Therapeutic misconception in clinical trials: fighting against it and living with it. / El equívoco terapéutico en los ensayos clínicos: combatirlo y convivir con él.

A clinical trial seeks information for the benefit of future patients and not necessarily for those who participate in the study. However, there are patients who believe that they will receive a direct therapeutic benefit by participating in a clinical trial, the so-called «therapeutic misconception¼. In this article, we describe the nature and extent of therapeutic misconception, which researchers can also experience. Its presence is especially important in phase 1 oncology trials and those with placebo group. To limit its occurrence, investigators have to ensure that participant information sheet are well written and to establish an effective and transparent discussion during the process of obtaining informed consent so that patients understand all aspects of their participation in the research and appreciate what this participation entails.

Factors impacting on length of stay and mortality of community-acquired pneumonia.

A 1-year retrospective multicentre study was performed to identify factors influencing hospital length of stay (LOS) and mortality of patients (n = 3233) admitted to hospital because of community-acquired pneumonia (CAP). Pneumonia severity index (PSI) high-risk classes (IV and V), positive blood culture, admission to an intensive care unit (ICU), multi-lobar involvement and alcohol consumption were associated independently with prolonged LOS. Tobacco smoking was associated with a reduced LOS. The LOS varied markedly among centres. Only PSI high-risk class, admission to ICU and multi-lobar involvement were associated with early, late and global mortality. Positive blood cultures, antimicrobial therapy according to treatment guidelines and the establishment of an aetiological diagnosis were linked to reduced late and global mortality. These data suggest that early mortality associated with CAP is highly dependent on the clinical status of the patient at presentation. Conversely, late mortality seems to be associated more closely with clinical management factors; hence, an aetiological diagnosis and compliance with appropriate therapeutic guidelines have a significant influence on outcome.

Quinolone resistance in female outpatient urinary tract isolates of Escherichia coli: age-related differences.

During a 1-year period, from November 2003 to October 2004, urinary Escherichia coli isolates were collected from 20 clinical microbiology laboratories across Spain. The main objective was to assess the resistance of E. coli to the antimicrobials most commonly prescribed for community-acquired urinary tract infections depending on the patient's age. A total of 2,230 valid E. coli strains from female outpatients were isolated and sent to a single central reference laboratory for confirmation and susceptibility testing using an agar dilution method. A two-sided chi-squared test was used to assess the differences in resistance between age groups (< or =65 and >65 years). E. coli resistance was found to be more common to ampicillin (52.1%), cotrimoxazole (26%) and quinolones (18%), whereas resistance to amoxicillin-clavulanic acid, cefuroxime axetil and fosfomycin were below 3%. In women older than 65 years, resistance to ciprofloxacin reached up to 29% compared with 13% of those in the under 65 age group (p <0.001). For cotrimozaxole, rates were 32% vs. 23% (p <0.001) and for ampicillin 56% vs. 50% (p=0.02), respectively. It was concluded that fosfomycin, amoxicillin-clavulanic acid and cefuroxime axetil are the most suitable antimicrobials for empirical treatment in Spain given the high 18% and 26% resistance rates to quinolones and cotrimoxazole, respectively. Being older than 65 years of age was associated with higher resistance rates to ciprofloxacin (29%). These results should be considered when recommending empirical therapy for acute cystitis in women.

Antimicrobial susceptibility of clinical Escherichia coli isolates from uncomplicated cystitis in women over a 1-year period in Spain.

