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Biomedical subjects

K A Rodvold

Publications and source records attributed to K A Rodvold.

At least 19 recordsLinked to original sources
PubMed2002

Levofloxacin penetration into epithelial lining fluid as determined by population pharmacokinetic modeling and monte carlo simulation.

Levofloxacin was administered orally to steady state to volunteers randomly in doses of 500 and 750 mg. Plasma and epithelial lining fluid (ELF) samples were obtained at 4, 12, and 24 h after the final dose. All data were comodeled in a population pharmacokinetic analysis employing BigNPEM. Penetration was evaluated from the population mean parameter vector values and from the results of a 1,000-subject Monte Carlo simulation. Evaluation from the population mean values demonstrated a penetration ratio (ELF/plasma) of 1.16. The Monte Carlo simulation provided a measure of dispersion, demonstrating a mean ratio of 3.18, with a median of 1.43 and a 95% confidence interval of 0.14 to 19.1. Population analysis with Monte Carlo simulation provides the best and least-biased estimate of penetration. It also demonstrates clearly that we can expect differences in penetration between patients. This analysis did not deal with inflammation, as it was performed in volunteers. The influence of lung pathology on penetration needs to be examined.

Adolescent↗
PubMed2001

Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects.

STUDY OBJECTIVE: To determine the steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levofloxacin and ciprofloxacin. DESIGN: Multiple-dose, open-label, randomized pharmacokinetic study. PARTICIPANTS: Thirty-six healthy, nonsmoking adult subjects were randomized either to oral levofloxacin, 500 or 750 mg once daily for five doses, or ciprofloxacin, 500 mg q12h for nine doses. INTERVENTIONS: Venipuncture, bronchoscopy, and BAL were performed in each subject at 4 h, 12 h, or 24 h after the last administered dose of antibiotic. MEASUREMENT AND RESULTS: Mean plasma concentrations of levofloxacin and ciprofloxacin were similar to those previously reported. For once-daily dosing of levofloxacin, 500 mg, the mean (+/- SD) steady-state concentrations at 4 h, 12 h, and 24 h in ELF were 9.9 +/- 2.7 microg/mL, 6.5 +/- 2.5 microg/mL, and 0.7 +/- 0.4 microg/mL, respectively; AM concentrations were 97.9 +/- 80.0 microg/mL, 36.7 +/- 23.4 microg/mL, and 13.8 +/- 16.0 microg/mL, respectively. For levofloxacin, 750 mg, the mean steady-state concentrations in ELF were 22.1 +/- 14.9 microg/mL, 9.2 +/- 5.3 microg/mL, and 1.5 +/- 0.8 microg/mL, respectively; AM concentrations were 105.1 +/- 65.5 microg/mL, 36.2 +/- 26.1 microg/mL, and 15.1 +/- 2.0 microg/mL, respectively. The concentrations of ciprofloxacin at 4 h and 12 h in ELF were 1.9 +/- 0.9 microg/mL and 0.4 +/- 0.1 microg/mL, respectively; AM concentrations were 34.9 +/- 23.2 microg/mL and 6.8 +/- 5.9 microg/mL, respectively. The differences in the ELF concentrations of the two levofloxacin groups vs those of the ciprofloxacin group were significant (p < 0.05) at each sampling time. CONCLUSIONS: Levofloxacin was more extensively distributed into intrapulmonary compartments than ciprofloxacin and achieved significantly higher steady-state concentrations in plasma and ELF during the 24 h after drug administration.

Adult↗
PubMed2001

Pharmacokinetics and pharmacodynamics of fluoroquinolones.

