Work productivity among treatment-naïve patients with genotype 1 chronic hepatitis C infection receiving telaprevir combination treatment.

Work productivity is impacted in hepatitis C virus (HCV)-infected patients and has been linked to treatment. In two Phase 3 trials, ADVANCE and ILLUMINATE, treatment-naïve genotype 1 chronic HCV-infected patients received 12-week telaprevir (T) with 24 (T12PR24)- or 48 (T12PR48)-week peginterferon alfa-2a/ribavirin. The objective of this analysis was to examine the impact of chronic HCV infection and its treatment with combination therapy on work productivity. The 5-item, self-reported work productivity questionnaire (WPQ) was administered in Phase 3 trials to assess unemployment status, days unable to work due to HCV/treatment, reduced hours worked and impact on productivity in prior 4 weeks. Descriptive statistics and multivariate regression analyses were employed in analyses of pooled trial data. About 1147 patients were included; 22% (n = 255) were unemployed at baseline, with 8% being unemployed due to health reasons. At week 12, there were no differences by treatment regimen in the number of days unable to work. At week 48, improvements were observed earlier among patients receiving the shorter duration of T combination treatment. Mean (95% CI) change from baseline in days unable to work was -0.48 (-0.85, -0.11) days for T12PR24, 1.43 (0.63, 2.24) days for T12PR48 and 1.24 (0.18, 2.30) days for PR48 with placebo. Predictors of days unable to work were identified and include demographic characteristics, pretreatment and on-treatment levels of fatigue, as well regional variation. In post hoc analyses of the ADVANCE and ILLUMINATE trials, work productivity decreased during the initial 12 weeks regardless of treatment group.

Quinolone pharmacokinetics in the elderly.

As a class, quinolones undergo both renal excretion and hepatic metabolism. The dominant elimination pathway is usually renal, where secretion by the proximal tubule results in renal clearances 1.5-4 times greater than creatinine clearance. The benefit of this two-pathway elimination is protection from excessive accumulation in patients with single-organ dysfunction. A number of investigations have been performed to assess how the changes in renal and hepatic function that occur in the elderly influence quinolone pharmacokinetics. For example, lomefloxacin serum concentrations are slightly higher in elderly subjects, whereas total clearance, renal clearance, and nonrenal clearance are reduced, in comparison with younger subjects. The decline in renal clearance can be explained, in part, by the parallel decline in creatinine clearance in the elderly. Dosage adjustments should not be necessary in elderly patients with only minor changes in renal function caused by age-related changes in physiology. Although the relationship between nonrenal clearance of lomefloxacin and age is slightly less precise than the relationship between total clearance and age, this may be explained by the age-related decline in hepatic function and perhaps by changes in metabolic function. Quinolones show little evidence of altered absorption or altered pharmacodynamics in the elderly. These age-related alterations in drug elimination due to normal physiologic changes are generally not significant enough to warrant changes in dosage regimens; however, disease effects, particularly alterations of renal function, appear to be more important than gradual changes in physiology characteristic of the aging population.

Assessment of health-related quality of life in kidney transplant patients receiving tacrolimus (FK506)-based versus cyclosporine-based immunosuppression. FK506 Kidney Transplant Study Group.

BACKGROUND: We evaluated health-related quality of life (HQL) in kidney transplant patients participating in a multicenter, prospective, randomized, phase III trial comparing tacrolimus to cyclosporine. HQL data were available for 303 of 412 patients and assessed with the SF-36 Health Survey and six multi-item scales: Current Health, Health Outlook, Health Distress, Fleming Self-Esteem, Bergner Physical Appearance, and Sexual Functioning. METHODS: Patients completed surveys at baseline, week 6, and months 3, 6, and 12. The mean change in HQL was evaluated by rejection occurrence and number of hospitalizations. Analysis of covariance was used to model endpoint HQL scores as a function of treatment group and baseline HQL. RESULTS: All scales but two met psychometric standards for group-level comparisons. Baseline demographics and HQL scores were not different by treatment. The mean HQL change was lower for patients with rejection compared with no rejection in seven of eight SF-36 scales and three of four remaining supplemental scales. One year after transplantation, study patients were functioning at least as well as half of the general population in Vitality and Role-Emotional Functioning, moving from the 18th percentile of the U.S. population scores to the 50th percentile for Vitality and 54th percentile for Role-Emotional Functioning. Patients improved their percentile ranking by at least 20 points in five of eight SF-36 scales. CONCLUSIONS: Patients with kidney disease demonstrate substantial HQL burden before transplantation, and transplantation is associated with substantial HQL improvements. Rejection is associated with less HQL improvement. Endpoint HQL values were significantly different (P<0.05) by treatment, favoring tacrolimus, in the Bergner Physical Appearance scale, which was designed to measure the HQL impact of side effects such as gingival hyperplasia and facial hirsutism on physical appearance.

