Increasing the effectiveness of antibiotic therapy by correcting immunologic disorders with vitamin A in patients with brucellosis

Experimental studies and clinical trials were performed on possible increase of antibiotic therapy efficacy in brucellosis patients by correction of the immunity disorders with vitamin A. It was experimentally shown that vitamin A increased cellular immunity and accelerated sanation of guinea pigs sensitized with Brucella abortus 19 BA. The clinical trials demonstrated that the use of vitamin A in a dose of 33,000 IU thrice a day for 10 to 12 days during the complex treatment of patients with acute (36 persons) and subacute (57 persons) brucellosis lowered the average period of manifestation of the disease clinical signs and formation of the antibodies, increased the skin allergic sensitivity, the lymphocyte blast cell transformation, the total number and subpopulations of the active T-cells, theophylline-resistant lymphocytes, phagocytic and metabolic activity of neutrophils, showed 1.5- and 2-fold increased in the frequency of the infection transformation into a chronic process in patients with acute or subacute brucellosis, respectively.     

Ciprofloxacin in the treatment of patients with brucellosis]

With the aim to estimate the clinical and immunological efficiency of the ciprofloxacin (cifloxinal) 105 patients with acute (51), subacute (19) and chronic (35) brucellosis were studied. Control group (17 patients with acute and 30 patients with chronic brucellosis) have been treated with combination of two antibiotics: doxycycline and rifampicin. Ciprofloxacin in a dose 500 mg bid within 14 days in acute stage and 20 days in chronic stage of disease essentially reduced duration of local inflammatory processes of brucellosis with simultaneous treatment of the chronic infection focus, provides good proximate and distant outcomes of treatment. Ciprofloxacin can be considered as an alternative drug for the treatment of brucellosis, more effective (clinically and immunologically) than a combination of two antibiotics: doxycycline and rifampicin.     

Isoprinosine in the treatment of herpes virus infections in children with leukaemia and malignant lymphoma

Isoprinosine was given to 15 children with lymphoblastic diseases and 3 adults during infections with herpes viruses - herpes simplex (HSV) and varicella-zoster viruses (VZV). The control group included 7 children who had previously suffered from infections with HSV and VZV without being treated with isoprinosine. The clinical observations showed a significant inhibitory effect of isoprinosine on viral infections, with the duration of the disease being shortened considerably. The authors think isoprinosine treatment to be justified in viral infections, especially in children with neoplastic diseases, because of the immunostimulating action of the drug, rapid clinical improvement and good tolerance of the drug.     

Evaluation of the treatment of chronic active hepatitis (HBsAg+) with isoprinosine. II. Immunological studies]

A two-month treatment of the chronic active hepatitis (HBsAg+) with isoprinosine produced quantitative and functional T-cells populations in patients with cellular response disorders. Immunological studies have shown that such an effect of isoprinosine lasted for about 4-5 months. Repeated administration of isoprinosine for one month normalized recurrent abnormalities in the monitored immunological parameters.     

The T mu- and T gamma-lymphocyte count and their ratio in patients with brucellosis of various focal natures

The content of T mu- and T gamma-lymphocytes and their ratio in patients having subacute and chronic brucellosis with different foci of infection have been studied. The relationship between the decrease in the levels of T mu- and T gamma-cells and the clinical form of the disease and its clinical manifestations, such as polyarthritis, has been established. Manifestations of disturbances in the T mu-cell/T gamma-cell ratio were more pronounced in patients with subacute brucellosis in whom the lesions of the osteoarticular system prevailed. The detected changes in the counts of immunoregulatory cells in brucellosis are assumed to be of pathogenetic importance.     

T mu and T gamma-lymphocyte counts and their ratio in patients with brucellosis

The levels of circulating T mu- and T gamma-lymphocytes in brucellosis patients have been studied in relation to the clinical form of the disease, the severity of the process and the allergic transformation of the body. A decrease in the content of lymphocytes, affecting mainly T mu-cells and less commonly T gamma-cells, as well as a change in their ratio has been revealed. The level of this decrease depended on the clinical form of brucellosis, the severity of the course of acute and subacute brucellosis, the phase of chronic brucellosis and the allergic transformation of the body. The disproportion of immunoregulating cells in brucellosis, revealed in this study, is supposed to be of pathogenetic importance.     

Results of the treatment of papilloma and bronchogenic carcinoma with interferon alpha

The results of treatment of two patients with bronchial tumor and papillomatosis with interferon alpha combined with cytostatics and isoprinosine are discussed. Interferon alpha was administered to the bronchi and directly into the tumors. Complete recovery was achieved in case of the bronchial papillomatosis and partial remission in case of cancer. It seems that combined interferon, cytostatic and isoprinosine therapy may prolong patients' survival.     

