that Th1 cells were significantly higher in the lungs of YFTL-treated mice at early infection time. The results suggest that YFTL-treatment down-regulates pulmonary inflammation, which facilitates a rapid infiltration of Th1 cells into the lungs. Moreover, the Th1 cells in the lungs were resolved faster at later time concomitant with increased the regulatory T cells (Tregs). The reduction of mycobacterial burden associated with improved tissue pathology, faster Th1 cell trafficking, and accelerated resolution of Th1 cells in the lungs of YFTL-treated mice indicates that YFTL improves mycobacterial clearance by maintaining lung homeostasis and dynamically regulating T cells in the lung parenchyma, and suggests that YFTL can be used as host-directed therapies that target immune responses to mycobacterial infection.

René Dubos, tuberculosis, and the "ecological facets of virulence".

Reflecting on his scientific career toward the end of his life, the French-educated medical researcher René Dubos presented his flowering as an ecological thinker as a story of linear progression-the inevitable product of the intellectual seeds planted in his youth. But how much store should we set by Dubos's account of his ecological journey? Resisting retrospective biographical readings, this paper seeks to relate the development of Dubos's ecological ideas to his experimental practices and his career as a laboratory researcher. In particular, I focus on Dubos's studies of tuberculosis at the Rockefeller Institute in the period 1944-1956-studies which began with an inquiry into the tubercle bacillus and the physiochemical determinants of virulence, but which soon encompassed a wider investigation of the influence of environmental forces and host-parasite interactions on susceptibility and resistance to infection in animal models. At the same time, through a close reading of Dubos's scientific papers and correspondence, I show how he both drew on and distinguished his ecological ideas from those of other medical researchers such as Theobald Smith, Frank Macfarlane Burnet, and Frank Fenner. However, whereas Burnet and Fenner tended to view ecological interactions at the level of populations, Dubos focused on the interface of hosts and parasites in the physiological environments of individuals. The result was that although Dubos never fully engaged with the science of ecology, he was able to incorporate ecological ideas into his thought and practices, and relate them to his holistic views on health and the natural harmony of man and his environment.

Infections Caused by Rapidly Growing Mycobacteria spp in Children and Adolescents With Cancer.

BACKGROUND: Rapidly growing mycobacteria (RGM) infections in pediatric oncology patients have not been completely characterized. METHODS: We reviewed medical records of oncology patients at St. Jude Children's Research Hospital (St. Jude) from 1990 to 2010 with RGM infections and summarized the results of previously published cases. RESULTS: Twenty-five St. Jude patients had 27 episodes of infection. Approximately half of the cases occurred in patients with hematological malignancies and in males; infections were more common in white patients. Most patients were not neutropenic or lymphopenic. The most common causative species were Mycobacterium chelonae, Mycobacterium abscessus, and Mycobacterium fortuitum. Most isolates were susceptible to amikacin and clarithromycin; all were susceptible to at least 1 of these. Treatment regimens varied considerably, particularly with respect to the duration of antimicrobial chemotherapy. Two St. Jude patients died; both had pulmonary infections. The literature search identified an additional 58 cases of infection. Localized catheter-associated infections were more common than bloodstream infections in the current series than in previous reports, and outbreaks were not recognized. Otherwise, the demographic and clinical characteristics of patients were similar. CONCLUSIONS: Localized catheter-associated infections were most common in this largest reported single center experience reported to date. Pulmonary infection is uncommon in children but, as in adults, has a high mortality rate. Relatively short-term antimicrobial treatment and surgical debridement of infected tissue, if present, may be as effective for catheter-associated infections as prolonged antimicrobial use and may reduce adverse drug effects in these patients, who are vulnerable to drug-drug interactions and toxicity.

Seguimiento de un brote de infección en tejido blando causado por Mycobacterium abscessus posterior a la mesoterapia en Venezuela / Follow-up on an outbreak in Venezuela of soft-tissue infection due to Mycobacterium abscessus associated with Mesotherapy

