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Biomedical subjects

J E Leggett

Publications and source records attributed to J E Leggett.

At least 19 recordsLinked to original sources
PubMed2001

Phenotypic resistance of Staphylococcus aureus, selected Enterobacteriaceae, and Pseudomonas aeruginosa after single and multiple in vitro exposures to ciprofloxacin, levofloxacin, and trovafloxacin.

The phenotypic resistance of selected organisms to ciprofloxacin, levofloxacin, and trovafloxacin was defined as a MIC of > or =4 microg/ml. The dynamics of resistance were studied after single and sequential drug exposures: clinical isolates of methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa were utilized. After a single 48-h exposure of a large inoculum to four times the initial MIC for the organism, the frequency of selection of resistant mutants of MSSA was greater for trovafloxacin than levofloxacin (P = 0.008); for E. cloacae, the frequency was highest for ciprofloxacin and lowest for levofloxacin and trovafloxacin; for S. marcescens, the frequency was highest for trovafloxacin and lowest for ciprofloxacin (P = 0.003). The results of serial passage experiments were analyzed both by the Kaplan-Meier product-limited method as well as by analysis of variance of mean inhibitory values. By both methods, MSSA and MRSA expressed mutants resistant to ciprofloxacin after fewer passages than were required for either levofloxacin or trovafloxacin. For the aerobic gram-negative bacilli, two general patterns emerged. Mutants resistant to trovafloxacin appeared sooner and reached higher mean MICs than did mutants resistant to levofloxacin or ciprofloxacin. Mutants resistant to ciprofloxacin appeared later and reached mean MICs lower than the MICs of the other two drugs studied. Even though individual strain variation occurred, the mean MICs were reproduced when the serial passage experiment was repeated using an identical panel of E. coli isolates. In summary, the dynamic selection of fluoroquinolone-resistant bacteria can be demonstrated in experiments that employ serial passage of bacteria in vitro.

Anti-Infective Agents↗
PubMed2000

Ambulatory use of parenteral antibacterials: contemporary perspectives.

Outpatient parenteral antimicrobial therapy (OPAT) offers increased patient comfort and convenience in appropriately selected patients who require parenteral antibacterial therapy, as well as opportunity for cost savings. Home-based programmes, with drugs being administered by the patient or the caregiver, have become the norm in the USA. Choice of drugs for OPAT is based on antimicrobial spectrum, dosage regimen, drug stability, toxicity profile, and cost. Over the past decade, availability of sophisticated programmable pumps has allowed a wider range of antimicrobial agents to be used in the ambulatory setting. The most popular antibacterial agents in OPAT programmes in the USA are vancomycin and beta-lactams.

Ambulatory Care↗
PubMed1998

Influence of assay methodology on the measurement of free serum ceftriaxone concentrations.

The influence of assay methodology on the measurement of the active free fraction of ceftriaxone in plasma was determined. The free fraction was measured by three methods: agar diffusion bioassay, precipitation of plasma protein with methanol followed by high-performance liquid chromatography (HPLC) of the supernatant, and ultrafiltration of plasma followed by HPLC of the filtrate. In human serum, the free ceftriaxone levels were significantly lower (P = 0.03) when measured on ultrafiltrates compared to the other two methods. This difference disappeared when dolphin serum was studied. After ultrafiltration, human serum was shown, by Scatchard plot analysis, to have two ceftriaxone binding sites. Species differences were also demonstrated. Hence, in humans, determination of free plasma ceftriaxone varies with the assay method employed.

Animals↗
PubMed1996

Mycobacterium gordonae in fiberoptic bronchoscopes.

BACKGROUND: Failure of high-level disinfection of bronchoscopes has caused several outbreaks of nosocomial infection or pseudoinfection involving mycobacteria. METHODS: Inocula (10(5) colony-forming units/ml and 10(8) colony-forming units/ml) of a clinical Mycobacterium gordonae isolate were used to contaminate bronchoscopes. Glutaraldehyde, iodophor, and peracetic acid disinfectants were evaluated in manual and automated disinfection procedures after 10- to 20-minute exposures at 20 degrees and > or = 25 degrees C. RESULTS: Four of five manual disinfectant procedures failed to eliminate experimental M. gordonae infection after 10-minute exposure at 20 degrees C. All five manual procedures tested at 20 degrees C were effective after 20-minute exposure to the five disinfectants (two 2% alkaline glutaraldehyde preparations, 3.2% alkaline glutaraldehyde, 75 ppm iodophor, and 0.5% glutaraldehyde-0.03% phenolic). Three of four manual (one 2% glutaraldehyde, 3.2% glutaraldehyde, and 0.5% glutaraldehyde-0.03% phenolic) and three automated (one 2% glutaraldehyde, 0.5% glutaraldehyde-0.03% phenolic, and 0.2% peracetic acid) disinfectant procedures eliminated contamination after a 10- to 12-minute exposure at > or = 25 degrees C. Effective total cycle times for the three automated procedures ranged from 20 to 45 minutes. CONCLUSIONS: Previously Environmental Protection Agency-approved tuberculocidal agents may be ineffective against M. gordonae when used according to label claims under normal clinical conditions. A minimum 20-minute exposure time at 20 degrees C is necessary for manual disinfection methods. Higher temperatures may improve disinfectant efficacy. Newer automatic disinfection machines may be as effective as traditional manual methods and also may reduce hazards to employees.