The pharmacokinetic characteristics of levofloxacin, moxifloxacin, and gatifloxacin include excellent oral bioavailability (90-99%), extensive penetration into tissues and body fluids, and an elimination half-life (6-12 hrs) that allows for once-daily dosing in patients with normal renal function. Levofloxacin and gatifloxacin primarily are excreted unchanged in the urine, whereas moxifloxacin undergoes hepatic metabolism. The pharmacodynamic values that correlate with successful clinical and microbiologic outcomes, as well as prevent emergence of bacterial resistance, are ratios of maximum or peak unbound drug concentration (Cmax) to minimum inhibitory concentration (MIC), and 24-hour unbound area under the concentration curve (AUC(0-24hr)) to MIC. For gram-negative infections, a Cmax:MIC greater than or equal to 10 and AUC(0-24hr):MIC greater than or equal to 125 are associated with increased probability of a successful outcome. For infections caused by Streptococcus pneumoniae, an AUC(0-24hr):MIC of 30 or more is suggested for favorable clinical outcomes. Pharmacokinetic and pharmacodynamic values influence rational therapeutic decisions in the selection and dosages of these drugs.

Acute Kidney Injury↗
PubMed2001

Pharmacodynamics of antiinfective therapy: taking what we know to the patient's bedside.

Applied pharmacokinetics has long been a lifeline of clinical pharmacy services. National surveys during the past decade documented clinical pharmacy services and demonstrated that a substantial rate of growth occurred in clinical pharmacokinetic consultations and management of drug therapy protocols. Pharmacodynamic principles of antiinfective agents are rapidly becoming a new paradigm of clinical pharmacy services. beta-Lactams, aminoglycosides, and fluoroquinolones represent the three classes of antiinfective agents that have made the most progress toward the clinical applications of pharmacodynamics. Pharmacodynamic parameters are being used to select and compare agents within an antiinfective class (e.g., fluoroquinolones), make modifications in the dosage (e.g., extended-interval dosing of aminoglycosides) and/or mode of administration (e.g., continuous infusion of beta-lactams), develop in vivo breakpoint determinations, and assess the development of bacterial resistance. In addition, pharmacodynamic parameters have influenced the clinical drug development of new (e.g., linezolid) and older (amoxicillin-clavulanate, fluoroquinolones) antiinfective agents. Further investigations are needed to explore the clinician's use of validated prediction methods and patient-specific pharmacodynamic parameters at the bedside. By linking pharmacokinetic services with pharmacodynamic principles, the opportunity for continued progress toward our assessment and decisions for successful clinical outcomes is possible with old and new antiinfective agents.

Anti-Bacterial Agents↗
PubMed2001

Cerebrospinal fluid concentrations of quinupristin-dalfopristin in a patient with vancomycin-resistant Enterococcus faecium [correction of faecalis] ventriculitis.

A 44-year-old man was treated successfully for vancomycin-resistant Enterococcus faecium (VREF) ventriculitis with intrathecal quinupristin-dalfopristin 1 mg, 2 mg, and 4 mg, and other intravenous antibiotics. Cerebrospinal fluid samples were collected before and after the 1-mg and 2-mg doses to determine the concentrations of quinupristin-dalfopristin and its active metabolites. Concentrations were above the minimum inhibitory concentration for VREF immediately after unclamping the extraventricular drain and were quantifiable for at least 7 hours.

Adult↗
PubMed2000

National survey of extended-interval aminoglycoside dosing.

A random sample survey of 500 acute care hospitals in the United States was conducted to evaluate the adoption of extended-interval aminoglycoside dosing (EIAD). The survey revealed that EIAD has been adopted in 3 of every 4 acute care hospitals, a 4-fold increase since 1993. Of the 74.7% of hospitals reporting EIAD, 64% had written guidelines. Equal or less toxicity (87.1%), equal efficacy (76.9%), and cost-savings (65.6%) were common rationales. There has been a trend toward higher adult dosages of gentamicin (e.g., >5 mg/kg/dose) and an increase in the adoption of EIAD across all age groups (neonatal, 11%, and pediatric, 23%). Monitoring of aminoglycoside concentrations has shifted to a single determination of concentration, at 6-18 h after drug administration. The most common methods of dosage adjustment for declining renal function were an interval extension with the same dose (47%) or use of the Hartford nomogram (32%).

