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Biomedical subjects

C H Nightingale

Publications and source records attributed to C H Nightingale.

At least 37 records · Page 2Linked to original sources
PubMed2000

Comparison of azithromycin leukocyte disposition in healthy volunteers and volunteers with AIDS.

Azithromycin, has been proved to be effective in the treatment and prophylaxis of a wide variety of infections. While the penetration of azithromycin into a number of types of mammalian cells has been well characterized, the influence of HIV infection on the intracellular disposition of this agent has not been studied. We therefore studied the disposition of azithromycin in polymorphonuclear (PMN) and mononuclear (MONO) leukocytes from six healthy volunteers and six volunteers with AIDS. After oral administration of a single 1200-mg dose of azithromycin (two 600-mg tablets), blood samples were collected over 6 days and intracellular azithromycin concentrations in MONOs and PMNs were measured. Analysis of the intracellular pharmacokinetics revealed an apparent difference in the MONO and PMN profile; this profile was similar for both groups. Intracellular concentrations of azithromycin remained high throughout the study period. Furthermore, no statistically significant differences in the intracellular area under the curve (11309+/-2543 vs. 16650+/-6254 for PMN; 14180+/-3802 vs. 21211+/-10001 for MONO) were observed between the healthy and AIDS populations, respectively. Our data confirm the extensive uptake of azithromycin by white blood cells both in healthy volunteers and in AIDS patients.

AIDS-Related Opportunistic Infections↗
PubMed2000

In vitro and in vivo influence of adjunct clarithromycin on the treatment of mucoid Pseudomonas aeruginosa.

Recent in vitro and in vivo data have substantiated the beneficial effects of macrolides/ azalides for use against Pseudomonas aeruginosa. While macrolides/azalides are not very potent in vitro antimicrobial agents against this pathogen, they appear to have an adjunctive role by either altering the course of infection owing to their inhibition of biofilm production or modulation of the host anti-inflammatory response, or both. To determine the in vitro and in vivo effects of clarithromycin as adjunctive therapy with ceftazidime against a mucoidproducing strain of P. aeruginosa, we performed a standard time-kill experiment and a pneumonia model in mice, respectively. Time-kill studies were performed over a 24 h period with varying concentrations of clarithromycin and ceftazidime alone or in combination. Synergic activity was noted with the use of 0.5 x MIC of ceftazidime combined with either 0.5 or 2 x MIC of clarithromycin. Neutropenic mice were infected with 10(8) cfu of mucoid P. aeruginosa intranasally to produce pneumonia and subsequently treated with oral clarithromycin (100 mg/kg) and/or sc ceftazidime (1500 mg/kg) as monotherapy or in combination. The addition of 5 days of clarithromycin to the ceftazidime regimen significantly improved survival as compared with the beta-lactam alone (48% versus 32%, P = 0.04). While a statistically significant difference was not detected with the addition of 3 days of clarithromycin therapy, a trend towards improved survival was noted with this regimen (38% versus 32%). These data demonstrate the adjunctive potential of clarithromycin when administered in combination with an antipseudomonal agent for the treatment of mucoid-producing Pseudomonas in acute respiratory infection.

Animals↗
PubMed2000

Modulation of efficacies and pharmacokinetics of antibiotics by granulocyte colony-stimulating factor in neutropenic mice with multidrug-resistant Enterococcus faecalis infection.

It has been demonstrated previously that, in non-neutropenic animals, interferon-gamma markedly enhances the efficacies of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The aim of our study was to determining whether granulocyte colony-stimulating factor (G-CSF) can be beneficial as an adjunct to gentamicin and vancomycin in the treatment of the same infection in neutropenic mice. After induction of neutropenia by cyclophosphamide, mice were inoculated ip with the organism. The infected animals received sc administrations of G-CSF, antibiotic or a combination of both agents at determined dosing regimens. Infected animals treated with G-CSF alone showed a dose-dependent increase in survival. The inoculum size used in establishing infection affected the effectiveness of the cytokine. Survival was significantly (P: < 0.01) better in the infected animals given gentamicin and vancomycin plus G-CSF than in those given antibiotics or G-CSF alone. The possibility of pharmacokinetic interaction between G-CSF and each of the antibiotics was examined. The cytokine significantly increased the plasma clearance of gentamicin, with a resultant decrease in the area under the concentration-time curve (AUC), while the disposition of vancomycin was not affected. This study suggests that G-CSF may be a useful adjunct to gentamicin and vancomycin for the treatment of multidrug-resistant E. faecalis infection in neutropenic patients.