A simple enzyme immunoassay for detecting brucellosis antibodies

Abstract A simple enzyme immunoassay was developed and evaluated for serological diagnosis of brucellosis in 25 patients with various forms of brucellosis and 292 control patients with other conditions and disorders. All brucellosis patients gave a positive test with the initial sample. In 3 acute, febrile brucellosis patients with follow-up sera taken during therapy a sharp drop in specific antibody was noted. There was a less pronounced antibody reduction in 1 chronic and 2 relapse patients and an antibody increase in 1 chronic and 1 relapse case. All control samples gave negative results. In addition, the assay was evaluated as a screening test with 315 sera from 'healthy' individuals living in a brucellosis focus and representing 15% of that population. 11.5% (34/293) of subjects with no reported history of brucellosis and 45% (10/22) of cases treated in the past gave a positive test result. The agreement in those samples between the assay and the serum agglutination test was 95.5%.     

Antibiotic binding by leukocytes from brucellosis patients

Antibiotic binding by leukocytes from patients with chronic brucellosis was studied in vitro. The pathogens were located intracellularly. The specimens were collected during the disease aggravation prior to the treatment and at the beginning of the remission after the routine therapy. It was found that during the disease aggravation at the intoxication peak and accumulation of a large number of Brucella in the cells binding of methacycline, rifampicin and gentamicin somewhat increased. After completion of the treatment course when the number of Brucella in the leukocytes markedly lowered, up to disappearance, the antibiotic binding decreased and reached the control figures. Penetration of erythromycin into the cells infected with Brucella lowered at the disease peak and remained at that level with an insignificant tendency to normalization at the beginning of the clinical remission after the treatment. The facts suggested that intracellular localization of the bacteria would change the quantitative characteristics of interaction of the cells, i.e. human leukocytes with antibacterial chemotherapeutic agents. The direction of the shifts must depend on the particular proportion of various types of mechanisms for penetration of drugs into the intracellular medium.     

Clinical Manifestations of Human Brucellosis: A Systematic Review and Meta-Analysis

Background

The objectives of this systematic review, commissioned by WHO, were to assess the frequency and severity of clinical manifestations of human brucellosis, in view of specifying a disability weight for a DALY calculation.

Methods/Principal Findings

Thirty three databases were searched, with 2,385 articles published between January 1990–June 2010 identified as relating to human brucellosis. Fifty-seven studies were of sufficient quality for data extraction. Pooled proportions of cases with specific clinical manifestations were stratified by age category and sex and analysed using generalized linear mixed models. Data relating to duration of illness and risk factors were also extracted. Severe complications of brucellosis infection were not rare, with 1 case of endocarditis and 4 neurological cases per 100 patients. One in 10 men suffered from epididymo-orchitis. Debilitating conditions such as arthralgia, myalgia and back pain affected around half of the patients (65%, 47% and 45%, respectively). Given that 78% patients had fever, brucellosis poses a diagnostic challenge in malaria-endemic areas. Significant delays in appropriate diagnosis and treatment were the result of health service inadequacies and socioeconomic factors. Based on disability weights from the 2004 Global Burden of Disease Study, a disability weight of 0.150 is proposed as the first informed estimate for chronic, localised brucellosis and 0.190 for acute brucellosis.

Conclusions

This systematic review adds to the understanding of the global burden of brucellosis, one of the most common zoonoses worldwide. The severe, debilitating, and chronic impact of brucellosis is highlighted. Well designed epidemiological studies from regions lacking in data would allow a more complete understanding of the clinical manifestations of disease and exposure risks, and provide further evidence for policy-makers. As this is the first informed estimate of a disability weight for brucellosis, there is a need for further debate amongst brucellosis experts and a consensus to be reached.     

Indices of phagocytosis of S and R forms of Brucella in patients with acute and chronic brucellosis caused by Brucella abortus

The characteristics of phagocytosis (phagocytic activity and phagocytic index) in patients with acute and chronic brucellosis have been studied with B. abortus S- and R-forms used as its objects. The study has revealed that higher characteristics of phagocytosis with respect to B. abortus S-forms are observed in patients with acute brucellosis, whereas in patients with chronic brucellosis taking a benign course phagocytosis is more intensive in respect of R-forms. In patients with frequent exacerbations of chronic brucellosis differences in the characteristics of phagocytosis with respect to B. abortus S- and R-forms are not statistically valid.     

