Systemic increased immune response to Nocardia brasiliensis co-exists with local immunosuppressive microenvironment

Human diseases produced by pathogenic actinomycetes are increasing because they may be present as opportunistic infections. Some of these microbes cause systemic infections associated with immunosuppressive conditions, such as chemotherapy for cancer, immunosuppressive therapy for transplant, autoimmune conditions, and AIDS; while others usually cause localized infection in immunocompetent individuals. Other factors related to this increase in incidence are: antibiotic resistance, not well defined taxonomy, and a delay in isolation and identification of the offending microbe. Examples of these infections are systemic disease and brain abscesses produced by Nocardia asteroides or the located disease by Nocardia brasiliensis, named actinomycetoma. During the Pathogenic Actinomycetes Symposium of the 16th International Symposium on Biology of Actinomycetes (ISBA), held in Puerto Vallarta, Mexico, several authors presented recent research on the mechanisms by which N. brasiliensis modulates the immune system to survive in the host and advances in medical treatment of human actinomycetoma. Antibiotics and antimicrobials that are effective against severe actinomycetoma infections with an excellent therapeutic outcome and experimental studies of drugs that show promising bacterial inhibition in vivo and in vitro were presented. Here we demonstrate a systemic strong acquired immune response in humans and experimental mice at the same time of a local dominance of anti inflammatory cytokines environment. The pathogenic mechanisms of some actinomycetes include generation of an immunosuppressive micro environment to evade the protective immune response. This information will be helpful in understanding pathogenesis and to design new drugs for treatment of actinomycetoma.     

Inactivation of staphylococcal virulence factors using a light-activated antimicrobial agent

Background  

One of the limitations of antibiotic therapy is that even after successful killing of the infecting microorganism, virulence factors may still be present and cause significant damage to the host. Light-activated antimicrobials show potential for the treatment of topical infections; therefore if these agents can also inactivate microbial virulence factors, this would represent an advantage over conventional antibiotic therapy. Staphylococcus aureus produces a wide range of virulence factors that contribute to its success as a pathogen by facilitating colonisation and destruction of host tissues.     

Evidence-based antibiotic therapy of diabetic foot infections

In addition to proper cleansing, debridement and local wound care, foot infections in diabetic patients require carefully selected antibiotic therapy. Serious infections necessitate hospitalization for initial parenteral broad-spectrum antibiotic therapy. Appropriately selected patients with mild infections can be treated as outpatients with oral (or even topical) therapy. Initial antibiotic selection is usually empirical, but definitive therapy may be modified based on culture results and the clinical response. Therapy should nearly always be active against staphylococci and streptococci, with broader-spectrum agents indicated if Gram-negative or anaerobic organisms are likely. In infected foot tissues levels of most antibiotics, except fluoroquinolones, are often subtherapeutic. The duration of therapy ranges from a week (for mild soft tissue infections) to over 6 weeks (for osteomyelitis). Recent antibiotic trials have shown that several intravenously or orally administered agents are effective in treating these infections, with no one agent or combination emerging as optimal. Suggested regimens based on the severity of infection are provided.     

Weak cytotoxic activity of miltefosine against clinical isolates of Acanthamoeba spp

Hexadecylphosphocholine (miltefosine) is an anticancer drug active in vitro against various protozoan parasites, and recently used for the treatment of disseminated Acanthamoeba infection. In the present study, we present results of weak cytotoxic activity of this potential amoebicidal agent for 2 of 3 clinical isolates of Acanthamoeba spp. Although the inhibition effect for all tested concentrations was apparent, and showed 100% eradication of trophozoites of Acanthamoeba castellanii strain at a concentration of 62.5 μM after 24 hr, the strains Acanthamoeba sp. and Acanthamoeba lugdunensis exhibited low sensitivity to hexadecylphosphocholine, even in high concentrations. The determined minimal trophocidal concentrations were 250 μM for Acanthamoeba sp. and 500 μM for A. lugdunensis after 24 hr of exposure. Although hexadecylphosphocholine is a potential agent for treatment of Acanthamoeba keratitis and systemic infections, in clinical practice the possible insusceptibility of the amoebic strain should be considered for optimizing therapy.     

