Clinical efficacy and toxicity of netilmicin in the treatment of gram-negative infections.

Netilmicin, a new semisynthetic aminoglycoside antibiotic, was used to treat 41 infections in 38 patients. The outcome of four infections could not be evaluated: two patients received inadequate therapy and two did not have gram-negative infections. Clinical improvement occurred in 36 (97%) of the 37 gram-negative infections, and bacteriologic cure occurred in 30 (86%) of the 35 evaluable infections. Therapeutic serum concentrations of netilmicin were readily achieved by both intramuscular and intravenous routes. Reversible ototoxic effects occurred in 1 (3%) of 35 courses of therapy evaluated, reversible nephrotoxic effects occurred in 5 (14%) of 36 courses and mild reversible alterations in liver function occurred in 3 (19%) of 34 courses. Netilmicin appears to be effective and safe in the treatment of aerobic gram-negative infections.     

Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections

Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.     

Pathogenesis of gram-negative bacterial infections in warmwater fish

Knowledge concerning the pathogenesis of many bacterial diseases in fish is limited, especially in those diseases that occur in warmwater species. This limited knowledge base is due to the relative recent emergence of warmwater fish culture as a major industry in many parts of the world, and to the previous economic insignificance of warmwater aquaculture and the bacterial pathogens affecting warmwater species. This article is an overview of the important gram-negative pathogens of warmwater fish, including members of the genera Aeromonas, Edwardsiella, Pasteurella, Pseudomonas, and Vibrio. The current knowledge of the pathogenesis of these organisms is emphasized, including: the source of the pathogen, its preferred site and method for attaching to and penetrating the host, its adaptations for surviving the host immune system, and its strategies for obtaining nutrients required for proliferation and growth. Although information for many of these pathogens is limited, the intent of this article is to provide a baseline for the development of future research projects. Increases in worldwide aquaculture production will result in a demand for knowledge about the pathogenesis of bacterial pathogens in warmwater fish, because of its importance in making health management decisions, in deciding on treatment regimens, and in the development of vaccines.     

Participation of gram-negative anaerobes in infections in hospitalized patients

The aim of the study was to assess the prevalence and antibiotic susceptibility profiles of strictly anaerobic Gram-negative bacteria isolated from clinical samples taken from hospitalized patients from 01.01.2007 to 31.12.2008. The specimens were cultured using media, incubated at 37 degrees C under anaerobic conditions. Biochemical identification and antibiotic susceptibility were done in an automated system ATB Expression (bioMerieux S.A, France). For selected strains of Bacteroides sp. sensitivity was determined using E-test (AB BIODISK, Sweden). Overall 1274 strains of obligate anaerobes were isolated. Gram-negative bacteria were cultured in number of 333 strains. Most frequently isolated was Bacteroides sp. (46,9%) and Prevotella sp. (29,7%). Isolated bacteria are still susceptible to imipenem (100%), metronidazole (100%) and beta-lactam antibiotics with beta-lactamase inhibitors: amoxicillin/clavulanate (97,8%) piperacillin/tazobactam (99,1%), ticarcillin/clavulanate (99,1%).     

Host-parasite interaction in serious infections due to gram-negative bacteria

Gram-negative rods such as Enterobacteriaceae and Pseudomonadaceae are normal habitants of the digestive tract. However, if defense mechanisms of the host are compromised by underlying diseases such as malignant neoplasms, renal insufficiency, extensive traumata, or immunosuppressive therapy, invasion of the blood-stream can occur. Gram-negative septicaemia is associated with high morbidity and mortality, despite intensive care and administration of potent antibiotics. A central role in the pathophysiology of life-threatening bacteraemia is attributed to endotoxin, a constituent of the gram-negative cell wall. This paper reviews current concepts of septic shock, the acquisition of gram-negative bacteraemia and the role of endotoxin. It also deals with a new approach to prevention and control of severe gram-negative infections using serotherapy based on the structure of endotoxin.     

A nontoxic, idiotope vaccine against gram-negative bacterial infections.

