New Predictive Equation for the Estimation of Plasma Concentrations of Formed Colistin in Patients Treated with Colistimethate Sodium for Multidrug-Resistant Gram-Negative Bacterial Infections.

BACKGROUND: The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. METHODS: The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with Css,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured Css,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. RESULTS: In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) Css,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of Css,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (Css,avg <1.5 mg/L). CONCLUSIONS: The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.

Impact of multidrug resistance on the virulence and fitness of Pseudomonas aeruginosa: a microbiological and clinical perspective.

Pseudomonas aeruginosa is one of the most common nosocomial pathogens and part of the top emergent species associated with antimicrobial resistance that has become one of the greatest threat to public health in the twenty-first century. This bacterium is provided with a wide set of virulence factors that contribute to pathogenesis in acute and chronic infections. This review aims to summarize the impact of multidrug resistance on the virulence and fitness of P. aeruginosa. Although it is generally assumed that acquisition of resistant determinants is associated with a fitness cost, several studies support that resistance mutations may not be associated with a decrease in virulence and/or that certain compensatory mutations may allow multidrug resistance strains to recover their initial fitness. We discuss the interplay between resistance profiles and virulence from a microbiological perspective but also the clinical consequences in outcomes and the economic impact.

A case-control study of the clinical and economic impact of infections caused by Carbapenemase-producing Enterobacterales (CPE).

PURPOSE: The aim was to analyse the clinical and economic impact of carbapenemase-producing Enterobacterales (CPE) infections. METHODS: Case-control study. Adult patients with CPE infections were considered cases, while those with non-CPE infections were controls. Matching criteria were age (± 5 years), sex, source of infection and microorganism (ratio 1:2). Primary outcome was 30-day mortality. Secondary outcomes were 90-day mortality, clinical failure, hospitalisation costs and resource consumption. RESULTS: 246 patients (82 cases and 164 controls) were included. Klebsiella pneumoniae OXA-48 was the most common microorganism causing CPE infections. CPE cases had more prior comorbidities (p = 0.007), septic shock (p = 0.003), and were more likely to receive inappropriate empirical and definitive antibiotic treatment (both p < 0.001). Multivariate analysis identified septic shock and inappropriate empirical treatment as independent predictors for 7-day and end-of-treatment clinical failure, whereas Charlson Index and septic shock were associated with 30- and 90-day mortality. CPE infection was independently associated with early clinical failure (OR 2.18, 95% CI, 1.03-4.59), but not with end-of-treatment clinical failure or 30- or 90-day mortality. In terms of resource consumption, hospitalisation costs for CPE were double those of the non-CPE group. CPE cases had longer hospital stay (p < 0.001), required more long-term care facilities (p < 0.001) and outpatient parenteral antibiotic therapy (p = 0.007). CONCLUSIONS: The CPE group was associated with worse clinical outcomes, but this was mainly due to a higher comorbidity burden, more severe illness, and more frequent inappropriate antibiotic treatment rather than resistance patterns as such. However, the CPE group consumed more healthcare resources and incurred higher costs.

Efficacy and safety of oral fosfomycin for asymptomatic bacteriuria in kidney transplant recipients: Results from a Spanish multicenter cohort.