MicroRNA Expression Patterns of CD8+ T Cells in Acute and Chronic Brucellosis

Although our knowledge about Brucella virulence factors and the host response increase rapidly, the mechanisms of immune evasion by the pathogen and causes of chronic disease are still unknown. Here, we aimed to investigate the immunological factors which belong to CD8+ T cells and their roles in the transition of brucellosis from acute to chronic infection. Using miRNA microarray, more than 2000 miRNAs were screened in CD8+ T cells of patients with acute or chronic brucellosis and healthy controls that were sorted from peripheral blood with flow cytometry and validated through qRT-PCR. Findings were evaluated using GeneSpring GX (Agilent) 13.0 software and KEGG pathway analysis. Expression of two miRNAs were determined to display a significant fold change in chronic group when compared with acute or control groups. Both miRNAs (miR-126-5p and miR-4753-3p) were decreased (p <0.05 or fold change > 2). These miRNAs have the potential to be the regulators of CD8+ T cell-related marker genes for chronic brucellosis infections. The differentially expressed miRNAs and their predicted target genes are involved in MAPK signaling pathway, cytokine-cytokine receptor interactions, endocytosis, regulation of actin cytoskeleton, and focal adhesion indicating their potential roles in chronic brucellosis and its progression. It is the first study of miRNA expression analysis of human CD8+ T cells to clarify the mechanism of inveteracy in brucellosis.     

Changes in vaginal microbiocenosis in patients with chronic pelvic inflammatory diseases following antibiotic therapy

The species composition of the vaginal microorganisms in healthy women and in patients with chronic pelvic inflammatory diseases before and after treatment in a gynecological hospital was studied. The study revealed that antibiotic therapy did not lead to complete clinical convalescence. During bacteriological investigation of patients changes in vaginal microbiocenosis, manifested by a decreased number of microbial species, an increased proportion of Escherichia coli, the occurrence of Staphylococcus aureus, a decreased number of Lactobacillus ssp., were observed. Antibiotic therapy aggravated the dysbiotic microbial picture of the vagina.     

Nutrient medium for the isolation of hemocultures from brucellosis patients]

To isolate brucellosis causative agent from the blood of patients against the background of antibiotic therapy the authors used for the first time the medium consisting of aminopeptide, beta-globulin agar with glucose, glycerine, and twin-60. No valuable food products--meat, liver--were required to prepare the medium; by-product of gamma-globulin production being used. With the aid of the suggested medium there was isolated 2.4 times more hemocultures than on the widely used meat-peptone medium. This is attributed to the presence in the medium of human protein, essential amino acids, and blood mineral substances, which, in combination, facilitated adaptation of brucellosis causative agent to the nutrient medium similar to human blood by composition. Economical effect in using the mentioned medium constituted 53.8% annually.     

Antibiotic therapy of intestinal infections complicated by toxicosis and exicosis in children with immunodeficiency syndromes]

Clinical processes of acute intestinal infections complicated by toxicosis and exicosis and some host immunological parameters were studied in infants with secondary immunodeficiency. A special treatment scheme was developed including combined use of antibiotics, human immune globulin administered intravenously and cytochrome C. The scheme provided a decrease in the treatment duration by 8.6 +/- 1.1 days. Advanced and chronic diseases and fatal outcomes were absent. It was concluded that the developed scheme increased host immunological reactivity and efficacy of antibiotic therapy. It was recommended for wide clinical use in pediatric clinical care.     

Analysis of PCR-diagnosis of brucellosis in human]

Polymerase chain reaction (PCR) was used for the diagnosis of brucellosis in humans with different forms of this disease. A high incidence (77.6%) of Brucella infection was revealed in the staff of cattle breeding centers with unfavorable situation with regard to brucellosis. Such a conclusion was made after PCR testing of native human sera. In acute brucellosis of humans amplification of the specific site of brucella DNA in PCR is possible only after extraction of DNA by a procedure adapted for DNA extraction from intact brucella cells. In chronic infection weak amplification of brucella genome DNA fragment was observed in investigation of native sera by the PCR. More expressed amplification product was recorded in PCR with a DNA precipitate from this serum obtained by ethanol precipitation. A still higher level of brucella DNA fragment amplification was observed after DNA extraction from sediment obtained by ethanol precipitation from this serum. These data confirmed the incomplete phagocytosis phenomenon at the early stage of infection, known in brucellosis pathogenesis, and allowed some hypotheses on the pathogenesis of chronic phase of brucellosis infection.     

