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Biomedical subjects

H F Chambers

Publications and source records attributed to H F Chambers.

At least 55 records · Page 3Linked to original sources
PubMed1992

Oral SCH 39304 as primary, salvage, and maintenance therapy for cryptococcal meningitis in AIDS.

To determine the efficacy and toxicity of SCH 39304 in the treatment and suppression of cryptococcal meningitis, we conducted a prospective, noncomparative study in three groups of patients: patients with acute cryptococcal meningitis, patients with acute cryptococcal meningitis in whom other therapies have failed (salvage), and patients who required maintenance therapy. As primary therapy, the patients received up to 14 days or 1 g of amphotericin B followed by SCH 39304 200 mg once daily for 12 weeks. As maintenance therapy, the patients received SCH 39304 600 mg once weekly for 12 months. Of five salvage patients, none completed the study. Two patients died, two patients clinically deteriorated, and one patient was noncompliant. Two of three patients with acute cryptococcal meningitis completed the 12-week primary therapy, and one patient was discontinued from therapy because of a skin rash (95% confidence interval, 14-100%). All four patients who were receiving weekly maintenance therapy followed up to 27 weeks were clinically stable with no change in their serum cryptococcal antigen titer from baseline when the study was prematurely terminated. Elevation of liver function test results developed in three patients and skin rash developed in one patient. The unique pharmacologic and pharmacokinetic properties of SCH 39304 (low incidence of toxicity, long serum half-life, and good penetration into the cerebrospinal fluid) lend promise to pursue other triazole antifungals at higher doses as primary therapy and less frequent dosing for maintenance therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Treatment of infection and colonization caused by methicillin-resistant Staphylococcus aureus.

The mechanism of methicillin resistance confers resistance to all available beta-lactam antibiotics; consequently, beta-lactam antibiotics have no role in therapy of methicillin-resistant Staphylococcus aureus (MRSA) infections. Vancomycin remains the drug of choice. Teicoplanin and daptomycin are two investigational antibiotics related to vancomycin in structure and in spectrum of activity. In clinical trials employing relatively low doses, neither was as effective as vancomycin. Trials at higher doses are on-going. Quinolones, ciprofloxacin in particular, have been used successfully to treat infections caused by MRSA; however, the usefulness of quinolones may be limited by the tendency of resistance to emerge during therapy. Quinolones probably should be used only in combination with another active agent, such as rifampin, when treating serious infections caused by MRSA. Other agents may be active in vitro against MRSA, but clinical data showing their effectiveness are lacking. Rifampin combination regimens appear most effectively to eradicate colonization with MRSA.

4-Quinolones↗
PubMed1991

Effect of protein binding of daptomycin on MIC and antibacterial activity.

A higher rate of clinical failures in patients treated with daptomycin (2 mg/kg of body weight, given once daily) compared with rates in patients treated with conventional regimens caused early termination of this comparative clinical trial. One explanation for these failures could be that daptomycin is highly protein bound and that the concentration of the unbound active drug is too low for antibacterial activity. To assess this explanation, we studied the binding of daptomycin to proteins by using an ultrafiltration method. pH (7.0 to 7.4), temperature (25 or 37 degrees C), or daily freezing and thawing over 2 months had no effect on binding of daptomycin to proteins. We found that daptomycin was bound to albumin (90%) at 4 g/100 ml. Binding of daptomycin was not concentration dependent (2.5 to 80 micrograms/ml). In human serum samples spiked with daptomycin, average binding was 94% +/- 2.4%. In 6 subjects given an intravenous infusion of daptomycin (3 mg/kg), average binding was 90% +/- 2.1%. Susceptibility studies showed that a concentration in serum 20 times the unbound concentration was needed to equal the MIC of the total drug. These results indicate that daptomycin is highly bound (90 to 94%) to albumin and that clinical failure to daptomycin can in part be explained by the low concentration of the unbound drug.

Adult↗
PubMed1991

Comparison of conventional susceptibility tests with direct detection of penicillin-binding protein 2a in borderline oxacillin-resistant strains of Staphylococcus aureus.

Six selected strains of Staphylococcus aureus classified as borderline oxacillin-resistant, according to standard disk diffusion and microdilution susceptibility test methods, and seven methicillin-resistant and seven methicillin-susceptible control strains were examined for the presence of penicillin-binding protein 2a (PBP 2a) by fluorography and immunoblotting and for DNA hybridization with a mec-specific probe in a dot blot assay. Oxacillin agar screen tests with and without NaCl supplementation were also performed with all strains. PBP 2a was detected both by fluorography and by immunoblotting in all seven methicillin-resistant control strains and in none of the susceptible controls. PBP 2a was detected in two borderline strains. Results of agar screen tests performed without NaCl supplementation were completely concordant with susceptibility determined by PBP 2a and mec detection methods. Agar screening with NaCl supplementation was less accurate. These findings were confirmed with 20 additional borderline strains. Direct detection methods for the presence of PBP 2a or mec, the gene encoding it, allow accurate and definitive classification of borderline strains. Further efforts to develop a rapid, clinically useful, antibody detection system for PBP 2a are warranted.

