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Biomedical subjects

C H Nightingale

Publications and source records attributed to C H Nightingale.

At least 55 records · Page 3Linked to original sources
PubMed1999

Pharmacodynamic comparisons of levofloxacin, ciprofloxacin, and ampicillin against Streptococcus pneumoniae in an in vitro model of infection.

The increasing frequency of penicillin-resistant pneumococcus continues to be of concern throughout the world. Newer fluoroquinolone antibiotics, such as levofloxacin, have shown enhanced in vitro activity against Streptococcus pneumoniae. In this study, the bactericidal characteristics and pharmacodynamic profiles of levofloxacin, ciprofloxacin, and ampicillin against four isolates of S. pneumoniae were compared by using an in vitro model of infection. Standard antibiotic dosing regimens which simulated the pharmacokinetic profile observed in humans were used. Control and treatment models were sampled for bacterial CFU per milliliter over the duration of each 24- or 48-h experiment. In addition, treatment models were sampled for MIC determinations and drug concentration. Regrowth of all isolates as well as an increase in MICs throughout the study period was observed in the ciprofloxacin experiments. A limited amount of regrowth was noted during levofloxacin therapy for one isolate; however, no change in MIC was detected for any isolate. Ampicillin showed rapid and sustained bactericidal activity against all isolates. In this study, ratios of effective fluoroquinolone area under the concentration-time curve (AUC):MIC values ranged from 30 to 55. Levofloxacin, owing to its larger AUC0-24 values, has excellent and sustained activity against different pneumococcal strains superior to that of ciprofloxacin.

Ampicillin↗
PubMed1999

Pharmacokinetics of rifapentine in subjects seropositive for the human immunodeficiency virus: a phase I study.

Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.

AIDS-Related Opportunistic Infections↗
PubMed1999

Mononuclear and polymorphonuclear leukocyte dispositions of clarithromycin and azithromycin in AIDS patients requiring Mycobacterium avium complex prophylaxis.

The intracellular dispositions of clarithromycin and azithromycin in AIDS patients requiring Mycobacterium avium complex (MAC) prophylaxis were studied. The dispositions of both drugs in mononuclear and polymorphonuclear leukocytes were markedly different. Our data support the proven efficacy of these agents for MAC prophylaxis since clarithromycin and azithromycin displayed sustained intracellular concentrations which exceeded their MICs for MAC throughout the dosing periods.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Pharmacokinetics of ticlopidine in the rabbit.

There is no information about the pharmacokinetics of ticlopidine in rabbits. Such information is valuable in designing appropriate dosing regimens for experimental studies of the drug with ultimate applications in man. The disposition kinetics of ticlopidine at three dose levels were evaluated in three groups of six rabbits which received 10, 50 or 100 mgkg(-1) drug once daily via the oral-gastric route. Blood samples were collected at predetermined times after the third dose. Plasma concentrations of the unchanged drug were determined by a validated liquid chromatography-mass spectrometry method with a limit of detection of 5 microg L(-1). There was a disproportionate increase in the mean maximum plasma concentration (Cmax) and the area under the plasma drug-concentration-time curve (AUC) for the 10 and 50 mgkg(-1) doses. The apparent terminal half-life (t1/2beta), apparent volume of distribution (Vdbeta/F), and total plasma clearance (CLp/F) of the drug were all dose-dependent. For example, t1/1beta for the 10, 50 and 100 mgkg(-1) doses were 1.04+/-0.10, 4+/-24+/-1.92 and 12.80+/-6.35 h, respectively, whereas the Vdbeta/F values for the corresponding doses were 214 31, 475 221 and 998+/-420 Lkg(-1), respectively. These results show that the 100-mgkg(-1) dose produces plasma ticlopidine concentrations similar to those found in man after administration of 250 mg of the drug. It is suggested that 100 mg kg(-1) might be the appropriate dose of ticlopidine for use in rabbit experimental studies with ultimate application to man.

Administration, Oral↗
PubMed1998

Use of a bioabsorbable polymer for the delivery of ofloxacin during experimental osteomyelitis treatment.