Rational antimicrobial pharmacotherapy of secondary infections in patients with pulmonary tuberculosis]

The results of 3-year (2002-2004) local microbiological monitoring of secondary infections due to opportunistic microflora that complicated the treatment of the main disease in patients of a regional (Moscow) tuberculosis hospital are presented. The monitoring revealed the leading microorganisms, the etiological agents of the secondary lower respiratory tract infection in the patients with pulmonary tuberculosis. The level of their resistance to the up-to-date antimicrobials was determined. Recommendations for optimization of antibacterial therapy of patients with pulmonary tuberculosis complicated by secondary lower respiratory tract infection due to opportunistic microorganisms were developed and validated.     

Clinical spectrum of invasive candidiasis in critically ill non-neutropenic patients

Invasive Candida spp. infections in non-neutropenic critically ill patients admitted to intensive care units can be classified as focal and systemic. Both types of infection usually occur after episodes of candidemia, although some focal infections may be of exogenous development, like those occurring after trauma or be device-related.The clinical spectrum of invasive Candida spp. infections includes focal urinary tract, abdominal, ocular, respiratory tract, renal and hepato-biliary infections, as well as systemic infections like candidemia and acute systemic candidiasis with multiorgan involvement after hematogenous seeding. Candida spp. isolates in "significant" samples, like synovial fluid, cerebrospinal fluid and blood cultures, represent true infection. However, the diagnosis of invasive infection based on "non-significant" samples, like surgical drains and digestive tract exudates, requires additional criteria. The total number of isolates from different sites, the presence of risk factors, the clinical host response, as well as severity of illness need to be taken into account for the diagnosis of invasive candidiasis. The clinical signs of systemic infection due to Candida spp. are completely non-specific and cannot be differentiated from bacterial peritonitis, urinary tract infection or bacteremia. These infections may be associated with signs of sepsis,severe sepsis, septic shock or multiorgan dysfunction. In the future clinical multicentre observational and interventional studies are necessary to reach agreement on clinical definitions and classification of invasive Candida spp. infections in critically ill non-immunocompromised patients.     

Treatment options in emerging mold infections

Although Zygomycetes, Fusarium spp, and Scedosporium spp are far less frequent causes of invasive fungal disease than Aspergillus and Candida, they are emerging. These types of infections in severely immunocompromised patients have a common feature: a poor clinical response to antifungal therapy. Infection is usually airborne, although local infections in cases of skin trauma are also possible. These fungi are resistant to some common antifungal agents; therefore, surgical debridement of the necrotic tissue, when possible, should be combined with specific systemic antifungal treatment in immunocompromised patients. In the absence of randomized clinical trials, most experience in the treatment of these infections is with amphotericin B. Experience with new antifungal agents is still limited, and recovery from neutropenia remains the main predictor of a favorable outcome.     

Quantitative relationships of the harmful effect of ionizing radiation on natural resistance of the organism to various infectious agents. Review of literature.

On the basis of an analysis of data from the literature and our own experimental results, the conclusion can be drawn that there is inverse linear dependence between the dose of irradiation and natural resistance of the organism to infection with various infectious agents. With increasing doses of irradiation, the irradiated organism is exposed to greatest risk from the part of the agents of intestinal infections and representatives of normal microflora. These are followed by agents of various diseases of microbial nature. The least decrease can be observed in resistance to viruses.     

Pathogenesis and treatment concepts of orthopaedic biofilm infections

Implant-associated infection is caused by surface-adhering bacteria persisting as biofilm. Periprosthetic joint infection is difficult to diagnose and treat. The high susceptibility of implanted devices to infection is because of a locally acquired host defense defect, and persistence is mainly because of the rapid formation of a biofilm resistant to host defense and antimicrobial agents. Successful treatment of periprosthetic joint infection requires the optimal surgical procedure combined with long-term antimicrobial therapy directed against surface-adhering microorganisms. Surgical treatment according to an algorithm has been validated in several observational studies. The role of rifampin against device-associated staphylococcal infection has been evaluated in an animal model, in observational studies and in a controlled trial. Given the limited efficacy of traditional antibiotics in implant-associated infections, novel strategies such as coating of the device, vaccination against biofilms, and quorum-sensing inhibitors are promising future options for prevention and treatment.     