Introducción Las infecciones de la piel y los tejidos blandos causadas por micobacterias no tuberculosas (MNT) se han asociado a procedimientos como inyecciones, liposucción, cirugía plástica y acupuntura. Estudiamos un brote de infección en tejidos blandos, debido a MNT posterior a mesoterapia, un procedimiento cosmético que consiste en inyectar una mezcla de sustancias para reducir hipotéticamente el tejido adiposo localizado. Métodos Se entrevistó a pacientes con lesiones en la piel, con antecedentes de mesoterapia, que acudieron al Departamento de Dermatología del Hospital Público de la Ciudad de Barinas, Venezuela, en el período comprendido entre noviembre de 2004 y febrero de 2005. Se tomaron muestras clínicas y ambientales para el aislamiento de micobacterias. Resultados Las entrevistas revelaron que 68 pacientes se infectaron con MNT. Todos recibieron tratamiento en el mismo centro estético, a cargo del mismo terapeuta y con el mismo producto. De las muestras de 5 pacientes se aisló Mycobacterium abscessus. Ninguna de las soluciones utilizadas en la mesoterapia estuvo disponible para el análisis, pero se aisló M. abscessus de una muestra del ambiente tomada en el centro cosmético. La tipificación de las cepas con técnicas basadas en PCR (ERIC-PCR, BOXA1R y RAPD) mostró que los aislados de los pacientes fueron indistinguibles entre sí, pero diferentes del aislado del medio ambiente del centro. Conclusión Lo más probable es que este brote se haya causado por un producto contaminado utilizado en la mesoterapia y no por una micobacteria del ambiente del centro. Hacemos énfasis en la importancia de un mejor control microbiológico de estos productos. Este brote, que afectó al menos a 68 pacientes, es en nuestro conocimiento el más grande descrito en la literatura médica posterior a mesoterapia (AU)

Introduction Skin and soft tissue infections caused by nontuberculous mycobacteria (NMT) are reported to be associated with injections, liposuction, plastic surgery, and acupuncture. Herein, we describe an outbreak of soft tissue infection due to NMT following mesotherapy, a cosmetic procedure involving injection of poorly defined mixtures alleged to reduce local adiposity. Methods Patients with skin lesions and a history of mesotherapy treatment, who visited the dermatology department of the public hospital in Barinas, Venezuela, from November 2004 to February 2005 were interviewed. Clinical and environmental samples were taken for mycobacteria isolation. Results The interviews revealed that 68 patients who had been treated for cosmetic purposes at the same clinic by the same therapist had received injections with the same product and were infected with NMT. Clinical specimens from 5 patients grew Mycobacterium abscessus. No mesotherapy solution was available for analysis but M. abscessus was isolated from an environmental sample in the clinic. PCR-based strain typing techniques (ERIC-PCR, BOXA1R and RAPD) showed that the patient's isolates were undistinguishable from each other but different from the environmental isolate. Conclusions This outbreak was likely caused by a contaminated injectable mesotherapy product and not by mycobacteria from the clinic environment. We emphasize the importance of better microbiological control of these products. To our knowledge, this outbreak, which affected at least 68 patients, appears to be the largest ever associated with mesotherapy and described in the literature (AU)

Tres casos de paniculitis por Mycobacterium abscessus posmesoterapia / Three Cases of Panniculitis due to Mycobacterium Abscessus After Mesotherapy

No disponible

No disponible

Experimental and clinical studies on Rifacinna--the new effective antituberculous drug (review).

A new rifamycin derivative 3-(4-cinnamyl-piperazinyl iminomethyl) rifamycin SV (T9) and its sodium salt (T11, Rifacinna((R))) were in vitro, in vivo, toxicologically and clinically investigated in comparison with rifampicin, rifapentine, rifabutin, rifalazil. Our experiments showed that Rifacinna exhibits excellent in vitro activity against Gram(+), Gram (-) aerobic, anaerobic pathogens and mycobacteria. Rifacinna is active against Staphylococcus, Streptococcus spp. including MRSA, with MIC90- 0.06-0.5 mg/L; against Gram(+), Gram (-) anaerobes with MIC90 0.5 - 1 mg/L; against Mycobacterium tuberculosis (MTB) with MIC90 0.062 mg/L; against MDR resistant MTB (25%-30 %) and Mycobacterium avium complex (MAC) strains with MICs 0.6-1.0 mg/L. It shows high intraphagocytic activity against MAC strains (0.06 0.125mg/L). Single daily dose 10 mg/kg provides complete erradication of mycobacteria in experimental generalized tuberculosis. Pharmacological studies established: excellent pharmacokinetic profile following single oral dose 10mg/kg Tmax 5-6 h, C(max) 5-9 mg/L, T1/2 33-34 h; low toxicity; no teratogenic and embryotoxic effects. The clinical study of Rifacinna shows higher therapeutic efficacy than Rifampicin in patients with infiltrative, disseminated and cavitary form of pulmonary tuberculosis, good tolerability and safety profile. Some of the recent patents related to the treatment of tuberculosis are discussed in this review article.