Assessment of the frequency and costs of posttransplantation hospitalizations in patients receiving tacrolimus versus cyclosporine.

We assessed the frequency and costs of hospitalizations in patients receiving tacrolimus (FK506) compared with patients receiving cyclosporine A for immunosuppression during 1 year after kidney transplantation. Four hundred twelve cadaveric kidney transplant recipients were randomized onto a phase III, prospective, multicenter, clinical trial. Hospital billing data were collected for 1 year posttransplantation. Total inpatient costs were calculated from billed charges and standardized to 1995 US dollars. Medical resource utilization rates and inpatient costs were compared between treatment groups using unpaired Student's t-tests. Complete billing data (transplantation and all posttransplantation hospitalizations) were available for 65% (268 of 412) of the study patients. Among tacrolimus and cyclosporine patients with complete billing data, the rates of allograft rejection were 32% and 47%, respectively (P=0.009), and the rates of rehospitalization during the year after transplantation were 53% and 63%, respectively (P=0.080). The mean per-episode rehospitalization costs were significantly lower among tacrolimus-treated patients compared with cyclosporine-treated patients ($7,495 v $11,497; P=0.031), and the mean total rehospitalization costs were significantly lower in the tacrolimus group compared with the cyclosporine group ($8,550 v $14,869; P=0.029). In addition, the total 1-year hospitalization costs (including transplantation and posttransplantation hospitalizations) were significantly lower in the tacrolimus group compared with the cyclosporine group ($53,435 v $61,191; P=0.046). Compared with cyclosporine-based immunosuppression, tacrolimus-based immunosuppression for kidney transplant recipients was associated with a significantly lower rate of rejection, which was associated with significantly lower per-episode rehospitalization costs, lower total 1-year rehospitalization costs, and lower total 1-year hospitalization costs.

Pharmacodynamics of bolus famotidine versus infused cimetidine, ranitidine, and famotidine.

A four-way crossover pilot study was conducted to compare the pharmacodynamic response of intermittent famotidine (20 mg every 12 hr) to continuous infusions of cimetidine (1200 mg/24 hr), ranitidine (150 mg/24 hr), and famotidine (40 mg/24 hr) in six normal male volunteers. Intragastric pH was monitored continuously for 24 hours. Comparisons included percent time during the 24-hour period that gastric pH was greater than pH 4.0, and pH 5.0, and also for the steady-state period of each regimen (12-24 hr). Although no statistically significant difference was observed for any of these comparisons, a clinically relevant trend was observed. In crossover experiments, famotidine intermittent infusions provided gastric pH readings above 4.0 and 5.0 for a longer duration than any of the continuous infusion regimens. Famotidine intermittent infusion regimens (20 mg every 12 hr) are at least equivalent to continuous infusions of cimetidine, ranitidine, and famotidine. Based on these findings, comparative studies in an appropriate critical care population would be beneficial, but any such studies must use a crossover design because of the even higher degree of intersubject variance in pH control. For this reason, the normal volunteer crossover model used here may provide important comparative information for the various regimens used in suppression of gastric acidity.

Cost-effectiveness of sparfloxacin compared with other oral antimicrobials in outpatient treatment of community-acquired pneumonia.