Host‐microbiome interactions in acute and chronic respiratory infections

Respiratory infection is a leading cause of global morbidity and mortality. Understanding the factors that influence risk and outcome of these infections is essential to improving care. We increasingly understand that interactions between the microbial residents of our mucosal surfaces and host regulatory systems is fundamental to shaping local and systemic immunity. These mechanisms are most well defined in the gastrointestinal tract, however analogous systems also occur in the airways. Moreover, we now appreciate that the host–microbiota interactions at a given mucosal surface influence systemic host processes, in turn, affecting the course of infection at other anatomical sites. This review discusses the mechanisms by which the respiratory microbiome influences acute and chronic airway disease and examines the contribution of cross‐talk between the gastrointestinal and respiratory compartments to microbe–mucosa interactions.     

The antibiotic prophylaxis of postoperative complications in breast cancer patients

The studies showed that infectious complications in patients operated for breast cancer (BC) most frequently developed after removal of the drainage tube resulting in poorer discharge favourable for development of infections. The causative agents in such cases are usually exogenous bacteria differing from endogenous ones (Staphylococcus epidermidis) inhabiting the human skin and sometimes contaminating the operative field. The endogenous bacteria are detectable bacteriologically in 60 per cent of the cases. Still, since the operation wound contains humoral and tissue immunity factors (specifically active against the host microflora) such bacteria rarely grow on artificial media (18 per cent) and even more rarely cause infections. Therefore, to prevent postoperative infections in patients with BC it should be recognized rational to use broad-spectrum antibacterial drugs such as ampiox, ampicillin, doxycycline, cephalosporins of the 2nd and 3rd generations, etc. for 5 to 6 days after the drainage removal. If an infection develops the preventive therapy should be replaced by an adequate therapy in accordance with the pathogen sensitivity.     

The inhibition of endotoxin-induced local inflammation by LDH virus or LDH virus-infected tumors is mediated by interferon

The footpad swelling reaction induced by local injection of S. marcescens lipopolysaccharide was found to be inhibited in mice given a transplantable tumor (TA3) or cell-free ascitic fluid from tumor-bearing mice. The tumor was shown to contain LDH virus, which is known to cause inapparent persistent infections in mice. Monoclonal antibodies directed against protein VP3 of the LDH virus could partially abrogate the anti-inflammatory effect of the TA3-ascitic fluid, and, conversely, the anti-inflammatory effect could be obtained by LDH virus isolated from the tumor and reproduced by serial passage of cell-free fluids. Inhibition of the footpad reaction was seen in the acute but not in the chronic phase of LDH virus infection, suggesting that the anti-inflammatory effect might be due to endogenous interferon (IFN) which, similarly, was only detectable in the acute phase. Newcastle disease virus, another potent interferon inducer, had a similar inhibitory effect on the footpad reactivity. Moreover, the inhibitory effect of LDH virus infection could partially be abrogated by administration of a polyclonal antibody directed against murine IFN-alpha,beta. Finally, passively administered natural murine IFN-alpha,beta or recombinant murine IFN-alpha 1 (but not recombinant murine IFN-beta) was found to cause inhibition of the footpad reaction. Since Gram-negative bacteria and their lipopolysaccharides have the ability to induce a systemic interferon response, our findings suggest that this interferon may play a modulatory role in local inflammation caused by these bacteria. Our findings also open a new perspective for interferon therapy of certain inflammatory reactions to bacterial infections.     

Prevention and treatment of nosocomial infections, with special reference to antibiotic policy

Hospital infections are of a major and growing health concern worldwide. They are the cause of appreciable economic loss, but what raises the particular alarm, both ethically and as a public health problem, is their continuous trend towards increasing lethality. The incidence of nosocomial infections can be prevented by creating a system of barriers that would interrupt their spread and transmission. Apart from strict adherence to general hygiene rules and the rational employment of examination methods it is essential in this respect that a prime attention is paid to the sensible use of antimicrobials, i.e. the persuance of a sound antibiotic policy. Its integral components are the systematic laboratory control, continuous epidemiological surveillance of bacterial drug resistance patterns, study of variations in the biological properties of multiple resistant bacterial strains, and the development of, and adherence to, effective and indicated treatment schedules. The particular problems related to bacterial enzyme activities and the genetic information (plasmids) coding for resistance to antimicrobials, as well as the virulence and pathogenicity of agents responsible for the onset of hospital infection are also discussed in this context. It is pointed out that for an effective hospital infection control it is essential to avoid the onesided pressure of badly applied antibiotic therapy.     