Experiments were performed to test the ability of mouse antiidiotopic mAb, specific for an antilipid A mAb, to act as a vaccine against gram-negative bacterial infections. Lipid A is a conserved region of bacterial LPS. Immunization with the antiidiotopic antibodies, coupled to an immunogenic carrier protein (hemocyanin), specifically induced anti-LPS antibody responses in animals from different species. In a mouse model, this immunization resulted in protection against both lethal gram-negative bacteremia and endotoxemia. The antiidiotopic antibodies, however, did not stimulate endotoxin-associated bioactivities, such as induction of TNF and IL-1. These results support the hypothesis that an idiotope vaccine can stimulate beneficial protective immunity against gram-negative infections without the toxicity inherent in LPS.     

Seasonal and temperature-associated increases in gram-negative bacterial bloodstream infections among hospitalized patients

Background

Knowledge of seasonal trends in hospital-associated infection incidence may improve surveillance and help guide the design and evaluation of infection prevention interventions. We estimated seasonal variation in the frequencies of inpatient bloodstream infections (BSIs) caused by common bacterial pathogens and examined associations of monthly BSI frequencies with ambient outdoor temperature, precipitation, and humidity levels.

Methods

A database containing blood cultures from 132 U.S. hospitals collected between January 1999 and September 2006 was assembled. The database included monthly counts of inpatient blood cultures positive for several clinically important Gram-negative bacteria (Acinetobacter spp, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) and Gram-positive bacteria (Enterococcus spp and Staphylococcus aureus). Monthly mean temperature, total precipitation, and mean relative humidity in the postal ZIP codes of participating hospitals were obtained from national meteorological databases.

Results

A total of 211,697 inpatient BSIs were reported during 9,423 hospital-months. Adjusting for long-term trends, BSIs caused by each Gram-negative organism examined were more frequent in summer months compared with winter months, with increases ranging from 12.2% for E. coli (95% CI 9.2–15.4) to 51.8% for Acinetobacter (95% CI 41.1–63.2). Summer season was associated with 8.7% fewer Enterococcus BSIs (95% CI 11.0–5.8) and no significant change in S. aureus BSI frequency relative to winter. Independent of season, monthly humidity, monthly precipitation, and long-term trends, each 5.6°C (10°F) rise in mean monthly temperature corresponded to increases in Gram-negative bacterial BSI frequencies ranging between 3.5% for E. coli (95% CI 2.1–4.9) to 10.8% for Acinetobacter (95% CI 6.9–14.7). The same rise in mean monthly temperature corresponded to an increase of 2.2% in S. aureus BSI frequency (95% CI 1.3–3.2) but no significant change in Enterococcus BSI frequency.

Conclusions

Summer season and higher mean monthly outdoor temperature are associated with substantially increased frequency of BSIs, particularly among clinically important Gram-negative bacteria.     

A Comparison between the Nephrotoxic Profile of Gentamicin and Gentamicin Nanoparticles in Mice

Aminoglycoside antibiotics are widely used against Gram‐negative infections. On the other hand, nephrotoxicity is a deleterious side effect associated with aminoglycoside therapy. Gentamicin is the most nephrotoxic aminoglycoside. Because of serious health complications ensue the nephrotoxicity induced by aminoglycosides, finding new therapeutic strategies against this problem has a great clinical value. This study has attempted to compare the nephrotoxic properties of gentamicin and a new nanosized formulation of this drug in a mice model. Animals were treated with gentamicin (100 mg/kg, i.p. for eight consecutive days) and nanogentamicin (100 mg/kg, i.p. for eight consecutive days). Blood urea nitrogen (BUN), plasma creatinine levels, and histopathological changes of kidney proximal tubule were monitored. It was found that gentamicin caused severe degeneration of kidney proximal tubule cells and an increase in serum creatinine and BUN. No severe injury was observed after nanogentamicin administration. This study proved that nanosized gentamicin is less nephrotoxic.     

Cytokines in the treatment of virus infections

The interferon (IFN) system consists of both the formation of the various IFN proteins, and the diverse cellular responses which these induce: these result from the intracellular changes which follow their binding to a specific cell surface receptor.There is only a single human gamma, omega and beta IFN; in contrast, there are 13 closely related chemical species (subtypes) of human alpha IFN, which are nevertheless chemically and biologically distinct.IFN preparations made from mass cultured human cells or by using recombinant DNA techniques are now readily available for clinical use. IFN have a major role in the defence of the body against virus infections. In acute virus infections, preformed exogenous IFN cannot be given soon enough to be of value. However, IFN- and IFN- have proved of considerable value in some chronic virus infections, particularly chronic virus hepatitis and chronic papillomavirus infections. The doses routinely used are associated with both acute and chronic toxic side effects. Also, some patients form specific neutralising antibodies against the particular IFN preparation injected, which may abrogate all the benefits of the treatment. Nevertheless, IFN are now established as agents for use in routine medical practice.Abbreviations TNF Tumour necrosis factor - IL-6 Interleukin-6 - eIF2 The protein initiation factor     

