Drug Cost Avoidance Resulting from Participation in Clinical Trials: A 10-Year Retrospective Analysis of Cancer Patients with Solid Tumors.

The objective of this single-center retrospective study was to describe the clinical characteristics of adult patients with solid tumors enrolled in cancer clinical trials over a 10-year period (2010-2019) and to assess drug cost avoidance (DCA) associated with sponsors' contributions. The sponsors' contribution to pharmaceutical expenditure was calculated according to the actual price (for each year) of pharmaceutical specialties that the Vall d'Hebron University Hospital (HUVH) would have had to bear in the absence of sponsorship. A total of 2930 clinical trials were conducted with 10,488 participants. There were 140 trials in 2010 and 459 in 2019 (228% increase). Clinical trials of high complexity phase I and basket trials accounted for 34.3% of all trials. There has been a large variation in the pattern of clinical research over the study period, whereas, in 2010, targeted therapy accounted for 79.4% of expenditure and cytotoxic drugs for 20.6%; in 2019, immunotherapy accounted for 68.4%, targeted therapy for 24.4%, and cytotoxic drugs for only 7.1%. A total of four hundred twenty-one different antineoplastic agents were used, the variability of which increased from forty-seven agents in 2010, with only seven of them accounting for 92.8% of the overall pharmaceutical expenditure) to three hundred seventeen different antineoplastic agents in 2019, with thirty-three of them accounting for 90.6% of the overall expenditure. The overall expenditure on antineoplastic drugs in clinical care patients not included in clinical trials was EUR 120,396,096. The total cost of antineoplastic drugs supplied by sponsors in a clinical trial setting was EUR 107,306,084, with a potential DCA of EUR 92,662,609. Overall, clinical trials provide not only the best context for the progress of clinical research and healthcare but also create opportunities for reducing cancer care costs.

Identification and diversity of multiresistant Corynebacterium striatum clinical isolates by MALDI-TOF mass spectrometry and by a multigene sequencing approach.

BACKGROUND: The genus Corynebacterium is composed of gram-positive bacteria that are widely distributed throughout the environment; these bacteria are also part of the normal microbiota of human skin and mucous membranes. Multiple studies have shown that species of this genus, including C. striatum, become pathogenic to humans under special conditions. Our aim was to determine the characteristics of clinical multiresistant strains of C. striatum that were isolated in our geographical region, to determine their diversity, and to compare them with the type strain and with related species. We studied fifty-two strains of C. striatum isolated from different hospitals from Mallorca, Spain, mainly from the Hospital Joan March in Bunyola, Mallorca. Most of the strains were isolated from sputum cultures of respiratory samples from patients with chronic obstructive pulmonary disease. To gain further insight into the genetic diversity of the strains, we analysed several housekeeping genes and other genes associated with antibiotic resistance. Strains were also characterised phenotypically by their antibiotic resistance profiles and by MALDI-TOF mass spectrometry analysis. RESULTS: The ITS1 region, gyrA and rpoB were chosen as the appropriate genes in the C. striatum genome to study the genetic diversity of C. striatum species and to discriminate between strains. After analysing these three genes, four sequence types (ST2, ST4, ST1 and ST11) were found to be the most abundant. Splits tree analysis of the strains demonstrated that these clinical isolates did not share any alleles with the type strain of the species. Recombination was detected within all of the C. striatum isolates, and different clonal populations were detected within the samples. CONCLUSIONS: Our results demonstrate that the isolates were best identified using gene-based molecular methods; using these methods, the isolated strains were determined to be different from the type strain of C. striatum. The ITS1 region and the gyrA and rpoB genes were selected because of their variability and were the most useful tools for discriminating between strains. The phenotype and antibiotype characteristics of the strains did not seem suitable for typing purposes. MALDI-TOF mass spectrometry can be a useful method for identifying and discriminating between C. striatum strains.

[Nosocomial spread of linezolid-resistant Staphylococcus hominis in two hospitals in Majorca]. / Diseminación nosocomial de Staphylococcus hominis resistente al linezolid en dos hospitales de Mallorca.