Current guidelines recommend against systematic screening or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of post-transplant AB, particularly due to the emergence of multidrug-resistant (MDR) uropathogens. Available clinical evidence supporting its use in this specific setting, however, remains scarce. We performed a retrospective study in 14 Spanish institutions from January 2005 to December 2017. Overall, 137 episodes of AB diagnosed in 133 KT recipients treated with oral fosfomycin (calcium and trometamol salts) with a test-of-cure urine culture within the first 30 days were included. Median time from transplantation to diagnosis was 3.1 months (interquartile range [IQR]: 1.1 - 10.5). Most episodes (96.4% [132/137]) were caused by gram-negative bacteria (GNB), and 56.9% (78/137) were categorized as MDR (extended-spectrum ß-lactamase-producing Enterobacterales [20.4%] and carbapenem-resistant GNB [2.9%]). Rate of microbiological failure at month 1 was 40.1% (95% confidence interval [95%CI]: 31.9 - 48.9) for the whole cohort and 42.3% (95%CI: 31.2 - 54.0) for episodes due to MDR pathogens. Previous urinary tract infection (odds ratio [OR]: 2.42; 95%CI: 1.11 - 5.29; P-value = 0.027) and use of fosfomycin as salvage therapy (OR: 8.31; 95%CI: 1.67 - 41.35; P-value = 0.010) were predictors of microbiological failure. No severe treatment-related adverse event were detected. Oral fosfomycin appears to be a suitable and safe alternative for the treatment (if indicated) of AB after KT, including those episodes due to MDR uropathogens.

Significant increase of CTX-M-15-ST131 and emergence of CTX-M-27-ST131 Escherichia coli high-risk clones causing healthcare-associated bacteraemia of urinary origin in Spain (ITUBRAS-2 project).

OBJECTIVES: To assess the microbiological characteristics of Escherichia coli causing healthcare-associated bacteraemia of urinary origin (HCA-BUO) in Spain (ITUBRAS-2 project), with particular focus on ESBL producers and isolates belonging to ST131 high-risk clone (HiRC). Clinical characteristics and outcomes associated with ST131 infection were investigated. METHODS: A total of 222 E. coli blood isolates were prospectively collected from patients with HCA-BUO from 12 tertiary-care hospitals in Spain (2017-19). Antimicrobial susceptibility and ESBL/carbapenemase production were determined. ST131 subtyping was performed. A subset of 115 isolates were selected for WGS to determine population structure, resistome and virulome. Clinical charts were reviewed. RESULTS: ESBL-producing E. coli prevalence was 30.6% (68/222). ST131 represented 29.7% (66/222) of E. coli isolates and accounted for the majority of ESBL producers (46/68, 67.6%). The C2/H30-Rx subclone accounted for most ST131 isolates (44/66) and was associated with CTX-M-15 (37/44) and OXA-1 enzymes (27/44). Cluster C1-M27 was identified in 4/10 isolates belonging to subclade C1/H30-R1 and associated with CTX-M-27. Additionally, ST131 isolates showed a high content of other acquired resistance genes, and clade C/ST131 isolates carried characteristic QRDR mutations. They were categorized as uropathogenic E. coli and had higher aggregate virulence scores. ST131 infection was associated with more complex patients, prior use of cephalosporins and inadequate empirical treatment but was not associated with worse clinical outcomes. CONCLUSIONS: ST131 HiRC is the main driver of ESBL-producing E. coli causing HCA-BUO in Spain, mainly associated with the expansion of subclade CTX-M-15-C2/H30-Rx and the emergence of CTX-M-27-C1/H30-R1 (Cluster C1-M27).

Comparison of Hospitalized Coronavirus Disease 2019 and Influenza Patients Requiring Supplemental Oxygen in a Cohort Study: Clinical Impact and Resource Consumption.