This study was performed to investigate the potential utility of ofloxacin-impregnated bioabsorbable polymers for osteomyelitis therapy. Pseudomonas aeruginosa osteomyelitis was induced in 48 New Zealand White rabbits. Four weeks after infection, the animals were randomized to one of four treatment groups: drug-free polymer, ofloxacin polymer, systemic ofloxacin, or ofloxacin polymer plus systemic ofloxacin. Twenty-eight days later, radiographs were taken of the affected area, the animals were killed, and bone was obtained for histologic evaluation, culture, and determination of ofloxacin concentrations. The percentage of sterile bone cultures was 33, 83, 75, and 91 for the groups treated with drug-free polymer, ofloxacin polymer, systemic ofloxacin, and ofloxacin polymer plus systemic ofloxacin, respectively. When compared with the drug-free polymer, both the ofloxacin polymer and the ofloxacin polymer plus systemic ofloxacin significantly improved the rate of sterilization. The mean concentrations of the drug in bone for the groups treated with ofloxacin polymer, systemic ofloxacin, and ofloxacin polymer plus systemic ofloxacin were 34.9 (range: 2-160), 1.9 (range: 0.8-3), and 26.0 microg/g (range: 9-100 microg/g), respectively. These data suggest that the DL-lactide:glycolide polymer studied is a suitable vehicle for the delivery of high local concentrations of ofloxacin and that these concentrations result in eradication of the bacterial pathogen in this rabbit model.

Animals↗
PubMed1998

Antibiotic use in the critical care unit.

The antimicrobial management of patients in the critical care unit is complex. Not only must the clinician be familiar with a number of clinical, microbiological, pharmacological, and epidemiological observations but also fundamental pharmacodynamic concepts. It is an understanding of these concepts that forms the basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. Antimicrobial selection is further complicated by the plethora of new antimicrobial agents available with varying clinical utility. Nowhere is this more evident than in the quinolone class of antibiotics. To aid the clinician in differentiating between quinolones it now seems reasonable to create a classification system akin to the generation grouping applied to the cephalosporins. Our classification is based upon the pharmacodynamic principles discussed within this article.

Aminoglycosides↗
PubMed1998

Influence of adjunctive ticlopidine on the treatment of experimental Staphylococcus aureus endocarditis.

Antiplatelet therapy has been shown to reduce the size of aortic vegetations in a rabbit model of Staphylococcus aureus endocarditis. In addition, adjunctive aspirin improved the sterilization rate as compared with antibiotic treatment alone. To study the influence of ticlopidine, another potent inhibitor of platelet aggregation, infected animals received either vancomycin (Vm) alone or in combination with ticlopidine. When ticlopidine was given prior to and during antimicrobial therapy, a reduction in vegetation weight was observed. Ticlopidine administered with antimicrobial therapy, not only caused a reduction in vegetation weight, but also improved the rate of sterilization. This study provides additional data regarding the potential clinical role of antiplatelet agents in the treatment of endocarditis.

Animals↗
PubMed1998

Comparison of bactericidal activity after multidose administration of clarithromycin, azithromycin, and ceruroxime axetil against Streptococcus pneumoniae.

The objective of this study was to compare the duration of serum bactericidal activity (SBA) for clarithromycin, azithromycin, and cefuroxime axetil in 12 young healthy volunteers after 5 days of therapy (dosed to steady-state) against two strains each of penicillin (PCN)-susceptible, -intermediate, and -resistant Streptococcus pneumoniae. This was a randomized, 3-way crossover study. All isolates were susceptible to clarithromycin (MICs 0.125 mg/l) and azithromycin (MICs 0.25-0.5 mg/l), while cefuroxime axetil susceptibilities correlated with PCN. Results showed that SBA was maintained for 100% of the dosing interval for clarithromycin and 50-100% for azithromycin regardless of PCN susceptibility when standard doses were employed. Cefuroxime axetil was active only against the PCN-susceptible isolate for 50% of the dosing interval, indicating that it should only be used for PCN-susceptible S. pneumoniae.

Anti-Bacterial Agents↗
PubMed1998

The pharmacodynamics of aminoglycosides.

