Effectiveness of fosfomycin trometamol as oral step-down therapy for bacteraemic urinary tract infections due to MDR Escherichia coli: a post hoc analysis of the FOREST randomized trial.

BACKGROUND: Fosfomycin is a potentially attractive option as step-down therapy for bacteraemic urinary tract infections (BUTI), but available data are scarce. Our objective was to compare the effectiveness and safety of fosfomycin trometamol and other oral drugs as step-down therapy in patients with BUTI due to MDR Escherichia coli (MDR-Ec). METHODS: Participants in the FOREST trial (comparing IV fosfomycin with ceftriaxone or meropenem for BUTI caused by MDR-Ec in 22 Spanish hospitals from June 2014 to December 2018) who were stepped-down to oral fosfomycin (3 g q48h) or other drugs were included. The primary endpoint was clinical and microbiological cure (CMC) 5-7 days after finalization of treatment. A multivariate analysis was performed using logistic regression to estimate the association of oral step-down with fosfomycin with CMC adjusted for confounders. RESULTS: Overall, 61 patients switched to oral fosfomycin trometamol and 47 to other drugs (cefuroxime axetil, 28; amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, 7 each; ciprofloxacin, 5) were included. CMC was reached by 48/61 patients (78.7%) treated with fosfomycin trometamol and 38/47 (80.9%) with other drugs (difference, -2.2; 95% CI: -17.5 to 13.1; P = 0.38). Subgroup analyses provided similar results. Relapses occurred in 9/61 (15.0%) and 2/47 (4.3%) of patients, respectively (P = 0.03). The adjusted OR for CMC was 1.11 (95% CI: 0.42-3.29, P = 0.75). No relevant differences in adverse events were seen. CONCLUSIONS: Fosfomycin trometamol might be a reasonable option as step-down therapy in patients with BUTI due to MDR-Ec but the higher rate of relapses would need further assessment.

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections: A Randomized Clinical Trial.

Importance: The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. Objective: To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. Design, Setting, and Participants: This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. Interventions: Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or parenteral ertapenem for the comparator group after 4 days. Main Outcomes and Measures: The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. Results: Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to ∞ percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI, -∞ to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). Conclusions and Relevance: This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections. Trial Registration: ClinicalTrials.gov Identifier: NCT02142751.

STI epidemic re-emergence, socio-epidemiological clusters characterisation and HIV coinfection in Catalonia, Spain, during 2017-2019: a retrospective population-based cohort study.

OBJECTIVES: To describe the epidemiology of sexually transmitted infections (STIs), identify and characterise socio-epidemiological clusters and determine factors associated with HIV coinfection. DESIGN: Retrospective population-based cohort. SETTING: Catalonia, Spain. PARTICIPANTS: 42 283 confirmed syphilis, gonorrhoea, chlamydia and lymphogranuloma venereum cases, among 34 600 individuals, reported to the Catalan HIV/STI Registry in 2017-2019. PRIMARY AND SECONDARY OUTCOMES: Descriptive analysis of confirmed STI cases and incidence rates. Factors associated with HIV coinfection were determined using logistic regression. We identified and characterized socio-epidemiological STI clusters by Basic Health Area (BHA) using K-means clustering. RESULTS: The incidence rate of STIs increased by 91.3% from 128.2 to 248.9 cases per 100 000 population between 2017 and 2019 (p<0.001), primarily driven by increase among women (132%) and individuals below 30 years old (125%). During 2017-2019, 50.1% of STIs were chlamydia and 31.6% gonorrhoea. Reinfections accounted for 10.8% of all cases and 6% of cases affected HIV-positive individuals. Factors associated with the greatest likelihood of HIV coinfection were male sex (adjusted OR (aOR) 23.69; 95% CI 16.67 to 35.13), age 30-39 years (versus <20 years, aOR 18.58; 95% CI 8.56 to 52.13), having 5-7 STI episodes (vs 1 episode, aOR 5.96; 95% CI 4.26 to 8.24) and living in urban areas (aOR 1.32; 95% CI 1.04 to 1.69). Living in the most deprived BHAs (aOR 0.60; 95% CI 0.50 to 0.72) was associated with the least likelihood of HIV coinfection. K-means clustering identified three distinct clusters, showing that young women in rural and more deprived areas were more affected by chlamydia, while men who have sex with men in urban and less deprived areas showed higher rates of STI incidence, multiple STI episodes and HIV coinfection. CONCLUSIONS: We recommend socio-epidemiological identification and characterisation of STI clusters and factors associated with HIV coinfection to identify at-risk populations at a small health area level to design effective interventions.

