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Biomedical subjects

W M Scheld

Publications and source records attributed to W M Scheld.

At least 127 records · Page 7Linked to original sources
PubMed1983

Moxalactam for the treatment of bacterial meningitis in children.

Increasing resistance to antibiotics in meningeal pathogens has stimulated a search for new antimicrobial agents for the treatment of bacterial meningitis. Moxalactam penetrates well into infected cerebrospinal fluid (CSF) and is highly active against most gram-negative bacteria. The clinical efficacy and safety of moxalactam in the treatment of childhood meningitis caused by Haemophilus influenzae (25 patients) or Neisseria meningitidis (five patients) was evaluated in a random, uncontrolled study. The penetration of the antibiotic into CSF was also evaluated in these patients and in another five children with bacterial meningitis. The clinical results were excellent, with 29 of 30 cases cured. The single adverse clinical reaction noted was the development of a wound hematoma in a postoperative patient; this problem may have been related to moxalactam therapy. The levels of moxalactam achieved in CSF greatly exceeded the minimal bactericidal concentrations for the infecting organisms. Moxalactam appears to be safe and effective as primary therapy for meningitis caused by H influenzae or N meningitidis.

Adolescent↗
PubMed1983

Imipenem therapy of experimental Staphylococcus aureus and Streptococcus faecalis endocarditis.

Imipenem was very active in vitro against 36 Staphylococcus aureus isolates from cases of infective endocarditis; the MBC90 was 0.06 mg/l (four- to eight-fold more active than nafcillin). The in-vitro activity of imipenem against 22 Streptococcus faecalis isolates from proven endocarditis cases was similar to that of penicillin G (MBC90 = 8 mg/l). Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph. aureus and Str. faecalis, respectively. The dosages were chosen to simulate closely serum antibiotic concentrations found in humans receiving standard parenteral regimens. Imipenem was more rapidly bactericidal than nafcillin in experimental staphylococcal endocarditis. The mean +/- S.D. Staph. aureus concentrations within aortic valve vegetations (log10 cfu/g) after 5 days of therapy were as follows: imipenem = 1.39 +/- 0.61 versus nafcillin 2.39 +/- 0.36 (P less than 0.02). Both the imipenem and nafcillin regimens resulted in 'sterile' vegetations in congruent to 50% of rabbits with experimental staphylococcal endocarditis after 5 days of therapy (P greater than 0.05). Imipenem was also equivalent to penicillin plus gentamicin in the therapy of experimental enterococcal endocarditis for 5 days, as assessed by the mean cfu/g vegetation and the percentage of vegetations rendered sterile. However, 7 days of therapy cured experimental enterococcal endocarditis in 72% of rabbits receiving penicillin plus gentamicin versus 20% for imipenem alone (P less than 0.05). Imipenem deserves further evaluation in the therapy of infective endocarditis, both in experimental animal models of infection and in humans. This agent may prove useful in the therapy of staphylococcal endocarditis in a variety of difficult clinical situations. Therapy of enterococcal endocarditis with imipenem alone is not advisable, pending further data.

Animals↗
PubMed1983

Effect of methylprednisolone on entry of ampicillin and gentamicin into cerebrospinal fluid in experimental pneumococcal and Escherichia coli meningitis.

The influence of methylprednisolone on the passage of ampicillin and gentamicin into and activity within cerebrospinal fluid was examined in two models of experimental meningitis. Steroid pretreatment reduced the concentrations of these drugs in purulent cerebrospinal fluid of rabbits with experimental pneumococcal and Escherichia coli meningitis (P less than 0.05). However, the resultant mean concentrations of these antibiotics in cerebrospinal fluid still exceeded the minimal bactericidal concentrations of the infecting organisms. The rate of bactericidal effect in vivo was unaffected by steroid therapy in each model. Methylprednisolone did not have deleterious effects on the course of treated experimental meningitis under these short-term (24-h) experiments.

Ampicillin↗
PubMed1983

Pharmacokinetics of aztreonam in patients with various degrees of renal dysfunction.