Bronchoscopes↗
PubMed1995

Staphylococcus aureus septic arthritis in patients on hemodialysis treatment.

We retrospectively reviewed hospital discharge diagnoses of septic arthritis over an 11-year period (1982 through 1992) at 3 medical centers; 11 episodes of septic arthritis were identified in patients on hemodialysis treatment. Of the 11 episodes, 9 were caused by Staphylococcus aureus; in 8 of 9, the blood cultures were positive for the organism and the infection was monoarticular. Concurrent infection of the dialysis access site occurred in 4 cases. Two patients died (22%). We postulate that repeated skin trauma and contact with health care personnel and facilities result in a high rate of nasal carriage of S aureus and, hence, an increased risk of bacteremia with its attendant complications such as septic arthritis. The use of mupirocin nasal ointment is reported to eradicate or suppress carriage in a high percentage of patients; some studies report that long-term suppressive therapy reduces the frequency of S aureus bacteremia.

Administration, Intranasal↗
PubMed1992

Misdiagnoses: a timely reminder.

This case report of an occult infection masquerading as palindromic arthritis was misdiagnosed for almost 2 years. The episodic bouts of erysipelas were not obvious, and it was even suggested that the silicone implanted 7 years previously could possibly be inciting an autoimmune disease. Approximately 2 years after the onset of the recurrent episodes of fever, myalgias, and arthralgias, coagulase-negative staphylococci were found residing in the valve stems of bilumen breast implants, which were removed. The symptom complex disappeared and has not recurred.

Adult↗
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↗
PubMed1990

Ampicillin and sulbactam pharmacokinetics and pharmacodynamics in continuous ambulatory peritoneal dialysis (CAPD).

The fixed combination antibiotic ampicillin/sulbactam may provide a new, safe, and effective method of treating dialysis-related bacterial peritonitis. The pharmacokinetics of this antibiotic combination were determined in patients receiving continuous ambulatory peritoneal dialysis (CAPD). The pharmacodynamic activity of this drug was also determined by use of mean bactericidal titers against selected bacterial strains. Six noninfected CAPD patients in a randomized two-way crossover study were given a fixed dose of ampicillin (2 gm) and sulbactam (1 gm) either intravenously or intraperitoneally. The mean peak ampicillin and sulbactam serum concentrations following intravenous dosing were 170.3 and 87.5 micrograms/mL, respectively. The mean peak serum concentrations of ampicillin and sulbactam following intraperitoneal dosing were 48.0 and 27.8 micrograms/mL, respectively. Absolute bioavailabilities of the intraperitoneal ampicillin and sulbactam doses were 60% and 68%. Both drugs exhibited similar distribution and elimination characteristics. Renal failure markedly reduced drug elimination. Intraperitoneal administration of ampicillin/sulbactam provided satisfactory inhibitory and bactericidal antibiotic titers for most organisms in dialysate at 6 h but not 24 h. Ampicillin/sulbactam (2 gm/1 gm) should be administered every 12 h to patients with peritoneal dialysis-related peritonitis.

Adult↗
PubMed1990

Comparative dose-effect relations at several dosing intervals for beta-lactam, aminoglycoside and quinolone antibiotics against gram-negative bacilli in murine thigh-infection and pneumonitis models.

Relatively few animal studies have investigated the influence of dosing regimens on the efficacy of antibiotics possessing different pharmacodynamic characteristics. We evaluated the impact of dosing interval on the relative efficacy and potency of beta-lactams, aminoglycosides, and ciprofloxacin against Pseudomonas aeruginosa. Escherichia coli, and Klebsiella pneumoniae in murine pneumonitis and thigh-infection models. We used a sigmoid dose-response model to determine the maximal bactericidal effect at 24 hours (Emax) and the total dose required to achieve 50% of Emax (P50) at several dosing intervals. P50S (a measure of drug potency, in mg/kg/day) for beta-lactams increased 14- to 73-fold with longer intervals in both models. Dosing interval had little impact on P50S for aminoglycosides or ciprofloxacin. Emax varied among drugs but displayed no dependence on dosing interval. This method of analysis allows comparison of efficacy and dependence of potency on dosing regimen among different classes of antibiotics.