The impact of the COVID-19 pandemic on Sexually Transmitted Infections surveillance data: incidence drop or artefact?

BACKGROUND: Before the COVID-19 pandemic, Sexually transmitted infections (STIs) were increasing in Europe, and Spain and Catalonia were not an exception. Catalonia has been one of the regions with the highest number of COVID-19 confirmed cases in Spain. The objective of this study was to estimate the magnitude of the decline, due to the COVID-19 pandemic, in the number of STI confirmed cases in Catalonia during the lockdown and de-escalation phases. METHODS: Interrupted time series analysis was performed to estimate the magnitude of decline in the number of STI reported confirmed cases - chlamydia, gonorrhoea, syphilis, and lymphogranuloma venereum- in Catalonia since lockdown with historical data, from March 13th to August 1st 2020, comparing the observed with the expected values. RESULTS: We found that since the start of COVID-19 pandemic the number of STI reported cases was 51% less than expected, reaching an average of 56% during lockdown (50% and 45% during de-escalation and new normality) with a maximum decrease of 72% for chlamydia and minimum of 22% for syphilis. Our results indicate that fewer STIs were reported in females, people living in more deprived areas, people with no previous STI episodes during the last three years, and in the HIV negative. CONCLUSIONS: The STI notification sharp decline was maintained almost five months after lockdown started, well into the new normality. This fact can hardly be explained without significant underdiagnosis and underreporting. There is an urgent need to strengthen STI/HIV diagnostic programs and services, as well as surveillance, as the pandemic could be concealing the real size of the already described re-emergence of STIs in most of the European countries.

Impact of De-escalation on Prognosis of Patients With Bacteremia due to Enterobacteriaceae: A Post Hoc Analysis From a Multicenter Prospective Cohort.

BACKGROUND: More data are needed about the safety of antibiotic de-escalation in specific clinical situations as a strategy to reduce exposure to broad-spectrum antibiotics. The aims of this study were to investigate predictors of de-escalation and its impact on the outcome of patients with bloodstream infection due to Enterobacteriaceae (BSI-E). METHODS: A post hoc analysis was performed on a prospective, multicenter cohort of patients with BSI-E initially treated with ertapenem or antipseudomonal ß-lactams. Logistic regression was used to analyze factors associated with early de-escalation (EDE) and Cox regression for the impact of EDE and late de-escalation (LDE) on 30-day all-cause mortality. A propensity score (PS) for EDE vs no de-escalation (NDE) was calculated. Failure at end of treatment and length of hospital stay were also analyzed. RESULTS: Overall, 516 patients were included. EDE was performed in 241 patients (46%), LDE in 95 (18%), and NDE in 180 (35%). Variables independently associated with a lower probability of EDE were multidrug-resistant isolates (odds ratio [OR], 0.50 [95% confidence interval {CI}, .30-.83]) and nosocomial infection empirically treated with imipenem or meropenem (OR, 0.35 [95% CI, .14-.87]). After controlling for confounders, EDE was not associated with increased risk of mortality; hazard ratios (HR) (95% CIs) were as follows: general model, 0.58 (.25-1.31); model with PS, 0.69 (.29-1.65); and PS-based matched pairs, 0.98 (.76-1.26). LDE was not associated with mortality. De-escalation was not associated with clinical failure or length of hospital stay. CONCLUSIONS: De-escalation in patients with monomicrobial bacteremia due to Enterobacteriaceae was not associated with a detrimental impact on clinical outcome.

