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1.  Attenuation by daptomycin of gentamicin-induced experimental nephrotoxicity. 
Previously, daptomycin was shown to reduce tobramycin nephrotoxicity in vivo (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew, and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). Female Sprague-Dawley rats were treated with saline (NaCl, 0.9%), daptomycin (10 mg/kg of body weight every 12 h, subcutaneously), gentamicin (30 mg/kg/12 h, intraperitoneally) or with a combination of daptomycin plus gentamicin over a 10-day period. Animals were killed 4, 10, and 20 days after the end of treatment. Four days after the end of drug administration, gentamicin and daptomycin levels in the renal cortices of animals treated with the combination of daptomycin and gentamicin were significantly higher than in those of rats given gentamicin or daptomycin alone (P < 0.01). Despite the higher cortical concentrations of gentamicin, rats given the combination of gentamicin and daptomycin had less reduction in renal cortex sphingomyelinase activity, less evidence of regeneration of cellular cortical cells ([3H]thymidine incorporation into cortex DNA), lower creatinine concentration in serum, and less histopathologic evidence of injury than rats given gentamicin alone. By immunogold technique, both daptomycin and gentamicin were localized to the lysosomes of proximal tubular cells, regardless of whether animals received the drugs alone or in combination. Interestingly, myeloid body formation occurred in both those animals given gentamicin alone and those given daptomycin plus gentamicin. No significant changes were observed for all groups between 10 and 20 days after the end of therapy, suggesting that the toxicity of gentamicin was not delayed by the concomitant injection of daptomycin. The results confirm that daptomycin can attenuate experimental gentamicin nephrotoxicity.
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PMCID: PMC188145  PMID: 8067733
2.  Subcellular distribution of daptomycin given alone or with tobramycin in renal proximal tubular cells. 
Previous studies in experimental animals showed that daptomycin, a lipopeptide antibiotic, protects against aminoglycoside nephrotoxicity (C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. N. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989; D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew, and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990). In order to better understand the mechanism involved in this protective effect, the subcellular distribution of daptomycin was investigated in the proximal tubular cells of animals treated with daptomycin alone or in combination with tobramycin. A first group of female Sprague-Dawley rats received a single intravenous injection of daptomycin at a dose of 100 mg/kg of body weight and were killed at 10 min, 1 h, or 24 h after the injection. Other groups of rats were treated during 10 days with saline (NaCl, 0.9%), tobramycin at dosages of 20 mg/kg/12 h, daptomycin at dosages of 10 mg/kg/12 h, or the combination tobramycin-daptomycin at the same dosages. At the time of sacrifice, the renal cortex of the right kidney of each animal was dissected, and small blocks of tissue were fixed, dehydrated, and embedded in Araldite 502 epoxy resin. The subcellular distribution of daptomycin and tobramycin was determined on ultrathin sections by immunogold labeling. Ten minutes after the injection of daptomycin alone, gold particles were seen over the brush border membrane and on the membranes of the endocytic vacuoles of proximal tubular cells. One hour after the injection, a similar distribution was seen and numerous gold particles were found over the lysosomes of proximal tubular cells. The results suggest that daptomycin might protect against aminoglycoside nephrotoxicity by interfering with the interaction between the aminoglycoside and phospholipids inside the lysosomes of proximal tubular cells.
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PMCID: PMC284424  PMID: 8192441
3.  Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin. 
The lipopeptidic antibiotic daptomycin is reported to reduce experimental tobramycin nephrotoxicity (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). In an attempt to explain these results, the in vivo and in vitro interactions between daptomycin and tobramycin were studied. Tobramycin alone and preincubated with negatively charged phospholipid bilayers (liposomes) was dialyzed against increasing concentrations of daptomycin in buffer at pH 5.4. A significant drop in the concentration of tobramycin was observed when daptomycin was added to the opposite half cells. Furthermore, daptomycin induced a concentration-dependent release of lipid-bound tobramycin. Gold labeling experiments showed that daptomycin could be incorporated into phospholipid layers. Female Sprague-Dawley rats were treated with daptomycin alone, with tobramycin alone, or with the combination over 2 to 10 days. Levels of daptomycin and tobramycin in serum were similar in all groups. The levels of tobramycin in the renal cortex increased significantly with time and, on day 10, reached values of 654 +/- 122 and 844 +/- 298 micrograms/g of tissue (mean +/- standard deviation; not significant) in animals treated with tobramycin and the combination of daptomycin-tobramycin, respectively. No significant difference was observed in the levels of tobramycin in the kidneys between animals treated with tobramycin or the daptomycin-tobramycin combination at any time. By contrast, daptomycin levels were significantly higher in the renal cortexes of animals treated with daptomycin-tobramycin in comparison with those in the renal cortexes of animals treated with daptomycin alone on days 6,8, and 10 (P < 0.01). For immunogold labeling studies, animals were killed 4 h after a single injection of daptomycin alone or daptomycin in combination with tobramycin. Daptomycin was found throughout the matrixes of the lysosomes of proximal tubular cells of animals treated with daptomycin alone. In animals treated with the combination of daptomycin and tobramycin, daptomycin was associated with intralysosomal myeloid bodies. Our results suggest that daptomycin might attenuate experimental aminoglycoside nephrotoxicity by interacting with the aminoglycoside, perhaps electrostatically, and thereby protecting intracellular targets of toxicity.
