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Biomedical subjects

W M Scheld

Publications and source records attributed to W M Scheld.

At least 109 records · Page 6Linked to original sources
PubMed1985

Pneumonia treated with imipenem/cilastatin.

In an open, prospective, multicenter trial the efficacy and tolerance of imipenem/cilastatin for the treatment of bacterial pneumonia was investigated. Forty-three adults were studied: 29 with nosocomial and 14 with community-acquired infections. Significant underlying disease was present in 91 percent of patients. Nosocomial infection was frequently associated with endotracheal intubation (48 percent), prior antibiotic therapy (48 percent), and recent surgery (31 percent). Most frequent sputum isolates included Pseudomonas aeruginosa (10, all nosocomial), Hemophilus influenzae (10), Escherichia coli (eight), Staphylococcus aureus (seven), and Streptococcus pneumoniae (six). Treatment with imipenem/cilastatin was associated with clinical cure in 93 percent of patients. Two of three failures and one superinfection occurred in association with isolates of Pseudomonas aeruginosa resistant to imipenem. Overall, six of 10 strains of Pseudomonas aeruginosa isolated prior to therapy developed resistance to imipenem after an average of 10 days of therapy. Adverse effects occurred in nine patients (21 percent) and included one case of pseudomembranous colitis. Monotherapy with imipenem/cilastatin of serious lower respiratory tract infections was relatively safe and highly effective with the exception of disease associated with P. aeruginosa.

Adult↗
PubMed1985

Yeast adhesion in the pathogenesis of endocarditis due to Candida albicans: studies with adherence-negative mutants.

Two spontaneous cerulenin-resistant mutants of Candida albicans, 4918-2 and 4918-10, were unable to adhere in vitro in fibrin-platelet clots. Because in vitro adherence correlates well with colonization of nonbacterial thrombotic endocarditis on traumatized valvular endocardium, 50% infectious dose studies were performed with a rabbit model of endocarditis. Wild-type C. albicans required 10(3.6) +/- 0.12 cfu in comparison with 10(5.73) +/- 0.31 and 10(7.3) +/- 0.21 cfu for mutants 4918-2 and 4918-10, respectively. The relative avirulence of mutant strains in producing endocarditis was not attributed to accelerated clearance of these strains from the bloodstream. In fact, clearance of wild-type and mutant strains was almost identical. In the same animals renal candidiasis was observed with all strains of C. albicans, although the number of cfu per gram of kidney was higher after infection with wild-type C. albicans. Thus, strains of C. albicans with reduced ability to adhere in vitro to a fibrin-platelet matrix are relatively avirulent in the rabbit endocarditis model.

Adhesiveness↗
PubMed1985

Effects of sub-bactericidal concentrations of antibiotics in experimental models of endocarditis.

Subinhibitory and sub-bactericidal concentrations of antibiotics significantly influence host-bacterial interactions. This paper reviews the pathogenesis of endocarditis and examines how subinhibitory concentrations of antibiotics may influence the course of the disease. At present significant effects have been documented only for the stage of bacterial adherence to the damaged valve.

Adhesiveness↗
PubMed1985

The influence of dosing schedules and cerebrospinal fluid bactericidal activity on the therapy of bacterial meningitis.

Bacterial meningitis represents an infection in an area of impaired host defence. Optimal therapy of meningitis requires attaining bactericidal activity within cerebrospinal fluid (CSF). Studies in experimental animal models of meningitis suggest that maximal rates of bacterial killing in vivo and optimal cure rates are achieved when CSF antibiotic concentrations exceed the MBC of the test strain by greater than or equal to ten-fold. The results of clinical trials support this conclusion. In addition, a variable post-antibiotic effect occurs in-vivo after short periods of exposure to antimicrobial activity, thus maintaining therapeutic efficacy with intermittent dosage regimens. These basic principles of therapy are outlined in this review and serve as a basis for rational treatment regimens. For most antibiotics, the optimal dose, dosage interval, and duration of therapy for bacterial meningitis remain to be established.