MIC of amoxicillin/clavulanate according to CLSI and EUCAST: discrepancies and clinical impact in patients with bloodstream infections due to Enterobacteriaceae.

Objectives: To compare results of amoxicillin/clavulanate susceptibility testing using CLSI and EUCAST methodologies and to evaluate their impact on outcome in patients with bacteraemia caused by Enterobacteriaceae. Patients and methods: A prospective observational cohort study was conducted in 13 Spanish hospitals. Patients with bacteraemia due to Enterobacteriaceae who received empirical intravenous amoxicillin/clavulanate treatment for at least 48 h were included. MICs were determined following CLSI and EUCAST recommendations. Outcome variables were: failure at the end of treatment with amoxicillin/clavulanate (FEAMC); failure at day 21; and 30 day mortality. Classification and regression tree (CART) analysis and logistic regression were performed. Results: Overall, 264 episodes were included; the urinary tract was the most common source (64.7%) and Escherichia coli the most frequent pathogen (76.5%). Fifty-two isolates (19.7%) showed resistance according to CLSI and 141 (53.4%) according to EUCAST. The kappa index for the concordance between the results of both committees was only 0.24. EUCAST-derived, but not CLSI-derived, MICs were associated with failure when considered as continuous variables. CART analysis suggested a 'resistance' breakpoint of > 8/4 mg/L for CLSI-derived MICs; it predicted FEAMC in adjusted analysis (OR = 1.96; 95% CI: 0.98-3.90). Isolates with EUCAST-derived MICs >16/2 mg/L independently predicted FEAMC (OR = 2.10; 95% CI: 1.05-4.21) and failure at day 21 (OR= 3.01; 95% CI: 0.93-9.67). MICs >32/2 mg/L were only predictive of failure among patients with bacteraemia from urinary or biliary tract sources. Conclusions: CLSI and EUCAST methodologies showed low agreement for determining the MIC of amoxicillin/clavulanate. EUCAST-derived MICs seemed more predictive of failure than CLSI-derived ones. EUCAST-derived MICs >16/2 mg/L were independently associated with therapeutic failure.

Impact of the MIC of piperacillin/tazobactam on the outcome for patients with bacteraemia due to Enterobacteriaceae: the Bacteraemia-MIC project.

OBJECTIVE: Our objective was to evaluate the impact of low versus borderline MIC of piperacillin/tazobactam on the clinical outcomes of patients with bacteraemia caused by Enterobacteriaceae who were treated with that antimicrobial. PATIENTS AND METHODS: A prospective observational multicentre cohort study was conducted in 13 Spanish university hospitals. Patients >17 years old with bacteraemia due to Enterobacteriaceae who received empirical piperacillin/tazobactam treatment for at least 48 h were included. Outcome variables were clinical response at day 21, clinical response at end of treatment with piperacillin/tazobactam and all-cause 30 day mortality. Univariate and multivariate logistic regression analyses were performed. RESULTS: Overall, 275 patients were included in the analysis; 248 (90.2%) in the low MIC group (≤ 4 mg/L) and 27 (9.8%) in the borderline MIC group (8-16 mg/L). The biliary tract was the most common source of infection (48.4%) and Escherichia coli was the most frequent pathogen (63.3%). Crude 30 day mortality rates were 10.5% and 11.1% for the low MIC group and the borderline MIC group, respectively (relative risk = 1.06, 95% CI = 0.34-3.27, P = 1). Multivariate analysis of failure at day 21 and at end of treatment with piperacillin/tazobactam and 30 day mortality showed no trend towards increased clinical failure or mortality with borderline MICs (OR = 0.96, 95% CI = 0.18-4.88, P = 0.96; OR = 0.47, 95% CI = 0.10-2.26, P = 0.35; OR = 1.48, 95% CI = 0.33-6.68, P = 0.6). CONCLUSIONS: We did not find that higher piperacillin/tazobactam MIC within the susceptible or intermediate susceptibility range had a significant influence on the outcome for patients with bacteraemia due to Enterobacteriaceae.