Systemic group B streptococcal disease in the neonate: characterization of an oral colonization model using the suckling rat

Aspiration or ingestion of contaminated amniotic fluid or vaginal secretions has been suggested as a cause of systemic group B streptococcal (GBS) infection in the neonate. Suckling rat studies disagree on whether systemic disease will develop after an oral challenge of GBS. Our goal was to determine if systemic GBS disease would occur following oral colonization in the suckling rat and the effect of bacterial, host and environmental factors. Suckling rat littermates received oral inoculation on one of the first four days of life with varying doses and strains of GBS. Studies confirmed gastric inoculation without aspiration. Mortality and bacteremia decreased with age, increased with dose, varied with strain, and increased with asphyxia. Autopsy confirmed sepsis, intestinal colonization, meningitis, and pneumonia. Bacteremia was associated with an abnormal immature: total neutrophil ratio at 24 hr, thrombocytopenia at 48 hr, and neutropenia at 72 hr after inoculation. GBS can cause systemic infection in the host after oral colonization which appears age-, dose, strain-, and environment-dependent. Evaluation of GBS entry in the susceptible host may facilitate therapies directed toward preventing mucosal invasion.     

Effect of antimicrobial therapy on bowel flora and bacterial infection in irradiated mice

Mice exposed to 10 Gy cobalt-60 radiation were given intramuscular antimicrobial therapy of gentamicin, or metronidazole, or a combination of the two. Mortality in the mice treated with metronidazole alone or in combination with gentamicin occurred earlier than in the controls (P less than 0.001). Microorganisms were recovered from the blood, spleen, and liver of the metronidazole-treated mice earlier than from other groups. The predominant organisms recovered from these animals were Enterobacteriaceae. Quantitative cultures of the ileal flora showed a decrease in the number of aerobic, facultative anaerobic and strict anaerobic bacteria after irradiation, and a subsequent increase only in the number of strict aerobic bacteria. As compared to untreated mice, a rapid decrease (by 8.8 logs) in the number of anaerobic flora occurred in the mice treated with metronidazole 5 days after irradiation. This was followed by a rapid increase in the number of aerobic organisms which coincided with the earlier mortality in this group. These data suggest that antimicrobial agents that decrease the number of the strict anaerobic component of the gut flora enhance systemic infection by aerobic or facultative anaerobic bacteria, and this facilitates mortality after irradiation.     

Pseudomonas aeruginosa flagellin and alginate elicit very distinct gene expression patterns in airway epithelial cells: implications for cystic fibrosis disease

Infection with the opportunistic pathogen Pseudomonas aeruginosa remains a major health concern. Two P. aeruginosa phenotypes relevant in human disease include motility and mucoidy. Motility is characterized by the presence of flagella and is essential in the establishment of acute infections, while mucoidy, defined by the production of the exopolysaccharide alginate, is critical in the development of chronic infections, such as the infections seen in cystic fibrosis patients. Indeed, chronic infection of the lung by mucoid P. aeruginosa is a major cause of morbidity and mortality in cystic fibrosis patients. We have used Calu-3 human airway epithelial cells to investigate global responses to infection with motile and mucoid P. aeruginosa. The response of airway epithelial cells to exposure to P. aeruginosa motile strains is characterized by a specific increase in gene expression in pathways controlling inflammation and host defense. By contrast, the response of airway epithelia to the stimuli presented by mucoid P. aeruginosa is not proinflammatory and, hence, may not be conducive to the effective elimination of the pathogen. The pattern of gene expression directed by flagellin, but not alginate, includes innate host defense genes, proinflammatory cytokines, and chemokines. By contrast, infection with alginate-producing P. aeruginosa results in an overall attenuation of host responses and an antiapoptotic effect.     

