Mark A. Gill

Population pharmacokinetics and use of Monte Carlo simulation to evaluate currently recommended dosing regimens of ciprofloxacin in adult patients with cystic fibrosis.

ABSTRACT Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC0–24)/MIC ratio of ≥125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one- and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC0–24/MIC ratio of ≥125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at α phase, 0.16 h; and half-life at β phase, 2.9 h. The overall fractional attainment of achieving an AUC0–24/MIC ratio of ≥125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 μg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC0–24/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC0–24/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.

Pharmacokinetics of meropenem in patients with intra-abdominal infections.

Noncompartmental and compartmental analyses of meropenem disposition in patients receiving 1-g intravenous intermittent infusions every 8 h were performed. Twelve patients (one woman and 11 men) participated in the meropenem pharmacokinetic analysis. Operative findings included perforated appendicitis (five patients), gangrenous appendicitis (five patients), peri-appendical abscess (one patient), and gunshot wound to the abdomen (one patient). The most common associated adverse drug reactions to meropenem were diarrhea and increased liver enzymes. The estimated noncompartmental pharmacokinetic parameters, mean +/- standard deviation, are as follows: maximum drug concentration in plasma, 47.58 +/- 17.59 micrograms/ml; half-life, 1.04 +/- 0.19 h; elimination rate constant, 0.68 +/- 0.12 h-1; area under the concentration-time curve from 0 h to infinity, 57.5 +/- 20.12 micrograms x ml/h; total plasma clearance, 315.40 +/- 71.94 ml/min; renal clearance, 136.7 +/- 89.20 ml/min; volume of distribution at steady state, 26.68 +/- 6.88 liters; and mean residence time, 1.47 +/- 0.28 h. The two-compartment model best described meropenem disposition in our patients. Our findings differed from estimates for healthy volunteers possibly because of the physiologic changes as a result of surgery. Our findings suggest that meropenem (1,000 mg) administered intravenously every 8 h provides adequate concentrations for most intra-abdominal infections.

Determination of fluconazole in human serum by solid-phase extraction and reversed-phase high-performance liquid chromatography.

A simple, rapid, and accurate reversed-phase octadecylsilyl high-performance liquid chromatographic method using solid-phase column extraction is described for measuring fluconazole in human serum. The column eluent was monitored by ultraviolet absorption at 210 nm. Fluconazole was extracted from diluted serum by adsorption on a small Bond-Elut C18 cartridge after the addition of UK48,134 as the internal standard and recovered by elution with methanol. The methanol was then evaporated to dryness and the residue reconstituted in 200 microliters of mobile phase and filtered prior to injecting an aliquot (50 microliters) onto an Adsorbosphere C18 column (4.6 x 250 mm, 5 microns particle size), using a mobile phase of 25 mM tris(hydroxymethyl)aminomethane-phosphate buffer (pH 7.0):acetonitrile (75:25, vol/vol). The retention times were 6.6 min for fluconazole and 9.0 min for the internal standard. The assay was precise, with inter- and intraassay coefficients of variation of less than or equal to 2.9% and less than or equal to 2.1%, respectively, and with good linearity (r = 1.000) in the range of 0.1 to 25 micrograms/ml. The duration of each analysis was 15 min and the minimum detectable serum concentration was 0.1 microgram/ml.

Utility of a transdermal delivery system for antihypertensive therapy. Part 1

A retrospective evaluation of patient-level Medicaid claims data from two states was undertaken to discern the fiscal utility of transdermally delivered clonidine versus both the oral formulation of clonidine and oral formulations of eight other antihypertensive agents. In the first phase of our two-part study, we compared paid claims data (n = 1,135) from Florida for transdermal and oral clonidine. Multivariate regression analysis was used to evaluate the incremental impact of six variables on health-care expenditures in the first year after patients were given a diagnosis of hypertension. These variables were: age, gender, prior utilization of medical services, regimen complexity, and dosage formulation. Patients prescribed transdermal clonidine experienced a significant (p less than or equal to 0.001) increase in prescription expenditures and significant reductions in the use of physician (p less than or equal to 0.05), laboratory (p less than or equal to 0.10), and hospital (p less than or equal to 0.05) services. Moreover, savings were maximized (p less than or equal to 0.001) where multi-drug regimens incorporated the transdermal delivery system. In the second phase of our study we compared paid claims data (n = 8,894) from South Carolina for transdermal clonidine and for nine oral antihypertensive agents: atenolol, captopril, clonidine, diltiazem, enalapril, metoprolol, prazosin, terazosin, and verapamil-SR. Once again, regression analysis was used, this time to evaluate the incremental impact of five variables on health-care expenditures in the first year post diagnosis: age, gender, prior utilization of medical services, regimen complexity, and Medication Possession Ratio (MPR), an index of compliance. The data from part 2 of our study revealed that patients assigned a b.i.d. oral antihypertensive agent experienced a significant reduction (p less than or equal to 0.05) in MPR and a significant (p less than 0.05) increase in health-care expenditures when compared to patients prescribed the transdermal delivery system and to patients prescribed once-daily oral medications. These data confirm previous findings concerning the impact of complicated dosing regimens on compliance in hypertensive patients. In this two-part paper we report the data from both phases of our study.