Outcome of Clostridium difficile-associated disease in solid organ transplant recipients: a prospective and multicentre cohort study.

Clostridium difficile-associated disease (CDAD) is the most common cause of nosocomial diarrhea. Information about CDAD in solid organ transplant (SOT) recipients is scarce. To determine its epidemiology and risk factors, we conducted a cohort study in which 4472 SOT patients were prospectively included in the RESITRA/REIPI (Spanish Research Network for the Study of Infection in Transplantation) database between July 2003 and July 2006. Forty-two episodes of CDAD were diagnosed in 36 patients. The overall incidence was 0.94%. Median onset of infection was 31.5 days (range 6-741); in half the cases, onset occurred during the first month after transplantation. In 26% of cases, there was no previous antibiotic use. Independent risk factors for CDAD using Cox regression analysis were previous use of first- and second-generation cephalosporins (HR 3.68; 95%CI 1.8-7.52; P < 0.001), ganciclovir prophylactic use (HR 3.09; 95%CI 1.44-6.62; P = 0.004) and corticosteroid use before transplantation (HR 2.95; 95%CI 1.1-7.9; P = 0.031). There were no deaths related to CDAD. In summary, the incidence of CDAD in SOT was low, most cases were diagnosed soon after transplantation and the prognosis was good.

Epidemiology, species distribution and in vitro antifungal susceptibility of fungaemia in a Spanish multicentre prospective survey.

OBJECTIVES: To update the knowledge of the epidemiology of fungaemia episodes in Spain, the species implicated and their in vitro antifungal susceptibilities. METHODS: Episodes were identified prospectively over 13 months at 44 hospitals. Molecular methods were used to determine the cryptic species inside the Candida parapsilosis and Candida glabrata complexes. Susceptibility to amphotericin B, anidulafungin, caspofungin, fluconazole, flucytosine, itraconazole, micafungin, posaconazole and voriconazole was determined by a microdilution colorimetric method. New species-specific clinical breakpoints (SSCBPs) for echinocandins, fluconazole and voriconazole were applied. RESULTS: The incidence of the 1357 fungaemia episodes evaluated was 0.92 per 1000 admissions. The incidence of Candida albicans fungaemia was the highest (0.41 episodes/1000 admissions), followed by Candida parapsilosis sensu stricto (0.22). Candida orthopsilosis was the fifth cause of fungaemia (0.02), outnumbered by Candida glabrata and Candida tropicalis. Interestingly, the incidence of fungaemia by C. parapsilosis was 11 and 74 times higher than that by C. orthopsilosis and Candida metapsilosis, respectively. Neither Candida nivariensis nor Candida bracarensis was isolated. Fungaemia was more common in non-intensive care unit settings (65.2%) and among elderly patients (46.4%), mixed fungaemia being incidental (1.5%). Overall susceptibility rates were 77.6% for itraconazole, 91.9% for fluconazole and 96.5%-99.8% for the other agents. Important resistance rates were only observed in C. glabrata for itraconazole (24.1%) and posaconazole (14.5%), and in Candida krusei for itraconazole (81.5%). CONCLUSIONS: Fungaemia is more common in non-critical patients. C. albicans is the most common species, followed by C. parapsilosis and C. glabrata. Nearly 90% of yeasts are susceptible to all antifungal agents tested. Resistance rates change moderately when applying the new SSCBPs.

Colonisation and infection due to Enterobacteriaceae producing plasmid-mediated AmpC ß-lactamases.