High usage of antibiotics in Spain has led to an increase in resistance in urinary Escherichia coli isolates in different geographic regions. The problem of resistance in urinary E. coli in Spain was investigated by gathering a large number of isolates from 20 different sites nationwide over a 1-year period from November 2003 to October 2004 in a large population of women. The objectives of this study were to assess the resistance to the antibiotics most commonly prescribed for community-acquired urinary tract infections (UTIs), according to age and different geographical areas of Spain, and to evaluate the potential association between geographical differences in quinolone consumption and resistance to E. coli. A total of 2,292 valid E. coli strains from female outpatients were isolated and sent to a single central reference laboratory for confirmation and susceptibility testing. Of these, 2,230 isolates were available for the age analysis. A two-sided chi2 test was used to identify differences in resistance between age groups. Antibiotic units per province were purchased from IMS and consumption was expressed in units per 1,000 people per year. Univariate correlation (Pearson coefficient) between resistance to ciprofloxacin and quinolone consumption was calculated using a two-sided p-value. Resistance shown by E. coli was more common to ampicillin (52.1%) and cotrimoxazole (26%), followed by quinolones (18%), whereas resistance to amoxicillin-clavulanic acid, cefuroxime-axetil and fosfomycin was less than 3%. In the subgroup of women aged >65 years, resistance to ciprofloxacin was 29% compared to 13% for the subgroup of women <65 years (p<0.001). For these same subgroups, resistance rates were 32% vs. 23% for cotrimoxazole (p<0.001) and 56% vs. 50% for ampicillin (p=0.02), respectively. Statistically significant correlations were found between consumption of quinolones and E. coli resistance to ciprofloxacin (r=0.5; p=0.025). Resistance of E. coli isolates to quinolones varied significantly according to geographical areas, ranging from a high of 16.5% and 16.6% in the southern and eastern regions of Spain, respectively, to a low of 8% in the north in women aged <65 years. Additionally, the susceptibility to quinolones of E. coli isolates recovered from women aged >65 years was significantly lower across all regions of Spain than that of isolates recovered from younger women. Fosfomycin, amoxicillin/clavulanic acid and cefuroxime-axetil are the most suitable antibiotics for empirical treatment in Spain given the high 18% and 26% resistance rates to quinolones and cotrimoxazole, respectively. Higher resistance rates to ciprofloxacin were associated with being aged 65 years and over. These data need to be considered when recommending empirical therapy for acute cystitis.

Effect of mode of administration on I-PSS scores in a large BPH patient population.

OBJECTIVES: The International Prostate Symptoms Score (I-PSS) was designed to be self-administered to patients with benign prostatic hyperplasia. This study tested for a possible mode of administration effect on the I-PSS and assessed the reliability of the I-PSS over time when modes of administration varied. METHODS: Benign prostatic hyperplasia patients over 50 years of age were recruited at 52 Spanish centres. The I-PSS was administered on two occasions 1 month apart. Patients were sequentially classified into groups A-D according to the mode of administration (S = self-administered, I = interview administered) at the two visits (A = S-S, B = S-I, C = I-S, and D = I-I). The intraclass correlation coefficient was used to assess test-retest reliability, and multiple regression analysis was used to test the effects of the mode of administration and the visit number on I-PSS scores. RESULTS: 926 patients (mean age 66 years) were evaluated. The mean I-PSSs symptoms score at visit 1 in groups A-D were, respectively, 13.19, 13.57, 12.06, and 12.29. Multiple regression analysis between-group scores were 0.93 points higher when the I-PSS was self-administered and 1.98 points lower at the second visit. The intraclass correlation coefficients were: group A = 0.77, group B = 0.70, group C = 0.67, and group D = 0.76. CONCLUSIONS: Interview administration of the I-PSS results in slightly lower scores. The reliability is higher when the same mode of administration is used at two recurrent visits.

Herpes simplex virus type 2 seroepidemiology in Spain: prevalence and seroconversion rate among sexually transmitted disease clinic attendees.