BACKGROUND: To compare clinical characteristics, outcomes, and resource consumption of patients with coronavirus disease 2019 (COVID-19) and seasonal influenza requiring supplemental oxygen. METHODS: Retrospective cohort study conducted at a tertiary-care hospital. Patients admitted because of seasonal influenza between 2017 and 2019, or with COVID-19 between March and May 2020 requiring supplemental oxygen were compared. Primary outcome: 30-day mortality. Secondary outcomes: 90-day mortality and hospitalization costs. Attempted sample size to detect an 11% difference in mortality was 187 patients per group. RESULTS: COVID-19 cases were younger (median years of age, 67; interquartile range [IQR] 54-78 vs 76 [IQR 64-83]; P < .001) and more frequently overweight, whereas influenza cases had more hypertension, immunosuppression, and chronic heart, respiratory, and renal disease. Compared with influenza, COVID-19 cases had more pneumonia (98% vs 60%, <.001), higher Modified Early Warning Score (MEWS) and CURB-65 (confusion, blood urea nitrogen, respiratory rate, systolic blood pressure, and age >65 years) scores and were more likely to show worse progression on the World Health Organization ordinal scale (33% vs 4%; P < .001). The 30-day mortality rate was higher for COVID-19 than for influenza: 15% vs 5% (P = .001). The median age of nonsurviving cases was 81 (IQR 74-88) and 77.5 (IQR 65-84) (P = .385), respectively. COVID-19 was independently associated with 30-day (hazard ratio [HR], 4.6; 95% confidence interval [CI], 2-10.4) and 90-day (HR, 5.2; 95% CI, 2.4-11.4) mortality. Sensitivity and subgroup analyses, including a subgroup considering only patients with pneumonia, did not show different trends. Regarding resource consumption, COVID-19 patients had longer hospital stays and higher critical care, pharmacy, and complementary test costs. CONCLUSIONS: Although influenza patients were older and had more comorbidities, COVID-19 cases requiring supplemental oxygen on admission had worse clinical and economic outcomes.

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients-Results of a Spanish multicenter cohort.

Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram-negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended-spectrum ß-lactamase-producing Enterobacteriaceae [14%] or carbapenem-resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5-2) was administered for a median of 7 days (IQR: 3-10). Clinical cure (remission of UTI-attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow-up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98-112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs.

Fosfomycin Trometamol versus Comparator Antibiotics for the Treatment of Acute Uncomplicated Urinary Tract Infections in Women: A Systematic Review and Meta-Analysis.

PURPOSE: We performed a systematic review and meta-analysis to compare the effectiveness and safety profile of fosfomycin vs comparator antibiotics in women with acute uncomplicated cystitis. MATERIALS AND METHODS: Relevant databases were searched using methods recommended by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. We assessed the risk of bias and confounders. The study primary end point was clinical or microbiological success, defined as complete (cure) and/or incomplete resolution of symptoms at the end of treatment (improvement) and/or microbiological eradication. RESULTS: After screening 539 articles 15 were included which recruited a total of 2,295 adult female patients. Of the studies 14 were used for microbiological eradication analysis. We used 11 of the 15 articles in a total of 1,976 patients for clinical resolution and 11 in a total of 1,816 patients for safety outcome analysis. No difference was found for clinical resolution in all comparators combined in 11 randomized controlled trials in a total of 1,976 patients (OR 1.16, 95% CI 0.91-1.49, p=0.13). No difference was found for microbiological eradication in 14 randomized controlled trials in a total of 2,052 patients (OR 1.03, 95% CI 0.83-1.30, p=0.09) or for safety outcome in 11 randomized controlled trials in a total of 1,816 patients (OR 1.17, 95% CI 0.86-1.58, p=0.33). Most adverse effects reported for fosfomycin were transient and single dose therapy seems to have resulted in better patient compliance. CONCLUSIONS: Single dose oral fosfomycin trometamol is equal to comparator regimens in terms of clinical and microbiological effectiveness and safety in women with microbiologically confirmed and/or clinically suspected, acute uncomplicated cystitis. It is associated with high patient compliance.

COVID-19 in Grade 4-5 Chronic Kidney Disease Patients.