Diagnostic value of serum concentrations of high‐mobility group‐box protein 1 and soluble hemoglobin scavenger receptor in brucellosis

Both cluster of differentiation (CD)4⁺ and CD8⁺ T lymphocytes play key roles in immunity to Brucella, in part because they secrete interferon (IFN)‐γ and activate bactericidal functions in macrophages. Therefore, use of markers of macrophage activation may have diagnostic and prognostic significance. High‐mobility group‐box 1 protein (HMGB1), a late‐onset pro‐inflammatory cytokine, is secreted by activated macrophages. Soluble hemoglobin scavenger receptor (sCD163) is a specific marker of anti‐inflammatory macrophages. The aim of this study was to investigate the diagnostic value of HMGB1 and sCD163 concentrations in brucellosis and its various clinical forms. Serum HMGB1 and sCD163 concentrations in 49 brucellosis patients were compared with those in 52 healthy control subjects. Both serum HMGB1 and sCD163 concentrations were significantly higher in brucellosis patients than in healthy controls (P < 0.001). There were no statistically significant differences in serum concentrations of HMGB1 and sCD163 between cases of acute, subacute and chronic brucellosis. Additionally, serum HMGB1 concentrations were positively correlated with sCD163 concentrations, whereas neither HMGB1 nor sCD163 concentrations were correlated with C‐reactive protein concentrations, white cell counts or erythrocyte sedimentation rates. Therefore, serum concentrations of HMGB1 and sCD163 may be diagnostic markers for brucellosis, but neither can be used to differentiate the three different forms of this disease (acute, subacute and chronic).     

Novel strategies for inhibition of bacterial biofilm in chronic rhinosinusitis

An important role has been recently reported for bacterial biofilm in the pathophysiology of chronic diseases, such as chronic rhinosinusitis (CRS). CRS, affecting sinonasal mucosa, is a persistent inflammatory condition with a high prevalence around the world. Although the exact pathological mechanism of this disease has not been elicited yet, biofilm formation is known to lead to a more significant symptom burden and major objective clinical indicators. The high prevalence of multidrug-resistant bacteria has severely restricted the application of antibiotics in recent years. Furthermore, systemic antibiotic therapy, on top of its insufficient concentration to eradicate bacteria in the sinonasal biofilm, often causes toxicity, antibiotic resistance, and an effect on the natural microbiota, in patients. Thus, coming up with alternative therapeutic options instead of systemic antibiotic therapy is emphasized in the treatment of bacterial biofilm in CRS patients. The use of topical antibiotic therapy and antibiotic eluting sinus stents that induce higher antibiotic concentration, and decrease side effects could be helpful. Besides, recent research recognized that various natural products, nitric oxide, and bacteriophage therapy, in addition to the hindered biofilm formation, could degrade the established bacterial biofilm. However, despite these improvements, new antibacterial agents and CRS biofilm interactions are complicated and need extensive research. Finally, most studies were performed in vitro, and more preclinical animal models and human studies are required to confirm the collected data. The present review is specifically discussing potential therapeutic strategies for the treatment of bacterial biofilm in CRS patients.     

Effectiveness of acipole in prevention of enteric dysbacteriosis due to antibacterial therapy]

Acipole (Lactobacillus acidophilus + Kefir greins) was used to manage antibiotic dysbacteriosis as an adverse reaction of antibacterial therapy. 120 patients treated with antibacterial drugs for acute pneumonia and exacerbations of chronic bronchitis were observed. 54 of them were treated under the routine regimen with antibiotics and 66 were additionally treated with the eubiotic acipole: 1 tablet (5 doses) 3 times a day 30 minutes before meal. Routine bacteriological examination of the feces was applied to all the patients. High frequency of bacteriologically revealed dysbacteriosis was stated. The therapy under the antibiotic + acipole regimen lowered the frequency of dysbacteriosis events and their severity. The fact that the use of acipole simultaneously with the routine antibacterial therapy prevented the development of dysbacteriosis clinical signs is of practical importance.     

Use of enrofloxacin in the treatment of canine brucellosis in a dog kennel (clinical trial)

To date, no totally effective antibiotic for the eradication of canine brucellosis has been found. The purpose of this study was to evaluate the efficacy of enrofloxacin in a kennel infected with Brucella canis. Twelve dogs, 2 males and 10 females (including 1 in estrus, 3 pregnant, and 6 in anestrus) infected with B. canis were given 5 mg/kg of enrofloxacin orally every 12 h for 30 days. Females received additional courses of enrofloxacin during the estral and luteal phases of the subsequent cycles (0-2 cycles). They were repeatedly mated by infected males. A serological follow-up was carried out for 38 months. The clinical, serological and bacteriological findings were recorded. In a trial carried out 14 months after the beginning of this study, all dogs were negative on the Rapid Slide Agglutination Test (RSAT). No abortions were observed. All mated female dogs conceived and gave birth to healthy puppies. Cultures of postpartum vaginal discharges (lochia) were negative for B. canis. Similar to other treatments, although enrofloxacin was not completely efficacious in treating canine brucellosis, it maintained fertility and avoided the recurrence of abortions, transmission of the disease to the puppies and dissemination of microorganisms during parturition. We inferred that enrofloxacin could be used as an alternative drug for the treatment of canine brucellosis.