Animals↗
PubMed2000

Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations.

Cefprozil, an oral semisynthetic cephalosporin, is commonly utilized in the treatment of respiratory-tract infections in children. While this agent has provided acceptable clinical success over a number of years, this study was undertaken to better define its pharmacodynamic profile against Streptococcus pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilized in the neutropenic murine thigh infection model. To simulate the pharmacokinetic profile of cefprozil in children, the renal function of mice was impaired with uranyl nitrate, and a commercially available cefprozil suspension (6 mg/kg of body weight) was administered orally every 12 h. Mice were infected with 10(6) to 10(7) CFU per thigh, and therapy was initiated 2 h later. At 0 and 24 h postinfection, thighs were harvested to determine bacterial density. Survival was assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5 to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication was dependent on the MIC. Killing of more than 2.6 log(10) CFU per thigh was observed with MICs of < or =3 microg/ml, while either minimal killing or growth was detected with MICs of > or =4 microg/ml. Mortality in untreated control animals was 100%. Animals infected with strains for which the MICs were < or =2 microg/ml survived the infection, whereas MICs exceeding 2 microg/ml resulted in substantial mortality. These studies demonstrate the effectiveness of cefprozil against isolates of the pneumococcus for which the MICs are < or =2 microg/ml using a drug exposure typically observed in children. These data support a susceptibility breakpoint of < or =2 microg/ml for cefprozil.

Animals↗
PubMed2000

Pharmacodynamics and pharmacokinetics of levofloxacin.

Principles of antibiotic pharmacodynamics include factors that are important for effective eradication of bacteria as well as the suppression of resistance. For effective eradication of bacteria and a good clinical outcome, a ratio for the area under the plasma concentration-time curve relative to the minimum inhibitory concentration (AUC/MIC) of greater than 100 is needed for gram-negative organisms, and a level of greater than 30 is required for gram-positive organisms. Pharmacodynamic principles can also be used to devise the optimal administration regimen for specific antimicrobial agents. Pharmacodynamic analysis of the activity of levofloxacin against Streptococcus pneumoniae revealed that, 99% of the time, actual hospitalized patients achieve an AUC/MIC of greater than 30. This indicates that levofloxacin will be very effective in treating S. pneumoniae infections in the majority of patients. Cost of treatment is an increasing concern voiced by healthcare providers and users alike. This has led to a much greater emphasis placed upon the cost of individual drugs used in the management of infections. However, when evaluating the cost of an antibiotic, it is extremely important that not only are the direct acquisition costs assessed, but consideration also given to other aspects incurring a financial burden, such as drug preparation cost, supplies, costs of treating adverse events or any treatment failures. It is only by having such a full assessment of costs that realistic financial comparisons can be made between different antibiotics.

Anti-Infective Agents↗
PubMed2000

Market factors that influence Medicare recipients' choice of health plan.

This study examines those market factors that were most influential regarding decision making made by Medicare recipients in choosing a particular health insurance plan. Since Medicare recipients can now choose health care insurance providers, companies are actively competing for this possibly very lucrative market share. A cross sectional cohort research design using a sample of 135 subjects was surveyed. Two separate groups of contributing factors to an individual's selection of a plan were measured. Factors such as level of understanding, level of perceived health, and satisfaction with the plan in terms of hospital choice were most important. Surprisingly, preference of marketing media did not provide any significant results.

Aged↗
PubMed2000

Moxifloxacin, a new antibiotic designed to treat community-acquired respiratory tract infections: a review of microbiologic and pharmacokinetic-pharmacodynamic characteristics.