OBJECTIVE: Since March 2008, several linezolid and teicoplanin-resistant Staphylococcus hominis (S. hominis) isolates have been recovered from patients admitted to the two major hospitals on the island of Majorca, Spain. For this reason, a study was conducted to determine the molecular epidemiology of these isolates and the mechanism of linezolid resistance. METHODS: The molecular epidemiology study was performed by pulsed-field gel electrophoresis (PFGE) analysis, after digestion with ApaI. Linezolid resistance mechanisms were evaluated by PCR amplification of a fragment of the domain V of the 23S rRNA gene (followed by sequencing) and cfr gene. RESULTS: From March 2008 to February 2009, 15 linezolid and teicoplanin-resistant S. hominis isolates were recovered from 14 patients. All of them, except one, were hospitalised in the intensive care units of either of the two institutions. Isolates were obtained mainly from blood cultures (9). The majority of infected patients (12 of 15 infectious episodes, 80.0%) had received courses of linezolid prior to detection of the resistant isolate. PFGE analysis revealed the presence of a unique clone among linezolid resistant S. hominis isolates. The G2576T mutation was detected in all the linezolid resistant strains. None of the resistant isolates showed a positive PCR for the cfr gene. All of the isolates were also resistant to penicillin, oxacillin, trimethoprim-sulfamethoxazole, ciprofloxacin, levofloxacin, and tobramicin; whereas all of them were susceptible to erythromycin, tetracycline, gentamicin, and daptomycin. The MIC of vancomycin was 4µg/ml for all the strains. CONCLUSIONS: The detection of linezolid resistant Staphylococci highlights the need to rationalise the use of linezolid, and maintain an active surveillance of its resistance to preserve the clinical usefulness of this antimicrobial.

[Pneumococcal pneumonia in the era of heptavalent pneumococcal conjugate vaccine]. / Neumonía neumocócica en la era de la vacuna conjugada heptavalente.

INTRODUCTION: To describe clinical features, complications, serotypes and antibiotic resistance in pneumococcal pneumonia in our environment after the generalization of the heptavalent conjugate vaccine (PCV-7) in paediatrics. MATERIAL AND METHODS: Prospective study of episodes of pneumococcal pneumonia, with positive cultures in patients treated in the emergency department from January 2006 to February 2010. RESULTS: We studied 346 episodes in 320 patients, 335 belonged to 309 adult patients, 221 (71.5%) males, median age 68 years (range 16-94), and 11 episodes to patients<15 years. Two-hundred and thirty seven (68.5%) episodes were community acquired. Bacteraemia was present in 130 (37.6%) cases, with a tendency towards an increased risk in patients < 65 years (OR=1.56, 95% CI 0.96- 2.56, P=.07). Thirteen (3.8%) patients developed empyema and 33 (9.5%) septic shock. The mean age of patients with empyema was lower (P=.03). In the multivariate analysis were related to the presence of bacteraemia: a history of chronic respiratory disease (OR=0.45, 95% CI 0.25-0.81, P=.008), positive urinary antigen (OR 2.02, 95% CI 1 13-3.62, P=.01) and pleural effusion (OR=3.86, 95% CI 1.79-8.35, P=.001). Shock was associated with Fine IV-V stage (OR=23.6, 95% CI 4.96-112.82, P<.001), age < 65 years (OR=4.47, 95% CI 1.75-11.39, P=.002) and pleural effusion (OR=4.15, 95% CI 1.65 to 10.41, P=.002). Increased mortality risk was associated with presence of any complication (OR=6.6, 95% CI 1.5-27.2, P=.009) and specifically septic shock (OR=3.3, 95% CI 1.06-10.3, P=.04). Most serotypes obtained were not included in the VNC-7. CONCLUSIONS: Pneumococcal pneumonia after generalisation of PCV-7 is mainly related to non-vaccine serotypes. Younger patients without respiratory disease are at increased risk of bacteraemia, empyema, and septic shock, the latter being associated with a higher mortality.

Evolution, Clinical and Microbiological Characteristics of Invasive Pneumococcal Disease since the Introduction of the Pneumococcal Conjugate Vaccine 13-Valent in Adults over 18 Years Old.

Invasive pneumococcal disease (IPD) presents high mortality in the population at risk. The aim of this work is to know the evolution, clinical and microbiological characteristics of IPD in the adult population of Majorca, since the introduction of a public funded program for pneumococcal conjugate vaccine (PCV-13) in the pediatric population in the Balearic Islands in 2016. For this purpose, a retrospective multicenter study was carried out in which all episodes of IPD in adult patients from the four hospitals of the public health system of Majorca were included, comparing the periods between 2012 and 2015 and between 2016 and 2019. Clinical variables, serotypes and antibiotic sensitivity were collected. There were 498 cases of IPD; 56.8% were male with a mean age of 67 (standard deviation: 16). Most infections were bacterial pneumonias (73.7%). Of the total cases, 264 (53%) presented complications. Of the 498 cases, 351 strains were obtained, of which 145 (41.3%) belong to vaccinal serotypes (included in the PCV-13 vaccine) and 206 (58.7%) to non-vaccinal serotypes (not included in the PCV-13 vaccine). The percentage of IPD caused by vaccinal serotypes was lower in the second period (47.8% vs. 34.5%; p = 0.012).