BACKGROUND: Only limited data on the seroprevalence of herpes simplex virus type 2 (HSV-2) are available from European countries. Until recently, serologic tests for HSV-2 serotyping have been hampered by cross-reactivity to type-common antigens. The present study aims at providing data on the prevalence of HSV-2 infection in a group of STD clinic attendees using a reliable type-specific immunoassay. GOAL: To evaluate the seroprevalence of HSV-2 and the accumulated incidence of clinical genital herpes infection in a sample of Spanish sexually transmitted disease (STD) clinic attendees. STUDY DESIGN: The study consisted of two parts. First, a cross-sectional study of HSV-2 seroprevalence was conducted in patients with STDs. Second, a prospective cohort study was undertaken to evaluate the accumulated incidence of infection by HSV-2 and of clinical episodes of genital herpes in HSV-2-negative patients included in the first study during a follow-up period of 6 to 18 months. RESULTS: Of the 374 patients (129 men, 245 women) studied, 25% were seropositive for HSV-2 (12% of men, 30% of women). Antibodies to HSV-2 were related to female gender (odds ratio, 2.7; P < 0.001) and to the number of sexual partners (odds ratio, 4.1; P < 0.001). Fifty-two percent of patients (145 of 281 patients) who were initially seronegative returned to the clinic for a second serologic testing, of whom 1% (2 of 145 patients) had seroconverted. None of the patients developed genital herpes during the follow-up period. CONCLUSION: The relatively high seroprevalence (25%) and the low rate (4%) of HSV-2 previously reported in the general population in Spain suggest that the virus circulation may be restricted to certain risk groups. Therefore, future healthcare measures may target specific groups, such as patients with STDs.

Influence of sociodemographic and health status variables on the American Urological Association symptom scores in patients with lower urinary tract symptoms.

OBJECTIVES: To evaluate the relationship between sociodemographic and health status variables and the American Urological Association Symptom Score (AUA-7) because low associations between clinical measures of lower urinary tract symptoms and scores on the AUA-7 suggest that symptoms may be influenced by other variables. METHODS: Sociodemographic, clinical, and health status variables were recorded for 666 patients with benign prostatic hyperplasia (BPH). BPH symptoms were measured with the AUA-7. Bivariate and multivariate analyses were used to determine correlations between sociodemographic and health status variables and AUA-7 scores. RESULTS: BPH-related variables (clinical rating of severity, number of BPH treatments, and being scheduled for surgery) were included in the final regression model, which explained 25% of the overall variability in scores. An additional 7% of the total variability was explained by other non-BPH-related variables (educational level, presence of depression/anxiety, and pain/discomfort). CONCLUSIONS: The AUA-7 is a robust questionnaire that is little influenced by sociodemographic variables and general health status. The educational level, mood, and presence of pain/discomfort of patients should be taken into account when interpreting scores, as a combination of these characteristics could mean a difference of up to 6 points on the AUA-7.

Whole cell lysate enzyme immunoassays vs. recombinant glycoprotein G2-based immunoassays for HSV-2 seroprevalence studies.

Seroepidemiology studies of herpes simplex virus type 2 (HSV-2) infections have been difficult to carry out because antibodies to HSV type 1 (HSV-1) show an extensive cross-reactivity with HSV-2 antigens. Many kits available currently are not entirely type specific for serodiagnosis of HSV-2 infections and therefore do not allow reliable discrimination of past exposure to these closely related alphaherpes viruses. Attempts to develop type-specific antigens have focused on the envelope glycoproteins, particularly glycoprotein G (gG). A cross-sectional study was carried out to examine the seroprevalence of antibodies to HSV-2 among healthy university students, using different methods: a whole cell lysate enzyme-linked immunosorbent assay (ELISA), two different ELISAs, and a newly developed immunoblot assay, the last three based on recombinant gG2. HSV-2 prevalence was 24 times higher with the whole cell lysate ELISA (31%; 95% confidence interval [CI]: 27-35%) than the ELISAs and the immunoblot assay based on recombinant gG2 (1.3%; 95% CI: 0.1-2.5%), thus showing the inaccuracy of commercial tests based on whole-antigen preparations for epidemiological studies. Laboratories should be cautious and ensure that commercial tests for HSV typing are based on type-specific glycoproteins.

Validation of a harmonized Spanish version of the IPSS: evidence of equivalence with the original American scale. International Prostate Symptom Score.