Animals↗
PubMed1985

Comparison of ceftriaxone and ampicillin plus chloramphenicol for the therapy of acute bacterial meningitis.

Ceftriaxone, a new third-generation cephalosporin, appears to be promising for the therapy of acute bacterial meningitis. The 90% MBCs of ceftriaxone against 54 recent cerebrospinal fluid isolates of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae were less than or equal to 0.06 to 0.25 micrograms/ml. We examined the efficacy and safety of ceftriaxone therapy of meningitis in Bahia, Brazil. The study was conducted in two phases; in phase A, ceftriaxone was coadministered with ampicillin. The mean cerebrospinal fluid concentrations of ceftriaxone 24 h after an intravenous dose of 80 mg/kg were 4.2 and 2.3 micrograms/ml on days 4 to 6 and 10 to 12 of therapy, respectively. These concentrations were 8- to more than 100-fold greater than the 90% MBCs against the relevant pathogens. In phase B, ceftriaxone (administered once daily at a dose of 80 mg/kg after an initial dose of 100 mg/kg) was compared with conventional dosages of ampicillin and chloramphenicol in a prospective randomized trial of 36 children and adults with meningitis. The groups were comparable based on clinical, laboratory, and etiological parameters. Ceftriaxone given once daily produced results equivalent to those obtained with ampicillin plus chloramphenicol, as judged by cure rate, case fatality ratio, resolution with sequelae, type and severity of sequelae, time to sterility of cerebrospinal fluid, and potentially drug-related adverse effects. The cerebrospinal fluid bactericidal titers obtained 16 to 24 h after ceftriaxone dosing were usually 1:512 to greater than 1:2,048 even late in the treatment course, compared with values of 1:8 to 1:32 in patients receiving ampicillin plus chloramphenicol. Ceftriaxone clearly deserves further evaluation for the therapy of meningitis; the optimal dose, dosing frequency (every 12 h or every 24 h), and duration of therapy remain to be determined.

Ampicillin↗
PubMed1985

Comparison of ciprofloxacin with azlocillin plus tobramycin in the therapy of experimental Pseudomonas aeruginosa endocarditis.

The efficacy of ciprofloxacin (Bay o 9867), a promising new quinolone, was compared with the efficacy of azlocillin plus tobramycin in rabbits with experimentally induced Pseudomonas aeruginosa endocarditis. The MBCs of ciprofloxacin, azlocillin, and tobramycin against the test strain were 0.5, 8, and 4 micrograms/ml respectively. Ciprofloxacin at a concentration of 50 mg/kg or azlocillin at a concentration of 200 mg/kg in combination with tobramycin at a concentration of 5 mg/kg was administered intramuscularly at 8-h intervals for 4 days. Both regimens produced median peak serum bactericidal titers of 1:8. The concentrations of ciprofloxacin, azlocillin, and tobramycin in serum, 1.8 +/- 0.7, 154 +/- 48, and 9.1 +/- 2.4 micrograms/ml (mean +/- standard deviation), respectively, closely approximated concentrations found in humans after accepted dosages. At the end of treatment, the titers of P. aeruginosa were 3.0 +/- 1.6 log10 CFU/g of vegetation (mean +/- standard deviation) for recipients of ciprofloxacin and 3.2 +/- 1.3 log10 CFU/g of vegetation for recipients of azlocillin plus tobramycin. These values compared with control titers of 7.3 +/- 1.6 CFU/g. These data indicate that at the doses used, ciprofloxacin was as effective as azlocillin plus tobramycin in the treatment of P. aeruginosa endocarditis in rabbits. Since the latter drug combination has proven efficacy, ciprofloxacin deserves further evaluation in the therapy of systemic infections in animal models and in humans.

Animals↗
PubMed1985

Pharmacokinetics of multiple-dose cefoperazone in hemodialysis patients.