Animals↗
PubMed1990

Binding of beta-lactam antibiotics to penicillin-binding proteins in methicillin-resistant Staphylococcus aureus.

Binding affinity of penicillin-binding proteins (PBP) of Staphylococcus aureus for several beta-lactam antibiotics was examined in a methicillin-susceptible strain and in two methicillin-resistant strains, one heterogeneous and one homogeneous, to determine relationships between PBP binding and expression of resistance. PBPs 1-4 had similar affinities in all three strains. PBP 2a affinities were similar in both resistant strains. For the susceptible strain and for the susceptible subpopulation of cells in the heterogeneous strain, growth inhibition correlated with binding to PBPs 1-3, suggesting that these PBPs mediate susceptibility in both. For resistant cells, growth inhibition correlated only with binding to PBP 2a, suggesting that this is the target in resistant cells. Determination of binding affinity for PBP 2a or the concentration that inhibits growth of the most resistant subpopulation of cells should be included in evaluation of beta-lactam antibiotics for potential activity against methicillin-resistant strains of S. aureus.

Anti-Bacterial Agents↗
PubMed1990

Binding affinity for penicillin-binding protein 2a correlates with in vivo activity of beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus.

The beta-lactam antibiotics ticarcillin, nafcillin, imipenem, and ampicillin, which differ in antibacterial activity against methicillin-resistant strains of Staphylococcus aureus, were examined for affinity to penicillin-binding protein (PBP) 2a, which mediates methicillin resistance. The relative efficacy of each antibiotic was compared to vancomycin in a rabbit model of aortic valve endocarditis caused by either a methicillin-susceptible or methicillin-resistant strain of beta-lactamase-producing S. aureus. beta-lactamase inhibitors clavulanate and sulbactam were used in combination with ticarcillin and ampicillin, respectively. All beta-lactam antibiotics were effective against the susceptible strain. beta-lactam antibiotic activity in vitro and in vivo against the resistant strain correlated with its affinity for binding to PBP 2a. Lack of efficacy of beta-lactam antibiotics for the resistant strain was due to an inability to eradicate the resistant subpopulation of cells. Vancomycin was the most effective agent.

Acyltransferases↗
PubMed1990

Effects of dosage, peak and trough concentrations in serum, protein binding, and bactericidal rate on efficacy of teicoplanin in a rabbit model of endocarditis.

The effect of dosage and the relative importance of peak and trough concentrations in serum for efficacy of teicoplanin were examined in a rabbit model of aortic valve endocarditis. Concentrations of teicoplanin in serum exceeded the MIC by several hundredfold, yet teicoplanin was less rapidly bactericidal than penicillin both in vitro and for endocarditis caused by a strain of Streptococcus sanguis. Because teicoplanin was 90% protein bound in rabbit serum, low free-drug concentrations probably resulted in less activity in vivo than in vitro. Because teicoplanin has a relatively low bactericidal rate and a high degree of protein binding, a sustained concentration in serum several times greater than the MIC may be important for efficacy in vivo. An intravenous regimen with relatively high peak concentrations in serum was less effective than an intramuscular regimen for endocarditis caused by a strain of Staphylococcus aureus, indicating that high peaks are unlikely to be an important determinant of efficacy. The therapeutically more relevant concentration in serum may be the trough.

Animals↗
PubMed1990

Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users.

The clinical courses of 13 consecutive intravenous drug users with Staphylococcus aureus endocarditis treated principally with vancomycin were reviewed. Two patients, one with only right-sided endocarditis and the other with tricuspid and mitral valve endocarditis, had recurrences of positive blood cultures 2 days after completing a 4-week course of vancomycin. Two patients, both of whom eventually were cured, had modifications of therapy because of bacteremia persisting 7 and 16 days into therapy. One patient required an operation for recurrent fevers, and the resected vegetation showed evidence of active infection. Time-kill studies performed with nafcillin and vancomycin for 10 isolates of S. aureus showed that vancomycin was less rapidly bactericidal than nafcillin. Although vancomycin is used as an alternative to penicillinase-resistant penicillins for treatment of staphylococcal endocarditis, these findings raise the question of whether it is equivalent to these drugs in efficacy.

Adult↗
PubMed1990

Characterization of mechanisms of resistance to beta-lactam antibiotics in methicillin-resistant strains of Staphylococcus saprophyticus.