We examined the cost-effectiveness of sparfloxacin compared with other selected oral antimicrobials in outpatient treatment of community-acquired pneumonia (CAP) using clinical pathway-based decision analysis. Cost estimates were obtained from medical claims databases and Medicare reimbursement schedules. Probability estimates were derived from published clinical trials, the medical literature, and clinical expert opinion. Overall adjusted efficacy rates were 89% for sparfloxacin, 79.4% for azithromycin, 77.8% for clarithromycin, 73% for cefaclor, 70.8% for amoxicillin-clavulanic acid, and 69% for erythromycin. The expected total cost/CAP episode of treatment with sparfloxacin was $216.07 compared with $258.97, $297.08, $345.75, $389.80, and $395.93 for azithromycin, clarithromycin, erythromycin, amoxicillin-clavulanic acid, and cefaclor, respectively. Therapy with sparfloxacin for managing CAP is cost effective-relative to other commonly prescribed antibiotics, resulting in net cost savings.

Prospective evaluation of risk factors for antibiotic-associated bleeding in critically ill patients.

A prospective surveillance program was initiated to determine the relative role of antibiotics containing N-methylthiotetrazole (NMTT) versus patient risk factors in producing antibiotic-associated bleeding. Five hundred forty-six critically ill patients with serum albumin 30 g/L or below were evaluated for evidence of a bleeding event as documented by clinical observation, hemoglobin changes, and transfusions. Bleeding events occurred in 16% of patients receiving an aminoglycoside combination, 10% receiving antibiotics with the NMTT side chain, and 14.5% receiving antibiotics not containing NMTT (p greater than 0.05). The bleeding rate was highest in febrile patients with cancer (14.5%) and lowest in those with a suspected or documented abdominal infection (10%) (p = 0.04), but within each patient group there was no difference among the antibiotics. We conclude that the use of NMTT-containing antibiotics is not an independent risk factor for bleeding, but the role of severity of illness may be underappreciated.

Comparison of responses to SF-36 Health Survey questions with one-week and four-week recall periods.

OBJECTIVE: To compare the measurement properties of acute (one-week recall) and standard (four-week recall) versions of SF-36 Health Survey (SF-36) scale scores. DATA SOURCES: SF-36 data collected from 142 participants (60% female, average age 39) in a clinical trial of an asthma medication: 74 patients randomized to the acute form and 68 to the standard. DATA COLLECTION: The SF-36 was self-administered at the time of a clinic visit (before clinical examination) to synchronize with clinical measures of disease severity at three different time points during the clinical trial: -2 weeks (two weeks before randomization to treatment), baseline (week 0 or randomization), and +4 weeks (four weeks after baseline). PRINCIPAL FINDINGS: The acute form yielded high-quality data; scales conformed to the assumptions of the summated ratings method used to score the standard SF-36; and scales had good distributional properties, were reliable, and had a factor content similar to the standard. The data indicated that while the acute form was more sensitive than the standard to change in health status associated with changes in acute symptoms, acute scale scores may not be comparable to national norms based on the standard, particularly for those scales that assess frequency of health events during a specified time period. CONCLUSIONS: Results support the use of the acute form in its intended applications; however, further research is required to document the generalizability of greater sensitivity of the acute form to recent changes in health and to explore whether norms based on the standard can be used to interpret the acute scale scores.

Development and validation of the ITG Health-Related Quality-of-Life Short-Form measure for use in patients with coronary artery disease. Integrated Therapeutics Group.

BACKGROUND: Available coronary artery disease (CAD)-specific health-related quality-of-life (HRQL) measures are not ideally suited for routine clinical practice. We report development of a valid and reliable CAD-specific short-form measure. HYPOTHESIS: The Integrated Therapeutics Group (ITG) CAD-specific short-form HRQL measure is reliable and valid for assessing the health status of patients with CAD. METHODS: In all, 409 patients (mean age 62.4 years) completed the 24-item CAD-specific HRQL questionnaire. Factor analysis was used to identify the scaling of the 24 CAD-specific items. Analysis of variance was used to reduce the number of items within each scale, and reliability (Cronbach's alpha), discriminant validity, and ceiling and floor effects of short-form scales were evaluated. Short-form scales were compared with the longer scales using relative validity coefficients. The CAD severity was assessed using New York Heart Association criteria, physician assessment, electrocardiogram results, the number of myocardial infarctions, and the number of CAD-specific medications. Clinical validity of short-form scales was then assessed based on their ability to discriminate across severity levels of these clinical criteria. RESULTS: Four scales were identified: Extent of Chest Pain, Functioning and Well-Being, Activities Level-Physical, and Activities Level-Social. The 24-item questionnaire was reduced to a 13-item short form, with reliability exceeding 0.70 for all four scales. Relative validity estimates comparing short-form to original scales ranged from 0.68 to 2.58. Mean scores varied significantly (p < 0.05) by clinical severity, supporting the discriminant validity of the ITG CAD short-form scales. CONCLUSIONS: The ITG CAD short form (used alone or with a general HRQL measure) is valid and practical for assessing patients with CAD.