We studied the pharmacokinetics of cefoperazone 2 g i.v. every 12 h for 7 days in 12 patients on hemodialysis with normal hepatic function. The half-life of indocyanine green was determined in each patient via ear oximetry. Serum levels of cefoperazone during dialysis were well described by a two-compartment multidose infusion model. From this model we determined the steady state volume of distribution (Vdss), elimination phase half-life during dialysis T1/2D) and off hemodialysis (T1/2), and the corresponding elimination rate constants (KeD and Ke). Multiple correlations between pharmacokinetic parameters, liver function, and physical characteristics of the patients were evaluated. The T1/2 of cefoperazone was 2.9 h off compared to 2.3 h during hemodialysis. The corresponding elimination rate constants were Ke = 0.45/h versus KeD = 0.80/h. Cefoperazone clearances were 78 ml/min off dialysis compared to 140 ml/min during hemodialysis. Vdss was 0.20 liters/kg. The indocyanine green half-life ranged from 1.8 to 4.6 min with a mean of 2.7 min. The ages of the patients correlated with the beta phase half-life (r = 0.68, p = 0.015). We found no significant correlations among the other parameters including hepatic enzymes and indocyanine green half-life. Thus, hemodialysis approximately doubles the elimination rate constant (clearance), but, assuming drug redistribution kinetics remain unchanged, only shortens half-life by about 20%. Scheduling of a 12-hour dosing regimen to coincide with the end of hemodialysis should obviate any need for alteration of dose. Cefoperazone is thus unique among cephalosporins, since the half-life does not change appreciably with end-stage renal disease or dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Microbial adhesion to fibronectin in vitro correlates with production of endocarditis in rabbits.

Microbial adhesion to the constituents of nonbacterial thrombotic endocarditis (NBTE) is an important early event in the pathogenesis of infective endocarditis. Fibronectin is a ubiquitous mammalian glycoprotein with diverse functions which binds to certain bacteria but not to others. In this study, we determined that fibronectin is present on the surface of NBTE (after catheter-induced aortic valve trauma) but not on normal rabbit cardiac valvular endothelium. The adhesion of various bacteria and yeasts to human fibronectin in tissue culture wells was then measured. Microorganisms with a high isolation frequency from endocarditis cases (Staphylococcus aureus, Candida tropicalis, C. albicans, Streptococcus faecalis, S. sanguis) bound significantly better (P less than 0.01) to fibronectin in vitro than other organisms (Escherichia coli, C. krusei, Pseudomonas aeruginosa) rarely implicated in this disease. Microbial adhesion to fibronectin correlated closely with the propensity of each organism to produce endocarditis in rabbits (e.g., ID50) with preexistent NBTE. A similar distribution was noted after binding of soluble radiolabeled fibronectin to bacteria in suspension. The results suggest that fibronectin, expressed on the surface of NBTE, may mediate microbial adhesion of circulating organisms to initiate colonization during the early pathogenesis of infective endocarditis.

Animals↗
PubMed1984

Rationale for clinical trials evaluating ceftriaxone in the therapy of bacterial meningitis.

Ceftriaxone is a promising antimicrobial agent in the therapy of bacterial meningitis. The rationale for the clinical evaluation of ceftriaxone in patients with meningitis is based on the following favorable characteristics: ceftriaxone has excellent in vitro activity (MBC90 0.25 microgram/ml or less) against the major meningeal pathogens including meningococci, pneumococci, group B streptococci, Hemophilus influenzae, and Escherichia coli, but it is inactive against Listeria monocytogenes; ceftriaxone is rapidly bactericidal within purulent cerebrospinal fluid in experimental animal models of meningitis induced by pneumococci, group B streptococci, H. influenzae, and E. coli; against most of the major meningeal pathogens, the activity attained in cerebrospinal fluid in human subjects with bacterial meningitis is high (1:512 or greater) and active concentrations of ceftriaxone persist in cerebrospinal fluid for prolonged periods compared with those of other cephalosporins; the results of clinical trials reported to date in patients with meningitis are encouraging. Ceftriaxone deserves further clinical evaluation in the treatment of bacterial meningitis; the optimal dose, frequency of administration, and duration of therapy remain to be determined.

