Prevention of Pyelonephritis Due to Escherichia coli in Rats with Gentamicin Stored in Kidney Tissue

Although gentamicin is known to accumulate and persist in the kidneys after systemic administration, its antibacterial activity at this site has not been determined. In the present study the accumulation of gentamicin in rat kidneys before infection prevented obstructive pyelonephritis due to Escherichia coli despite heavy urinary tract infection in the obstructed pelvis; thus the kidneys were protected against infection in the absence of effective levels of gentamicin in the urine. Stored gentamicin also protected pyelonephritic rats from relapse after complete obstruction of the kidneys. The level of antimicrobial activity of gentamicin in whole kidney tissue was 95% less than that anticipated on the basis of levels measured after dilution of kidney tissue homogenates; this low level of activity apparently was due in part to high concentrations of solutes. In view of these results in rats, the possibility must be considered that despite reduced activity, gentamicin storage might be useful in the prophylaxis of kidney infection in patients with abnormalities of the urinary tract. In the treatment of established kidney infection, the dose of gentamicin could be reduced and the interval of its administration increased for minimal toxicit

Synergism of Ampicillin and Gentamicin against Obstructive Pyelonephritis Due to Escherichia coli in Rats

Rats with obstructive pyelonephritis due to Escherichia coli were treated for different intervals with ampicillin and gentamicin either alone or in combination. The combination of ampicillin and gentamicin was synergistic in vitro and significantly more effective in vivo than was either drug alone. After treatment for 10 days, the combination of ampicillin and gentamicin was the only regimen that sterilized all of the pyelonephritic kidneys. The importance of achieving sterility was illustrated by the observation that severe infection and acute pyelonephritis recurred after religation of the ureter in 12 (71%) of 17 ampicillin-treated animals that had harbored as few as 46 organisms per kidney before ligation. A synergistic combination of antibiotics rapidly sterilizes obstructed pyelonephritic kidneys. In view of the particular risk of renal infection in the presence of urinary obstruction in humans, synergistic antibiotic combinations may be useful in the treatment of obstructive pyelonephritis in human

Bactericidal/Permeability-Increasing Protein Inhibits Induction of Macrophage Nitric Oxide Production by Lipopolysaccharide

A recombinant (r) NH2-terminal fragment of bactericidal/permeability-increasing protein, rBPI23, was shown to inhibit murine macrophage nitric oxide (NO) production elicited by lipopolysaccharide (LPS) plus interferon-β (IFN-β). Normal mouse plasma amplified NO synthesis (measured as NO-2 release) at LPS concentrations of 1-10 ng/mL, and antibody to the plasma LPS-binding protein (LBP) partially inhibited N02 release in the presence of normal mouse plasma. rBPI23 (1 µg/mL) effectively inhibited LPS-dependent NO-2 release in the presence or absence of normal mouse plasma. Fifty percent inhibition of IFN-β/LPS-elicited NO-2 production or of binding of fluoresceinated LPS was obtained with ∼0.2 µg/mL rBPI23. These results provide a basis for studies of rBPI23 effects on NO synthase activity in murine models of gramnegative sepsi

Lipopolysaccharide (LPS)-Binding Protein In Human Serum Determines The Tumor Necrosis Factor Response Of Monocytes To LPS

Lipopolysaccharide (LPS)-binding protein (LBP) and CD14 represent key elements in monocyte activation by LPS. The mean concentration of LBP was 18.1 µg/mL in normal serum and 40-60 µg/mL in serum of patients with septic shock, independent of the fact that patients had gram-negative or other infections. Ten percent normal serum presented large concentrations of LPS (in the microgram range) to monocytes. Only when diluted 1:100 was LBP in plasma a limiting factor for monocyte activation, as measured by tumor necrosis factor (TNF) release. When LBP was depleted from serum with anti-LBP antibodies, the resulting serum did not support TNF release of monocytes upon LPS challenge. In conclusion, monocyte activation resulting in TNF secretion was related to LBP, which is abundantly present in normal serum, and elevated two to three times in patients with septic shoc

Competition between Bactericidal/Permeability-Increasing Protein and Lipopolysaccharide-Binding Protein for Lipopolysaccharide Binding to Monocytes