Pharmacokinetics and pharmacodynamics of acid-suppressive agents in patients with gastroesophageal reflux disease.

Key pharmacokinetic and pharmacodynamic aspects of gastric acid-suppressive agents in patients with gastroesophageal reflux disease (GERD) are discussed. The acid-suppressive potencies of the histamine H2-receptor antagonists vary widely because of differences in clearance and other factors. The durations of action of cimetidine, ranitidine, and famotidine are similar to the dosage intervals usually chosen (6, 8, and 12 hours, respectively). Single bedtime doses of these drugs will effectively treat duodenal ulcer disease, but GERD requires a different approach since its symptoms are not well controlled by partial (less than 24-hour) suppression of gastric acid. One way to achieve greater efficacy in treating GERD is to administer higher doses more frequently. Another approach is to adjust the dosage upward until symptoms disappear. The improved acid-suppression characteristic of the proton-pump inhibitors was quickly applied to GERD therapy. Unlike the H2 antagonists, omeprazole completely suppresses circadian peaks in acid secretion, and omeprazole performs better than ranitidine in clinical trials. The use of omeprazole is limited, however, by concerns over secondary elevation of serum gastrin and the association between achlorhydria and gastric carcinoma in rats. Omeprazole may offer cost advantages over other agents. Because the effective dosages of all these agents vary, individualized dosage-adjustment strategies are necessary. Pharmacists can help to optimize treatment by monitoring pharmacodynamic markers. With a flexible approach to drug and dosage selection, it should be possible to manage GERD in most patients in a cost-effective manner.

Theophylline toxicity secondary to ciprofloxacin administration.

We report the case of a 79-year-old woman who presented from a skilled nursing facility to the emergency department with signs and symptoms of theophylline toxicity and a serum theophylline concentration of 53.7 mg/L. The patient had been on a regular regimen of aminophylline for two months, with the addition of ciprofloxacin three days before arrival as the only identifiable potential cause of theophylline intoxication. She was monitored and treated conservatively with serial doses of activated charcoal, which resulted in a reduction of her serum theophylline level to a therapeutic concentration in 15 hours without adverse sequelae. The number of cases of theophylline intoxication secondary to concurrent ciprofloxacin administration is likely to increase, especially in nursing home populations, and it should be suspected when these patients present to the ED with the appropriate signs and symptoms. Management of theophylline intoxication should be based on clinical presentation as well as concentrations of the drug.

Mathematical examination of dual individualization principles. (III): Development of a scoring system for pneumonia staging and quantitation of response to antibiotics: results in cefmenoxime-treated patients.

OBJECTIVE: In order to quantitatively express the important, time-related aspects of response to antimicrobial therapy in patients with pneumonia, we required validated measures of the time course of events during the infection. To quantitate the changes in clinical status in relation to changes in cultures, we developed a scoring system to be used for patient assessment during therapy. DESIGN: Retrospective data collection, prospective analysis of factors. SETTING: Intensive care unit, Millard Fillmore Hospital. PATIENTS: Twenty-eight patients with nosocomial pneumonia. MAIN OUTCOME MEASURES: Clinical parameters were assessed daily for the duration of antimicrobial therapy. Using linear regression, the rate of clinical change in each patient treated was quantified. Eradication of the pathogen was determined by serial cultures of the infection site. RESULTS: Seventeen of the patients demonstrated eradication of the organism, and 11 demonstrated persistence of the pathogen (7 were considered colonization). The system described the patients at baseline in that the mean baseline scores were similar in both groups of patients (p = 0.79). Patients in whom the pathogen was eradicated showed a rate of clinical improvement significantly different from those who had persistence of the organism (p = 0.04). In patients demonstrating eradication, the time to eradication inversely correlated with the rate of clinical improvement (p < 0.05). Of the ten parameters descriptive of the disease, those most sensitive to change after eradication of bacteria were body temperature, bacterial Gram stain, white blood cell Gram stain, and volume of sputum. CONCLUSIONS: In this set of pneumonia patients, the scoring system effectively quantified both baseline and time-related changes in clinical status. The system distinguished between the clinical course of the patient with organism eradication versus organism persistence. A shorter time to eradication was associated with a better clinical response. Prospective study of the system will determine its sensitivity.