OBJECTIVES: To investigate the epidemiology and clinical features of infections caused by Enterobacteria producing plasmid-mediated AmpC ß-lactamases (pAmpC), which are emerging as a cause of resistance to extended-spectrum cephalosporins. METHODS: A prospective multicentre cohort of patients with infection/colonisation due to pAmpC-producing Enterobacteriaceae was performed in 7 Spanish hospitals from February throughout July 2009. pAmpCs were characterised by PCR and sequencing. RESULTS: 140 patients were included; organisms isolated were Escherichia coli (n = 100), Proteus mirabilis (n = 20), Klebsiella pneumoniae (n = 17), and others (n = 3). Overall, 90% had a chronic underlying condition. The acquisition was nosocomial in 43%, healthcare-associated in 41% (14% of those were nursing home residents), and community in 16%. Only 5% of patients had no predisposing feature for infection with multidrug-resistant bacteria. Nineteen percent of patients were bacteraemic. Inappropriate empirical therapy was administered to 81% of bacteraemic patients, who had a crude mortality rate of 48%. The most frequent enzyme was CMY-2 (70%, predominantly in E. coli and P. mirabilis) followed by DHA-1 (19%, predominantly in K. pneumoniae). CONCLUSION: pAmpC-producing Enterobacteriaceae caused nosocomial, healthcare-associated and community infections mainly in predisposed patients. Invasive infections were associated with high mortality which might be partly related to inappropriate empirical therapy.

Pneumonia in allogeneic stem cell transplantation recipients: a multicenter prospective study.

Pneumonia is a common cause of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) but updated and prospective information is partial. The aim of this nationwide prospective study is to determine the current epidemiology, etiology, and outcome of pneumonia in allo-HSCT recipients. From September-2003 to November-2005, 112 episodes in 427 consecutive allo-HSCT recipients were included (incidence 52.2 per 100 allo-HSCT/yr), and 72 of them (64.3%) were microbiologically defined pneumonia. Bacterial pneumonia (44.4%) was more frequent than fungal (29.2%) and viral pneumonia (19.4%). The most frequent microorganisms in each group were: Escherichia coli (n = 7, 8.9%), Streptococcus pneumoniae (n = 4, 5.0%), cytomegalovirus (n = 12, 15.4%), and Aspergillus spp. (n = 12, 15.4%). The development of pneumonia and chronic graft-versus-host disease (GVHD) was associated with increased mortality after allo-HSCT, and the probability of survival was significantly lower in patients that had at least one pneumonia episode (p < 0.01). Pneumonia development in the first 100 d after transplantation, fungal etiology, GVHD, acute respiratory failure, and septic shock were associated with increased mortality after pneumonia. Our results show that pneumonia remains a frequent infectious complication after allo-HSCT, contributing to significant mortality, and provide a large current experience with the incidence, etiology and outcome of pneumonia in these patients.

Valganciclovir as pre-emptive therapy for cytomegalovirus infection in allogeneic haematopoietic stem cell transplant recipients.

BACKGROUND: In haematopoietic stem cell transplant (HSCT) recipients, cytomegalovirus (CMV) infection contributes significantly to morbidity and mortality in both the early and late post-transplant period. Ganciclovir (GCV) is the treatment of choice for CMV, but requires intravenous administration, a fact that complicates its long-term use. Oral valganciclovir (VGCV) and intravenous GCV were recently shown to have similar efficacy for pre-emptive CMV treatment in solid organ transplant recipients, but relatively limited data are available in HSCT recipients. The objectives of this study were to compare the efficacy of VGCV versus intravenous GCV or foscarnet (FOS) for pre-emptive therapy of active CMV infection in allogeneic HSCT and to determine the incidence of adverse effects and relapses. METHODS: This was a 2-year prospective, comparative cohort study in which 237 episodes of pre-emptive therapy for active CMV infection were collected in 166 allogeneic HSCT recipients out of 717 included in the Spanish Network for Research on Infection in Transplantation (RESITRA/REIPI) database. Intravenous GCV was the first-line treatment in 112 episodes, intravenous FOS in 38 episodes, and oral VGCV in 87 episodes. RESULTS: VGCV was used as pre-emptive therapy for active CMV infection in 87 episodes. Excluding episodes considered as relapse, VGCV was as successful (91.4% [74/81]) as GCV (83.7% [87/14]) or FOS (75.8% [25/33]). In the VGCV arm, 7 (8.6%) cases were considered treatment failures: 4 (4.9%) because of adverse events, 1 (1.2%) due to persistent viral activity and 2 (2.5%) based on clinical decision. There were also 6 (7.4%) cases of recurrent infection. No statistically significant differences were found when compared to GCV or FOS. CONCLUSIONS: In allogeneic HSCT recipients, VGCV seemed effective and safe in the pre-emptive therapy of active CMV infection.