Absolute Bioavailability and Pharmacokinetics of Linezolid in Hospitalized Patients Given Enteral Feedings

ABSTRACT Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens which are common causes of infections in hospitalized patients. Many such patients rely on the intravenous or enteral route for nutrition and drug administration. Therefore, the bioavailability of linezolid administered enterally in the presence of enteral feedings in hospitalized patients was examined. Eighteen subjects were assessed in a randomized single-dose crossover study; 12 received continuous enteral feedings, while 6 did not (controls). Both groups received linezolid 600 mg intravenously and orally (control) or enterally, with the alternate route of administration separated by a 24-h washout period. Pharmacokinetic parameters derived from noncompartmental and compartmental analysis incorporating linear and nonlinear elimination pathways were compared between groups: F, Ka, Vs, K23, K32, Vmax, Km, and K20 (bioavailability, absorption rate constant, volume of central compartment normalized to body weight, intercompartmental rate constants, maximum velocity, Michaelis-Menten constant, and elimination rate constant, respectively). Pharmacokinetic (PK) data were available from 17 patients. The linezolid oral suspension was rapidly and completely absorbed by either the oral or enteral route of administration. Bioavailability was unaltered in the presence of enteral feedings. PK estimates remain similar regardless of the model applied. At the therapeutic dose used, only slight nonlinearity in elimination was observed. A linezolid oral suspension may be administered via the enteral route to hospitalized patients without compromise in its excellent bioavailability and rapid rate of absorption. Compartmental pharmacokinetic analysis offers a more flexible study application, since bioavailability (F) can be estimated directly with intermixed intravenous/oral doses without a need for a washout period.

Potential role of macrolide antibiotics in the management of cystic fibrosis lung disease.

Current management of cystic fibrosis (CF) lung disease includes the use of antibiotics, nutritional support, and airway clearance therapies. However, despite recent advances in pharmacologic therapies including DNase and aerosolized tobramycin, deterioration in lung function persists. Recent investigations have shed new light on the pathogenic mechanisms by which Pseudomonas aeruginosa establishes itself within the airways of patients with CF and contributes to the progressive decline in lung function. In particular, the presence of biofilms and other virulence mechanisms allow evasion of local host defenses and establishment of a chronic localized inflammatory response resulting in lung damage. Macrolide antibiotics appear to have a promising role in the management of CF lung disease even though they do not exhibit intrinsic antipseudomonal activity. Recent evidence demonstrates that they can disrupt quorum sensing, a cell-to-cell signaling process linked to the formation of biofilms. In addition, they inhibit NF-&kgr;b and AP-1, nuclear factors that control the expression of proinflammatory cytokines. Their ability to decrease sputum viscosity and increase sputum clearance may complement existing airway clearance therapies. Preliminary clinical trials have shown modest improvement in pulmonary function.

Absolute Bioavailability and Intracellular Pharmacokinetics of Azithromycin in Patients with Cystic Fibrosis

ABSTRACT Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg; P < 0.01) and body mass index (19.7 versus 23.2; P < 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h; P = 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%; P = 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h−1; P = 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h−1; P < 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 ± 6.0 mg/liter) far exceeded the maximum serum drug concentration (∼50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.

Stability and Antibacterial Activity of Cefepime during Continuous Infusion

ABSTRACT The stability of cefepime during simulated continuous infusion was determined with a motorized portable infusion pump worn over a period of 24 to 36 h. Susceptibility testing on cefepime solutions over time indicates that the degradation products do not exhibit antibacterial activity. Cefepime stability at 24 h following continuous infusion was 94.3% ± 1.0%, which supports the use of continuous infusion.

A wide interindividual variability of urinary 6β-hydroxycortisol to free cortisol in 487 healthy Japanese subjects in near basal condition

The frequency distribution of CYP3A activity was investigated by measuring ratios of urinary 6&bgr;-hydroxycortisol to free cortisol in 487 healthy subjects to determine whether a genetic polymorphism for this cytochrome enzyme exists in “native-born” Japanese persons. Spot urine samples (from 9:00 am to 12:00 pm) were collected for measurement of 6&bgr;-hydroxycortisol and free cortisol by high-performance liquid chromatography with a CN column after extracting with a solid-phase column (Bond-Elut C18). The frequency distribution of the urinary 6&bgr;-hydroxycortisol to free cortisol was widely distributed among subjects but with no clear bimodality by a probit plot. Furthermore, the frequency distribution assessed on a new normal test variable plot indicated the possible existence of a CYP3A sexual dimorphism. Mean 6&bgr;-hydroxycortisol levels were higher in women (n = 249) than in men (n = 238) by 1.7-fold, and this difference was statistically significant (P < 0.01). These results show that a CYP3A genetic polymorphism in Japanese persons, based on 6&bgr;-hydroxycortisol excretions, likely does not exist, but there appears to be a broad unimodal distribution of enzyme activity in the population.

Surgically treated gangrenous or perforated appendicitis. A comparison of aztreonam and clindamycin versus gentamicin and clindamycin.

A randomized, double-blinded, controlled clinical study of 84 patients with surgically treated gangrenous or perforated appendicitis was done to compare the efficacy of the combination of aztreonam, the first monobactam antibiotic, with gentamicin when either was combined with clindamycin. Fifty-six patients who were treated with aztreonam and clindamycin (A/C) and 28 patients who were treated with gentamicin and clindamycin (G/C) fulfilled criteria for evaluation. A matched historic control group of 56 G/C patients was also included for comparison. All measures of outcome, including days of fever, hospitalization, antibiotic therapy, and the incidence of antibiotic failures, were similar. It was concluded that aztreonam was as effective as gentamicin in this study and may offer some advantages with regard to toxicity and serum drug level monitoring.