Ana M. Planes

Epidemiology and Predictors of Mortality in Cases of Candida Bloodstream Infection: Results from Population-Based Surveillance, Barcelona, Spain, from 2002 to 2003

ABSTRACT We conducted population-based surveillance for Candida bloodstream infections in Spain to determine its incidence, the extent of antifungal resistance, and risk factors for mortality. A case was defined as the first positive blood culture for any Candida spp. in a resident of Barcelona, from 1 January 2002 to 31 December 2003. We defined early mortality as occurring between days 3 to 7 after candidemia and late mortality as occurring between days 8 to 30. We detected 345 cases of candidemia, for an average annual incidence of 4.3 cases/100,000 population, 0.53 cases/1,000 hospital discharges, and 0.73 cases/10,000 patient-days. Outpatients comprised 11% of the cases, and 89% had a central venous catheter (CVC) at diagnosis. Overall mortality was 44%. Candida albicans was the most frequent species (51% of cases), followed by Candida parapsilosis (23%), Candida tropicalis (10%), Candida glabrata (8%), Candida krusei (4%), and other species (3%). Twenty-four isolates (7%) had decreased susceptibility to fluconazole (MIC ≥ 16 μg/ml). On multivariable analysis, early death was independently associated with hematological malignancy (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.1 to 10.4). Treatment with antifungals (OR, 0.05; 95% CI, 0.01 to 0.2) and removal of CVCs (OR, 0.3; 95% CI, 0.1 to 0.9) were protective factors for early death. Receiving adequate treatment, defined as having CVCs removed and administration of an antifungal medication (OR, 0.2; 95% CI, 0.08 to 0.8), was associated with lower odds of late mortality; intubation (OR, 7.5; 95% CI, 2.6 to 21.1) was associated with higher odds. The incidence of candidemia and prevalence of fluconazole resistance are similar to other European countries, indicating that routine antifungal susceptibility testing is not warranted. Antifungal medication and catheter removal are critical in preventing mortality.

Effectiveness of Cloxacillin with and without Gentamicin in Short-Term Therapy for Right-Sided Staphylococcus aureus Endocarditis: A Randomized, Controlled Trial