Moxifloxacin (BAY 12-8039) is a new 8-methoxy-fluoroquinolone antibacterial agent. The minimum inhibitory concentration for 90% of organisms (MIC90) is less than 0.25 mg/L for commonly isolated community-acquired respiratory tract pathogens including penicillin-susceptible and -resistant Streptococcus pneumoniae, Haemophilus sp, and Moraxella catarrhalis, and less than 1.0 mg/L for atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. To date, emergence of resistance to moxifloxacin has been uncommon, including selection of resistance under experimental conditions (methicillin-sensitive Staphylococcus aureus, S. pneumoniae). A postantibiotic effect is observed for both gram-positive and gram-negative bacteria. Human pharmacokinetics in healthy volunteers after a single 400-mg oral dose were mean maximum concentration (Cmax) 3.2 mg/L, area under the curve (AUC) 37 mg x hour/L, and terminal elimination half-life 12.0 hours. At steady-state, Cmax and AUC were approximately 4.5 mg/L and 48 mg x hour/L, respectively. Because of a balanced system of excretion, no dosage adjustments are required in patients with renal or hepatic impairment. Moxifloxacin also has excellent penetration into upper and lower respiratory tissues. Laboratory pharmacodynamic models suggest that MIC and AUC values predict therapeutic response. Notably, the drug can be administered once/day and is not associated with drug interactions secondary to altered hepatic metabolism. In addition, since its metabolism does not involve the cytochrome P450 system, many common drug interactions are absent. The agent is being investigated in clinical trials and shows promise as a safe and effective once-daily treatment of respiratory infections. In addition, its chemical structure and pharmacokinetic and pharmacodynamic properties indicate that it has enhanced potential to minimize emergence of bacterial resistance, which should make it an excellent choice for treating respiratory tract infections now and in the future.

Anti-Infective Agents↗
PubMed2000

Comparison of the serum and intracellular pharmacokinetics of azithromycin in healthy and diabetic volunteers.

STUDY OBJECTIVE: To compare serum and intracellular pharmacokinetics of azithromycin in healthy volunteers and patients with diabetes. DESIGN: Open-label, parallel study. SETTING: Clinical research center. SUBJECTS: Twelve patients with diabetes and 12 healthy volunteers. INTERVENTIONS: Subjects were given a single 500-mg dose of azithromycin followed by 250 mg/day for 2 days. Blood samples were obtained just before and after the third dose for up to 24 hours for serum and 168 hours for intracellular measurement of azithromycin. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were calculated by noncompartmental methods and compared with a t test. The groups did not differ in maximum concentration, time to maximum concentration, or area under the concentration-time curve in serum or polymorphonuclear cells (PMNs). Differences in the PMN:serum ratio were observed at the 24-hour time point (healthy 1209 +/- 432, diabetic 859 +/- 286, p=0.051). CONCLUSION: In general, the pharmacokinetics of azithromycin are comparable in diabetics and healthy volunteers. Accumulation of drug in macrophages was slightly lower in patients.

Adult↗
PubMed2000

Magnesium sulfate in eclampsia and pre-eclampsia: pharmacokinetic principles.

Magnesium sulfate (MgSO4) is the agent most commonly used for treatment of eclampsia and prophylaxis of eclampsia in patients with severe pre-eclampsia. It is usually given by either the intramuscular or intravenous routes. The intramuscular regimen is most commonly a 4 g intravenous loading dose, immediately followed by 10 g intramuscularly and then by 5 g intramuscularly every 4 hours in alternating buttocks. The intravenous regimen is given as a 4 g dose, followed by a maintenance infusion of 1 to 2 g/h by controlled infusion pump. After administration, about 40% of plasma magnesium is protein bound. The unbound magnesium ion diffuses into the extravascular-extracellular space, into bone, and across the placenta and fetal membranes and into the fetus and amniotic fluid. In pregnant women, apparent volumes of distribution usually reach constant values between the third and fourth hours after administration, and range from 0.250 to 0.442 L/kg. Magnesium is almost exclusively excreted in the urine, with 90% of the dose excreted during the first 24 hours after an intravenous infusion of MgSO4. The pharmacokinetic profile of MgSO4 after intravenous administration can be described by a 2-compartment model with a rapid distribution (a) phase, followed by a relative slow beta phase of elimination. The clinical effect and toxicity of MgSO4 can be linked to its concentration in plasma. A concentration of 1.8 to 3.0 mmol/L has been suggested for treatment of eclamptic convulsions. The actual magnesium dose and concentration needed for prophylaxis has never been estimated. Maternal toxicity is rare when MgSO4 is carefully administered and monitored. The first warning of impending toxicity in the mother is loss of the patellar reflex at plasma concentrations between 3.5 and 5 mmol/L. Respiratory paralysis occurs at 5 to 6.5 mmol/L. Cardiac conduction is altered at greater than 7.5 mmol/L, and cardiac arrest can be expected when concentrations of magnesium exceed 12.5 mmol/L. Careful attention to the monitoring guidelines can prevent toxicity. Deep tendon reflexes, respiratory rate, urine output and serum concentrations are the most commonly followed variables. In this review, we will outline the currently available knowledge of the pharmacokinetics of MgSO4 and its clinical usage for women with pre-eclampsia and eclampsia.

