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Biomedical subjects

M A Sande

Publications and source records attributed to M A Sande.

At least 91 records · Page 5Linked to original sources
PubMed1989

Influence of antibiotic dose, dosing interval, and duration of therapy on outcome in experimental pneumococcal meningitis in rabbits.

We examined the influence of several pharmacokinetic parameters on cure rates in rabbits with experimental pneumococcal meningitis. When the duration of treatment was kept constant, cure rates improved as the individual dose of ampicillin was increased. On the other hand, when four doses of ampicillin at 60 mg/kg of body weight, producing peak concentrations in cerebrospinal fluid (CSF) of approximately 40 times the MBC, were administered at intervals of 24 instead of 4 h and the duration of therapy was thus prolonged from 12 to 72 h, cure rates also increased (85 versus 25%; P less than 0.01). These high cure rates were achieved even though bacterial titers in CSF 24 h after the first dose had reached levels similar to those present at the beginning of therapy. Cure in these animals was explained by the fact that the second ampicillin dose reduced bacterial titers in CSF significantly more than did the first dose (5.2 versus 2.5 log10 CFU/ml; P less than 0.02). The clinical relevance of these observations remains to be determined.

Ampicillin↗
PubMed1988

Cholestasis and disseminated cytomegalovirus disease in patients with the acquired immunodeficiency syndrome.

A cholestatic syndrome caused by papillary stenosis and sclerosing cholangitis (PS/SC) has been recently described as a complication of the acquired immunodeficiency syndrome (AIDS). Cytomegalovirus has been implicated as an etiologic factor in this syndrome. Consecutive cases of disseminated cytomegalovirus disease and viremia were reviewed for evidence of cholestasis. In 12 of 36 (33 percent) patients with cytomegalovirus infection (gastrointestinal disease [eight of 16 patients] or retinitis [four of 20 patients]), cholestatic liver enzyme abnormalities developed within three months of the diagnosis of cytomegalovirus disease. Radiologic imaging demonstrated biliary dilation in three of nine (33 percent) patients studied. Review of serial liver function tests showed no effect of ganciclovir therapy on the course of cholestatic abnormalities. AIDS patients without CMV end-organ disease were also reviewed for evidence of cholestasis. Six of 15 AIDS patients with positive blood culture results for cytomegalovirus had cholestatic liver enzyme abnormalities compared with four of 36 AIDS patients with negative viral blood culture results (p = 0.023, Fisher's exact test). Patients with cytomegalovirus retinitis, gastrointestinal disease, or viremia appear to be at increased risk for the development of cholestasis. In 3 to 11 percent of patients with cytomegalovirus retinitis or gastrointestinal disease, PS/SC may develop. This clinical association supports an etiologic role for cytomegalovirus in the PS/SC syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Influence of granulocytes on brain edema, intracranial pressure, and cerebrospinal fluid concentrations of lactate and protein in experimental meningitis.

Brain water content (brain edema), intracranial pressure, and cerebrospinal fluid (CSF) concentrations of lactate and protein increased significantly during 24 h of experimental meningitis due to Streptococcus pneumoniae, but changes were similar in normal and neutropenic rabbits. In sterile meningitis induced by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP), low and high doses of fMLP were equally effective in inducing CSF pleocytosis, whereas only high doses of fMLP caused brain edema. High doses of fMLP injected intracisternally during pneumococcal meningitis also increased brain water content. The fMLP did not significantly increase intracranial pressure or CSF concentrations of lactate or protein in sterile or pneumococcal meningitis, nor did it cause brain edema in neutropenic animals. Thus, granulocytes may contribute to brain edema during meningitis if adequately stimulated, but intracranial pressure and CSF protein and lactate concentrations appear independent of granulocytes. Stimulation does not appear to occur early in meningitis, when granulocytes were without effect on brain edema.

Animals↗
PubMed1988

Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia.