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PMCID: PMC284536  PMID: 8031040
4.  Concentrations of teicoplanin in serum and atrial appendages of patients undergoing cardiac surgery. 
The concentrations of teicoplanin in sera and heart tissues of 49 patients undergoing coronary bypass were measured. Each patient received a 6- or 12-mg/kg dose of teicoplanin administered in a slow intravenous bolus injection over 3 to 5 min beginning at the time of induction of anesthesia. Mean +/- standard error of the mean concentrations in serum were, for the two doses, respectively, 58.1 +/- 1.7 and 123.3 +/- 7.4 micrograms/ml 5 min after administration and 22.2 +/- 0.7 and 56.5 +/- 2.8 micrograms/ml at the time of removal of atrial appendages. Mean +/- standard error of the mean concentrations in tissue were 70.6 +/- 1.7 and 139.8 +/- 2.2 micrograms/g, respectively, giving mean tissue/serum ratios of 3.7 +/- 0.3 and 2.8 +/- 0.2, respectively. Teicoplanin penetrates heart tissue readily and reaches levels in the serum far in excess of the MICs for most pathogens that have been found to cause infections following open heart surgery.
PMCID: PMC171908  PMID: 2149493
5.  Prolonged endotoxemia enhances the renal injuries induced by gentamicin in rats. 
The aim of this study was to evaluate the role of chronic endotoxemia in the nephrotoxicity of gentamicin (GM). Saline or Escherichia coli lipopolysaccharide (LPS) was administered to conscious rats by continuous intravenous perfusion (1 mg/kg per day for 7 days) from a subcutaneously implanted osmotic pump. Twenty-four hours after surgery (day zero), treatment with saline or GM (15 mg/kg; intraperitoneally, twice a day) was started for 5 days. Levels of LPS in plasma measured by Limulus amoebocyte lysate activity decreased significantly from days 1 through 8. At days 5 and 8, the cortical concentrations of GM were higher in the LPS-perfused and GM-treated group (LPS plus GM) than they were in the saline-perfused and GM-treated group (saline plus GM) (P less than 0.05). Blood urea nitrogen and serum creatinine remained at normal levels throughout the experiment. A significant increase of cortical tubular cell regeneration was observed in the LPS plus GM animals as compared with regeneration observed in the other groups (saline plus saline, LPS plus saline, and saline plus GM), as measured by [3H]thymidine incorporation into DNA. Moreover, histopathological nephrotoxicity scores showed a synergistic toxic effect between LPS and GM. These results demonstrate that chronic perfusion of low doses of LPS potentiates the nephrotoxicity of GM.
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PMCID: PMC171712  PMID: 2360824
6.  Differential distributions in tissues and efficacies of aztreonam and ceftazidime and in vivo bacterial morphological changes following treatment. 
The differential tissue distributions of aztreonam and ceftazidime within fibrin clots infected with Pseudomonas aeruginosa, Enterobacter cloacae, and Serratia marcescens, their efficacies, and the in vivo bacterial morphological changes induced by these drugs were evaluated. Rabbits were given intravenously a single dose of 100 mg of either agents/kg of body weight. In the cores of the clots, the peak levels of both drugs were much lower than those observed in the peripheries and in serum. Aztreonam's half-lives within the peripheries and in the cores of the fibrin clots were up to six times higher than observed in serum, while ceftazidime's half-lives in clots were twice that observed in serum. This resulted in a much greater penetration ratio for aztreonam than for ceftazidime. Both drugs controlled the growth of P. aeruginosa in vivo, but E. cloacae and S. marcescens responded better to ceftazidime. Morphological changes were more abundant in the peripheries than in the cores of the clots. In the control group, P. aeruginosa's morphology in the cores was different than that in the peripheries of the clots. Against P. aeruginosa, aztreonam did induce morphological changes in the cores while ceftazidime did not. Electron microscopic studies revealed that morphological changes associated with aztreonam seemed different than those of ceftazidime. Along with elongation of bacteria, more bow tie and herniated bacteria were observed with aztreonam. Though both agents selectively affect PBP 3, as manifested by elongated bacteria, they induce in the peripheries of the clots thickening, breaks, and detachment in bacterial cell walls, alterations which are generally associated with antibiotics affecting PBP 1a and 1b.