Adolescent↗
PubMed2000

Dosage adjustments for antibacterials in obese patients: applying clinical pharmacokinetics.

Obesity is associated with physiological changes that can alter the pharmacokinetic parameters of many drugs. Vancomycin and the aminoglycosides are the only antibacterials that have been extensively investigated in the obese population. The apparent volume of distribution (Vd) and total body clearance of vancomycin are increased in obese patients and have a better correlation with total bodyweight (TBW) than with ideal bodyweight (IBW). The Vd of aminoglycosides is increased in obesity and can be estimated from an adjusted bodyweight that accounts for a fraction of the excess bodyweight (TBW - IBW). These observed changes in pharmacokinetic parameters of vancomycin and aminoglycosides in obese patients may necessitate a deviation from the commonly recommended dosages administered to non-obese individuals. There are limited data regarding the pharmacokinetics of other antibacterial classes in obese patients. The available information for cephalosporins suggests that dosages may need to be increased in obese patients in order to obtain similar serum and tissue concentrations as in non-obese patients. Additional pharmacokinetic studies of other antibacterial classes are required in this special patient population.

Aminoglycosides↗
PubMed1999

Modified time-kill assay against multidrug-resistant Enterococcus faecium with novel antimicrobial combinations.

This study used a modified time-kill assay to compare the in-vitro activity of chloramphenicol and quinopristin/dalfopristin combined with vancomycin, ampicillin or gentamicin against multidrug-resistant Enterococcus faecium. The assay uses standardized time-kill methods with the following modifications: centrifugation of the test tubes at 1-2 h intervals, removal of supernatant and resuspension of bacteria in media containing antibiotic concentrations corresponding to simulated steady-state serum concentrations. None of the agents, alone or in combination, produced bactericidal or synergic activity. The modified time-kill assay more closely simulates in-vivo conditions and may provide a better qualitative assay to determine the interaction between antimicrobial agents and bacteria.

Ampicillin↗
PubMed1999

Clinical pharmacokinetics of clarithromycin.

Clarithromycin is a macrolide antibacterial that differs in chemical structure from erythromycin by the methylation of the hydroxyl group at position 6 on the lactone ring. The pharmacokinetic advantages that clarithromycin has over erythromycin include increased oral bioavailability (52 to 55%), increased plasma concentrations (mean maximum concentrations ranged from 1.01 to 1.52 mg/L and 2.41 to 2.85 mg/L after multiple 250 and 500 mg doses, respectively), and a longer elimination half-life (3.3 to 4.9 hours) to allow twice daily administration. In addition, clarithromycin has extensive diffusion into saliva, sputum, lung tissue, epithelial lining fluid, alveolar macrophages, neutrophils, tonsils, nasal mucosa and middle ear fluid. Clarithromycin is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and has an active metabolite, 14-hydroxyclarithromycin. The reported mean values of total body clearance and renal clearance in adults have ranged from 29.2 to 58.1 L/h and 6.7 to 12.8 L/h, respectively. In patients with severe renal impairment, increased plasma concentrations and a prolonged elimination half-life for clarithromycin and its metabolite have been reported. A dosage adjustment for clarithromycin should be considered in patients with a creatinine clearance < 1.8 L/h. The recommended goal for dosage regimens of clarithromycin is to ensure that the time that unbound drug concentrations in the blood remains above the minimum inhibitory concentration is at least 40 to 60% of the dosage interval. However, the concentrations and in vitro activity of 14-hydroxyclarithromycin must be considered for pathogens such as Haemophilus influenzae. In addition, clarithromycin achieves significantly higher drug concentrations in the epithelial lining fluid and alveolar macrophages, the potential sites of extracellular and intracellular respiratory tract pathogens, respectively. Further studies are needed to determine the importance of these concentrations of clarithromycin at the site of infection. Clarithromycin can increase the steady-state concentrations of drugs that are primarily depend upon CYP3A metabolism (e.g., astemidole, cisapride, pimozide, midazolam and triazolam). This can be clinically important for drugs that have a narrow therapeutic index, such as carbamazepine, cyclosporin, digoxin, theophylline and warfarin. Potent inhibitors of CYP3A (e.g., omeprazole and ritonavir) may also alter the metabolism of clarithromycin and its metabolites. Rifampicin (rifampin) and rifabutin are potent enzyme inducers and several small studies have suggested that these agents may significantly decrease serum clarithromycin concentrations. Overall, the pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug interactions occur with clarithromycin compared with older macrolides such as erythromycin and troleandomycin.