Single, large, daily aminoglycoside doses in animals are less toxic than conventional dosing, and higher drug concentrations in vitro produce more-rapid bacterial killing. Thus, we compared various aminoglycoside dosing schedules in neutropenic (n = 153) and nonneutropenic (n = 192) guinea pigs with Pseudomonas aeruginosa pneumonia. Equivalent tobramycin dosages were given: 5 mg/kg every 4 h or 30 mg/kg every 24 h. Animals were serially killed during therapy, and quantitative lung cultures were performed. Bacterial titers in lungs dropped rapidly in all tobramycin-treated animals, both neutropenic and nonneutropenic, during the initial 16 h of therapy. In nonneutropenic guinea pigs, lung titers remained constant despite continued 4-h dosing. With subsequent 24-h dosing, titers continued to drop, and by 72 h there were a significant number of animals with sterile lungs (P less than .01). In neutropenic guinea pigs given tobramycin every 24 h, bacterial regrowth occurred; thus, therapy was ineffective. Adding mezlocillin, however, suppressed regrowth; thus, combination therapy was superior (P less than .05).

Animals↗
PubMed1987

Efficacy of ciprofloxacin in animal models of infection: endocarditis, meningitis, and pneumonia.

Animal models of infection are very useful tools for identifying those situations in which antibacterial drugs, including the quinolones, may play special roles, i.e., for positioning a drug correctly for its role in the treatment of human disease. Ciprofloxacin has been studied extensively in discriminative animal models of infection, and its efficacy in the treatment of these infections has been compared with that of standard therapy. In a rabbit model of staphylococcal endocarditis, ciprofloxacin was as effective as nafcillin alone, as well as nafcillin and gentamicin in combination, in treating rabbits with methicillin-susceptible Staphylococcus aureus endocarditis. Additionally, its activity was equal to that of vancomycin in reducing vegetation titers in rabbits with methicillin-resistant staphylococcal endocarditis. In a rabbit model of pseudomonal meningitis, ciprofloxacin was as effective as the combination of ceftazidime and tobramycin in lowering bacterial titers. However, in this model, serum levels of ciprofloxacin (6 micrograms/ml) necessary to achieve a bactericidal effect in the cerebrospinal fluid were slightly higher than levels targeted for humans. In a model of pseudomonal pneumonia in neutropenic guinea pigs, the efficacy of ciprofloxacin was compared with that of tobramycin and ceftazidime, both alone and in combination: ciprofloxacin was as effective in lowering bacterial counts as was the combination of ceftazidime plus tobramycin and its activity was superior to that of either drug alone. Thus, data from studies of ciprofloxacin in the treatment of endocarditis, meningitis, and pneumonia in animal models of infection suggest that this quinolone may play an important role in the therapy of these difficult-to-manage infections in humans.

Animals↗
PubMed1987

Risk of transmitting the human immunodeficiency virus, cytomegalovirus, and hepatitis B virus to health care workers exposed to patients with AIDS and AIDS-related conditions.

This prospective cohort study was designed to evaluate the risk of occupational transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and cytomegalovirus (CMV) to health care workers with intensive exposure to HIV-infected patients. Seventy-five percent of the 270 subjects had been exposed to patients with AIDS and AIDS-related conditions (ARC) for at least one year before enrollment, 18% worked in specialized AIDS units, and 35% sustained a total of 342 accidental parenteral exposures to HIV-infected body fluids. At the time of enrollment, none had antibody to HIV, and none of the 175 subjects retested 10 months later had acquired antibody. No evidence of increased risk of acquiring CMV or HBV was obtained. These results indicate that health care workers are at minimal risk for HIV, CMV, and HBV transmission from occupational exposure to patients with AIDS or ARC, even when intensively exposed for prolonged periods of time.

AIDS-Related Complex↗
PubMed1987

Antibiotic therapy, endotoxin concentration in cerebrospinal fluid, and brain edema in experimental Escherichia coli meningitis in rabbits.