Tricuspid valve endocarditis is a common infection in intravenous drug users and is caused by Staphylococcus aureus in more than 80% of cases [1-4]. Right-sided endocarditis is less aggressive than left-sided disease [5]. The prognosis for patients with isolated tricuspid valve endocarditis caused by S. aureus is generally favorable, and the condition promptly responds to medical therapy [6]. For this reason, and because of the difficulty of hospitalizing patients with right-sided endocarditis for 4 to 6 weeks [7], there has been considerable interest in short courses of intravenous treatment for managing this condition [8]. Several recent studies [9-11] have shown that a combination of a penicillinase-resistant penicillin and an aminoglycoside given for 2 weeks is useful in most patients with uncomplicated, right-sided S. aureus endocarditis. However, the efficacy of a penicillinase-resistant penicillin as single-agent therapy given for 2 weeks has not yet been evaluated. Thus, the benefit of adding an aminoglycoside to short-course regimens is only theoretical [8]. We did a randomized clinical trial to compare the efficacy of cloxacillin alone with that of cloxacillin plus gentamicin as short-course therapy for right-sided S. aureus endocarditis in intravenous drug users. Methods Patients All patients who were suspected of having right-sided staphylococcal endocarditis, who were hospitalized at our institution between March 1988 and February 1993, and who admitted that they used intravenous drugs were considered for inclusion in our study. Patients who presented with tricuspid endocarditis caused by S. aureus according to the criteria shown in Table 1 were eligible. The institutional review board of our hospital approved the study, and all patients gave informed consent. Table 1. Diagnostic Criteria for Tricuspid Valve Infective Endocarditis Patients were excluded if they had any of the following: allergy to study medications, infection with methicillin-resistant S. aureus, confirmed or suspected left-sided endocarditis shown by clinical examination (indicated by characteristic regurgitation murmur or systemic embolization) or echocardiography (indicated by vegetation or valvular insufficiency), vegetation on the pulmonic valves shown by echocardiography, systemic complications requiring prolonged therapy (osteomyelitis, abscesses that could not be drained surgically), or antibiotic therapy given for longer than 48 hours before hospitalization. Clinically significant hemodynamic compromise, extensive pulmonary embolism, and large tricuspid vegetations were not considered exclusion criteria. Study Design and Treatment Our study was an open, randomized trial. Consecutive patients were randomly assigned to receive cloxacillin, 2 g intravenously every 4 hours for 14 days, alone or combined with gentamicin, 1 mg/kg of body weight intravenously every 8 hours for the first 7 days. Randomization was done using a random-number table in sets of 10: In each consecutive set, 5 patients received cloxacillin alone and 5 received combination therapy. A sealed envelope labeled with the randomization number was opened at the start of treatment. The decision to start treatment was based on microbiological criteria (positive blood cultures) or clinical criteria (fever and evidence of pulmonary embolism or poor general condition attributable to the infection). Thus, some patients were randomly assigned to treatment before the results of some procedures (echocardiography and isolation of microorganism) that might have uncovered exclusion criteria were available. Follow-up Initial patient assessment included medical history, physical examination, chest radiography, radionuclide body scanning with technetium pyrophosphate, electrocardiography, and the following laboratory tests: complete blood count, standard blood chemistries, urinalysis, serologic testing for human immunodeficiency virus (HIV), and lymphocyte subpopulation counts (when the HIV test result was positive). Standard laboratory tests and chest radiography were done every week. Two-dimensional transthoracic echocardiography was done within 4 days of hospital admission and at the end of treatment. Blood cultures were done at the time of hospital admission, 3 days after the initiation of treatment, and 2 days after the end of treatment. Aerobic and anaerobic cultures were done by using the BACTEC NR 660 System (Becton Dickinson, Mountain View, California). Follow-up visits were scheduled at 2 weeks and at 1, 3, and 6 months after the end of therapy. At the 2-week visit, a physical examination, standard laboratory tests, chest radiography, and two blood cultures were done. Subsequent blood cultures were done only if evidence suggested infection. Nine patients did not attend a follow-up visit; outcome information for these patients was obtained by telephone. Evaluation Criteria In all patients who met the exclusion criteria after random assignment, treatment was modified accordingly. In the intention-to-treat analysis, these patients were considered to have had treatment failure. Three primary end points were considered to indicate treatment failure: 1) death during treatment, 2) continued clinical or microbiological evidence of active infection after 2 weeks of therapy, and 3) relapse of staphylococcal infection. Clinical recovery was defined as the disappearance of clinical evidence of infection and the absence of radiologic abnormalities (pleural effusion or active pulmonary abscesses) at 14 days of treatment. Bacteriologic recovery was defined as a negative blood culture obtained 48 hours after the end of treatment. Successful therapy was defined as clinical and microbiological recovery without subsequent relapse. Patients who showed signs of active infection after 14 days of treatment continued to receive cloxacillin for 2 more weeks. Relapses were treated with cloxacillin alone for 4 weeks. To differentiate between relapse and reinfection, we considered clinical criteria (resumption of drug use and duration of symptom-free interval after stopping treatment) and comparison of S. aureus isolates by phage-typing. Phage-typing was done at the National Reference Center of Microbiology, Virology and Immunology, Majadahonda, Madrid, by using the international set of phages applied sequentially at the standard test dilution and a 1:100 test dilution; typing was also done after heat treatment. Reverse phagotyping was done as described elsewhere [12]. The duration of fever and appearance of complications during treatment were also evaluated. In patients without previous renal dysfunction, acute renal insufficiency was defined as a serum creatinine level greater than 176.8 mol/L. In patients with previous renal dysfunction, renal insufficiency was defined as an increase in the serum creatinine level of more than 50%. Statistical Analysis We did two analyses. An intention-to-treat analysis was done for all randomly assigned patients, and an efficacy analysis was done after we excluded patients who were found, after treatment began, to have met an exclusion criterion. We used the Fisher exact test to compare categorical baseline characteristics and outcomes of the two groups, and we used the Student t-test or the Mann-Whitney U test to compare continuous characteristics and outcomes. In the primary efficacy analysis, we compared the rates of successful treatment. Because we assumed that treatment would be successful in 95% of patients who received combination therapy [9], we estimated that almost 38 evaluable patients had to receive each regimen in order for us to detect a difference in efficacy of 20% or more, with a power of 80% at a one-sided level of 0.05. Because we anticipated that 10% to 15% of patients might have to be excluded after random assignment, 45 patients were assigned to each group. Two-tailed P values were used for all calculations; thus, the power of the study to find no differences in the efficacy of the two regimens was 70%. Results Patients During the 5-year study period, 45 patients were randomly assigned to each treatment group. Of these 90 patients, 6 (13%) of those assigned to receive cloxacillin alone and 8 (18%) of those assigned to receive combination therapy were later excluded for the following reasons. Three patients (1 receiving cloxacillin alone and 2 receiving combination therapy) had endocarditis caused by Streptococcus viridans; 7 patients (3 receiving cloxacillin alone and 4 receiving combination therapy) had involvement of the mitral, aortic, or pulmonic valves; 3 patients (1 receiving cloxacillin alone and 2 receiving combination therapy) were allergic to penicillin or had methicillin-resistant S. aureus infection; and 1 patient receiving cloxacillin alone had osteomyelitis. Two patients (1 in each group) refused further in-hospital treatment 5 and 8 days after enrollment, respectively. Thus, 74 patients (38 receiving cloxacillin alone and 36 receiving combination therapy) remained available for the efficacy analysis. Clinical, radiologic, and echocardiographic findings and laboratory values were similar in the two groups. The exclusion of 16 patients from the efficacy analysis after randomization did not change these similarities (Table 2). Table 2. Selected Baseline Characteristics of 74 Patients Evaluable for the Efficacy Analysis* Efficacy of Therapy Table 3 shows the outcome of all patients randomly assigned to treatment, as determined by the intention-to-treat analysis. A successful overall outcome was seen in 34 of the 45 patients (76% [95% CI, 61% to 87%]) assigned to receive cloxacillin only and 31 of the 45 patients (69% [CI, 53% to 82%]) assigned to receive combination therapy (P > 0.2). Table 3. Outcome of All Randomly Assigned Patients according to Treatment Regimen (Intention-to-Treat Analysis) Table 4 shows the outcomes for the 74 patients that were available for the efficacy analysis. Treatment was successful in 34 of the