Animals↗
PubMed1984

Bacterial meningitis in the patient at risk: intrinsic risk factors and host defense mechanisms.

Bacterial meningitis remains a relatively common disease worldwide (40,000 cases per year in the United States) and the mortality rate has not improved in over 30 years. Certain host factors increase the risk of acquiring meningitis and include: age (increased at extremes of life), male sex, low socioeconomic status (crowding), black race, recent nasopharyngeal carriage of a virulent strain, absence of specific bactericidal antibody, maternal factors at birth (neonatal disease), various immunologic defects (neonates, antibody or terminal complement component deficiency, splenectomy, and immunosuppression including the acquired immune deficiency syndrome), and certain chronic diseases (such as alcoholism, cirrhosis, and diabetes mellitus). Bacterial meningitis represents an infection in an area of impaired host resistance. The blood-brain barrier is a major protective mechanism for the central nervous system against circulating bacteria. However, once bacteria gain entry into the subarachnoid space, host defenses are inadequate. Polymorphonuclear leukocytes are at a disadvantage in the fluid medium of the cerebrospinal fluid and surface phagocytosis is inefficient. In addition, antibody and complement concentrations are low (or absent) in purulent cerebrospinal fluid early in the disease course. Functional opsonic and bactericidal activity is lacking; therefore, efficient phagocytosis of encapsulated meningeal pathogens is limited. The result is huge population densities (often 10(7) to 10(8) cfu per milliliter) of bacteria in cerebrospinal fluid. This finding suggests that bactericidal antibiotics with cerebrospinal fluid concentrations much greater than the minimal bacterial concentration of the pathogen are optimal for therapy of meningitis; this principle has been shown in experimental animal models and supported by therapeutic studies in human subjects.

Aged↗
PubMed1984

Rationale for optimal dosing of beta-lactam antibiotics in therapy for bacterial meningitis.

This review considers the five major principles governing optimal dosing of beta-lactam antibiotics in therapy for bacterial meningitis: off the entry of passage of antibiotics into CSF, (2) the antimicrobial activity of beta-lactams within the purulent CSF in vivo, (3) the bactericidal activity within the CSF, (4) the route and mode of drug administration together with the postantibiotic effect, and (5) the duration of therapy. Special attention is paid to the third principle, bactericidal activity within the CSF, employing the model of the newer, third-generation cephalosporins used in the treatment of meningitis caused by gram-negative aerobic bacilli.

Animals↗
PubMed1984

Effect of hemodialysis and peritoneal dialysis on aztreonam pharmacokinetics.

Aztreonam, a new monobactam, will be widely used because of its broad aerobic gram-negative bacterial coverage and its apparent low risk of allergic phenomena in penicillin/cephalosporin-sensitive patients. We examined aztreonam kinetics in patients during hemodialysis and in the interdialytic period and in patients on continuous ambulatory peritoneal dialysis (CAPD), and related aztreonam to urea clearance (CL). In hemodialysis patients, aztreonam serum half-life was 7.9 hr between and 2.7 hr during dialysis sessions. CLserum, CLrenal, and CLother were 24.4, 0.5, and 23.9 ml/min, respectively, during the interdialytic period. Four hours of dialysis removed 38.2% (range, 27 to 58%) of antibiotic. CL of aztreonam by hemodialysis was 36.6 to 43.2 ml/min, 50 to 77% greater than interdialytic CL. CL of urea by hemodialysis was 112.4 to 115.6 ml/min; CLaztreonam/CLurea ratio was 0.28 to 0.33 during the hemodialysis sessions. During CAPD, aztreonam serum half-life after intravenous dosing was 7.1 hr; dialysate recovery, 9.7% of the dose; CLserum, CLrenal, CLperitoneal dialysis, and CLother were 23.8, 0.5, 2.1, and 21.3 ml/min, respectively. CLurea by CAPD was 6.5 ml/min. Thus, CLaztreonam during CAPD was 32% of CLurea. Aztreonam was detectable in dialysate at 48 hr (eight exchanges) after peritoneal administration in the first exchange. Hemodialysis and CAPD patients given aztreonam treatment should receive the standard dose of aztreonam as a loading dose, followed by one-fourth the loading dose at standard dose intervals. Hemodialysis patients should receive a supplemental dose equal to half their usual maintenance dose immediately after each dialysis session. For CAPD patients with peritonitis due to susceptible organisms, a 1-g i.v. loading dose followed by a 0.5-g i.p. dose every 6 hr is suggested. In any individual patient undergoing hemodialysis or CAPD, the relationship between CLurea and CLaztreonam should allow appropriate antibiotic dose adjustment.