Recently, a more complete understanding of the pharmacodynamics of aminoglycosides has been recognized, indicating that this class of antibiotics exhibits both concentration-dependent bactericidal activity and a postantibiotic effect. This pharmacodynamic information, along with better knowledge of the mechanisms responsible for aminoglycoside toxicity, established the foundation for once-daily aminoglycoside dosing regimens. This new approach to aminoglycoside dosing appears to be safe, efficacious, and cost-effective, resulting in its increasing popularity in clinical practice.

Aminoglycosides↗
PubMed1998

Penetration kinetics of 5-fluorouracil into pancreatic fluid in post-pancreatoduodenectomy patients.

Our aim was to investigate the pharmacokinetic behavior of 5-fluorouracil (5-FU) in pancreatic fluid and to evaluate its penetration characteristics in post-pancreatoduodenectomy patients. After completing the external drainage of the pancreatic duct during pancreatoduodenectomy surgery, eight patients were administered 1.0 g 5-FU i.v. by a 5 min infusion after the eighth day post-surgery on average. Blood and pancreatic fluid were collected, and the 5-FU concentrations were determined by HPLC assay. Their pharmacokinetic parameters were obtained by PCNONLIN and statistical analysis was performed. The Cmax was 20.03 +/- 18.25 mg/l in pancreatic fluid with a Tmax of 15.6 +/- 9.5 min following i.v. administration and 49.69 +/- 20.75 mg/l in plasma. 5-FU in plasma and pancreatic fluid were all in conformity with a non-linear model with a K(m) of 1098.08 +/- 1426.57 and 11.08 +/- 6.38 mg/l, respectively. The concentrations in pancreatic fluid were similar to that observed in plasma with an average penetration index up to 1.01 +/- 0.49. It is suggested therefore that 5-FU is capable of penetrating from blood into the pancreas as evidenced by the observed pancreatic concentrations.

Body Fluids↗
PubMed1998

Prophylaxis of acute osteomyelitis with absorbable ofloxacin-impregnated beads.

We investigated the use of an ofloxacin-impregnated bioabsorbable composite for the prevention of acute Staphylococcus aureus osteomyelitis. New Zealand White rabbits were anesthetized, the femur was exposed, and a cortical hole was drilled. Animals were randomly given drug-free composites or ofloxacin-impregnated composites; the composites were placed at the site of injury, and the incision was closed. One hour later, all animals were intravenously inoculated with 5 x 10(4) CFU of S. aureus and observed for 28 days. Bone culture data revealed that S. aureus was isolated from 3 of 12 rabbits in the ofloxacin composite group and 9 of 11 animals in the control group (P = 0.02). Radiographic evaluation revealed that the drug-free group had a significantly (P = 0.01) greater degree of radiographic evidence of infection than the group given ofloxacin composites. Although a limited number of histologic samples were available, these data also paralleled the radiographic and culture data. This study demonstrates the effectiveness of the implantable ofloxacin bioabsorbable composites to prevent the development of acute osteomyelitis.

Absorption↗
PubMed1998

Pharmacokinetics of 5-fluorouracil and its penetration into pancreatic juice in dogs.

AIM: To study the pharmacokinetic behavior of 5-fluorouracil (5-FU) in pancreatic juice in dogs and its correlation with 5-FU in plasma, and to evaluate its penetration characteristics. METHODS: After placing a pancreatico-drainage tube, 8 dogs were injected 5-FU 250 mg i.v. Blood and pancreatic samples were collected and the 5-FU concentrations were determined by HPLC. The pharmacokinetic parameters were obtained with statistical analysis. RESULTS: The mean slopes of the terminal phase (K10) in plasma and pancreatic juice were 9.4 h-1 and 10.2 h-1, respectively (P > 0.05). The pharmacokinetic behaviors of 5-FU in plasma and pancreatic juice fitted a nonlinear model. Its penetration index was 3.39 +/- 2.84. The penetration of 5-FU from blood to pancreatic juice was relatively rapid, demonstrating a consistently higher concentration in pancreatic juice than in plasma. CONCLUSIONS: The elimination phase of 5-FU in plasma was similar to that in pancreatic juice, indicating that they were in the same kinetic compartment.