The resistance mechanisms of methicillin-resistant strains of Staphylococcus saprophyticus were characterized. Penicillin-binding protein (PBP) studies demonstrated an inducible PBP identical to PBP 2a in the membranes of these isolates. The amount of beta-lactamase produced was minimal. PBP 2a is responsible for the methicillin resistance observed in these strains of S. saprophyticus.

Anti-Bacterial Agents↗
PubMed1989

Low-level methicillin resistance in strains of Staphylococcus aureus.

Two strains of Staphylococcus aureus expressing borderline or low-level methicillin resistance by one or more in vitro test methods were examined for resistance in vivo and for biochemical and genetic markers of methicillin resistance. In vivo, nafcillin was equally effective against experimental aortic valve endocarditis in rabbits, regardless of whether they were infected by a fully susceptible or a low-level-resistant strain. Resistance did not emerge during therapy. For the more resistant of the two low-level-resistant strains, methicillin was as effective as nafcillin. Nafcillin was ineffective against endocarditis caused by a truly methicillin-resistant strain, and resistance emerged on therapy. The low-level-resistant strains did not produce the low-affinity penicillin-binding protein 2a that is associated with methicillin resistance and did not contain DNA that hybridized with probes that recognized the methicillin resistance determinant. Low-level resistance in S. aureus is a phenomenon that is biochemically and genetically distinct from true methicillin resistance. These strains actually are susceptible to beta-lactam antibiotics. The clinical problem posed by these strains is not a therapeutic one but, instead, one of how to differentiate them from those that are truly methicillin resistant.

Animals↗
PubMed1989

Daptomycin (LY146032) for prevention and treatment of experimental aortic valve endocarditis in rabbits.

The efficacy of daptomycin (LY146032), a vancomycinlike lipopeptide antibiotic, was compared with that of antibiotics commonly in use for prevention and treatment of experimental aortic valve endocarditis in rabbits. Strains of Staphylococcus aureus. S. epidermidis, Streptococcus sanguis, and Enterococcus faecalis were used to establish endocarditis. A single 10-mg/kg dose of daptomycin and a single 25-mg/kg dose of vancomycin were both effective in prevention of endocarditis produced by strains of S. aureus and S. sanguis. Daptomycin was more effective than vancomycin for prevention of endocarditis caused by the strain of S. epidermidis. A single dose of daptomycin also was more effective in prevention of staphylococcal and enterococcal endocarditis than were single-dose regimens of cefazolin (100 mg/kg) and the combination of ampicillin (30 mg/kg) plus gentamicin (3 mg/kg), respectively. For treatment of endocarditis, daptomycin (10 mg/kg) as a single daily dose was as effective as regimens of either vancomycin or beta-lactam antibiotics for staphylococcal and enterococcal endocarditis. Daptomycin, however, was not as effective as a single daily dose of 600,000 U of procaine penicillin for endocarditis caused by the strain of S. sanguis.

Animals↗
PubMed1988

Right-sided Staphylococcus aureus endocarditis in intravenous drug abusers: two-week combination therapy.

STUDY OBJECTIVE: To determine the efficacy of short-course combination regimens for selected cases of Staphylococcus aureus endocarditis in intravenous drug abusers. DESIGN: Open study of nafcillin and tobramycin or vancomycin and tobramycin administered for 2 weeks with no further therapy. SETTING: County hospital. PATIENTS: Consecutive sample of 53 intravenous drug abusers with relatively uncomplicated right-sided S. aureus endocarditis, defined by clinical and echocardiographic criteria, and without renal insufficiency, extrapulmonary metastatic infectious complications requiring prolonged therapy or surgery for cure, meningitis, methicillin-resistant organism, aortic or mitral valve involvement, or pregnancy. INTERVENTIONS: Nafcillin, 1.5 g intravenously every 4 hours, plus tobramycin, 1 mg/kg body weight intravenously every 8 hours, administered for 2 weeks. Vancomycin, 30 mg/kg per day intravenously, in two or three divided doses, was used instead of nafcillin for patients allergic to penicillin. MEASUREMENTS AND MAIN RESULTS: Forty-seven of 50 patients (94%; 95% CI, 87 to 99+) treated with the nafcillin and tobramycin combination were cured. Only 1 of 3 patients treated with vancomycin plus tobramycin (33%, 95% CI, 2 to 86) was cured. CONCLUSIONS: Selected patients with S. aureus endocarditis can be treated safely and effectively with a 2-week course of nafcillin plus tobramycin. Only one of three patients treated with vancomycin plus tobramycin was cured, but three patients are too few to define with confidence the efficacy of this regimen.

Adult↗
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↗