We investigated the effect of cefotaxime and chloramphenicol on endotoxin concentrations in cerebrospinal fluid (CSF) and on the development of brain edema in rabbits with Escherichia coli meningitis. Both antibiotics were similarly effective in reducing bacterial titers. Cefotaxime, but not chloramphenicol, induced a marked increase of endotoxin in CSF, from log10 1.5 +/- 0.8 to log10 2.8 +/- 0.7 ng/ml (P less than .01). This result was associated with an increase in brain water content (405 +/- 12 g of water/100 g of dry weight compared with 389 +/- 8 g in untreated controls; P less than .01), whereas in animals treated with chloramphenicol, brain water content was identical to controls. The cefotaxime-induced increase in endotoxin concentration and brain edema were both neutralized by polymyxin B, which binds to the lipid A moiety of endotoxin, or by a monoclonal antibody to lipid A. These results indicate that treating gram-negative bacillary meningitis with selected antibiotics induces increased endotoxin concentrations in CSF that are associated with brain edema.

Animals↗
PubMed1987

Evaluation of combination chemotherapy in a lightly anesthetized animal model of Pseudomonas pneumonia.

Gram-negative bacillary pneumonia is a major cause of morbidity and mortality in hospitalized patients. The use of synergistic combinations of aminoglycosides and beta-lactams for therapy of this infection has been recommended but remains controversial. We designed a new model of Pseudomonas pneumonia in a lightly sedated guinea pig by using a long-acting anesthetic to impair natural respiratory defenses. We used this model to compare the efficacy of ceftazidime and tobramycin alone and in combination in the therapy of Pseudomonas pneumonia. The two antibiotics were shown to be synergistic in vitro for the strain of Pseudomonas aeruginosa tested. Treated animals receiving both antibiotics had fewer viable bacteria remaining in lung tissues (P less than 0.05) and exhibited a trend towards improved survival in comparison to animals receiving a single drug. In this model of Pseudomonas pneumonia, in vitro synergy was reflected by increased efficacy in vivo.

Animals↗
PubMed1986

Challenging conventional aminoglycoside dosing regimens. The value of experimental models.

Although newer antimicrobials look promising for the treatment of serious gram-negative infections, aminoglycosides still remain part of the mainstay of their therapy. Traditional intermittent therapy is based upon the premise that high serum aminoglycoside concentrations are toxic. However, the rate of bacterial killing for aminoglycosides is also a concentration-dependent phenomenon. Two animal models of Pseudomonas pneumonia were utilized to examine the efficacy of non-traditional aminoglycoside dosing regimens, i.e., single, high daily doses versus the conventional, intermittent low doses of aminoglycosides. Other recent data suggest that toxicity might also be less with the large, single daily dose regimen. The current dosing strategy used for aminoglycosides may not be maximizing their therapeutic potential, nor minimizing their toxicities.

Aminoglycosides↗
PubMed1986

Serum bactericidal titer as a predictor of outcome in endocarditis.

A study was conducted in 89 rabbits with experimental aortic valve endocarditis caused by three different strains of Staphylococcus aureus to determine whether there was a correlation between the peak serum bactericidal titer of the four drugs tested and the vegetation titer. After four days of therapy both the rabbits with and those without sterile vegetations had median peak bactericidal titers of 1 : 8. The mean vegetation titers did not correlate with the mean bactericidal titers. The serum bactericidal test does not measure the relative rate of killing of the bacteria by the drugs. Although the test remains clinically useful for documentation of bactericidal activity, the minimum level of activity necessary for the test to serve as a predictor of outcome remains to be defined.

Animals↗
PubMed1986

Novel approaches for the use of aminoglycosides: the value of experimental models.

Although newer antimicrobials look promising for the treatment of serious Gram-negative infections, the aminoglycosides still remain part of the mainstay of their therapy. Traditional intermittent therapy is based upon the premise that high serum aminoglycoside concentrations are toxic. However, the rate of bacterial killing for aminoglycosides is also a concentration-dependent phenomenon. An animal model of pseudomonas pneumonia and staphylococcal endocarditis has been used to examine the efficacy of non-traditional aminoglycoside dosing regimens, i.e. single, large daily doses or constant infusions, versus the conventional, intermittent low doses of aminoglycosides. Results demonstrate that high peak concentrations are more efficacious. Other recent data suggest that toxicity might also be less with the large, single daily-dose regimen. The way in which we have been dosing aminoglycosides may not be maximizing their therapeutic potential, nor minimizing their toxicities.

Aminoglycosides↗