Animals↗
PubMed1999

Multi-drug resistance in chronic lymphocytic leukemia.

We evaluated 45 chronic lymphocyte leukemia (CLL) patients for the presence of multi-drug resistance (MDR) by the ex vivo techniques: 1) a functional assay utilizing doxorubicin (dox) retention with modulation; 2) a cytotoxicity assay (MTT) with modulation; 3) and four monoclonal antibodies. Ex vivo tests were correlated with disease stage and prior treatment, and were repeated as patients became resistant to alkylating agents, fludarabine and VAD chemotherapy (infusion of vincristine, dox, and oral dexamethasone). The majority of patients (64.4%) were in early stage and were untreated (62.2%). P-glycoprotein (p-gp 170) was detected most frequently by the monoclonal antibody MRK-16 (48%) and by functional modulation of dox retention by PSC-833 (40.6%) and by functional modulation of the MTT assay with vincristine (0.29) and dox (0.39) with PSC-833 at 1.0 microg/mL. Functional modulation of dox retention with PSC-833 was significantly associated with stage, but not with either the MTT assay or any of the monoclonal antibodies. None of the tests correlated with prior chlorambucil treatment. Correlation of dox retention with the monoclonal antibodies was mild to moderate and became stronger following chlorambucil treatment. Three patients who became resistant to VAD were found to express p-gp 170. We conclude that MDR can frequently be detected in patients with CLL. Furthermore, the expression of p-gp 170 increases with advancing stage, but not prior alkylating agent therapy. The functional expression of p-gp 170 increases with advancing stage and prior treatment and correlates well with monoclonal antibody detection (especially MRK-16). Patients who become resistant to VAD more frequently express p-gp 170 by a variety of techniques. PSC-833 is a more potent modulator of MDR than cyclosporin-A (CsA) ex vivo, and correlates better with stage of disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Therapeutic drug monitoring of vancomycin in a morbidly obese patient.

The authors describe the therapeutic drug monitoring of vancomycin in a man who is morbidly obese. Because serum vancomycin concentration (SVC) monitoring continues to be deemphasized, nomogram use will likely increase. However, vancomycin dosing nomograms have not been studied in patients who are morbidly obese. Furthermore, in nomograms that incorporate body weight, it is unclear whether ideal or total body weight (IBW and TBW, respectively) should be used to dose the morbidly obese. Therefore, the authors retrospectively evaluated four nomograms (Moellering, Matzke, Lake-Peterson, and Rodvold) and an individualized method in the simulated vancomycin dosing of their patient. Total body weight was more accurate than IBW in selecting a vancomycin dose when using the individualized method and in all nomograms except the Matzke nomogram. The Rodvold nomogram and the individualized method yielded the most appropriate doses. All nomograms suggested dosing intervals that were unacceptably short; the individualized method suggested an appropriately longer interval. Thus, if nomograms or the individualized method are used to empirically dose vancomycin, TBW--not IBW--should be used. Because these nomograms yielded inappropriately short dosing intervals in the patient, it is likely that patients who are morbidly obese represent a unique population in which at least one set of SVCs are necessary to select an appropriate dosing regimen.

Anti-Bacterial Agents↗
PubMed1997

In-vitro activity of a new oral streptogramin, RPR 106972, alone and in combination with rifampicin or ciprofloxacin against Legionella spp.