Invasive Pneumococcal Disease in Patients Infected with HIV: Still a Threat in the Era of Highly Active Antiretroviral Therapy

We studied all human immunodeficiency virus (HIV)-infected patients with invasive pneumococcal disease who received their diagnosis during 1996-2002 to investigate the incidence of this disease in the highly active antiretroviral therapy era and to study the influence of CD4 lymphocyte count on the clinical presentation and outcome of disease. The overall incidence of invasive pneumococcal disease was 11.3 cases per 100,000 person-years in adult patients without known HIV infection and 677 cases per 100,000 person-years in HIV-infected patients. This incidence remained stable over the study period. Clinical presentation, severity of illness, and number of recurrent episodes were similar in patients with CD4+ cell counts of >200 or < or =200 cells/ microL. Patients receiving trimethoprim-sulfamethoxazole (TMP-SMZ) were more likely to present with TMP-SMZ-resistant pneumococci than were those who were not receiving this agent (76.7% vs. 43.6%; P=.007). The mortality rate was high (21%).

Candidemia in neonatal intensive care units: Barcelona, Spain.

Background: Candida spp. are increasingly important hospital-acquired pathogens in neonatal intensive care units (NICU) and cause considerable mortality in preterm infants. Most studies have been limited to a single institution. The aim of this study was to determine the epidemiology of candidemia in all Barcelona NICUs. Methods: We conducted prospective population-based surveillance for candidemia in Barcelona, Spain, during 2002–2003. This report focuses on the results from 5 participating hospitals with NICUs. Results: We detected 24 cases, resulting in an annual incidence of 32.6 cases per 100,000 live births and 1.1 cases per 100 NICU discharges. Median gestational age was 27.5 weeks (range, 24–40.5), and there were 21 cases among very low birth weight infants. Among the 20 (83%) cases evaluated for the presence of end organ infection, endophthalmitis occurred in 2 cases, and endocarditis, meningitis and peritonitis occurred in 1 case each. Candida parapsilosis was the most frequent species isolated (67%). All isolates were fluconazole-susceptible. Crude mortality was 21%. Conclusions: The preponderance of C. parapsilosis candidemias observed in Barcelona NICUs is similar to reports from the literature. Morbidity and mortality associated with neonatal candidemia remain high.

