Patient characteristics and refusal to participate in a head and neck cancer intervention trial: experience of two tertiary UK head and neck cancer centres.

INTRODUCTION: Randomised clinical trials are an essential component for robust clinical evaluation. They are expensive to deliver but can fail to achieve the required outcomes. This paper reports details of trial recruitment in a head and neck Patient Concerns Inventory intervention trial from two UK head and neck tertiary centres. MATERIALS AND METHODS: Data were collected for a pragmatic cluster preference randomised control trial with 15 consultants recruiting patients treated with curative intent after a diagnosis of head and neck cancer (all sites, disease stages, treatments). Ethical approval was given to report on those not recruited by the following characteristics: trial site, trial arm, age, sex, tumour site, overall stage, index of multiple deprivation quintile, timeframe. RESULTS: There were 368 patients approached who remained eligible and 80 (22%) declined to participate. Logistic regression suggested that age group (p = 0.008) and index of multiple deprivation quintile group (p = 0.003) were independent predictors of refusal. CONCLUSIONS: Although recruitment to the trial was very good, it raised the issue of lower recruitment in the more deprived older group and lower social economic strata. Innovative ways need to be explored to facilitate the 'hard to reach' group contributing to, and benefiting from, clinical trials.

Antibiotic dosing issues in lower respiratory tract infection: population-derived area under inhibitory curve is predictive of efficacy.

Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC; AUIC). The AUIC values in these studies were based on measured MICs and measured serum concentrations. This study evaluates AUIC estimates made using population pharmacokinetic parameters, and MICs from an automated microbiological susceptibility testing system. A computer database review over 2 years yielded 81 patients at Millard Fillmore Hospital with a culture-documented gram-negative LRTI who had been treated with piperacillin and an aminoglycoside, ceftazidime, ciprofloxacin or imipenem. Their AUIC values were estimated using renal function, drug dosages and MIC values. Outcome groups (clinical and microbiological cures and failures) were related to the AUIC values using Kruskal-Wallis ANOVA, linear regression and classification and regression tree (CART) analysis. A significant breakpoint for clinical cures was an AUIC value at least 72 SIT(-1) x 24 h (inverse serum inhibitory titre integrated over time). All antibiotics performed significantly better above this value than below it. Clinical cure was well described by a Hill-type equation. Within the piperacillin/aminoglycoside regimen, most of the activity came from the piperacillin, which had a higher overall AUIC value than the aminoglycoside. AUIC estimations based upon MIC values derived from the automated susceptibility testing method differed from NCCLS breakpoint data and from tube dilution derived values in this hospital by as much as three tube dilutions. These automated methods probably overestimated the MIC values of extremely susceptible organisms. The lack of precise MIC estimates in automated clinical microbiology methods impairs the use of AUIC to prospectively optimize microbiological outcome. Even ignoring this limitation and using the values as they are reported, the results of this analysis suggest that AUIC targets between 72 and 275 SIT(-1) x 24 h are useful in predicting clinical outcome.

Pharmacokinetics of Oral Azithromycin in Serum, Urine, Polymorphonuclear Leucocytes and Inflammatory vs Non-Inflammatory Skin Blisters in Healthy Volunteers.

Two open-label studies were conducted to assess the serum, urine, polymorphonuclear (PMN) and red blood cell (RBC) pharmacokinetics of a 5-day course (1500mg total) of oral azithromycin. Inflammatory and non-inflammatory blisters were also induced to study the propensity of azithromycin to preferentially concentrate at a model infection site. 14 subjects participated in the two studies and tolerated azithromycin and the study methods well. Comodelling of the serum and urine data demonstrated very extensive distribution into peripheral compartments, low renal clearance (7% of total oral clearance) and an extended terminal half-life (79 hours). PMN leucocyte concentrations peaked at 119 mg/L following the final dose and remained above 60 mg/L 7 days after the final dose. The ratio of blister to serum AUCs was significantly higher in inflammatory (2.2) vs non-inflammatory (1.2) blisters (p < 0.02). The extensive uptake of azithromycin into PMNs coupled with the accumulation of azithromycin into an inflammatory compartment (e.g. infection site) support the hypothesis that PMN leucocytes laden with azithromycin migrate to sites of inflammation, thereby enhancing local concentrations. These studies further demonstrate the unique pharmacokinetic properties of azithromycin and its preferential delivery by phagocytes to the site of infection.