Cytokines in the treatment of fungal infections

The incidence of invasive fungal infections in the immunocompromized host has increased during the past decade. Even the recently developed antifungal drugs are unable to cure these infections in patients with severely impaired host defense mechanisms. Cytokines have great potential to augment host resistance and as adjunctive therapy of invasive mycoses. We discuss the mechanisms of host defense against invasive candidiasis, aspergillosis, and cryptococcosis, and review the use of cytokines and growth factors in this setting. Interleukin-1 has been shown effective in an animal model of disseminated candidiasis, even during severe granulocytopenia. Interferon- has been very effective as a modulator of resistance against a variety of fungal infectionsin vitro. The effect of interferon- against disseminated candidiasis has been demonstrated in a mouse model. Activation of neutrophils is the main mechanism by which interferon- enhances the elimination ofCandida, and consequently the agent is not effective in severly granulocytopenic animals. Data on the role of colony-stimulating factors against fungal pathogens are accumulating, and trials with these agents for hematologic patients with invasive fungal infections are now being performed.Abbreviations CGD chronic granulomatous disease - G-CSF granulocyte colony-stimulating factor - M-CSF monocyte colony-stimulating factor - GM-CSF granulocyte-monocyte colony-stimulating factor - IFN- interferon-gamma - IL interleukin - LAK lymphokine-activated killer - LPS lipopolysaccharide - MDP muramyl dipeptide - NK natural killer - PMN polymorphonuclear leukocytes - rh recombinant human - ROI reactive oxygen intermediates - TNF tumor necrosis factor     

Caspase-6 promotes activation of the caspase-11-NLRP3 inflammasome during gram-negative bacterial infections

The innate immune system acts as the first line of defense against infection. One key component of the innate immune response to gram-negative bacterial infections is inflammasome activation. The caspase-11 (CASP11)-nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is activated by cytosolic lipopolysaccharide, a gram-negative bacterial cell wall component, to trigger pyroptosis and host defense during infection. Although several cellular signaling pathways have been shown to regulate CASP11-NLRP3 inflammasome activation in response to lipopolysaccharide, the upstream molecules regulating CASP11 activation during infection with live pathogens remain unclear. Here, we report that the understudied caspase-6 (CASP6) contributes to the activation of the CASP11-NLRP3 inflammasome in response to infections with gram-negative bacteria. Using in vitro cellular systems with bone marrow-derived macrophages and 293T cells, we found that CASP6 can directly process CASP11 by cleaving at Asp59 and Asp285, the CASP11 auto-cleavage sites, which could contribute to the activation of CASP11 during gram-negative bacterial infection. Thus, the loss of CASP6 led to impaired CASP11-NLRP3 inflammasome activation in response to gram-negative bacteria. These results demonstrate that CASP6 potentiates activation of the CASP11-NLRP3 inflammasome to produce inflammatory cytokines during gram-negative bacterial infections.     

Chemotherapy of newborns with intestinal infections caused by opportunistic gram-negative aerobic bacteria]

A clinical bacteriological examination was applied to 100 newborns with intestinal infections caused by opportunistic gram-negative aerobes. There was a correlation between the decrease in the quantity of the bifidobacteria and the predominance of various species of opportunistic gram-negative aerobes and their associations, as well as high sensitivity of clinical isolates of the opportunistic bacteria to phosphocin, gentamicin, polymyxin and specific bacteriophages. The study showed that the combined use of antibiotics with the biopreparations (the specific bacteriophages and bifidumbacterin) was effective in treating the newborns with the above mentioned infections.     

Antibiotic sensitivity of gram-negative opportunistic bacteria isolated from the feces of newborn infants with intestinal infections

Antibiotic sensitivity of 136 pure cultures of gram negative aerobic potentially pathogenic bacteria was assayed. The bacteria were isolated from feces of newborns with intestinal infections. It was shown that the majority of the strains were resistant to 4-5 antibiotics widely used in treatment of patients. However, they were sensitive to gentamicin and polymyxin M.