Epidemiology and antifungal susceptibility of bloodstream fungal isolates in pediatric patients: a Spanish multicenter prospective survey.

Data on fungemia epidemiology and antifungal susceptibility of isolates from children are scarce, leading frequently to pediatric empirical treatment based on available adult data. The present study was designed to update the epidemiological, mycological, and in vitro susceptibility data on fungal isolates from children with fungemia in Spain. All fungemia episodes were identified prospectively by blood culture over 13 months at 30 hospitals. Tests of susceptibility to amphotericin B, flucytosine, fluconazole, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, and micafungin were performed at participant institutions by a microdilution colorimetric method. New species-specific clinical breakpoints for fluconazole, voriconazole, and echinocandins were also applied. A total of 203 episodes of fungemia in 200 children were identified. A higher proportion of fungal isolates was from general wards than intensive care units (ICU). Candida parapsilosis (46.8%), Candida albicans (36.5%), Candida tropicalis (5.9%), Candida glabrata (3.9%), and Candida guilliermondii (2.5%) were the leading species. C. parapsilosis was the predominant species except in neonates. C. albicans was the most frequent in neonatal ICU settings (51.9%). Intravascular catheter (79.3%), surgery (35%), prematurity (30%), and neutropenia (11%) were the most frequent predisposing factors. Most Candida isolates (95.1%) were susceptible to all antifungals. When the new species-specific clinical breakpoints were applied, all C. parapsilosis isolates were susceptible to echinocandins except one, which was micafungin resistant. This is the largest published series of fungemia episodes in the pediatric setting. C. parapsilosis is the most prevalent species in Spain, followed by C. albicans and C. tropicalis. Resistance to azole and echinocandin agents is extremely rare among Candida species. The fluconazole resistance rate in Spain has decreased in the last 10 years.

Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort.

BACKGROUND: It is necessary to clarify the incidence of and risk factors for tuberculosis (TB) among solid-organ transplant (SOT) recipients as well as changes in the chronology, clinical presentation, and prognosis of the disease. METHODS: A total of 4388 SOT recipients were monitored prospectively at 16 transplant centers included in the Spanish Network for Research in Infectious Diseases (REIPI). TB episodes were studied, and the incidence rate was calculated. Certain variables were analyzed, by Cox regression analysis, as potential risk factors for TB. RESULTS: Among the 4388 SOT recipients, 21 cases of TB were reported (0.48%). The median duration of follow-up was 360 days (range, 0-720 days). The global incidence of TB was 512 cases per 10(5) patients per year (95% confidence interval [CI], 317-783), which was higher than that in the general population in Spain (18.9 cases per 10(5) inhabitants per year; relative risk [RR], 26.6). The highest incidence (2072 cases per 10(5) patients per year; 95% CI, 565-5306) was observed among lung transplant recipients (RR, 73.3). Of the TB cases, 95% occurred within the first year after transplant, and 76% were pulmonary forms. Crude mortality was 19.0%, and attributable mortality was 9.5%. Multivariate analysis identified recipient age (RR, 1.05; 95% CI, 1.0-1.1) and receipt of a lung transplant (RR, 5.6; 95%, 1.9-16.9) as independent risk factors. CONCLUSIONS: TB incidence is increased among SOT recipients. The risk factors identified were age and receipt of a lung transplant. TB-attributable mortality (9.5%) is still high.

Inactivation of the hmgA gene of Pseudomonas aeruginosa leads to pyomelanin hyperproduction, stress resistance and increased persistence in chronic lung infection.