Animals↗
PubMed1998

Formulary review of the carbapenems: comparison of imipenem/cilastatin and meropenem.

In comparison with imipenem, meropenem exhibits closely similar microbiological activity. Although meropenem has slightly greater gram-negative activity against organisms, like Pseudomonas aeruginosa and Burkholderia cepacia, imipenem demonstrates more intense gram-positive activity, particularly towards Enterococcus faecalis which may reduce or even cancel out, the clinical relevance of these microbiological differences. However, an aminoglycoside is usually added in the treatment of serious infections from these bacteria. The pharmacokinetics of these two agents are also closely similar both in normal healthy volunteers and in patients with normal or impaired renal function. Moreover, there is little, if any, difference in the acquisition costs for meropenem and imipenem in most hospitals. Cost-avoidance with meropenem is, therefore, mainly the result of less frequent dosing and the ability to administer meropenem by rapid intravenous injection. Additionally, meropenem's FDA approved indication for central nervous system infection offers an additional advantage when compared to imipenem/cilastatin. It was for these reasons that our hospital's Pharmacy and Therapeutics Committee replaced imipenem/cilastatin with meropenem.

Carbapenems↗
PubMed1998

Myoglobin clearance during continuous veno-venous hemofiltration with or without dialysis.

The management of acute myoglobinuric renal failure, the major complication of rhabdomyolysis, continues to be a treatment dilemma for the clinician as limited therapeutic options are available. Previously, we have demonstrated that continuous arteriovenous hemofiltration (CAVH) is an effective technique for removing myoglobin in an animal model. In the present study, swine were administered four grams of equine myoglobin intravenously and underwent the continuous veno-venous hemofiltration (CVVH) procedure for six hours each. Animals were studied in each of the following groups: CVVH at a pump rate 100 ml/minute, CVVH at a pump rate 200 ml/minute and CVVH at a pump rate 100 ml/minute plus dialysis at a dialysate flow rate of one Liter/h. Once the filtering process was initiated there was a rapid and sustained production of ultrafiltrate in all groups. The amount of myoglobin excreted in the ultrafiltrate over the six-hour filtering period was 688, 948 and 570 mg which corresponded to 17, 24 and 14 percent of the administered dose, respectively, for the three treatments. In comparison to previous CAVH experiments, CVVH removed more circulating myoglobin and the addition of the dialysis component did not appear to improve removal. Based on these findings, it appears that the CVVH hemofiltration system is a viable option for the removal of systemic myoglobin.

Animals↗
PubMed1997

Influence of piperacillin-tazobactam on pharmacokinetics of gentamicin given once daily.

The effect of piperacillin-tazobactam on the pharmacokinetics of gentamicin given once daily was studied. Healthy adult volunteers each received four drug regimens in randomized order: gentamicin 7 mg/kg i.v. once daily (1) by itself, (2) with piperacillin 4 g and tazobactam 0.5 g (both as the sodium salt) every six hours i.v., (3) with piperacillin 4 g and tazobactam 0.5 g i.v. every eight hours, and (4) with piperacillin 8 g and tazobactam 1 g by continuous i.v. infusion over 24 hours. All the gentamicin doses were infused over 30 minutes two hours after piperacillin-tazobactam. Blood samples were drawn before and at the end of each gentamicin infusion and at intervals up to 12 hours after the start of each gentamicin infusion. Samples were assayed for gentamicin concentration by an enzyme-multiplied immunoassay technique and for piperacillin and tazobactam concentrations by high-performance liquid chromatography. Six women and four men completed all four drug regimens. For the gentamicin-alone regimen, the mean +/- S.D. area under the concentration-versus-time curve was 78.06 +/- 10.28 micrograms/mL.hr, the mean +/- S.D. peak concentration (30 minutes after the end of an infusion) was 20.28 +/- 2.54 micrograms/mL, and the mean +/- S.D. half-life was 2.41 +/- 0.24 hours. The values for gentamicin alone did not differ significantly from those for gentamicin in any of the combination regimens. Coadministration of once-daily gentamicin and piperacillin-tazobactam in various i.v. infusion regimens did not affect the pharmacokinetics of once-daily gentamicin.

Adolescent↗