PMCID: PMC163720  PMID: 9021198
7.  Time-restricted feeding schedules modify temporal variation of gentamicin experimental nephrotoxicity. 
The effect of timing of gentamicin dosing relative to food access periods was evaluated in experimental animals. Female Sprague-Dawley rats were treated for 4 and 10 days with gentamicin (40 mg/kg of body weight/day) intraperitoneally at either 0700, 1300, 1900, or 0100 h according to three food presentation schedules: food was available from 0800 to 1600 h in the first group, from 1600 to 0000 h in the second group, and from 0000 to 0800 h in the last group. Animals were thus subjected to a restricted feeding period. Results indicate that time-restricted feeding schedules displace the peak and the trough of gentamicin-induced renal toxicity, as evaluated by changes in the inhibition of sphingomyelinase activity, cellular regeneration (incorporation of [3H]thymidine into DNA of renal cortex), and blood urea nitrogen and serum creatinine levels, as well as histopathological lesions observed after 10 days of treatment. In fact, the toxicity was minimal when gentamicin was injected during the feeding period, while the maximal toxicity was found when gentamicin was administered during the fasting period. It is concluded that the feeding period can modulate aminoglycoside nephrotoxicity. The time of dosing of gentamicin relative to the time of feeding seems to be a more important modulator of gentamicin nephrotoxicity than the light-dark cycle.
PMCID: PMC163942  PMID: 9210668
8.  Attenuation of gentamicin-induced nephrotoxicity in rats by fleroxacin. 
The effect of fleroxacin on gentamicin-induced nephrotoxicity was evaluated with female Sprague-Dawley rats. Animals were injected during 4 or 10 days with saline (NaCl; 0.9%), gentamicin alone at doses of 10 and 40 mg/kg of body weight/12 h (subcutaneously), fleroxacin alone at a dose of 25 mg/kg/12 h (intraperitoneally), or the combination gentamicin-fleroxacin in the same regimen. Gentamicin induced a dose- and time-dependent renal toxicity as evaluated by gentamicin cortical levels, sphingomyelinase activity in the renal cortex, histopathologic and morphometric analysis, blood urea nitrogen and serum creatinine levels, and cellular regeneration ([3H]thymidine incorporation into DNA of cortical cells). The extent of these changes was significantly reduced when gentamicin was given in combination with fleroxacin. Although the mechanisms by which fleroxacin reduces the nephrotoxic potential of gentamicin are unknown, we propose that the fleroxacin-gentamicin combination enhances exocytosis activity in proximal tubular cells, as suggested by the higher excretion of urinary enzymes and lower cortical levels of gentamicin observed in animals treated with the combination fleroxacin-gentamicin compared with those treated with gentamicin alone. The protective effect of fleroxacin on gentamicin nephrotoxicity should be investigated further.
PMCID: PMC163893  PMID: 9174177
9.  Association of nitric oxide production by kidney proximal tubular cells in response to lipopolysaccharide and cytokines with cellular damage. 
Recent findings suggest that nitric oxide (NO) is an important biologic mediator which exerts a wide variety of effects on numerous physiological and pathophysiological processes. L-Arginine is oxidized to L-citrulline with concomitant NO production; as a result, nitrate and nitrite accumulates. This study was conducted to determine the potential NO production by proximal tubular cells (PTC) in response to bacterial lipopolysac-charides (LPS) and cytokines and to evaluate the cytotoxic effect associated with NO release. After a 7-day stimulation with LPS (100 micrograms/ml), interleukin-1 beta (IL-1 beta) (10 ng/ml), and tumor necrosis factor alpha (TNF-alpha) (10 ng/ml), the nitrate and nitrite levels were determined by a spectrophotometric method based on the Griess reaction. Moreover, alpha-methylglucopyranoside phosphate and lactate dehydrogenase release and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay served as indicators of sodium-dependent hexose transport integrity and cell death, respectively. IL-1 beta and TNF-alpha used alone or together or combined with LPS led to a significant generation of NO by PTC. Our results also demonstrate that NO induced by LPS and cytokines could inhibit sodium-dependent transport and could induce PTC damage.