OBJECTIVES: To validate the use in Spain of a linguistically harmonized Spanish version of the International Prostate Symptom Score (IPSS Sp), and to compare it with the original American scale (IPSS Am). METHODS: Validity and reliability were studied in 59 patients with benign prostatic hyperplasia (BPH) (age >50 years) and 68 control subjects without BPH (age 18 to 49 years). Construct validity was assessed by correlating IPSS Sp scores with the EuroQol-5D (EQ-5D), the Psychological General Well-Being Index (PGWBI), and item 8 (quality of life) of the IPSS. Discriminatory power was assessed by calculating the area under the receiver operating characteristic (ROC) curve. Reliability was evaluated using the test-retest method, and internal consistency was assessed using Cronbach's alpha. Sensitivity to change was expressed as the effect size in preintervention versus postintervention scores in 26 additional patients with BPH (age >50 years) who underwent transurethral resection of the prostate. RESULTS: Correlations of the IPSS Sp were -0.07 to 0.36 with EQ dimensions; -0.29 with the EQ visual analogue scale score; 0.14 to 0.41 with PGWBI dimensions; and 0.72 with item 8 of the IPSS. ROC area was 0.95 +/- 0.02 (standard error). Using a cutoff point of 7, sensitivity was 83% and specificity was 98%. Test-retest reliability was 0.92 and Cronbach's alpha was 0.79. Mean preoperative and postoperative IPSS Sp scores were 25.56 and 8.48, respectively (P < 0.001 ). Overall effect size was 2.52. These results are similar to those of the original American scale. CONCLUSIONS: This Spanish translation of the IPSS is valid, reliable, and sensitive to clinical change and has demonstrated equivalent psychometric properties to the original American instrument. Scores obtained with the two instruments can therefore be reliably compared and aggregated when statistically appropriate.

Ten-language translation and harmonization of the International Prostate Symptom Score: developing a methodology for multinational clinical trials.

OBJECTIVE: Production of cross-culturally adapted and harmonized translations of the International Prostate Symptom Score (I-PSS) into 10 languages (Canadian French, Danish, Dutch, Flemish, French, German, Italian, Norwegian, Spanish, Swedish) by means of an appropriate methodology. METHODS: A method based on state-of-the-art guidelines about translation of questionnaires was developed which consisted of forward-translation, rating of clarity, common language and cultural adequacy, group discussion and consensus, testing for comprehension in lay subjects, back-translation and rating for conceptual equivalence. RESULTS: The study lasted 3 months. Items 1-7 scored high for clarity, common language and cultural adequacy (mean range 5.3-9.8) as also did item 8 (5.1-9.7). Only 10% of items were rated less than 5.0. Comprehension tests in lay subjects produced comments in 10% of items, most frequently in items 2, 7, and 8, and response categories for items 1-6. Comparisons between the back-translations and the source version showed that 84% of all items, 88% of response categories for items 1-6, 100% of response categories for item 7, and 75% of response categories from item 8 were conceptually equivalent. CONCLUSION: The present set of 10 translations plus the original I-PSS questionnaire can be used in multi-country studies in which benign prostatic hyperplasia symptoms are to be assessed using the I-PSS and the data collected from different countries can be legitimately aggregated.

Single-dose rufloxacin versus 3-day norfloxacin treatment of uncomplicated cystitis: clinical evaluation and pharmacodynamic considerations.