Evaluation of a short form for measuring health-related quality of life among pediatric asthma patients.

BACKGROUND: This study was undertaken to derive and validate a short form parent-completed questionnaire to measure health-related quality of life (HRQL) in pediatric asthma patients. OBJECTIVE: The objectives of this study were to (1) use stepwise analysis to derive a shorter questionnaire from the original long-form questionnaire and (2) determine the tradeoff in precision between the long- and short-form surveys. METHODS: One hundred eighty-one pediatric asthma patients were enrolled from 4 sites. A parent of each patient completed a general and an asthma-specific questionnaire during routine office visits from June 1995 to January 1997. The questionnaire included the Child Health Questionnaire Parent Form 50, a general HRQL survey, and a 17-item asthma-specific battery assessing daytime symptoms, nighttime symptoms, and functional limitations. All scales were scored from 0 to 100, with higher scores indicating better HRQL. Analysis of variance models were used to derive short-form scales from the 17-item long-form scales, and the final asthma-specific short-form scale structure was confirmed with use of stepwise regression. Scale reliability was assessed with Cronbach's alpha. Validity of the short-form questionnaire was assessed by comparing mean scale scores according to the level of asthma severity defined by several clinical criteria. Asthma severity was assessed with use of percent predicted FEV(1), frequency and type of symptoms, parent rating of disease severity, physician rating of disease severity, and resource use (emergency department use and hospitalizations). The relative validity of each of the short-form scales was measured by comparing the proportion of variance explained by each of the short-form scales compared with the respective long-form scales. RESULTS: The 17-item asthma-specific battery was reduced to 8 items, the Integrated Therapeutics Group Child Asthma Short Form. The daytime and nighttime symptom scales for each contain 2 items and the functional limitations scale 4 items. Reliability was greater than 0.70 for each of the short-form scales. The absence of ceiling and floor effects indicates each scale's ability to detect changes at both low and high levels of functioning. Lower (poorer) mean HRQL scores for severe cases compared with mild cases, for all disease severity indicators, demonstrated clinical validity. Relative validity estimates, comparing the proportion of explained variance of the short-form scales with that of the long-form scales, ranged from 0. 85 to 1.20, indicating a similar ability to measure change. CONCLUSIONS: This study documents the development of a brief, multidimensional, 8-item questionnaire for measuring HRQL in pediatric asthma patients. The brevity of the questionnaire makes it practical for use in practice settings and to monitor patients.

Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients.

Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1.h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days: and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.

Effects of ranitidine and sucralfate on ketoconazole bioavailability.

Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections. Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study compared the effects of concomitant sucralfate administration with ranitidine administration on the pharmacokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive 400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine, administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone or ketoconazole with sucralfate (P less than 0.01). Continuous gastric pH monitoring allowed correlation between the decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of sucralfate on ketoconazole bioavailability.

The responsiveness of disease-specific and generic health measures to changes in the severity of asthma among adults.