Clinical isolates of Pseudomonas aeruginosa that hyperproduce a dark-brown pigment are quite often found in the lungs of chronically infected patients, suggesting that they may have an adaptive advantage in chronic infections. We have screened a library of random transposon insertions in P. aeruginosa. Transposon insertions resulting in the hyperproduction of a dark-brown pigment were found to be located in the hmgA gene, which putatively encodes the enzyme homogentisate-1,2-dioxygenase. Complementation studies indicate that hmgA disruption is responsible for the hyperproduction of pyomelanin in both laboratory and clinical isolates. A relationship between hmgA disruption and adaptation to chronic infection was explored and our results show that the inactivation of hmgA produces a slight reduction of killing ability in an acute murine model of lung infection. On the other hand, it also confers decreased clearance and increased persistence in chronic lung infections. Whether pyomelanin production is the cause of the increased adaptation to chronicity or just a side effect of hmgA inactivation is a question to be studied in future; however, this adaptation is consistent with the higher resistance to oxidative stress conferred in vitro by the pyomelanin pigment. Our results clearly demonstrate that hmgA inactivation leads to a better adaptation to chronic infection, and strongly suggest that this mechanism may be exploited in naturally occurring P. aeruginosa strains.

Valganciclovir as treatment for cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection causes morbidity in solid organ transplant (SOT) recipients, either by direct injury or in association with chronic allograft rejection or other opportunistic infections. Ganciclovir is the treatment of choice, but this agent requires intravenous administration, which affects its feasibility for long-term use. Valganciclovir, which has an oral bioavailability of 60%, has proven to be useful for prophylaxis of CMV infection in high-risk SOT recipients and for treating retinitis in persons with acquired immunodeficiency syndrome. OBJECTIVE: To compare the efficacy of valganciclovir (alone or as sequential therapy after a regimen of intravenous ganciclovir) with intravenous ganciclovir alone for preemptive therapy or treatment of CMV disease (viral syndrome or focal disease) in SOT recipients and to determine the incidence of adverse effects and relapses. METHODS: In this 2-year prospective, comparative cohort study, 376 episodes of preemptive therapy or treatment of CMV disease were recorded among 334 of 3467 SOT recipients included in the Spanish Network for Research on Infection in Transplantation (RESITRA) database. Intravenous ganciclovir was the first-line treatment in 170 episodes; valganciclovir followed by intravenous ganciclovir was administered in 82 episodes, and valganciclovir alone was administered in 112 episodes. RESULTS: Valganciclovir was used as preemptive therapy or treatment for CMV disease in 84 and 28 episodes, respectively. Duration of treatment was longer in valganciclovir recipients than in ganciclovir recipients for both preemptive therapy (21 vs. 15 days; P < .001) or viral syndrome treatment (21 vs. 18 days; P < .01). In the valganciclovir arm, 94 (83.9%) of 112 episodes were treated successfully, with no statistical difference in the success rates versus the ganciclovir arm (85.8%) or ganciclovir-valganciclovir arm (95.1%). Eighteen episodes (16.1%) treated with valganciclovir were considered to have resulted in treatment failure (because of persistent antigenemia in 4 [3.6%], on the basis of clinical decision in 7 [6.2%], and because of recurrent disease in 7 [6.2%]). There were no incidents in which valganciclovir treatment was withdrawn because of toxicity. CONCLUSION: Valganciclovir is safe and useful for preemptive therapy and treatment of CMV disease.

Pseudomonas aeruginosa RsmA plays an important role during murine infection by influencing colonization, virulence, persistence, and pulmonary inflammation.