[Anaerobic bloodstream infections: study of 68 episodes]. / Bacteriemia por anaerobios estrictos: estudio de 68 pacientes.

INTRODUCTION: There is some controversy regarding the current rates of anaerobic bacteremia. Some authors have described an increasing incidence in recent years, whereas others report declining rates. There is even debate over whether to routinely perform anaerobic blood cultures. We present a prospective analysis of anaerobic bloodstream infections diagnosed at our medical center from January 2003 to May 2008. RESULTS: Sixty-eight patients had bloodstream infection caused exclusively by anaerobic bacteria. Median age was 64+/-19 years and 63.2% had at least one comorbid condition, including 20.6% with a solid neoplasm, often related to the gastrointestinal tract. The main focus of anaerobic bacteremia was the abdomen (42.6%). The most common isolates were several species from the Bacteroides fragilis group (36.7%), Clostridium spp. (17.6%), Peptostreptococcus spp. (16.1%), and Prevotella spp. (16.1%). Empirical antimicrobial treatment was adequate in 69.1%. Overall mortality was 23.5%, and bacteremia-related mortality was 9.2%. Sepsis, septic shock, and a Pitt score >4 were independent predictors of mortality. CONCLUSIONS: The incidence of anaerobic bacteremia in our hospital was 0.89 cases per 1000 hospital admissions. Patients at high risk were elderly persons with associated underlying diseases including malignant disease. Mortality was high.

Pneumococcal infections in elderly patients attending hospital since PCV-13 authorization in Spain.

OBJECTIVES: To study the characteristics and outcomes of pneumococcal infections in patients aged ≥65 years since the authorization of the 13-valent pneumococcal conjugate vaccine (PCV-13) in Spain. METHODS: All pneumococcal pneumonias, empyemas or primary bacteraemias treated at two hospitals in Majorca from 2010 to 2015 were included. Clinical variables, serotypes, and antibiotic susceptibility were collected. RESULTS: Two hundred and forty-nine pneumonias, 11 primary bacteraemias, and 2 empyemas in 243 patients were studied; 181 (69.1%) men, median age 76 years (range: 66-99). Seven (2.6%) were pneumococcal-vaccinated. Bacteraemia was present in 127 (61.9%) cases and related to a higher severity, p= 0.02, and not having chronic lung disease, p = 0.002. Ninety-seven (37%) episodes involved complications and 30 (11.5%) patients died. Mortality was related with the presence of complications at admission, p < 0.001. Only septic shock was more frequent in patients ≥65 years during the period 2010-2015 compared to the period 2006-2010: 38 of 262 (14.5%) vs. 17 of 212 (8%), p = 0.02. Most infections (57.6%) were due to PCV-13 serotypes but were not related to a worse prognosis. The proportion of PCV-13 serotypes tended to decrease from 61% (non-invasive) and 80% (invasive) in 2010-2011 to 33% and 47% in 2014-2015. The antibiotic susceptibility remained stable. CONCLUSIONS: Rates of pneumococcal vaccination in elderly patients with pneumococcal infections were very low. Except for septic shock, the main outcome variables (including mortality) were similar to the ones observed in the period preceding PCV-13 authorization. PCV-13 serotypes were responsible for most infections although they showed a decreasing trend.

Evolution of pneumococcal infections in adult patients during a four-year period after vaccination of a pediatric population with 13-valent pneumococcal conjugate vaccine.