The in-vitro activity of RPR 106972, a new oral streptogramin, was compared with that of erythromycin, ciprofloxacin, and rifampicin against 45 Legionella spp. While rifampicin was the most active of all agents tested, RPR 106972 demonstrated activity comparable to that of erythromycin and ciprofloxacin. Usually, indifference was seen when RPR 106972 was tested in combination with rifampicin or ciprofloxacin.

Ciprofloxacin↗
PubMed1997

Pharmacokinetics and pharmacodynamics of two multiple-dose piperacillin-tazobactam regimens.

The pharmacokinetics and pharmacodynamics of two multiple-dose regimens of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) were evaluated at steady state for 12 healthy adult volunteers. Inhibitory and bactericidal activities for the two regimens were determined with five American Type Culture Collection (ATCC) organisms (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Bacteroides fragilis). The percentage of time that plasma concentrations remained above the MIC (T > MIC) for each organism and dosage regimen was calculated. Areas under the inhibitory (AUIC0-24) and bactericidal activity (AUBC0-24) curves were calculated with the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal titers determined for each dosage regimen. In order to assess the validity of predicted measures of bactericidal (AUC0-24/MBC) and inhibitory (AUC0-24/MIC) activity to determine bacteriological response to beta-lactam antimicrobial agents, AUC0-24/MBC and AUC0-24/MIC values were compared with measured AUBC0-24 and AUIC0-24 values. Total body clearance values were equivalent for piperacillin (183.96 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m2, P > 0.05) and tazobactam (184.71 +/- 19.89 versus 184.87 +/- 18.35 ml/min/1.73 m2, P > 0.05) following the administration of the 3.375-g-every-6-h and 4.5-g-every-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC0-24) for piperacillin (967.74 +/- 135.56 microg x h/ml versus 978.88 +/- 140.96 microg x h/ml) and tazobactam (120.14 +/- 15.78 microg x h/ml versus 120.01 +/- 16.22 microg x h/ml) revealed no significant differences (P > 0.05) between the 3.375-g-every-6-h and 4.5-g-every-8-h regimens, respectively. Both regimens provided T > MIC values of > 60% for all organisms tested. Measured values of bactericidal (AUBC) and inhibitory (AUIC) activity were significantly different (P < 0.05) from predicted values (AUC0-24/MBC and AUC0-24/MIC) for all organisms studied with the exception of the bactericidal activity for P. aeruginosa and S. aureus. Additionally, ATCC organisms possessing the same MICs and MBCs exhibited great differences in measured AUBC0-24 and AUIC0-24 values. Reasons for this difference may be inherent differences in organism specific susceptibility.

Adult↗
PubMed1997

Pharmacokinetics of intramuscularly administered aminosidine in healthy subjects.

Aminosidine is an older, broad-spectrum aminoglycoside antibiotic that has been shown to be effective in in vitro and animal models against multiple-drug-resistant tuberculosis and the Mycobacterium avium complex. The objective of this randomized, parallel trial was to characterize the single-dose pharmacokinetics of aminosidine sulfate in healthy subjects (eight males, eight females). Sixteen adults (mean [+/- standard deviation] age, 27.6 +/- 5.6 years) were randomly allocated to receive a single, intramuscular aminosidine sulfate injection at a dose of 12 or 15 mg/kg of body weight. Serial plasma and urine samples were collected over a 24-h period and used to determine aminosidine concentrations by high-performance liquid chromatographic assay. A one-compartment model with first-order input, first-order output, and a lag time (Tlag) and with a weighting factor of 1/y2 best described the data. Compartmental and noncompartmental pharmacokinetic parameters were estimated with the microcomputer program WinNonlin. One subject was not included (15-mg/kg group) because of the lack of sampling time data. On average, subjects attained peak concentrations of 22.4 +/- 3.2 microg/ml at 1.34 +/- 0.45 h. All subjects had plasma aminosidine concentrations below 2 microg/ml at 12 h, and all but two subjects (one in each dosing group) had undetectable plasma aminosidine concentrations at 24 h. The dose-adjusted area under the concentration-time curve from 0 h to infinity of aminosidine was identical for the 12- and 15-mg/kg groups (9.29 +/- 1.5 versus 9.29 +/- 2.2 microg x h/ml per mg/kg; P = 0.998). Similarly, no significant differences (P > 0.05) were observed between dosing groups for peak aminosidine concentration in plasma, time to peak aminosidine concentration in plasma, Tlag, apparent clearance, renal clearance, elimination rate constant, and elimination half-life. A significant difference was observed for the volume of distribution (0.35 versus 0.41 liters/kg; P = 0.037) between the 12 and 15 mg/kg dosing groups. Now that comparable pharmacokinetic profiles between dosing groups have been demonstrated, therapeutic equivalency testing via in vitro pharmacokinetic and pharmacodynamic modelling and randomized clinical trials in humans should be conducted.