The Spectrum of Pneumococcal Empyema in Adults in the Early 21st Century

BACKGROUND Increased rates of empyema have been reported in children after the introduction of the pneumococcal conjugate vaccine (PCV7). Our objective was to describe the risk factors for pneumococcal empyema in adults and to analyze the differences in the incidence, disease characteristics, and serotype distribution between the pre- and post-PCV7 eras. METHODS An observational study of all adults hospitalized with invasive pneumococcal disease (IPD) who presented with empyema in 2 Spanish hospitals was conducted during the periods 1996-2001 (prevaccine period) and 2005-2009 (postvaccine period). Incidences of empyema were calculated. A multivariate analysis was performed to identify variables associated with pneumococcal empyema. RESULTS Empyema was diagnosed in 128 of 1080 patients with invasive pneumococcal disease. Among patients aged 18-50 years, the rates of pneumococcal pneumonia with empyema increased from 7.6% to 14.9% (P = .04) and the incidence of pneumococcal empyema increased from 0.5 to 1.6 cases per 100,000 person-years (198% [95% confidence interval {CI}, 49%-494%]). The incidence of empyema due to serotype 1 increased significantly from 0.2 to 0.8 cases per 100,000 person-years (253% [95% CI, 67%-646%]). Serotype 1 caused 43.3% of cases of empyema during the postvaccine period. Serotypes 1 (odds ratio [OR], 5.88; [95% CI, 2.66-13]) and 3 (OR, 5.49 [95% CI, 1.93-15.62]) were independently associated with development of empyema. CONCLUSIONS The incidence of pneumococcal empyema in young adults has increased during the postvaccine period, mainly as a result of the emergence of serotype 1. Serotypes 1 and 3 are the main determinants of development of this suppurative complication.

Bacteremia Caused by Capnocytophaga Species in Patients with Neutropenia and Cancer: Results of a Multicenter Study

We investigated 28 cases of bacteremia caused by Capnocytophaga species that occurred during an 8-year period, most of which were in patients with hematologic malignancy and neutropenia. Infections were uncomplicated, without serious organ involvement and without any apparent source except ulcerations of the oropharyngeal mucosa, and only 1 isolate showed resistance to beta-lactam antibiotics; 9 of 16 isolates were resistant to ciprofloxacin.

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

BackgroundFew 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. MethodsStudy 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. ResultsTwo 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. ConclusionsIn 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.

Impact of the 2009 influenza A H1N1 pandemic on invasive pneumococcal disease in adults

Abstract Background: The incidence of invasive pneumococcal disease (IPD) appears to be associated with influenza. The objectives of this study were to evaluate the changes in IPD incidence and clinical data as well as the trends in Streptococcus pneumoniae serotype distribution in adults during the peak period of the 2009 influenza A H1N1 pandemic (IAP). Methods: We performed a prospective multicentre study on IPD from week 42 to 48, 2009 in an area of Barcelona (Catalonia, Spain) covering 1,483,781 adult inhabitants. Serotyping was done by Quellung reaction. The data from 2009 were compared to those from the same periods in 2008 and 2010. Results: Two hundred and three cases of IPD were detected during 2009, compared with 182 in 2008 and 139 in 2010. The incidence of IPD during the 7-week study period in 2009 (2.89) was statistically higher than that observed in 2008 (1.96) and 2010 (1.46). IAP was confirmed in 3/30 patients during the 2009 study period. Patients with IPD in 2009 were significantly healthier and younger than those in the other years, although the mortality was higher than in 2008 (p = 0.05) and 2010 (p > 0.05). Eleven (10 non-PCV-7) serotypes not present in 2008 appeared in 2009. Conclusions: During weeks 42 to 48, in which the 2009 IAP peaked in Catalonia, the incidence of IPD was statistically higher than that observed in the same time period in 2008 and 2010, with some differences in the epidemiological data, showing a close relationship between S. pneumoniae and influenza.