The objective of the study was to compare the validity of asthma-specific and generic health outcome measures in relation to changes in the severity of asthma and to treatment. Adult patients (n = 142) participating in a randomized placebo-controlled trial at six clinics were assessed at baseline, prior to the withdrawal (placebo) or continuation of treatment with Vanceril and again after 8 weeks. The criterion measures of change in severity included pulmonary function expressed as the percent predicted FEV1, five physician-assessed asthma severity measures (cough, chest tightness, wheezing, shortness of breath and overall condition) and two patient-assessed severity measures (night-time symptoms and overall symptoms). The 8 week change scores were estimated for all generic and specific measures and the results were compared across groups of patients who did and did not change in terms of clinical criteria of disease severity and across treatment groups. The responsiveness of each generic and specific measure was estimated independently using the relative validity (RV) methodology, which compares F-ratios for the mean change scores across measures in analyses of the same comparison groups. RV coefficients estimate how much worse each measure discriminated between comparison groups, relative to the best measure (RV = 1.0). Four standardized asthma-specific measures and a total scale score (based on the Marks questionnaire), an individualized asthma-specific scale measuring limitations in activities most important to each patient (based on the Juniper method) and two newly-developed scales measuring physical and psychosocial symptoms were used as outcome measures, generic health outcome measures included eight functional health and well-being scales as well as the physical and mental health summary scales from the SF-36 health survey. A standardized asthma-specific scale was most valid in discriminating between groups of patients who did and did not change according to all of the clinical criterion variables studied and in discriminating between treated and untreated groups. Different scales performed best, depending on the clinical criterion. The asthma-specific Marks breathlessness scale was significant in all nine comparisons (RV = 0.62-1.0) and was most valid in discriminating between groups in six of nine tests. The overall scale also performed well in all comparisons (RV = 0.58-1.0). The newly-developed physical symptoms scale was significant in discriminating between groups in eight out of nine tests (RV = 0.52-1.0) and was most valid in three of the nine, including the treatment comparison. The psychosocial impact scale discriminated significantly in eight of the nine comparisons (RV = 0.16-0.38), but was less valid than other specific measures. The asthma-specific individualized activities scale discriminated significantly in seven of the nine tests, but performed less well than the other specific measures (RV = 0.21-0.35) and was not significant in the treatment comparison. One or more SF-36 scales discriminated significantly between groups in all nine comparisons. Two of those scales (physical functioning and role-physical) were consistently more valid than the others (RV = 0.17 and 0.58, respectively) and were the only two generic scales that discriminated between groups of patients defined in terms of changes in FEV1 (RV = 0.26-0.58). The SF-36 physical summary scale discriminated significantly between groups in all nine comparisons (RV = 0.19-0.61) and was the most valid generic measure in the treatment comparison (RV = 0.55). The SF-36 mental summary scale was significant only for the two patient-assessed changes in disease severity (RV = 0.31 and 0.32) and for physician-assessed overall severity (RV = 0.12). A comprehensive battery of generic and specific measures is likely to be most useful in understanding the impact of changes in disease severity on the functional health and well-being of adults with asthma, a

Mathematical examination of dual individualization principles (II): The rate of bacterial eradication at the same area under the inhibitory curve is more rapid for ciprofloxacin than for cefmenoxime.

OBJECTIVE: To compare two antibiotics at equal ranges of area under the inhibitory curve (AUIC) exposure to determine if the rate of bacterial eradication differed between these antibiotics. DESIGN: Retrospective comparison of two previously collected studies of similar patients with nosocomial pneumonia. SETTING: Hospitalized patients, most intubated in critical care units with nosocomial pneumonia. PARTICIPANTS: Patients treated with either i.v. ciprofloxacin (n = 74) or the i.v. third-generation cephalosporin cefmenoxime (n = 43) were compared for their length of treatment required to eradicate bacterial pathogens from their respective infection sites, using serial cultures from the site of infection. All patients were also assessed for clinical outcomes. Serum samples were obtained to evaluate individual patient antibiotic pharmacokinetics, which were used to model pharmacodynamics of response. The HPLC assay used for each antibiotic had interday coefficients of variation < 10 percent. Serum concentration versus time profiles were fit using the computer program ADAPT II to determine pharmacokinetic parameters for each patient. The primary drug exposure measure that related to response was the AUIC, calculated as steady-state AUC0-24/minimum inhibitory concentration. RESULTS: AUIC values in the patients ranged from 6.0 to more than 7000, yet the AUIC value was highly predictive of time to bacterial eradication (p < 0.001). Although more than 75 percent of patients eventually achieved eradication of pathogens from tracheal aspirate cultures, ciprofloxacin and cefmenoxime differed significantly in the time required to sterilize these cultures. At appropriate AUIC values (> 250) for ciprofloxacin, the median time to eradication was two days, while cefmenoxime (also at AUIC values > 250) required six days to achieve the same result. CONCLUSIONS: We conclude that the more rapid in vitro bacterial killing, which is characteristic of ciprofloxacin at optimal AUIC values, can manifest in vivo as more rapid clearance of bacteria from the respiratory tract of patients, even when both agents are controlled for initial antibacterial exposure (i.e., same AUIC).