Animals↗
PubMed1999

Interferon-gamma effects on activities of gentamicin and vancomycin against Enterococcus faecalis resistant to the drugs: an in vitro study with human neutrophils.

The emergence of multidrug-resistant enterococci presents a major therapeutic challenge since there is currently no clearly effective antimicrobial therapy for these infections. The combinatorial effects of interferon-gamma (IFN-gamma) with gentamicin and/or vancomycin against a clinical isolate of drug-resistant Enterococcus faecalis, were evaluated in an in vitro system with human neutrophils. Following inoculation of cultures of human neutrophils with the organism, treatments were initiated immediately after the infection and the number of viable bacteria was determined at 12, 18 and 24 h. Antibiotics were applied at concentrations close to their clinically achievable serum trough and peak levels. Treatment with IFN-gamma alone induced a maximal growth inhibition of up to 40% at a concentration of 100 U/ml. Addition of the cytokine to either therapeutic trough or peak concentrations of gentamicin and vancomycin, or a combination of both antimicrobials, was associated with a significant (P < 0.01) enhancement of anti-enterococcal activity compared with the effects of the agents alone. Investigation of a potential underlying mechanism of anti-enterococcal action of IFN-gamma reveals that it is, most probably, largely due to an activated secretion of the microbicidal reactive oxygen intermediates by neutrophils. The results of this study show that there is a possibility that IFN-gamma could be a useful adjunct in the treatment of multidrug-resistant E. faecalis.

Combined Modality Therapy↗
PubMed1999

Comparative efficacies of levofloxacin and ciprofloxacin against Streptococcus pneumoniae in a mouse model of experimental septicaemia.

The in vivo efficacies of levofloxacin and ciprofloxacin were compared against three clinical isolates of Streptococcus pneumoniae, using a mouse protection model. Two strains (SP 22 and SP 28) were penicillin-sensitive while one strain (SP 46) was penicillin-resistant. Each strain had identical susceptibility to both drugs. Using mice with renal impairment induced by uranyl nitrate injection, the elimination half-life of each antibiotic was prolonged to approximate human pharmacokinetic profiles of the drugs. The dosing regimen of each drug that yielded serum levels in mice which mimic human therapeutic concentrations of the drugs, were designed. One hour after intraperitoneal inoculation with minimum lethal dose of each strain, either levofloxacin at a dosing regimen of 10.6 mg/kg every 8 h or ciprofloxacin at 9.5 mg/kg every 8 h was subcutaneously administered for a total of six or 15 doses. In treatment, monitored daily for 5-8 days, levofloxacin resulted in higher survival compared with ciprofloxacin for the three strains. For example, percent survival following levofloxacin treatment recorded at day 4 postinfection with SP 22, SP 28 and SP 46 were 41, 90 and 30%, respectively, while the corresponding values after ciprofloxacin treatment were 27, 75 and 16%, respectively. However, statistical analysis did not reveal a significant difference (p > 0.05). The lack of significant difference observed in the efficacies of both drugs reflected the comparability of their 24-h AUC/MIC ratios. It is suggested that, with some strains of S. pneumoniae, the efficacy of levofloxacin may be equivalent to that of ciprofloxacin in the treatment of systemic pneumococcal infections caused by susceptible strains of the organism.

Acute Kidney Injury↗
PubMed1999

Beneficial effect of combination antiplatelet therapy on the development of experimental Staphylococcus aureus endocarditis.

Previous studies in our laboratory have shown that antiplatelet agents, aspirin and ticlopidine, in clinically relevant concentrations influence the development and treatment of experimental endocarditis. To study the influence of combination antiplatelet treatment on the development of aortic vegetations, infected animals received either aspirin alone, ticlopidine alone, aspirin plus ticlopidine or no antiplatelet therapy. The combination antiplatelet treated group had a statistically significant (P = 0.043) reduction of the vegetative weight as compared with the untreated controls. While both the single antiplatelet agent groups showed a reduction in the size of the vegetation, neither achieved statistical significance. None of the treatment groups significantly altered the bacterial density relative to untreated controls. These findings reveal that the combination of aspirin and ticlopidine, two potent inhibitors of platelet aggregation with different mechanisms of action, act synergistically to optimally reduce the weight of aortic valve vegetations.