We have studied the pharmacokinetics of 1-g intravenous doses of aztreonam in four groups of six volunteers each, distinguished by their creatinine clearances (greater than 80, 30 to 80, 10 to 29, and less than 10 ml/min). Subjects received 1 g of aztreonam intravenously without any complications. Aztreonam serum and urine levels were measured by microbiological methods and by high-pressure liquid chromatography, and unbound serum aztreonam was determined by ultrafiltration. Serum levels were well described by a two-compartment infusion model. From this model we determined steady-state volume of distribution, alpha distribution phase half-life, beta elimination phase half-life, and total clearance of aztreonam. The mean of beta elimination phase half-life ranged from 2 h in normal subjects to 6 h in anephric patients. The total clearance of aztreonam correlated closely with corrected creatinine clearance calculated from serum creatinine, age, and sex (r = 0.97, P less than 0.001) and ranged from a mean value of 107 ml/min in normal subjects to 29 ml/min in functionally anephric patients. Some 75% of aztreonam excretion was renal. Urinary recovery of aztreonam ranged from 58% of the administered dose in normal subjects to 1.4% in uremic patients. Free aztreonam in serum correlated inversely with creatinine clearance (P less than 0.001). A nomogram was developed as a guide for adjustment of aztreonam dosage according to renal function.

Adult↗
PubMed1983

Evaluation of aztreonam in experimental bacterial meningitis and cerebritis.

Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with ampicillin, ampicillin plus chloramphenicol, and gentamicin in rabbits with experimental meningitis induced by, respectively, ampicillin-susceptible Haemophilus influenzae, ampicillin-resistant H. influenzae, and Escherichia coli. Aztreonam was also compared with gentamicin in experimentally induced E. coli cerebritis in rats. Doses of the various agents were delivered that produced near-peak concentrations in serum comparable to those attained in humans on standard parenteral regimens. The percent penetration [( concentration in cerebrospinal fluid/concentration in serum] X 100) of aztreonam into purulent rabbit cerebrospinal fluid was 23% (versus 12, 27, and 21%, respectively, for ampicillin, chloramphenicol, and gentamicin). In experimental meningitis in vivo, aztreonam was more rapidly bactericidal than was ampicillin in ampicillin-susceptible H. influenzae meningitis, ampicillin or chloramphenicol in ampicillin-resistant H. influenzae meningitis, or gentamicin in E. coli meningitis. In the therapy of experimental cerebritis, the early stage of brain abscess formation, aztreonam reduced the numbers of E. coli in rat brain as rapidly as did gentamicin. Aztreonam deserves further evaluation in acute gram-negative bacterial infections of the central nervous system in both experimental animals and in humans.

Animals↗
PubMed1983

Influence of preformed antibody on the pathogenesis of experimental Candida albicans endocarditis.

The influence of preformed antibody on the induction of experimental Candida albicans endocarditis was investigated by both in vitro and in vivo techniques. Preincubation of C. albicans with immune serum (raised in rabbits by intravenous injection of Formalin-killed yeast cells) decreased adhesion to the constituents of nonbacterial thrombotic endocarditis, e.g., fibrin plus platelets, in vitro. Two different methods, with radiolabeled or viable yeast cells, were confirmatory and demonstrated decreased adhesion of immune serum-treated C. albicans cells to 0 to 7.8% of control values (P less than 0.001). These results correlated with protection from the development of C. albicans endocarditis in the immunized rabbits. The mean (+/- standard deviation) infectious dose for 50% of the animals was 10(5.29) +/- 10(0.07) in 48 control animals versus 10(7.11) +/- 10(0.22) in 37 immunized rabbits (P less than 0.001). These studies suggest that humoral antibody may protect against C. albicans endocarditis, perhaps through inhibition of adhesion, a crucial early step in the pathogenesis of endocarditis.

Adhesiveness↗
PubMed1983

Susceptibility of brain to aerobic, anaerobic, and fungal organisms.

The utility of an experimental animal model is dependent on its ability to simulate the actual clinical situation. With a stereotaxic injection procedure, the susceptibility of rat brain to the spectrum of organisms commonly associated with human brain abscess was determined. Two strains of Escherichia coli were more infective than Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes. Even between the E. coli strains it was possible to document significant differences in degree of infectivity. The E. coli strain with the K-1 capsular polysaccharide was significantly more infective than the E. coli strain without the capsular polysaccharide. The brain was also susceptible to Candida albicans, but at a level higher than any of the aerobic bacteria examined. Brain infection could not be created when microaerophilic or obligately anaerobic organisms alone were injected.