Adult↗
PubMed1997

Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers.

The steady-state concentrations of clarithromycin and azithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained in intrapulmonary samples during bronchoscopy and bronchoalveolar lavage from 40 healthy, nonsmoking adult volunteers. Mean plasma clarithromycin, 14-(R)-hydroxyclarithromycin, and azithromycin concentrations were similar to those previously reported. Clarithromycin was extensively concentrated in ELF (range of mean +/- standard deviation concentrations, 34.4 +/- 29.3 microg/ml at 4 h to 4.6 +/- 3.7 microg/ml at 24 h) and AM (480 +/- 533 microg/ml at 4 h to 99 +/- 50 microg/ml at 24 h). The concentrations of azithromycin in ELF were 1.01 +/- 0.45 microg/ml at 4 h to 1.22 +/- 0.59 microg/ml at 24 h, and those in AM were 42.7 +/- 28.7 microg/ml at 4 h to 41.7 +/- 12.1 microg/ml at 24 h. The concentrations of 14-(R)-hydroxyclarithromycin in the AM ranged from 89.3 +/- 52.8 microg/ml at 4 h to 31.3 +/- 17.7 microg/ml at 24 h. During the period of 24 h after drug administration, azithromycin and clarithromycin achieved mean concentrations in ELF and AM higher than the concomitant concentrations in plasma.

Administration, Oral↗
PubMed1997

Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children.

The increased use of vancomycin in neonatal and paediatric patients has prompted numerous pharmacokinetic studies and the development of many empirical administration methods. The majority of dosage guidelines use the relationship between pharmacokinetic parameters and patient variables such as chronological age, bodyweight, and/or measures of renal function. Currently, those dosage guidelines which are based upon postconceptional age and bodyweight seem to provide the best options for empirical administration in neonates and infants. In addition, serum creatinine may prove to be a useful guide to the empirical administration of vancomycin in neonates older than 7 to 14 days. Several investigators have reported the individualisation of dosage regimens based on pharmacokinetic-based administration methods. The most common techniques employed have been Sawchuk-Zaske method and Bayesian forecasting. However, only a limited number of studies have evaluated either empirical administration or individualised administration techniques in patient populations outside those of the original reports; this makes choosing between the methods difficult. Pharmacokinetic data and administration recommendations have gradually become available in special paediatric patient populations. The majority of studies have focused on patients requiring cardiopulmonary bypass surgery or with burns, cancer or central nervous system infections. However, a limited amount of information is available regarding vancomycin disposition in children older than 1 year of age with and without end-stage renal failure. The monitoring of serum vancomycin concentrations may be useful in selected neonatal and paediatric patient populations, especially where large interpatient variability occurs and administration guidelines are not clearly established. Similar to the literature on adults, the lack of conclusive evidence concerning the relationship between serum vancomycin concentrations and therapeutic responses leaves this topic open to debate.

Anti-Bacterial Agents↗