OBJECTIVES: To describe the distribution of vaccine and non-vaccine pneumococcal serotypes from adult patients for different clinical scenarios, after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV-13) for children. METHODS: This was a prospective study of pneumococcal infections in adult patients (January 2010 to April 2014) in Hospital Son Llàtzer, Mallorca (Spain). Two different periods of time were compared, the first before (first period) and the second after (second period) the introduction of PCV-13. Information related to clinical characteristics, outcomes of infection, pneumococcal serotypes, and antibiotic susceptibility was collected. RESULTS: We studied 407 episodes (371 patients), 201 in the first period and 206 in the second period. The majority of patients were male; the median patient age was 68 (range 15-99) years. Infections due to PCV-13 serotypes decreased from 59.7% to 47.6% (p=0.014), mainly serotypes 3, 7, 18C, 19F, and 23F. In the second period, PCV-13 serotypes were the cause of pneumonia in 58.2% of cases and in 40.8% of invasive infections, but these serotypes were not related with any outcome variable. No differences in hospital or intensive care unit admission, severity, or mortality were observed between the two periods. Susceptibility to penicillin (98.2% vs. 95.1%, p=0.03) and amoxicillin (96.5% vs. 91%, p=0.007) was slightly higher in the first period. CONCLUSIONS: Although a reduction in infections due to vaccine serotypes was observed, close to half of infections in adult patients were caused by PCV-13 serotypes. Even after pediatric vaccination with PCV-13, vaccine serotypes were still responsible for most pneumonia and invasive disease, underscoring the importance of implementing current guidelines and extending vaccination to other risk groups.

[Cryptococcus neoformans arthritis in a renal transplant recipient]. / Artritis por Cryptococcus neoformans en receptor de trasplante renal.

We present a Cryptococcus neoformans knee joint infection in a diabetic renal transplant patient treated with steroids, cyclosporin, and mycofenolate mofetil. We discuss reported cases of cryptococcal arthritis.

[Current treatment of dermatophytosis]. / Tratamiento actual de las dermafitosis.

The aim of this review is to discuss topical and systemic antifungal treatment of dermatophyte infections with current antifungal drugs.

[Three cases of imported histoplasmosis in our hospital]. / A propósito de tres casos de histoplasmosis importada en nuestro hospital.

Since 1999 we have observed three cases of imported histoplasmosis in our hospital. One was an immunocompetent individual and two further patients were immunosuppressed (renal transplantation and HIV infection C3). Two patients were born in endemic areas (Equatorial Guinea and Ecuador) and a third patient had a history of previous travel to the Peruvian Amazonia. The different clinical presentations and diagnostic tools of histoplasmosis are discussed.

[Successful treatment with voriconazol of a Pseudallescheria boydii fungus ball in a HIV positive patient and previous tuberculosis]. / Tratamiento eficaz con voriconazol de un fungoma pulmonar por Pseudallescheria boydii en un paciente con infección por VIH y tuberculosis previa.

We herein describe a patient with a Pseudallescheria boydii fungus ball in a tuberculous lung cavity, which was successfully treated four years earlier. The patient was HIV positive classified as C3 with a previous history of i.v. heroin abuse. The clinical presumptive diagnosis was radiologically established combined with histological examination. Culture of tissue confirmed and proved the fungal etiology. In vitro MIC values for voriconazole (0.5 mg/ml) guided antifungal prophylactic treatment before surgical eradication of the fungus ball since the patient was immunosuppressed. We discuss the clinical spectrum of P. boydii infections and currently medical approach.

Afectación osteoarticular por Streptococcus pneumoniae tras la autorización de las vacunas conjugadas / Osteoarticular infections caused by Streptococcus pneumoniae since authorization of conjugate vaccines

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Invasive pneumococcal disease in HIV-infected adults: clinical changes after the introduction of the pneumococcal conjugate vaccine in children.

BACKGROUND: Few data exist on the implications of widespread use of 7-valent pneumococcal conjugate vaccine in children in the invasive pneumococcal disease (IPD) in HIV-infected adults. We conducted a multicenter study to analyze differences in clinical presentation of IPD between HIV-infected and non-HIV-infected adults in the prevaccine and postvaccine era. METHODS: Study of all cases of IPD in HIV-infected adults diagnosed since 1996 to 2010. Episodes were classified into prevaccine (1996-2001), early postvaccine (2002-2004), and late postvaccine period (2005-2010). For each case, we identified an HIV-negative control patient with IPD matched by hospital, age, and vaccine period. RESULTS: Two hundred twenty-one episodes of IPD in HIV-infected patients were diagnosed. The incidence of IPD decreased from 7.81 to 3.69 episodes per 1000 patient-years (-53%; 95% confidence interval: -65% to -36%, P < 0.001) between prevaccine and late postvaccine period. There was an 81% (95% confidence interval: -88% to -69%, P < 0.001) decrease of IPD caused by vaccine serotypes. In late postvaccine period IPD in HIV-infected patients was associated to higher rates of respiratory failure (28.4% vs. 48.4%, P = 0.011), greater intensive care unit admission (8.2% vs. 21.7%, P = 0.02) and a higher need for mechanical ventilation (5.9% vs. 16.3%, P = 0.033). In the prevaccine period, non-HIV-infected patients had a more severe illness than in those with HIV infection; however, these differences disappeared in the late postvaccine period. CONCLUSIONS: In the late postvaccine era, the incidence of IPD in HIV-infected patients has decreased, however, clinical presentation seems to have changed to a more severe illness. The widespread use of highly active antiretroviral therapy, polyssacharide vaccine, and 7-valent pneumococcal conjugate vaccine has contributed to these changes.