PMCID: PMC163750  PMID: 9055992
10.  Effects of fasting on temporal variations in nephrotoxicity of gentamicin in rats. 
Evidence for temporal variations in the nephrotoxicity of low doses of aminoglycosides were recently shown by using specific and sensitive parameters of renal toxicity. The aim of the present study was to evaluate the effect of a short period of fasting on the temporal variations in the renal toxicity of gentamicin. Twenty-eight normally fed (i.e., food and water were available ad libitum throughout the experiment) female Sprague-Dawley rats (weight, 175 to 220 g) and 28 fasted rats (i.e., only water was available during a 12-h fast before and a 24-h fast after gentamicin injection) were used. The animals were synchronized on a 14-h light, 10-h dark cycle (lights on at 0600 h) for 1 week before gentamicin administration. In July 1993, each group of animals was treated with a single intraperitoneal injection of saline (NaCl, 0.9%) or gentamicin (150 mg/kg of body weight) at either the peak (1400 h) or the trough (0200 h) of the previously determined toxicity. On day 1, the 24-h urinary excretion of beta-galactosidase, N-acetyl-beta-D-glucosaminidase, and gamma-glutamyltransferase was significantly higher in normally fed animals treated with gentamicin at 1400 h than in their time-matched controls and in normally fed animals treated at 0200 h (P < 0.01), which had normal levels of these enzymes. By contrast, the urinary excretion of these enzymes was significantly higher in both groups of gentamicin-treated, fasted rats than in their time-matched control groups (P < 0.01), reaching levels similar to those measured in normally fed rats treated at 1400 h. The accumulation of gentamicin was significantly lower in the renal cortex of normally fed rats treated at 0200 h than in rats treated at 1400 h (P < 0.05), but this time-dependent difference was not found in fasted rats treated at 0200 and 1400 h. Immunogold labeling done on ultrathin sections and observed by electron microscopy showed a similar subcellular localization of gentamicin in normally fed and fasted rats treated at either 1400 or 0200 h. These results suggest that the feeding period is of crucial importance in the temporal variations of the nephrotoxicity of gentamicin in rats.
PMCID: PMC163178  PMID: 8851591
11.  Temporal variation in nephrotoxicity of low doses of isepamicin in rats. 
The temporal variation in the nephrotoxicity of low doses of isepamicin was studied in male Sprague-Dawley rats treated with a single daily intraperitoneal injection of saline (NaCl, 0.9%) or isepamicin (80 mg/kg of body weight) at either 0800, 1400, 2000, or 0200 h for 4 and 10 days. On day 10, the cellular regeneration (incorporation of [3H] thymidine into DNA of renal cortex) and cortical accumulation of isepamicin were significantly higher in animals treated at 1400 h than at 0200 h (P < 0.01). Immunogold labeling studies showed that isepamicin was essentially localized in the lysosomes of proximal tubular cells in all treated groups, but the density of the gold particles over the lysosomes was higher in animals treated at 1400 than at 0200 h. The results of the present study show that the renal toxicity of isepamicin was maximal at 1400 h (midlight period) and minimal at 0200 h (middark period).
PMCID: PMC163205  PMID: 8851618
12.  Comparative pharmacokinetics, distributions in tissue, and interactions with blood proteins of conventional and sterically stabilized liposomes containing 2',3'-dideoxyinosine. 
The pharmacokinetics and distribution in tissue of 2',3'-dideoxyinosine (ddI) encapsulated in sterically stabilized liposomes have been evaluated in rats. Most of the sterically stabilized liposomes concentrated in the spleen with a peak level at 24 h after their intravenous injection. An extended half-life in plasma was observed for sterically stabilized liposomes (14.5 h) compared with that of conventional liposomes (3.9 h). The systemic clearance of ddI incorporated in sterically stabilized liposomes was 180 times lower than that of the free drug. The levels of in vitro and in vivo protein binding on both conventional and sterically stabilized liposomes were also evaluated. Results suggest that the amount of proteins associated with liposomes might not be the only factor involved in the in vivo clearance of liposomes, as this process may also be influenced by the nature of the bound blood proteins.
PMCID: PMC163088  PMID: 8787911
13.  Differential increased survival of staphylococci and limited ultrastructural changes in the core of infected fibrin clots after daptomycin administration. 
A possible explanation for the difficulties encountered in curing deep fibrin-embedded infections is that antibiotic diffusion inside the infected fibrin matrix is not homogeneous and is insufficient to neutralize the pathogen. To evaluate this conjecture, the differential pharmacodynamics of daptomycin in fibrin clots infected with methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis was estimated. Daptomycin (20 or 50 mg/kg of body weight) was infused over 30 min. Fibrin clots and blood samples were evaluated from 0.5 to 42 h after the injections. The half-lives of daptomycin in serum and fibrin clot were close to identical after the two doses and averaged 5.4 and 22 h, respectively. The mean areas under the concentration-time curves from 0 to 42 h (AUC0-infinity) for daptomycin concentrations in serum and infected clots were 575 +/- 36.7 and 215 +/- 6.2 micrograms/g/h after administration of 20 mg/kg and 1,089 +/- 39.9 and 326 +/- 16.8 micrograms/g/h after administration of 50 mg/kg. A concentration gradient from the periphery to the core of the clots was observed in many clots up to 18 h after treatment. Mean peak concentrations in the core of the clots reached 60% of the peripheral values (P < 0.05) and were delayed for at least 3 h compared with the peripheral peak concentrations. AUC0-42 h of daptomycin concentration in the periphery and the core of clots were significantly different (P < 0.01). Survival of microorganisms was better in the core than in the periphery, with as much as a 3 log10 CFU/g difference between the center and the surface of the clot. Bacterial examination by transmission electron microscopy also showed noticeable differences in ultrastructural changes between those in the periphery and those in the core of the clots. In conclusion, the pharmacokinetics of daptomycin are significantly different at the periphery and within the core of fibrin clots, which may have led to the higher bacterial survival in the core of clots. Limited diffusion of daptomycin in fibrin, an essential component of the vegetation in bacterial endocarditis, could explain at least in part some of the treatment failures.
PMCID: PMC163083  PMID: 8787906
14.  Liposomal encapsulation of foscarnet protects against hypocalcemia induced by free foscarnet. 
Hypocalcemia and an increase in creatinine level are the most important serious effects associated with foscarnet (PFA) therapy. In an animal model, we have explored the potential protective role of liposome-encapsulated foscarnet (LE-PFA) on these metabolic abnormalities. PFA administered as one bolus injection (0.5 or 1.0 g/kg) caused significant rapid decreases (approximately 20%) in the levels of calcium and phosphorus in serum within a few minutes and up to 30 min after injection. LE-PFA did not induce any of these changes, while peak levels in serum and the half-life of this formulation were much higher than those of the free drug. PFA administered for 2 weeks (340 or 500 mg/kg/day) resulted in no changes in creatinine or blood urea nitrogen levels in serum at the low-dosage level, but at the higher-dosage level, the creatinine level in serum increased by day 5 posttreatment. Furthermore, there was no increase in the creatinine or blood urea nitrogen level after 2 weeks of treatment with LE-PFA at a dosage of 35 mg/kg/day. When the pharmacokinetics of both free PFA and LE-PFA were compared, the plasma half-life of the encapsulated drug was approximately four times longer than that of the free drug. In addition, the systemic clearance of LE-PFA was approximately one-fifth of that of the free drug. In conclusion, free PFA causes hypocalcemia and hypophosphatemia and increases the creatinine level in serum, whereas the LE form of this drug seems to protect against the abnormal changes in calcium and phosphorus levels caused by the free drug. By preventing hypocalcemia and increasing its half-life, LE-PFA can be used at lower doses and at longer intervals. Clinical investigations of these formulations may be worthwhile.
PMCID: PMC162866  PMID: 8540701
15.  L-651,392, a potent leukotriene inhibitor, controls inflammatory process in Escherichia coli pyelonephritis. 
In this study, the relationship between leukotrienes, peritubular cell infiltration with polymorphonuclear cells (PMNs) and renal tubular damage was investigated in a rat model of acute ascending pyelonephritis. Infection was induced by the injection of 10(5) CFU of Escherichia coli into the bladder and occlusion of the left ureter for 24 h. Treatment of infected animals was started 24 h after the induction of pyelonephritis with either hydrocortisone (25 mg/kg of body weight per day), the leukotriene inhibitor L-651,392 (10 mg/kg/day), or the vehicle of L-651,392 and was maintained for 5 days. At the end of treatment, the animals were killed, serum was collected, and both kidneys were removed for colony counts and histopathology. Renal function was evaluated by the measurement of blood urea nitrogen levels and creatinine clearance. The numbers of PMNs and mononuclear cells (MNs) in the cortex and medulla were recorded for all groups on plastic sections done from the left kidney. Infection alone (vehicle of L-651,392) resulted in intensive interstitial infiltration and a severe tubular destruction in the cortex. Treatment with hydrocortisone did not prevent PMN migration and tissue damage. By contrast, treatment with L-651,392 resulted in a significant reduction in PMNs (P < 0.001 in comparisons with all other groups) and greater preservation of the tubular structure despite identical bacterial counts than in the group receiving hydrocortisone. We conclude that L-651,392 prevents inflammatory cells from reaching the site of infection and protects the kidney from tubular damage associated with inflammation during pyelonephritis. Inhibitors of leukotrienes should be further investigated for their potential benefit as adjuvants to antibiotherapy in the treatment of pyelonephritis.
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PMCID: PMC284592  PMID: 7979288
16.  Increased renal uptake of gentamicin in endotoxemic rats receiving concomitant thromboxane A2 antagonist therapy. 
Antimicrobial Agents and Chemotherapy  1993;37(12):2727-2732.
This report describes the effects of endotoxin and a thromboxane receptor antagonist, L-655,240, on kidney function and the intrarenal pharmacokinetics of aminoglycosides. The rationale for these studies was that thromboxane antagonists may eventually be used in combination with aminoglycosides in patients with gram-negative sepsis and endotoxemia. As aminoglycosides are nephrotoxic and endotoxin has already been shown to increase the renal uptake of gentamicin, we investigated the possibility that thromboxane antagonists might interfere with the nephrotoxic potential of both substances. A decrease in the volume of distribution and an increase in the intracortical concentration of gentamicin were observed in animals given endotoxin. Compared with animals given endotoxin alone, those which received endotoxin plus L-655,240 had significant accumulation of gentamicin in the renal cortex and medulla, as determined by the area under the concentration-time curve, and a significant reduction in the total clearance of the antibiotic (P < 0.05). This difference in uptake could not be attributed to hypotension or changes in the glomerular filtration rate or renal plasma flow. L-655,240 alone did not modify gentamicin pharmacokinetics but did decrease p-aminohippuric acid secretion. Thromboxane antagonists in the context of endotoxemia increase intrarenal uptake of aminoglycosides. If these compounds are to be used as therapeutic agents when endotoxin is present, their influence on renal handling of nephrotoxic drugs needs to be considered. Multiple-dosing regimens deserve investigation.
PMCID: PMC192792  PMID: 8109943
17.  Endotoxin-tobramycin additive toxicity on renal proximal tubular cells in culture. 
Aminoglycoside-induced renal damage is enhanced in animals with Escherichia coli pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy. The toxic effect of endotoxin and tobramycin, alone or in combination, was investigated in primary cultures of rabbit proximal tubular cells grown to confluence in serum-free medium. Sodium-dependent uptakes of Pi and alpha-methylglucopyranoside (MGP) and enzymatic activities (lactate dehydrogenase [LDH] released as a marker of cell necrosis and gamma-glutamyltransferase [GGT] and N-acetyl-beta-D-glucosaminidase [NAG] present in the homogenate as markers of brush border membrane and lysosome integrity) were measured. Cells were exposed to (i) endotoxin (20 mg/liter), tobramycin (1 mM), or endotoxin plus tobramycin for 48 h, or (ii) endotoxin (100 mg/liter), tobramycin (4 mM), or endotoxin plus tobramycin for 72 h. Endotoxin alone did not alter Pi uptake, but tobramycin inhibited Pi uptake through a decrease in Vmax. The effect was not enhanced by the combination of endotoxin and tobramycin. Endotoxin and tobramycin alone exerted no significant effect upon MGP uptake, but strong inhibition of the Vmax was observed after exposure to a combination of endotoxin plus tobramycin, without alteration of the Km. Endotoxin decreased residual GGT activity in the cell homogenate. Tobramycin increased LDH release in the medium and NAG activity in the homogenate. Endotoxin plus tobramycin resulted in an additive effect upon LDH and NAG activities. In conclusion, by disturbing apical membrane integrity, endotoxin increased tobramycin toxicity in vitro in the absence of serum hormonal mediator.
PMCID: PMC245004  PMID: 1673835
18.  Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats. 
Daptomycin is a new biosynthetic antibiotic which belongs to a new class of drugs known as lipopeptides. The objective of this study was to evaluate the effects of daptomycin and vancomycin on tobramycin-induced nephrotoxicity. Female Sprague-Dawley rats were treated during 4 and 10 days with either saline (NaCl, 0.9%) or tobramycin at doses of 4 and 40 mg/kg per day (given every 12 h [q12h] intraperitoneally). Each treatment was combined with saline, daptomycin at a dose of 20 mg/kg per day (given q12h subcutaneously), and ancomycin at a dose of 50 mg/kg per day (given q12h subcutaneously). Daptomycin and vancomycin had no effect on the intracortical accumulation of tobramycin. Daptomycin did not accumulate in renal tissue even after 10 days of treatment. Tobramycin given at a dose of 40 mg/kg per day during 10 days induced a significant inhibition of sphingomyelinase activity in the renal cortex (P less than 0.01) and increased cellular regeneration (P less than 0.01), as measured by the incorporation of [3H]thymidine into DNA of the renal cortex. These changes were minimal when daptomycin was combined with tobramycin. Histologically, signs of tobramycin toxicity were also less severe in the presence of daptomycin. The intracortical accumulation of vancomycin was not modified by tobramycin. The sphingomyelinase activity was significantly more inhibited (P less than 0.01) when vancomycin was associated with tobramycin (4 and 40 mg/kg) without affecting the rate of [3H]thymidine incorporation into DNA. Histologically, signs of tobramycin toxicity were not affected by vancomuycin, but the cellular vacuolizations which were also observed in vancomycin-treated animals were still present in the proximal tubular cells of animals that were treated with the combination vancomycin-tobramycin. This study strongly suggests that daptomycin protects animals from tobramycin-induced nephrotoxicity but that vancomycin may enhance the effect of tobramycin. We conclude that daptomycin is safe and protects kidney cells from tobramycin-induced nephrotoxicity.
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PMCID: PMC171535  PMID: 2158272
19.  Intrarenal distribution of vancomycin in endotoxemic rats. 
We previously observed that the intrarenal distribution of aminoglycosides was modified by Escherichia coli endotoxin in the absence of any major renal physiological disturbance or histological changes. In the present study, we evaluated the role of E. coli endotoxin on the intrarenal distribution of vancomycin. At the beginning of the experiment, female Sprague-Dawley rats were infused intravenously with saline (control) or endotoxin (0.25 mg/kg) during 15 min. Thereafter, saline was constantly infused for the following 4 h. Two hours after the beginning of the infusion, animals were injected intravenously with a single dose of vancomycin (20 mg/kg). The drug levels in serum; renal cortex, medulla, and papilla; and urine were evaluated from 0.08 to 24 h after injection. Analysis of the area under the curve of the drug concentration in the different kidney components versus time showed a higher accumulation of vancomycin in the renal cortex and medulla in the endotoxin-infused rats than in the normal rats (P less than 0.01). Endotoxin was associated with an increase in the half-life in serum (P less than 0.01) and a lower elimination rate constant. The total clearance of vancomycin from plasma was significantly decreased in endotoxin-treated rats (P less than 0.01). These results demonstrate that endotoxin modifies the renal handling of vancomycin.
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PMCID: PMC172705  PMID: 2817853
20.  Influence of indomethacin on the intrarenal uptake of gentamicin in endotoxemic rats. 
Gentamicin is a commonly used antibiotic for the treatment of gram-negative-bacterial infections. Bacterial endotoxin is liberated during antibiotic therapy, and we have shown that endotoxemic animals accumulate more aminoglycosides in their renal parenchyma than normal animals. Vasoactive mediators, such as prostaglandins and thromboxanes, are released after endotoxin and are involved in inflammation. Indomethacin, a nonsteroidal anti-inflammatory drug known to inhibit the synthesis of these hormones, was infused intravenously as a bolus (3.0 mg/kg) or as a bolus followed by a continuous infusion (0.75 mg/kg per h) to rats given gentamicin. Levels of gentamicin in serum and kidney were increased 2 h post-antibiotic treatment in the endotoxemic animals. Renal function was not significantly disturbed. Indomethacin given as a bolus failed to correct the disturbed intrarenal pharmacokinetics of gentamicin induced by endotoxin. However, a bolus followed by continuous infusion of indomethacin resulted in low cortical and high papillary levels of antibiotic. These changes were correlated with the inhibition of prostaglandin synthesis from the kidney. These observations suggest an important role for prostaglandins in the interaction among endotoxin, aminoglycosides, and the kidney. Specific inhibitors of arachidonic acid metabolites should be investigated to further understand the mechanisms of this interaction.
PMCID: PMC172651  PMID: 2802560
21.  Pharmacokinetics and tissue penetration of fleroxacin after single and multiple 400- and 800-mg-dosage regimens. 
Antimicrobial Agents and Chemotherapy  1988;32(10):1515-1520.
The pharmacokinetics and suction-induced blister fluid penetration of fleroxacin following single and multiple (every 24 h for 5 days) oral administration of 400- and 800-mg-dosage regimens were studied in 12 young male volunteers. Plasma and urine samples up to 72 h were assayed by high-pressure liquid chromatography. The peak levels of fleroxacin in plasma were significantly higher after multiple dosing of 800 mg (14.3 versus 8.2 micrograms/ml; P less than 0.01) but not after the last 400-mg dose (6.7 versus 5.0 micrograms/ml). Increased elimination half-life occurred after multiple dosing of 800 mg, from 13.45 +/- 2.94 to 15.60 +/- 3.16 h (P less than 0.05). Mean peak concentrations in blister fluid were significantly different when the first (3.7 +/- 0.8 and 7.7 +/- 1.8 micrograms/ml for 400 and 800 mg, respectively) and last (5.7 +/- 0.9 and 12.3 +/- 2.1 micrograms/ml for 400 and 800 mg, respectively) doses were compared (P less than 0.01). The percentage of blister fluid (BF) penetration (AUCBF/AUCplasma, where AUC is area under the concentration-time curve) yielded values greater than 100% (range, 113.7 to 132.6%). After multiple administration of 800 mg, fleroxacin was cleared from the body more slowly: from 98.80 ml/min after a single dose to 77.72 ml/min following 800 mg every 24 h (P less than 0.01). Saturation of apparent nonrenal clearance is suggested to explain this difference. Fleroxacin was well tolerated by the volunteers.
PMCID: PMC175910  PMID: 3142338
22.  Enoxacin penetration into human prostatic tissue. 
Concurrent enoxacin concentrations in serum and prostatic tissue were determined in 14 patients. The mean ratios of enoxacin concentration in tissue over concentration in serum were 1.4 +/- 0.2 (standard error of the mean). The levels in serum and prostatic tissue were above the MICs for most urinary pathogens.
PMCID: PMC175883  PMID: 3196004
23.  Plasma bactericidal activity after administration of erythromycin estolate and erythromycin ethylsuccinate to healthy volunteers. 
In a crossover design study, we compared the plasma bactericidal activities of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) after administration of a single oral dose to 12 healthy volunteers. Both erythromycin esters displayed very good plasma bactericidal activities against Streptococcus pneumoniae. The median bactericidal titers produced in plasma against Streptococcus pyogenes and Streptococcus pneumoniae were significantly higher with erythromycin estolate than with the ethylsuccinate ester at both 2 and 8 h after dosing (P less than 0.05 by Student's t test). Both erythromycin esters showed rather weak bactericidal activity against Branhamella catarrhalis; a further look at these results indicated that erythromycin estolate presented 50% of the plasma samples at 2 h with bactericidal titers superior or equal to 1:8, versus 11% for the ethylsuccinate ester. Of the 60 plasma bactericidal activity tests performed against Staphylococcus aureus, only 6 (10%) and 3 (5%) exhibited titers of 1:8 or greater for erythromycin estolate and erythromycin ethylsuccinate, respectively. Clinical trials are warranted in which these products are compared in infections other than Streptococcus pyogenes pharyngitis, for which the clinical superiority of erythromycin estolate has been demonstrated.
PMCID: PMC172382  PMID: 3142349
24.  Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections. 
In a prospective, randomized, multicenter study, the efficacy and safety of cefoperazone and the combination ampicillin-tobramycin as initial therapy for patients with severe acute biliary tract infections were compared. Of 77 patients initially entered in the study, definite severe biliary tract infection was confirmed in 67. Sixty-four patients completed treatment. At the end of treatment, 35 of 36 (97%) patients given cefoperazone and 23 of 28 (82%) given ampicillin-tobramycin were cured of their infection (P = 0.07). Pathogens were recovered from the bile in 32 patients; microbiological cures were observed in 18 of 19 (94%) patients receiving cefoperazone and 8 of 13 (62%) receiving ampicillin-tobramycin (P = 0.03). Thirteen patients had septicemia. None (0%) of the eight septicemic patients from the cefoperazone group, but two of five (40%) from the ampicillin-tobramycin group, were clinical failures. Of the isolated pathogens, 51% were resistant to ampicillin, while the resistance rate was 4% for tobramycin and 1% for cefoperazone (P less than 0.001). Biliary concentrations of cefoperazone were maintained at high levels--236 +/- 87 micrograms/ml up to 12 h after administration. Even in the presence of severe obstruction, cefoperazone levels in the bile and gallbladder wall were above MICs for most pathogens. Cefoperazone may be considered as an excellent alternative in the therapy of severe biliary tract infections.
PMCID: PMC172383  PMID: 3056255
25.  Pharmacokinetic advantages of erythromycin estolate over ethylsuccinate as determined by high-pressure liquid chromatography. 
The pharmacokinetics of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) were compared in 12 healthy volunteers after single doses and after repeated oral doses (every 8 h). High-pressure liquid chromatography with electrochemical detection was used to determine concentrations in plasma and urine of estolate, ethylsuccinate, and erythromycin base. The maximum concentration of drug in the serum, the half-life, and the area under the curve for erythromycin estolate were significantly greater than those of erythromycin ethylsuccinate after both regimens. After single and multiple doses, the respective areas under the curve of erythromycin base generated by estolate formulation were 3 and 1.6 times greater (P less than 0.05) than those of ethylsuccinate. The lower percentage of hydrolysis of erythromycin estolate (41 versus 69%) combined with its longer half-life (5.47 versus 2.72 h) and its larger area under the curve (30.61 versus 4.68 micrograms/h/ml, after multiple doses) could explain these differences. This study underscores the need for a specific high-pressure liquid chromatography assay and the importance of wide variability, rate-limited processes, changes with multiple doses, and the appearance of a second peak when one studies the pharmacokinetics of erythromycin esters. The pharmacokinetic data presented in this study reinforce the clinical advantages of erythromycin estolate over erythromycin ethylsuccinate.
PMCID: PMC172220  PMID: 3259856

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