Animals↗
PubMed1999

Influence of adjunctive interferon-gamma on treatment of gentamicin- and vancomycin-resistant Enterococcus faecalis infection in mice.

Increasing antibiotic resistance and the development of multidrug-resistance in the enterococci has complicated the treatment of serious enterococcal infections. It has been demonstrated in vitro that interferon-gamma (IFN-gamma) significantly augments the activities of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The present study was aimed at determining whether this beneficial effect of IFN-gamma on antienterococcal antibiotic activity can be validated in vivo. Following intraperitoneal inoculation in mice with a gentamicin- and vancomycin-resistant E. faecalis clinical isolate, the animals received IFN-gamma, antibiotic or a combination of both agents, subcutaneously, at determined dosing regimens. Treatment with IFN-gamma alone significantly improved survival of infected animals in a dose-dependent manner. High dose IFN-gamma was not beneficial and the level of enterococcal infectious burden influenced the effectiveness of the cytokine. The addition of IFN-gamma to therapy with gentamicin or vancomycin, or a combination of both antibiotics was associated with a marked increase in survival of infected non-neutropenic mice compared to treatments with the agents alone. However, the same treatments made in infected neutropenic mice did not show an enhancement effect by IFN-gamma after a combination therapy with antibiotics. In a study to examine pharmacokinetic interactions, concurrent administration with IFN-gamma significantly modified the disposition of gentamicin but not that of vancomycin. The results of this study suggest that the use of IFN-gamma in combination with vancomycin or gentamicin is a new treatment option that might improve the outcome of therapy of multidrug-resistant E. faecalis infections.

Animals↗
PubMed1999

Protective effect of trovafloxacin, ciprofloxacin and ampicillin against Streptococcus pneumoniae in a murine sepsis model.

Trovafloxacin is a new fluoroquinolone that has potent microbiological activity against the pneumococcus, including penicillin-resistant strains. To evaluate the protective effect of trovafloxacin, ciprofloxacin and ampicillin against penicillin-susceptible, -intermediate and -resistant strains of Streptococcus pneumoniae, an intraperitoneal, immunocompetent mouse model of sepsis was used. The minimum lethal dose (MLD) for each isolate was determined in duplicate. A single sc dose of each antibiotic was administered over a wide range of doses 1 h after the ip inoculation of the test isolate at the MLD. The assessment of the protective dose for 50% of the population (PD50) for each antimicrobial/bacteria combination was performed in triplicate and the PD50 value was calculated at the end of 5 days. Results showed that trovafloxacin provided PD50 values that were significantly lower than those of ciprofloxacin for all isolates. For the penicillin-susceptible and -intermediate isolates, the PD50 values of ampicillin were significantly lower than those for either of the fluoroquinolones studied; however, trovafloxacin was statistically superior to both ciprofloxacin and ampicillin against the penicillin-resistant strain. Therefore, regardless of penicillin susceptibility, trovafloxacin has potent activity against Streptococcus pneumoniae and may be a viable alternative for the treatment of penicillin-resistant isolates.

Ampicillin↗
PubMed1999

Oral bioavailability and pharmacokinetics of trovafloxacin in patients with AIDS.

Trovafloxacin pharmacokinetics were evaluated in 12 subjects with AIDS. By using a randomized design, single 200-mg doses of oral trovafloxacin and intravenous alatrofloxacin were administered. The mean absolute bioavailability was 91%. The pharmacokinetics of trovafloxacin when administered orally as the active form or intravenously as the prodrug (alatrofloxacin) are not altered in subjects with AIDS compared to those in healthy adults.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Beneficial effect of adjunctive azithromycin in treatment of mucoid Pseudomonas aeruginosa pneumonia in the murine model.

While a time-kill methodology noted no appreciable improvement in bactericidal activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen, data from the murine pneumonia model showed that the addition of AZM significantly improved survival compared to treatment with CAZ alone. These data suggest that AZM might be a useful adjunctive therapy in the management of pneumonia resulting from mucoid isolates of Pseudomonas aeruginosa.

Animals↗