Adult↗
PubMed1984

The postantibiotic effect in the treatment of experimental meningitis caused by Streptococcus pneumoniae in rabbits.

The relevance of a postantibiotic effect in the treatment of pneumococcal meningitis was evaluated in a rabbit model. After administration of a single intravenous bolus of ampicillin at various dosages, such an effect was observed in all animals. The duration of this effect in vivo (2.5-18 hr) was consistently longer than that in vitro (1-4.3 hr); however, in rabbits the postantibiotic effect was eliminated by the administration of intravenous plus intracisternal beta-lactamase. In an assessment of the potential therapeutic benefit of the postantibiotic effect, the efficacy to two regimens of treatment with different intervals between doses was compared. One group of animals received ampicillin every 4 hr and another every 12 hr. With sufficiently high doses, drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration for most of the 4-hr interval but for only about one-third of the 12-hr interval. The rate of cure was similar for the two regimens and approximated 100% when peak drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration by at least 10-fold.

Ampicillin↗
PubMed1984

In vitro binding of Candida albicans yeast cells to human fibronectin.

The binding of Candida albicans yeast cells to human fibronectin (Fn), a major glycoprotein of mammalian cells, was studied using an in vitro assay. Adherence was quantitated in microtiter dishes coated with Fn to which radiolabeled yeast cells were added. Under optimum conditions of the assay, i.e., 1 mM CaCl2 and 70 micrograms Fn protein, approximately 40% of the radiolabeled yeast cells adhered to the Fn. Adherence to Fn was greater at 30 degrees C than at 4 degrees C and was greater with viable yeast cells than with heat-killed cells. Candida albicans (two strains) and C. tropicalis adhered to Fn to a greater extent than C. pseudotropicalis, C. krusei, or Saccharomyces cerevisiae. Pretreatment of C. albicans with chymotrypsin, pronase, or papain, but not pepsin, decreased adherence to Fn. Blocking experiments using mannan, sugars, or amino sugars were carried out by preabsorbing the Fn with each of the above-mentioned compounds. Candida mannan blocked adherence of C. albicans to Fn. The mannan effect was dose dependent. However, adherence of C. albicans to Fn was not significantly reduced by mannose, glucose, or several other sugars. The role of FN as a receptor for the binding of C. albicans yeast cells to buccal and vaginal epithelial cells was investigated also using an in vitro assay. We determined, using indirect fluorescent antibody techniques, that both buccal and vaginal epithelial cells possessed Fn. In addition, yeast cells, when pretreated with Fn, showed reduced adherence with buccal and vaginal cells when compared with nontreated cells. These studies may indicate a role for Fn in the adherence of C. albicans to buccal and vaginal epithelial cells.

Candida↗
PubMed1983

Treatment of experimental brain abscess with penicillin and chloramphenicol.

Recent reports have indicated that antibiotic therapy alone may be successful in resolving brain abscesses. We utilized an animal model of brain abscess to evaluate the efficacy of penicillin with and without chloramphenicol in preventing the development of brain abscess. When penicillin therapy was initiated at the time of bacterial contamination and continued for four days, the bacteria were eliminated. When therapy was delayed for 24 hr, the number of bacteria in brain tissue samples was significantly reduced, but all samples still contained bacteria. When therapy was delayed for 48 hr, there was no therapeutic benefit. Addition of chloramphenicol to each of these regimens did not significantly alter the results. Extending the duration of therapy to eight days provided no improvement over the results obtained after four days.

Animals↗