The ability of Pseudomonas aeruginosa to cause a broad range of infections in humans is due, at least in part, to its adaptability and its capacity to regulate the expression of key virulence genes in response to specific environmental conditions. Multiple two-component response regulators have been shown to facilitate rapid responses to these environmental conditions, including the coordinated expression of specific virulence determinants. RsmA is a posttranscriptional regulatory protein which controls the expression of a number of virulence-related genes with relevance for acute and chronic infections. Many membrane-bound sensors, including RetS, LadS, and GacS, are responsible for the reciprocal regulation of genes associated with acute infection and chronic persistence. In P. aeruginosa this is due to sensors influencing the expression of the regulatory RNA RsmZ, with subsequent effects on the level of free RsmA. While interactions between an rsmA mutant and human airway epithelial cells have been examined in vitro, the role of RsmA during infection in vivo has not been determined yet. Here the function of RsmA in both acute and chronic models of infection was examined. The results demonstrate that RsmA is involved in initial colonization and dissemination in a mouse model of acute pneumonia. Furthermore, while loss of RsmA results in reduced colonization during the initial stages of acute infection, the data show that mutation of rsmA ultimately favors chronic persistence and results in increased inflammation in the lungs of infected mice.

Inactivation of the mismatch repair system in Pseudomonas aeruginosa attenuates virulence but favors persistence of oropharyngeal colonization in cystic fibrosis mice.

The inactivation of the mismatch repair (MMR) system of Pseudomonas aeruginosa modestly reduced in vitro fitness, attenuated virulence in murine models of acute systemic and respiratory infections, and decreased the initial oropharyngeal colonization potential. In contrast, the inactivation of the MMR system favored long-term persistence of oropharyngeal colonization in cystic fibrosis mice. These results may help in understanding the reasons for the low and high prevalences, respectively, of hypermutable P. aeruginosa strains in acute and chronic infections.

Characterization of a large outbreak by CTX-M-1-producing Klebsiella pneumoniae and mechanisms leading to in vivo carbapenem resistance development.

All extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae isolates from patients admitted to and adult intensive care unit were prospectively documented from 2002 to 2005, when a large outbreak (51 patients affected) of multiresistant ESBL-producing Klebsiella pneumoniae infection was detected. The involvement of a single K. pneumoniae clone was demonstrated by pulsed-field gel electrophoresis. In addition to the ESBL-mediated resistance, the epidemic strain uniformly showed cross-resistance to ciprofloxacin, gentamicin, tobramycin, trimethoprim-sulfamethoxazole, and tetracycline, whereas resistance to the beta-lactam-beta-lactamase inhibitor combinations was variable. The ESBL involved was CTX-M-1, as demonstrated by isoelectric focusing, PCR amplification, and sequencing. CTX-M-1 as well as the aminoglycoside resistance determinants were encoded in a 50-kb plasmid that could be transferred to Escherichia coli only by transformation. In two of the infected patients, carbapenem resistance development (MICs of 8 to 12, 16, and >32 microg/ml for imipenem, meropenem, and ertapenem, respectively) was documented, both in clinical samples and in intestinal colonization studies. The analysis of the outer membrane proteins of the carbapenem-susceptible and -resistant isolates revealed that the former expressed only one of the two major porins, OmpK36, whereas the latter did not express either of them. In one of the cases, the lack of expression of OmpK36 was demonstrated to be mediated by the interruption of the coding sequence by the insertion sequence IS26. This is the first report of a large outbreak of CTX-M-1-producing Enterobacteriaceae and, curiously, the first documented description in the literature of CTX-M-1 in K. pneumoniae, despite the fact that this enzyme has been found in multiple species. Furthermore, we document and characterize for the first time carbapenem resistance development in CTX-M-1-producing Enterobacteriaceae.

Effect of porins and plasmid-mediated AmpC beta-lactamases on the efficacy of beta-lactams in rat pneumonia caused by Klebsiella pneumoniae.

The in vivo activities of imipenem, meropenem, and cefepime were studied in a model of rat pneumonia caused by a plasmid-mediated AmpC beta-lactamase ACT-1-producing Klebsiella pneumoniae strain (K. pneumoniae strain 12) and a derivative porin-deficient mutant (K. pneumoniae strain 12dp). No differences between these activities were seen with K. pneumoniae 12. Only meropenem showed an activity slightly better than that of imipenem with K. pneumoniae 12dp.