Animals↗
PubMed1983

Bactericidal versus bacteriostatic antibiotic therapy of experimental pneumococcal meningitis in rabbits.

A rabbit model of pneumococcal meningitis was used to examine the importance of bactericidal vs. bacteriostatic antimicrobial agents in the therapy of meningitis 112 animals were infected with one of two strains of type III Streptococcus pneumoniae. Both strains were exquisitely sensitive to ampicillin, minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC)<0.125 mug/ml. The activity of chloramphenicol against the two strains varied: strain(1)-MIC 2 mug/ml, MBC 16 mug/ml; strain(2)-MIC 1 mug/ml, MBC 2 mug/ml. Animals were treated with either ampicillin or chloramphenicol in dosages that achieved a peak bactericidal effect in cerebrospinal fluid (CSF) for ampicillin against both strains. Two different dosages were used for chloramphenicol. The first dosage achieved a peak CSF concentration of 4.4+/-1.1 mug/ml that produced a bacteriostatic effect against strain(1) and bactericidal effect against strain(2). The second dosage achieved a bactericidal effect against both strains (mean peak CSF concentration 30.0 mug/ml). All animals were treated intramuscularly three times a day for 5 d. CSF was sampled daily and 3 d after discontinuation of therapy for quantitative bacterial cultures. Results demonstrate that only antimicrobial therapy that achieved a bactericidal effect in CSF was associated with cure. Over 90% of animals treated with one of the bactericidal regimens (i.e., animals in which the bacterial counts in CSF dropped >5 log(10) colony-forming units [cfu]/ ml after 48 h) had sterile CSF after 5 d of treatment. On the other hand, the regimen that achieved bacteriostatic concentrations (CSF drug concentrations between the MIC and MBC) produced a drop of 2.4 log(10) cfu/ml by 48 h; however, none of the animals that survived had sterile CSF after 5 d. These studies clearly demonstrate in a strictly controlled manner that maximally effective antimicrobial therapy of experimental pneumococcal meningitis depends on achieving a bactericidal effect in CSF.

Ampicillin↗
PubMed1982

Pharmacokinetics of cefaclor in renal failure: effects of multiple doses and hemodialysis.

The pharmacokinetics of cefaclor were characterized in 15 functionally anephric patients on hemodialysis. Each patient received a 500-mg oral dose of cefaclor every 8 h for 10 days. Multiple serum drug levels were measured by bioassay on day 0 (no hemodialysis), day 10 during hemodialysis, and as single determinations 1 h after administration on days 1, 3, and 5. Analysis of cefaclor kinetics in these 15 patients along with kinetics from 24 previously studied patients showed that weight was the best single predictor of volume of distribution. The corrected creatinine clearance (calculated from serum creatinine, age, and sex) proved to be the best predictor of drug half-life (r = 0.969). Thus, a single serum creatinine test provided a better estimated of cefaclor half-life than a 24-h urine collection. Cefaclor was cleared with an average serum half-life of 2.9 h without hemodialysis and 1.5 h during hemodialysis. Cefaclor serum levels measured 1 h after administration on days 0, 1, 3, and 5 showed no evidence of accumulation. Thus, cefaclor may be administered orally in multiple doses without accumulation in functionally anephric patients. In patients on dialysis, dosage interval or quantity should be increased to compensate for doubled drug clearance dialysis.

Administration, Oral↗
PubMed1982

Clindamycin therapy of experimental Staphylococcus aureus endocarditis.

The efficacy of clindamycin in the treatment of experimental endocarditis in rabbits was compared with that of nafcillin. Both drugs were administered intramuscularly three times daily for 5 days, clindamycin at doses of 6.25, 12.5, 25, or 50 mg/kg and nafcillin at a dose of 200 mg/kg. The minimum inhibitory and bactericidal concentrations (0.125 microgram/ml) of clindamycin for the test strain of Staphylococcus aureus were very similar to the corresponding concentrations (0.25 microgram/ml) of nafcillin. The effectiveness of clindamycin against the experimental endocarditis was dose dependent. The therapeutic accomplishments of the two highest clindamycin doses were equivalent to those attained with 200 mg of nafcillin per kg. The rates of sterilization of vegetations were equal when the serum bactericidal titers of these drugs were greater than or equal to 1:8. In special situations the administration of clindamycin in high doses could prove useful in the treatment of S. aureus endocarditis.

Animals↗
PubMed1982

Comparison of cefoperazone with penicillin, ampicillin, gentamicin, and chloramphenicol in the therapy of experimental meningitis.

Cefoperazone was compared with penicillin against Streptococcus pneumoniae, gentamicin against Escherichia coli, and ampicillin and chloramphenicol against Haemophilus influenzae in the therapy of experimental meningitis in rabbits. Meningitis was produced by intracisternal inoculation into cerebrospinal fluid, and all antibiotics were administered intravenously over 8 h in dosages that would achieve serum levels comparable to those found in humans. The mean percent penetration into purulent cerebrospinal fluid, expressed as (cerebrospinal fluid concentration/serum concentration) x 100%, was 2.6% for penicillin, 22.0% for gentamicin, 12.1% for ampicillin, 23.8% for chloramphenicol, and 6.4% for cefoperazone. The mean cerebrospinal fluid antibiotic concentrations exceeded the minimum bactericidal concentration for the test strain in each experimental model, except for ampicillin in experimental meningitis due to the beta-lactamase-producing H. influenzae. Cefoperazone produced a significantly faster bactericidal effect after 4 h of treatment when compared with penicillin (P = 0.037) and ampicillin (P = 0.01) in meningitis caused by S. pneumoniae and H. influenzae (ampicillin susceptible), respectively. In meningitis caused by E. coli, cefoperazone was significantly (P = 0.006) more rapidly bactericidal after 8 h of treatment when compared to gentamicin. In addition, cefoperazone was significantly more rapidly bactericidal than either ampicillin or chloramphenicol in experimental meningitis due to beta-lactamase-producing H. influenzae. Cefoperazone deserves further evaluation in the therapy of bacterial meningitis in humans.

Ampicillin↗
PubMed1982

Factors influencing the pathogenesis and prevention of infective endocarditis.

It seems appropriate in a symposium dedicated to the examination of septicemia, that one of the topics for discussion should be the examination of the factors which allow circulating bacteria to adhere to intracardiac or vascular endothelium. In the last 10-12 years our understanding of the pathogenesis of this disease has increased markedly. This can be attributed to a large extent to the development by Dr Freedman and hist colleagues at Yale of reproducible, simple, inexpensive animal model of infective endocarditis. The purpose of this discussion will by to summarize studies aimed at helping to explain why bacteria stick to cardiac valves, what forms the stimulus for vegetation propagation, and some new idea for possible prevention of this event.

Adhesiveness↗
PubMed1982

Cerebrospinal fluid prognostic indices in experimental pneumococcal meningitis.

The prognostic value of initial and sequential determinations of quantitative bacterial concentrations, leukocytes, glucose, lactate, lactic acid dehydrogenase, and creatine phosphokinase in CSF was examined in rabbits with experimental pneumococcal meningitis while they were receiving equivalent, rapidly bactericidal antibiotic therapy. The following mean CSF variables correlated with death due to meningitis: (1) an early (day 1) high bacterial titer and lactate concentration with simultaneous low leukocyte count and glucose level and (2) late (day 3) elevated lactate and lactic acid dehydrogenase levels and leukocyte count. A high concentration of bacteria inoculated into the CSF and a high plasma glucose level also adversely influenced prognosis. Careful analysis of these variables may identify high-risk patients with pneumococcal meningitis and ultimately may be useful in gauging the therapeutic response.

Animals↗
PubMed1981

Pathophysiological correlates in bacterial meningitis.

This review summarises briefly several areas of importance in the pathogenesis of bacterial meningitis. These subjects include: (1) factors that predispose to the development of disease and relevant host defense mechanisms; (2) microbial virulence factors; (3) the route(s) of entry for bacteria into the cerebrospinal fluid (CSF); (4) the role of pathological changes in the central nervous system; (5) particulate clearance mechanisms operative in the CSF system; and (6) the physiological alteration in normal intracranial homeostatic processes.

Animals↗