The bactericidal/permeability-increasing protein (BPI) inhibits the lipopolysaccharide (LPS)mediated activation of monocytes. Due to its inhibitory activity for various LPS, BPI has therapeutic potential in endotoxic shock. To be efficient in vivo, BPI should overcome the action of LPS-binding protein (LBP), a serum molecule that increases the expression of LPS-inducible genes via CD 14 of monocytes. rBPI23, a recombinant fragment of BPI, prevented in a dose-dependent manner the binding and the internalization of LPS mediated by LBP. Consequently, rBPI23 also inhibited LPS-induced tumor necrosis factor (TNFα) synthesis from monocytes. LPS- and LBP-mediated activation of monocytes was totally inhibited when LPS was preincubated with rBPI23. Adding rBPI23 at the same time as LBP resulted in an important but partial inhibition of TNFα release, but this inhibition vanished with delaying the time of addition of rBPI23. These studies suggest that the inhibitory activity of BPI is related to its ability to compete with LBP for LP

Increased Circulating Soluble Cd14 Is Associated With High Mortality In Gram-Negative Septic Shock

The soluble glycoprotein sCD14 binds lipopolysaccharide, a complex that activates endothelial cells and that may be crucial in gram-negative sepsis, Therefore, serum sCD14 was analyzed in 54 patients with gram-negative septic shock and in 26 healthy controls, sCD14 was tested by ELISA and Western blotting, Patients had higher sCD14 concentrations than controls (median, 3.23 vs. 2.48 µg/mL, P = .002). Increased levels were associated with high mortality (median, 4.2 µg/mL in nonsurvivors vs. 2.8 µg/mL in survivors, P = .001). sCD14 was found in two isoforms (49 and 55 kDa) in monocyte cultures. In sera only one of either form was detectable. Controls had the 49-kDa form, and patients had either the 49- or 55-kDa form, but patients with high levels of sCD14 had only the 55-kDa form. Twenty-one (53%) of 39 with the 55-kDa form and 8 (57%) of 14 with the 49-kDa form died. Thus, the level of sCD14 but not its biochemical form had a prognostic value in patients with gram-negative septic shoc

Invasive candidiasis: comparison of management choices by infectious disease and critical care specialists

Objective: To compare the management of invasive candidiasis between infectious disease and critical care specialists. Design and setting: Clinical case scenarios of invasive candidiasis were presented during interactive sessions at national specialty meetings. Participants responded to questions using an anonymous electronic voting system. Patients and participants: Sixty-five infectious disease and 51 critical care physicians in Switzerland. Results: Critical care specialists were more likely to ask advice from a colleague with expertise in the field of fungal infections to treat Candida glabrata (19.5% vs. 3.5%) and C. krusei (36.4% vs. 3.3%) candidemia. Most participants reported that they would change or remove a central venous catheter in the presence of candidemia, but 77.1% of critical care specialists would start concomitant antifungal treatment, compared to only 50% of infectious disease specialists. Similarly, more critical care specialists would start antifungal prophylaxis when Candida spp. are isolated from the peritonal fluid at time of surgery for peritonitis resulting from bowel perforation (22.2% vs. 7.2%). The two groups equally considered Candida spp. as pathogens in tertiary peritonitis, but critical care specialists would more frequently use amphotericin B than fluconazole, caspofungin, or voriconazole. In mechanically ventilated patients the isolation of 104 Candida spp. from a bronchoalveolar lavage was considered a colonizing organism by 94.9% of infectious disease, compared to 46.8% of critical care specialists, with a marked difference in the use of antifungal agents (5.1% vs. 51%). Conclusions: These data highlight differences between management approaches for candidiasis in two groups of specialists, particularly in the reported use of antifungal

Epidemiology of Candidemia in Swiss Tertiary Care Hospitals: Secular Trends, 1991-2000

Candida species are among the most common bloodstream pathogens in the United States, where the emergence of azole-resistant Candida glabrata and Candida krusei are major concerns. Recent comprehensive longitudinal data from Europe are lacking. We conducted a nationwide survey of candidemia during 1991-2000 in 17 university and university-affiliated hospitals representing 79% of all tertiary care hospital beds in Switzerland. The number of transplantations and bloodstream infections increased significantly (P < .001). A total of 1137 episodes of candidemia were observed: Candida species ranked seventh among etiologic agents (2.9% of all bloodstream isolates). The incidence of candidemia was stable over a 10-year period. C. albicans remained the predominant Candida species recovered (66%), followed by C. glabrata (15%). Candida tropicalis emerged (9%), the incidence of Candida parapsilosis decreased (1%), and recovery of C. krusei remained rare (2%). Fluconazole consumption increased significantly (P < .001). Despite increasing high-risk activities, the incidence of candidemia remained unchanged, and no shift to resistant species occurre

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure