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D N Gilbert

Publications and source records attributed to D N Gilbert.

At least 19 recordsLinked to original sources
PubMed1992

General guidelines for the clinical evaluation of anti-infective drug products. Infectious Diseases Society of America and the Food and Drug Administration.

This document provides new general guidelines for the design and execution of studies evaluating anti-infective drugs for the prevention or treatment of infectious diseases. The first step in evaluation is the determination of in vitro microbial susceptibility. Next, studies are conducted in animals. Several animal models provide information useful in the prediction of appropriate dosing and activity in humans. If the results of these studies are favorable, staged clinical trials are then conducted. These guidelines reflect changes in the practice of medicine, dealing with topics such as the switch from parenteral to oral drug administration during a course of therapy, treatment in settings other than acute-care hospitals, and the use of alternative comparison drugs for the study of indications or dosing schedules not covered by the product label. Because further changes in practice are anticipated, the present guidelines will need to be updated and revised periodically.

Animals↗
PubMed1992

Evaluation of new anti-infective drugs for the treatment of infective endocarditis. Infectious Diseases Society of America and the Food and Drug Administration.

These guidelines describe the design and implementation of clinical trials to assess the safety and efficacy of anti-infective drugs for the treatment of infective endocarditis. Identification and enrollment of patients in clinical trials is based on a modification of traditional criteria. To accrue a sufficient number of patients, only those with streptococcal or staphylococcal endocarditis should be included in studies. Results of treatment with approved drugs allow for projection of expected bacteriologic cure rates and survival rates. Prospective randomized, double-blind studies are recommended. These guidelines are based on the premise that future protocols may include shorter courses of therapy, combinations of drugs, or progression from parenteral to oral therapy. Clinical response is judged as cure, failure, or indeterminate; there is no "improved" category. Microbiologic response is categorized as eradication, persistence, or relapse. When a patient has shown no clinical evidence of active disease for a protracted period, there may be no need to perform a posttreatment blood culture; for such patients, the microbiologic response is termed presumptive eradication. Several months of follow-up may be necessary to detect late relapses.

Anti-Infective Agents↗
PubMed1992

Duration of the protective effect of polyaspartic acid on experimental gentamicin nephrotoxicity.

It is known that daily polyaspartic acid (PAA) protects the kidney from gentamicin nephrotoxicity in a standardized rat model despite marked cortical accumulation of the aminoglycoside. The present experiments address the duration of PAA protection. When administered every other day, PAA provided functional and histologic protection against gentamicin-induced toxicity. A stepwise reduction in nephroprotection occurred as the dosage interval was prolonged.

Animals↗
PubMed1992

Determinants of the in vitro interaction of polyaspartic acid and aminoglycoside antibiotics.

The in vitro interaction of polyaspartic acid (PAA) with aminoglycosides was evaluated using double diffusion in agar, dialysis chambers and changes in the optical density of test solutions. The results document a reversible, presumably electrostatic interaction that is optimized at a pH of approximately 5.0, by the absence of proteins over 800 Da, and at a 20:1 or 10:1 molar ratio of aminoglycoside to PAA. The PAA-aminoglycoside complex lost antibacterial activity and the ability to inhibit pronase E enzymatic activity. These results allow generation of a hypothesis as to the mechanism whereby PAA prevents aminoglycoside experimental nephrotoxicity.

Aminoglycosides↗
PubMed1992

Zidovudine pharmacokinetics in five HIV seronegative patients undergoing continuous ambulatory peritoneal dialysis.

A few reports in the literature describe zidovudine (AZT) pharmacokinetics in patients undergoing hemodialysis; however, the effect of continuous ambulatory peritoneal dialysis (CAPD) on the drug's disposition has not been studied. The pharmacokinetics of AZT were evaluated in five patients, age 37-62 years, who were seronegative for the human immunodeficiency virus and were undergoing CAPD. Serial plasma, urine, and dialysate samples were collected after oral administration of AZT 200 mg. Samples were assayed using radioimmunoassay (RIA). Model-independent analysis was used to determine total plasma clearance, apparent volume of distribution, mean residence time, and half-life. Net peritoneal dialysis clearance was calculated to measure the effect of CAPD on AZT disposition. We found wide interpatient variability in AZT pharmacokinetics. Peak serum concentrations ranged from 0.3-47.8 microns and area under the curve from 0.5-26.1 mg x hour/L. These differences resulted in corresponding differences in clearance (range 66-3176 ml/min/1.73 m2) and volume of distribution (range 16-825 L). Interpatient variability in glucuronidation may partially account for this variability. Net peritoneal dialysis clearance of AZT was 5 ml/minute. Although the effect of peritoneal dialysis on AZT disposition was negligible, clinicians should be aware of the large differences in the way in which individual patients with renal dysfunction handle this drug.

Administration, Oral↗
PubMed1991

Failure of treatment with teicoplanin at 6 milligrams/kilogram/day in patients with Staphylococcus aureus intravascular infection. The Infectious Diseases Consortium of Oregon.

Patients with blood cultures positive for gram-positive cocci were enrolled in a prospective randomized double-blind comparative trial of vancomycin at 15 mg/kg every 12 h versus teicoplanin at 6 mg/kg every 12 h for three doses and then 6 mg/kg every 24 h. A total of 54 patients were randomized, and 40 were evaluable. Of the 40, 9 had infection of indwelling vascular catheters. Four infections were due to Staphylococcus aureus, and five were due to Staphylococcus epidermidis. In concert with catheter removal, all patients were treated successfully, regardless of which drug they were taking. Of 31 patients without an indwelling catheter, 19 were infected with S. aureus, and 12 of the 19 had either endocarditis or mycotic aneurysm. Six of eight patients given teicoplanin failed treatment, as opposed to one of four patients given vancomycin (P = 0.14). Of greater concern, four of four patients with left-sided endocarditis or mycotic aneurysm failed to recover when given teicoplanin, as opposed to one of three patients given vancomycin (P = 0.07). Although not quite statistically significant, the unexpectedly high number of treatment failures with teicoplanin resulted in a decision to discontinue patient enrollment. It is suggested that future trials explore the efficacy of larger doses of teicoplanin.

Adult↗
PubMed1991

Long-term protection of polyaspartic acid in experimental gentamicin nephrotoxicity.

Polyaspartic Acid (PAA) protects the kidney from experimental gentamicin nephrotoxicity despite large increases in renal cortical gentamicin content. In these experiments, prominent cytoplasmic vacuoles were noted in all animals that received PAA with or without gentamicin. The present study showed that there were no renal structural or functional consequences of PAA given alone or with gentamicin for up to 14 days, followed by a 16-week washout period. Creatinine clearance was similar to that of controls in animals that received gentamicin and in those that received PAA alone. Thus, complete functional protection was conferred by PAA and gentamicin, confirming previous reports from our laboratory. There was no protection by PAA from the nephrotoxic effects of mercuric chloride and cis-platinum.

Animals↗
PubMed1991

Once-daily aminoglycoside therapy.

The once-daily administration of aminoglycosides is an attractive concept. In animal experiments and clinical trials, there is either a reduction in or no influence on the risk of toxicity. Less frequent dosing reduces the contact time between host tissue binding sites and drug. Thanks to the PAE and perhaps other as-yet-unrecognized factors, the fall in the level in serum below the MIC does not appear to impair antibacterial efficacy; in fact, the higher peak level in serum may enhance drug efficacy early in a dosage interval. In neutropenic patients, the in vivo PAE may be lost or small-colony variants with a shorter PAE may be selected unless a concomitant beta-lactam is administered. Because it will be some time before data from clinical trials in the United States are available, because the results from the international trials are encouraging, and because there is potential benefit to patients, it seems reasonable for infectious diseases consultants to cautiously initiate the educational process necessary to implement once-daily aminoglycoside therapy in their institutions.

Aminoglycosides↗
PubMed1990

The implications for Europe of revised FDA guidelines for clinical trials with anti-infective agents.

This article summarizes the current collaborative effort between the US Food und Drug Administration and the Infectious Diseases Society of America for the purpose of generating new General and Disease/Organism Specific Guidelines for the evaluation of anti-infective agents. Examples of proposed changes from draft documents are presented. The final documents may assist European colleagues in their efforts to establish a standardized new drug registration process by 1992. An area of mutual interest is the acceptability of safety and efficacy data from international clinical trials. In the interest of human and financial economies, both US and European Guidelines need to clarify the conditions, or criteria, for the conduct of valid 'off-shore' clinical trials.

Anti-Infective Agents↗
PubMed1989

Polyaspartic acid prevents experimental aminoglycoside nephrotoxicity.

The influence of the polyamino acid polyaspartic acid (PAA) on experimental aminoglycoside nephrotoxicity was determined. PAA prevented all measured functional and pathologic evidence of gentamicin nephrotoxicity for less than or equal to 27 d of study. All the animals given PAA, either alone or with gentamicin, developed prominent cytoplasmic vacuoles in the cells of the renal proximal convoluted tubules; the vacuoles in rats given just PAA differed from those observed in rats given PAA plus gentamicin. Rats given PAA plus gentamicin accumulated roughly 10 times more renal aminoglycoside as did rats given gentamicin alone. Immunohistochemical localization studies confirmed the presence of increased amounts of gentamicin in the cytoplasm of the tubular cells of animals given gentamicin plus PAA. PAA did not alter the in vitro antimicrobial activity of gentamicin versus Escherichia coli or Pseudomonas aeruginosa. These studies demonstrate the ability of PAA to prevent experimental gentamicin nephrotoxicity.

Animals↗
PubMed1989

Influence of daptomycin on staphylococcal abscesses and experimental tobramycin nephrotoxicity.

The antibacterial efficacies of daptomycin and vancomycin were compared in male Fischer rats with subcutaneous abscesses caused by either methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant S. aureus (MRSA). The influence of daptomycin on tobramycin nephrotoxicity was also assessed. MSSA or MRSA abscesses were treated with subcutaneous daptomycin (10 mg/kg every 12 h), vancomycin (125 mg/kg every 12 h), or diluent (every 12 h) for 5 to 10 days. Rats in both antibiotic treatment groups had lower abscess bacterial counts than did controls at days 5 and 10 (P less than 0.0025). The daptomycin treatment groups had lower abscess bacterial counts than did the vancomycin treatment groups for MSSA at day 5 (P less than 0.0025) and day 10 (P less than 0.025) and for MRSA at day 10 (P less than 0.0025). Nephrotoxicity treatment groups included animals treated for 3, 7, 10, 14, and 17 days with subcutaneous diluent (every 12 h), daptomycin (20 mg/kg every 12 h), tobramycin (40 mg/kg every 12 h), and the combination of daptomycin and tobramycin. Compared with controls, animals treated with daptomycin alone exhibited no detectable nephrotoxicity. Rats given tobramycin alone developed functional and histopathologic abnormalities from days 7 through 17. Animals treated with daptomycin and tobramycin for 14 days had a lower mean concentration of creatinine in serum (P less than 0.005), higher mean creatinine clearance values (P less than 0.05), and less cortical tubular cell regeneration (P less than 0.05) than did rats treated with tobramycin alone. In rats with staphylococcal subcutaneous abscesses, daptomycin was superior to vancomycin in treating both MSSA and MRSA. Daptomycin alone caused no detectable renal injury, and in rats given daptomycin combined with tombramycin, there was less histologic and functional renal injury than in animals given tobramycin alone.

Abscess↗
PubMed1989

Use of antimicrobial agents in renal failure.

Many antimicrobial agents are excreted primarily by the kidneys, and hence, to avoid toxicity and maintain efficacy, dosage adjustments are necessary. After estimating a patient's creatinine clearance, an appropriate dosage adjustment is easily accomplished. The adjustments for aminoglycosides are simplified by the use of a suggested once-daily, or once every other day dosage regimen.

Aminoglycosides↗
PubMed1988

The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abscess.

The influence of dosage regimen on the nephrotoxicity, ototoxicity, and antibacterial efficacy of tobramycin was assessed in Fisher rats with Pseudomonas aeruginosa subcutaneous abscesses. A subcutaneous tobramycin dose of 10 mg/kg every 4 h resulted in peak and trough serum concentrations that approximated those currently recommended for patients. Subsequently, the influence of this subcutaneous dosage regimen was compared with three other regimens that administered the same total daily dose: 20 mg every 8 h, 30 mg every 12 h, and 60 mg every 24 h. Renal injury was assessed by measuring inulin clearance and in vivo synthesis of renal DNA and by histopathology. Cochlear histology was also assessed. The number of P. aeruginosa per abscess was quantitated. In animals with infected abscesses, there was a consistent trend of greater kidney injury with the more-frequent dosage regimens. There was no evidence of cochlear toxicity in any group. All regimens were equally effective in reducing the number of P. aeruginosa in subcutaneous abscesses.

Abscess↗
PubMed1988

Microsomal protein synthesis inhibition: an early manifestation of gentamicin nephrotoxicity.

Aminoglycoside antibiotics achieve bacterial killing by binding to bacterial ribosomes and inhibiting protein synthesis. To examine whether similar mechanisms could be present in renal tubular cells prior to the onset of overt proximal tubular necrosis due to these drugs, we isolated microsomes from Fischer rats given 20 mg/kg gentamicin every 12 h subcutaneously for 2 days and from vehicle-injected controls. Concomitant studies of renal structure, function, and mitochondrial respiration were carried out. [3H]leucine incorporation into renal microsomes of treated animals was reduced by 21.9% (P less than 0.01), whereas brain and liver microsomes from the same animals were unaffected. Gentamicin concentration in the renal microsomal preparation was 56 micrograms/ml, a value 7- to 10-fold above concentrations necessary to inhibit bacterial growth. Conventional renal function studies were normal (blood urea, serum creatinine, creatinine clearance). Treated animals showed only a mild reduction of inulin clearance, 0.71 compared with 0.93 ml.min-1.100 g-1 in controls (P less than 0.05), and an increase in urinary excretion of N-acetylglucosaminidase of 20 compared with 14.8 units/l (P less than 0.05). Renal slice transport of p-aminohippuric acid, tetraethylammonium, and the fractional excretion of sodium were well preserved. There was no evidence, as seen by light microscopy, of proximal tubular necrosis. Mitochondrial cytochrome concentrations were normal and respiratory activities only slightly reduced. Processes similar to those responsible for bacterial killing could be involved in experimental gentamicin nephrotoxicity before overt cellular necrosis.

Animals↗
PubMed1987

Oral ciprofloxacin therapy for chronic contiguous osteomyelitis caused by aerobic gram-negative bacilli.

Twenty adult patients with chronic contiguous osteomyelitis caused by aerobic gram-negative bacilli were enrolled in an open, prospective cooperative study to determine the effect of oral ciprofloxacin therapy in a dosage of 750 mg every 12 hours. There were 14 men and six women, with a mean age of 55 years. Fifteen of the 20 patients had undergone previous unsuccessful attempts at therapy; seven of the 20 patients had clinically important underlying diseases. Osteomyelitis involved the sternum in three patients and the bones of the lower extremity in 17 patients. Initial surgical debridement was performed in 15 of 20 patients. The predominant organism isolated was Pseudomonas aeruginosa, which was found as a single pathogen in 13 patients and as part of a polymicrobic flora in three patients. Based on posttreatment follow-up of seven to 21 months, clinical cure was achieved in 13 of 20 (65 percent) patients and bacteriologic cure was achieved in 14 of 20 (70 percent) patients. Minimal inhibitory concentrations of ciprofloxacin against P. aeruginosa increased during therapy in four of 16 (25 percent) patients. Minor gastrointestinal side effects occurred in five patients. Oral ciprofloxacin was an effective and safe therapy in patients with chronic contiguous osteomyelitis due to aerobic gram-negative bacilli.

Adult↗
PubMed1987

Guidelines for evaluating new antimicrobial agents.

Evaluating new antimicrobial agents is governed mostly by interaction between the pharmaceutical industry and the Food and Drug Administration (FDA). Clinical trials are designed to comply with FDA guidelines published in 1977. Basic principles of the 1977 guidelines remain valid; however, changes in the clinical application of anti-infective agents and in the accepted design of clinical trials have occurred. Some changes are inconsistent with the requirements of the 1977 documents. Members of the Infectious Diseases Society of America (IDSA) have the perspective and knowledge needed to assist in updating the 1977 guidelines. It is proposed that the IDSA establish a formal working relationship with the FDA to review and modernize the 1977 guidelines. Industry participation in this process is desirable. If the IDSA can help orchestrate guideline revision in an environment of mutual respect and cooperation, the result may be a more efficient drug-evaluation process that continues to protect the public interest and is more consistent with contemporary concepts of treatment for infectious disease.

Anti-Infective Agents↗
PubMed1986

Modification of experimental aminoglycoside nephrotoxicity.

Some of the factors that modify experimental aminoglycoside nephrotoxicity are reviewed. Maneuvers ready to be tested for effectiveness in the clinical use of these drugs are highlighted. The use of concomitant penicillins and changes in dosing strategy seem to be particularly exciting new leads toward elimination of clinical aminoglycoside nephrotoxicity.

Aminoglycosides↗