The efficacy and safety of rufloxacin (400 mg, single dose) were compared to those of norfloxacin (400 mg twice a day for 3 days) for the treatment of women with uncomplicated cystitis. In addition, urine levels, drug level/MIC ratio, and urine antibacterial activity 72 to 84 h after treatment initiation were determined in a subgroup of patients for pharmacodynamic assessment. A total of 203 women were included and treated in this open, randomized clinical trial; 100 patients received norfloxacin, whereas 103 received rufloxacin. Of these, 156 (74 and 82 patients in the norfloxacin and rufloxacin groups, respectively) were considered bacteriologically evaluable. At the first follow-up visits (3 to 12 days after starting the treatment), bacteriological cure rates were 99 and 94% for norfloxacin and rufloxacin, respectively. Seventy-nine percent (119 of 150) of bacteriologically cured patients attended a long-term follow-up visit (4 to 6 weeks after starting the treatment), where a relapse rate of 4% (2 of 54) and 5% (3 of 64) were found in the norfloxacin and rufloxacin groups, respectively. The pharmacodynamic evaluation performed in 35 patients showed similar median urine levels (approximately equal to 25 micrograms/ml) and urine antibacterial activity for both treatment groups against initial isolates, despite a higher norfloxacin level/MIC ratio due to the lower MIC of norfloxacin. Twenty-one patients (20%) in the rufloxacin group and 12 patients (12%) in the norfloxacin group reported 39 and 16 adverse events, respectively, almost all of them being mild and lasting < 24 h. Overall, gastrointestinal reactions were the most frequent adverse events reported. However, 12 patients treated with rufloxacin reported 15 central nervous system adverse events. This study shows that single doses of rufloxacin are as effective as a norfloxacin 3-day standard treatment in uncomplicated cystitis. The results obtained with rufloxacin are consistent with its pharmacodynamic properties.

Ex vivo antibacterial properties of rufloxacin compared with those of norfloxacin in a study with healthy volunteers.

Twelve adult males participated in a randomized crossover phase I clinical trial comparing serum bactericidal titers (SBTs), urine bactericidal titers (UBTs), and urine killing rates (UKRs) against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213, after the administration of single 400-mg doses of rufloxacin and norfloxacin at different times up to 72 h postdose. SBTs were significantly higher (P < 0.05) against E. coli from 8 to 48 h and against S. aureus from 4 to 24 h with rufloxacin. UBTs for E. coli were higher (P < 0.05) for norfloxacin at early sample times (0 to 8 h) but higher for rufloxacin (P < 0.05) at sample times from 16 h on for both E. coli and S. aureus. Similar UKRs were obtained for both quinolones for 0 to 2 h and 8 to 12 h, but the UKR was maintained for 72 h with rufloxacin. The high and sustained mean levels of rufloxacin in urine (> 35 micrograms/ml), median UBTs (> 32 for E. coli and 16 for S. aureus) and UKRs for E. coli suggest prolonged urine antibacterial activity (for at least 72 h) and its use as a single 400-mg dose in the treatment of uncomplicated cystitis.

Randomised controlled trial of efficacy of albendazole in intra-abdominal hydatid disease.

The efficacy of albendazole in hydatid disease is still unclear, because there has been no study that assessed the status of the parasite after treatment. The significance of albendazole-induced echographic changes in the cyst therefore cannot be judged. We did a prospective, controlled, randomised, open study of albendazole in patients with liver hydatid disease, and assessed parasite viability after treatment. 18 patients received no albendazole treatment (controls), 18 received albendazole (10 mg/kg daily) for 1 month (group A), and 19 received the drug for about 3 months (group B). Echography was done before and during treatment; all patients underwent surgery on completion. Parasite (protoscolex viability and development of cysts in mice) and ultrastructure studies were done for all cysts removed. 8 (50%) of cysts in the control group, 13 (72%) in group A, and 16 (94%) in group B were non-viable (p = 0.015). Protoscolex and cyst viability were significantly (p = 0.039 and p = 0.018, respectively) lower in treated patients than in controls. Treatment was also significantly associated with total cyst membrane disintegration. 68% of cysts treated for 3 months showed echographic changes, and only 1 of 20 cysts showing echographic changes during treatment was judged viable. The efficacy of albendazole at a dose of 10 mg/kg daily for 3 months suggests that it is a suitable alternative to surgery in uncomplicated hydatid liver disease, as initial treatment.