Prognosis of COPD patients requiring frequent hospitalization: role of airway infection.

RATIONALE: A subgroup of patients with chronic obstructive pulmonary disease require frequent hospitalization because of exacerbations of the disease. We hypothesized that airway infection by non-usual pathogens is a major factor driving hospitalization needs in these patients. OBJECTIVES: 1) To describe the clinical and functional characteristics of a cohort of COPD patients requiring > or =2 hospitalizations per year; 2) to determine prospectively their microbiological pattern during exacerbations; and, 3) to analyze the prognostic value of several clinical, functional and microbiological variables with respect to hospitalizations and mortality. METHODS: Open cohort study of 116 COPD patients who had been hospitalized at least twice during the last 12 months. Patients were followed for an average of 21 months. MEASUREMENTS AND MAIN RESULTS: Clinical data, forced spirometry and 6min walking distance were determined, and the BODE index was calculated, at the time of inclusion in the study. During follow-up, sputum culture was obtained during exacerbations, and hospitalization and mortality were collected every two months. Mean age was 71 yrs, and 94% of patients were male. Main findings show that: 1) not all patients had severe disease according to either the degree of airflow limitation or the BODE index; 2) non-usual pathogens, mainly Pseudomonas aeruginosa, other gram-negative non-fermentative rods and Enterobacteriaceae, were isolated among 71.1% of the sputum obtained during exacerbations; and, 3) these pathogens were associated with poor prognosis and frequent hospitalization. CONCLUSIONS: Airway infection by non-usual pathogens appears to be a key driver of frequent hospitalizations and mortality in COPD.

Nosocomial outbreak of Corynebacterium striatum infection in patients with chronic obstructive pulmonary disease.

We describe an unusual cluster of Corynebacterium striatum infections in 21 patients with chronic obstructive pulmonary disease (COPD) admitted to a medium-size respiratory unit. Eleven isolates from eight patients occurred simultaneously within a month. C. striatum is a potentially pathogenic microorganism with the ability to produce nosocomial infectious outbreaks and respiratory colonization in patients with advanced COPD.

[Bacteremia in very elderly patients: risk factors, clinical characteristics and mortality]. / Bacteriemia en pacientes muy ancianos: factores de riesgo, características clínicas y mortalidad.

INTRODUCTION: There is little information on bacteremia in very elderly patients. This study describes the characteristics of bacteremia in this population. METHODS: This is a prospective study investigating bacteremia episodes in patients over 80 years old in comparison with episodes in patients aged 18-64 and 65-79 years. RESULTS: A total of 146 bacteremia episodes were analyzed in patients over 80 years old. Comorbidity was documented in 66.4% and immunodeficiency in 6.8% of patients. Among the total, 82.2% had no underlying disease or a disease considered non-fatal. Eighty episodes were community-acquired. The main infectious foci included primary (25.3%) and urinary tract (20.5%) infection, and the most frequent isolates were Escherichia coli (28.2%), coagulase-negative Staphylococcus (14.7%) and S. aureus (13.6%). Sepsis or septic shock occurred in 55.5% of the cases, and 31 patients died due to a bacteremia-related cause. Immunodeficiency was less frequent in patients over 80 years old, but they had a higher proportion of community-acquired infections and gram-negative infections. Bacteremia-related mortality was highest in the oldest group of patients and was associated with a fatal or ultimately fatal underlying disease, S. aureus infection, and inappropriate empirical antibiotic treatment. A lower Pitt severity score was related to lower mortality risk. CONCLUSIONS: Very elderly bacteremic patients showed a lower frequency of immunodeficiency, a higher percentage of community-acquired and gram-negative infections. Bacteremia-related mortality was greater in the most elderly group and was associated with fatal or ultimately fatal underlying disease, S. aureus infection and initiation of inappropriate empirical antibiotic treatment.