Effect of helium-neon laser rays on the processes of postradiation recovery in the skeletal muscles of old rats

The present experiments were conducted to determine the stimulant effect of helium-neon laser on the postradiation recovery in irradiated uninjured skeletal muscle of rats aged 2-2.5. This was indicated by a restored ability of the muscle for posttraumatic regeneration. The both hind rat legs were exposed to local irradiation of 20 Gy and following laser therapy (8-9 procedures at 3 min each, impulsive or continuous one). Then both musculus gastrocnemius were cut across 30 days after irradiation. It was shown that laser therapy employed before injury of the irradiated muscle accelerated fibrin resorption and improved connective tissue, but slightly stimulated muscular tissue. Impulse laser therapy was more favourable for state of skin and healing of the skin wound after irradiation.     

TAM mediates adaptation of carbapenem-resistant Klebsiella pneumoniae to antimicrobial stress during host colonization and infection

Gram-negative pathogens, such as Klebsiella pneumoniae, remodel their outer membrane (OM) in response to stress to maintain its integrity as an effective barrier and thus to promote their survival in the host. The emergence of carbapenem-resistant K. pneumoniae (CR-Kp) strains that are resistant to virtually all antibiotics is an increasing clinical problem and OM impermeability has limited development of antimicrobial agents because higher molecular weight antibiotics cannot access sites of activity. Here, we demonstrate that TAM (translocation and assembly module) deletion increases CR-Kp OM permeability under stress conditions and enhances sensitivity to high-molecular weight antimicrobials. SILAC-based proteomic analyses revealed mis-localization of membrane proteins in the TAM deficient strain. Stress-induced sensitization enhances clearance of TAM-deficient CR-Kp from the gut lumen following fecal microbiota transplantation and from infection sites following pulmonary or systemic infection. Our study suggests that TAM, as a regulator of OM permeability, represents a potential target for development of agents that enhance the effectiveness of existing antibiotics.     

Experimental endocarditis model of methicillin resistant Staphylococcus aureus (MRSA) in rat

Endovascular infections, including endocarditis, are life-threatening infectious syndromes. Staphylococcus aureus is the most common world-wide cause of such syndromes with unacceptably high morbidity and mortality even with appropriate antimicrobial agent treatments. The increase in infections due to methicillin-resistant S. aureus (MRSA), the high rates of vancomycin clinical treatment failures and growing problems of linezolid and daptomycin resistance have all further complicated the management of patients with such infections, and led to high healthcare costs. In addition, it should be emphasized that most recent studies with antibiotic treatment outcomes have been based in clinical settings, and thus might well be influenced by host factors varying from patient-to-patient. Therefore, a relevant animal model of endovascular infection in which host factors are similar from animal-to-animal is more crucial to investigate microbial pathogenesis, as well as the efficacy of novel antimicrobial agents. Endocarditis in rat is a well-established experimental animal model that closely approximates human native valve endocarditis. This model has been used to examine the role of particular staphylococcal virulence factors and the efficacy of antibiotic treatment regimens for staphylococcal endocarditis. In this report, we describe the experimental endocarditis model due to MRSA that could be used to investigate bacterial pathogenesis and response to antibiotic treatment.     

3-Year experience of use of cefepime (Maxipime) for the treatment of hospital infections in a specialized surgical hospital]

Microbiological and clinical monitoring for 3 years (from 2001 to 2003) confirmed high clinical and microbiological efficacy of cefepime (Maxipime, Bristol-Myers-Squibb) in the treatment of infectious complications in patients with solid tumors in an oncologic hospital. It should be noted, however, that high efficacy of cefepime and wide ranges of the indications to its use do not allow to consider it as an agent for the treatment of all possible complications in such patients. The drug is not active against enterococci, not always clinically sufficiently effective in the treatment of Pseudomonas aeruginosa infections, it is impossible to use cefepime in monotherapy of suspected anaerobic infections. Therefore, widespread uncontrolled use of cefepime should be prohibited. It should be prescribed strictly by the indications with the account of the pathogen susceptibility, the infection severity and the recommended doses and regimens. The use of cefepime is undoubtedly valid when other antimicrobials fail or when empirical antimicrobial therapy of severe cases is required, including those under intensive care.