Non-tuberculous mycobacterial infections.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms in contrast to those belonging to the M. tuberculosi complex (MTB). NTM infects and causes disease only in hosts with local or general predisposing factors. Lung infection following inhalation of NTM is the most common NTM disease but soft tissue infections may occur in connection with contaminated trauma or surgery. Microbiological diagnosis is obtained by microscopy for acid-fast bacteria (AFB) on secretions or biopsies, and by culture on special media. With the high specificity of MTB- polymerase chain reaction (PCR), a positive AFB smear combined with negative MTB-PCR denotes infection with NTM. Sophisticated species diagnosis of cultured NTM is attained by various molecular methods, where 16S rDNA-sequencing remains the gold standard. The panorama of infection with different rapidly growing (RGM) or slowly growing mycobacteria (SGM) in Sweden is described. Sensitivity testing in vitro to antimycobacterial drugs against NTM does not always preclude the in vivo efficacy. Standard antimycobacterial treatment regimens have been defined for infection with several NTM species. Sensitivity testing should be performed in selected cases only, as in case of relapse or suspected development of resistance of the NTM strain. The spectrum of disease caused by NTM species that display a very low pathogenic potential is likely to widen over time as severe immunosuppression will continue to be prevalent in several patient categories.

Nontuberculous mycobacterial infections.

OBJECTIVE: To review the epidemiology, clinical manifestations, diagnosis, and treatment of nontuberculous mycobacterial infections other than Mycobacterium avium complex (MAC). DATA SOURCES: A MEDLINE search of English-language literature pertaining to nontuberculous mycobacteria other than MAC was performed. Additional literature was obtained from reference lists of pertinent articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Information judged by the author to be pertinent was selected for discussion. DATA SYNTHESIS: Mycobacterial infections, including those caused by nontuberculous mycobacteria other than MAC, have assumed greater importance over the past decade, due in part to the changing spectrum of immunosuppression as manifested by organ transplantation and HIV infection. Many pathogenic nontuberculous mycobacteria have been identified that are associated with a wide variety of localized, organ-specific, and systemic infections. Of concern, these organisms exhibit variable, species-specific susceptibility to traditional antimycobacterial drugs and other antimicrobials. In addition, long treatment courses and adjunctive surgical therapy are often required to effect cure. Important antimicrobials for the management of these infections include cefoxitin, imipenem/cilastatin, aminoglycosides (other than streptomycin), tetracyclines, macrolides, and trimethoprim/sulfamethoxazole, as well as traditional antimycobacterials. CONCLUSIONS: Nontuberculous mycobacteria have assumed an increasing role in disease etiology in both nonimmunocompromised and immunocompromised individuals. Advent of rapid diagnostic techniques and susceptibility testing has allowed the clinician to identify these organisms and initiate effective treatment on a more timely basis with an improved chance for cure. Few therapeutic agents are available for treatment of these infections, many of which are not considered classic antimycobacterials.

Applications for green fluorescent protein (GFP) in the study of host-pathogen interactions.

The green fluorescent protein (GFP) from Aequorea victoria is a novel fluorescent marker that has potential use in the study of bacterial pathogenicity. To explore some of the potential applications of GFP to the study of host-parasite interactions, we constructed two GFP expression vectors suitable for different facultative intracellular bacterial pathogens. The first expression vector was tested in the enteric pathogens, Salmonella typhimurium and Yersinia pseudotuberculosis, and the second vector tested in Mycobacterium marinum (Mm). Both expression vectors were found to be stable and to direct high levels of GFP synthesis. Standard epifluorescence microscopy was used to detect all three bacterial pathogenic species during the early and late stages of infection of live mammalian cells. Mm expressing gfp was also visualized in infected animal tissues. gfp expression did not adversely affect bacterial survival, nor did it compromise entry into mammalian cells or their survival within macrophages. In addition, all three gfp-expressing bacterial pathogens could be detected and sorted in a flow cytometer, either alone or in association with epithelial cells or macrophages. Therefore, GFP not only provides a convenient tool to image pathogenic bacteria, but allows the quantitative measurement of bacterial association with mammalian cells.

Rat polyarthritis: induction with adjuvants constituted with mycobacteria (and oils) from the environment.

Mycobacteria inhabiting plants, soils and water can cause arthritis in rats. The list of arthritogenic mycobacteria from animal sources must also be extended. The arthritogenic activity is present in dead bacteria and resists extraction into ethanol-ether (1:1 v/v). Polyarthritis is only induced in conjunction with certain (oily) lipids = coarthritogens: some of these lipids are present in/on skin, intestines, etc. Isostearic acid is also a coarthritogen. Preliminary observations suggest the leprosy bacillus (M. leprae) is not arthritogenic but may confer immunity to the M. tuberculosis arthritogen. Some adjuvant-active corynebacteria/propionibacteria did not cause polyarthritis in 2 rat strains (DA, PVG) responding vigorously to mycobacterial arthritogens.