4-Quinolones↗
PubMed1989

Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models.

Animal studies that compare antibiotics have used only a limited number of doses administered at intervals chosen without regard for their pharmacodynamic effects of pharmacokinetic profiles. We compared the relative efficacy and potency of three beta-lactams and two aminoglycosides in lung and thigh-infection models in neutropenic mice by defining the maximum attainable antimicrobial effect at 24 h (Emax) and the total dose required to reach 50% of maximum effect (P50) at several dosing intervals. For beta-lactams, Emaxs were similar, whereas P50s increased 10- to 50-fold with longer intervals in both models. Aminoglycosides were significantly more bactericidal in the lung than in the thigh, and dosing interval had little impact on P50s in either model. Recognizing the variable impact of dosing interval on efficacy for different classes of antibiotics is mandatory for the proper design and interpretation of comparative trials.

Animals↗
PubMed1989

Use of serum ultrafiltrate in the serum dilution test.

Although pooled human serum diluent is advocated in the serum dilution test, its use may compensate for protein binding defects in patients and yield nonrepresentative titers. To test this hypothesis, comparison was made of serum ultrafiltrate (molecular weight cutoff less than or equal to 30,000) serially diluted into either pooled serum ultrafiltrate or Mueller-Hinton broth with patient serum samples diluted into pooled human serum in 111 assays from 55 patients and 6 volunteers. Of 111 bactericidal titers in ultrafiltrate and/or Mueller-Hinton broth, 101 were within a single twofold dilution of titers in pooled human serum. Nine of 10 discordant titers involved highly bound drugs and were usually higher in ultrafiltrate than in pooled human serum. In seven additional volunteers with renal failure, titers in ultrafiltrate and in each volunteer's serum were higher than those diluted in pooled human serum (P = .002). Recommended methods using pooled serum diluent may not accurately predict actual bactericidal titers in patients with abnormal protein binding.

Anti-Bacterial Agents↗
PubMed1989

Enhancing effect of serum ultrafiltrate on the activity of cephalosporins against gram-negative bacilli.

A few studies have suggested that the inhibitory effect of serum on activity of broad-spectrum cephalosporins is less than that predicted by the degree of protein binding. Microdilution MICs of ceftriaxone, cefoperazone, moxalactam, and ceftizoxime were therefore determined against ATCC and clinical strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus in Mueller-Hinton broth containing either human albumin (as 0, 2.5, or 5% solution) or heat-inactivated human serum (as 0, 25, 50, or 95% solution). Arithmetic linear dilutions were used to improve accuracy. For standard bacterial strains, MICs in the presence of 5% albumin were higher than in broth alone by multiples of 10.9 to 21 for ceftriaxone, 5.5 to 16.4 for cefoperazone, 1.9 to 3.7 for moxalactam, and 1.1 to 1.4 for ceftizoxime, as expected by their protein binding. MICs in the presence of 95% serum were similar to those in 5% albumin for all four drugs against S. aureus and P. aeruginosa but were 2.2- to 4.8-fold lower (P less than 0.001) against E. coli and K. pneumoniae. Similar findings were observed at lower protein concentrations and with clinical isolates, except that for some strains of P. aeruginosa MICs were lower in serum than in albumin. Individual sera from five subjects gave comparable results. The addition of serum ultrafiltrate to albumin-containing solutions reduced MICs of ceftriaxone and cefoperazone 1.6- to 7.4-fold against E. coli and K. pneumoniae (P less than 0.01) but did not alter the MICs for S. aureus. Serum may contain an ultrafiltrable component(s) that enhances the activity of third-generation cephalosporins against many gram-negative bacilli.

Blood Proteins↗
PubMed1988

Pharmacokinetics and pharmacodynamics of cefoperazone-sulbactam in patients on continuous ambulatory peritoneal dialysis.

This study was conducted to determine the pharmacokinetics of the fixed combination antibiotic cefoperazone-sulbactam in patients receiving continuous ambulatory peritoneal dialysis (CAPD). In addition, the pharmacodynamic profile of this combination was determined by the use of mean bactericidal titers against selected bacterial strains. Six noninfected CAPD patients were given a fixed dose of cefoperazone (2 g) and sulbactam (1 g) either intravenously or intraperitoneally over 10 min in a randomized, two-way crossover fashion. The mean peak cefoperazone concentration in serum after intravenous administration was 280.9 micrograms/ml. The mean peak concentration in serum after intraperitoneal cefoperazone administration was 38.9 micrograms/ml and occurred 2 to 4 h postdose. The mean peak sulbactam concentration in serum after intravenous administration was 82.2 micrograms/ml. The mean peak concentration in serum after intraperitoneal sulbactam administration was 24.4 micrograms/ml and occurred at 6 h. The absolute bioavailability of the intraperitoneal dose was 61% for cefoperazone and 70% for sulbactam. Cefoperazone total body and renal clearances were unaffected by renal failure and dialysis. However, both clearance values for sulbactam were reduced markedly. Only intraperitoneal dosing provided peak inhibitory and bactericidal titers in dialysate for all organisms tested. Intravenous dosing provided satisfactory dialysate titers only for very susceptible bacterial strains. End-stage renal disease and CAPD do not alter cefoperazone pharmacokinetics; however, sulbactam dosing may need to be adjusted.

Adult↗
PubMed1988

Lipid X protects mice against fatal Escherichia coli infection.

Lipid X, the major monosaccharide precursor of lipid A, is nontoxic and has previously been shown to protect mice and sheep from the harmful effects of endotoxin. To test the hypothesis that lipid X could be therapeutic against infections with gram-negative organisms, neutropenic ICR mice were infected by intramuscular inoculation of Escherichia coli and subsequently treated with lipid X alone or in combination with the antibiotic ticarcillin. Lipid X slightly prolonged survival; treated mice had a significantly improved rate of survival 18 h after intramuscular inoculation as compared with controls (P less than 0.025). By 24 h, however, this difference disappeared. When lipid X was combined with ticarcillin, survival differences were both significant and prolonged. Treatment of mice with one to two doses of lipid X for a total dose of 1 mg intravenously and with 1,200 mg of ticarcillin per kg every 6 h improved survival over a 48-h treatment period from 5 to 23% (P less than 0.0025). Treatment with lipid X and ticarcillin over a broad range of antibiotic dosages in 362 mice demonstrated improved survival of two- to fourfold (P less than 0.0001 at 24 h after inoculation, P less than or equal to 0.0005 at 48 h, and P less than or equal to 0.0001 at 5 days). Lipid X enabled the dose of ticarcillin necessary to protect 50% of mice from death to be reduced by two- to fivefold. Pretreatment with lipid X was not necessary to improve survival: 16 of 17 (94%) infected and visibly ill animals that received lipid X and ticarcillin 6 h after thigh inoculation survived versus 30 of 44 (68%) control animals treated with ticarcillin alone (P less than 0.0001). Lipid X had no antimicrobial activity in vitro. Lipid X is a novel agent that enhances survival in an animal model of severe infection with gram-negative organisms.

Animals↗
PubMed1987

Changes in k, rb, and na transport to shoots after anoxia.

The effect of anoxia on subsequent uptake and transport of K, Rb, and Na was examined with seedlings of barley (Hordeum vulgare L.), corn (Zea mays L.), and tall fescue (Lolium x Festuca hybrid derivative) to further our understanding of xylem loading. Roots were incubated in solutions depleted of O(2) by flushing with N(2) gas. After 1 hour exposure, plants were returned to aerated solutions for 16 hours prior to measuring uptake and transport. For each species, anoxia pretreatment significantly enhanced Na transport to the shoot. The rate of Na accumulation into roots, however, was not affected. There was no enhancement of either K or Rb accumulation in shoots, indicating specificity for Na transport. A minimum exposure to anoxia of 30 minutes and a minimum of 12 hours elapsed time was necessary to achieve the maximum rate of Na transport to the shoot in barley seedlings. Accumulation of Na in the shoot of both the control and anoxia pretreated barley plants was inhibited by anoxia and by addition of the proline analog, l-azetidine-2-carboxylic acid, during the uptake period. Enhancement of Na transport was associated with a proportional increase in the rate of synthesis of a membrane bound protein with a molecular weight of 78,000 daltons.

Journal Article↗
PubMed1979

Rapid Changes in Translocation Patterns in Soybeans following Source-Sink Alterations.

The effects of source-sink alterations on the translocation patterns to soybean ("Fiskeby V") pods were studied using a pod leakage technique. The distribution of assimilates from a source leaf using double pulse experiments was followed at the pods at the source node and the node immediately below. Alterations were made by shading, illuminating, or excising two-thirds of the leaf area of the leaf at the node below. In control experiments both pulses exhibited identical time-course patterns at both nodes. Shading the lower leaf during the first half of the experiment and illuminating during the second reduced the distribution of (14)C-assimilate to the lower node's pods from the source leaf by approximately 30 to 50% while having no effect at the source node. Illuminating the lower leaf during the first half of the experiment followed by excision of two-thirds of that leaf's area and shading increased the import from the source leaf by 4- to 33-fold relative to the control while reducing the distribution to the source node by up to 40%. The change in distribution pattern took place in less than 30 minutes with no apparent change in the source leaf net photosynthesis or in the rate of movement to the pods. The results indicate that any alterations in the source-sink balance will quickly produce a change in the distribution patterns to the pods.

Journal Article↗