INTRODUCTION: Chronic kidney disease (CKD) increases the risk of mortality during coronavirus disease 2019 (COVID-19) episodes, and some reports have underlined the high incidence and severity of this infection in dialysis patients. Information on COVID-19 in nondialysis CKD patients is not available yet. CASE REPORTS: Here we present 7 patients with grade 4-5 CKD who developed symptomatic COVID-19; they comprise 2.6% of our 267 advanced CKD patients. The estimated GFR was between 12 and 20 mL/min during the month prior to COVID-19. The 3 major symptoms were fever, cough, and dyspnea, and 5 patients showed bilateral pneumonia. Hydroxychloroquine, azithromycin, ceftriaxone, and steroids were the most frequently prescribed drugs. Two patients needed noninvasive mechanical ventilation. All patients showed minimal to moderate kidney function deterioration during admission, with an eGFR decline below 5 mL/min in 6 cases. No patient required acute dialysis. Six patients were discharged alive and remained dialysis free athe t the time of reporting, and one 76-year-old patient died. CONCLUSIONS: COVID-19 affects grade 4-5 CKD patients, but prognosis may be acceptable if prompt supportive measures are applied. These findings should be confirmed in larger cohorts, and further observations will be needed to understand the full spectrum of clinical features and the optimal approach to COVID-19 in patients with advanced CKD.

Linezolid Dosing in Patients With Liver Cirrhosis: Standard Dosing Risk Toxicity.

BACKGROUND: Limited data regarding altered linezolid pharmacokinetics in patients with liver cirrhosis are available. The objective of this study was to evaluate the pharmacokinetics, efficacy and safety of linezolid in cirrhotic patients. METHODS: A case-control 1:1 study of patients undergoing linezolid therapeutic drug monitoring was conducted between January 2015 and June 2017. Cases with liver cirrhosis were matched with controls by age, body weight, comorbidities, renal function, and intensive care unit (ICU) admission. RESULTS: Fifty-two patients were included, 26 in each group. Patients with Child-Pugh Scores A, B, and C were 1 (3.8%), 13 (50.0%), and 12 (46.2%), respectively. Cases had higher median linezolid trough plasma concentrations than controls [20.6 (17.4) versus 2.7 (11.3); P < 0.001)] and more frequently achieved an optimal pharmacodynamic index [26 (100%) versus 16 (61.5%); P = 0.002]. In addition, potentially toxic concentrations and treatment discontinuation due to overexposure and hematological toxicity were also more frequently seen in cirrhotic patients. Overall clinical cure rate was high (67.4%), and in-hospital mortality was 28.8%. No differences in clinical outcomes were observed between both groups. CONCLUSIONS: Linezolid showed a high clinical cure rate. Nevertheless, plasma concentrations and treatment discontinuation due to hematological toxicity were higher in cirrhotic patients. Liver cirrhosis may influence linezolid pharmacokinetics and question the use of standard doses. Therapeutic drug monitoring of linezolid would be valuable in these patients.

Risk of hospital readmission and associated factors after a positive sample for a multidrug-resistant microorganism.

BACKGROUND: To determine the risk of hospital readmission and associated factors in patients with a positive sample for multidrug-resistant microorganisms (MRM) and to analyze whether there is a higher risk of hospital readmission with some of the more common MRM. METHODS: Retrospective cohort study (2012-16) performed in a tertiary-care teaching hospital in Barcelona. Patients were divided into two groups, depending on the presence or absence of an MRM-positive sample during hospital admission. Logistic regression models were used to estimate the risk of hospital readmission in the first 30 and 90 days, and the first year for patients with an MRM-positive sample compared with those without. The models were stratified by the presence or absence of an MRM-positive sample and by grouped Charlson comorbidity index. RESULTS: We included 983 patients with an MRM-positive sample and 39 323 patients without. The risk of hospital readmission in the first 30 days was 41% higher in admitted patients with an MRM-positive sample (95%CI=1.17 to 1.69) than in those without. Stratified models showed similar results to the overall results for all Charlson comorbidity index groups. When the models were stratified by the presence of an MRM-positive sample, methicillin-resistant Staphylococcus aureus showed the highest risk of readmissions within the more common MRM [103% (95%CI=1.10 to 3.75)]. CONCLUSION: MRMs seem to be an important risk factor for hospital readmissions both among patients with and without comorbidities. Specific types of MRM may represent a higher risk for hospital readmissions than other MRMs, depending on the particular environment or hospital.

A Before-and-After Study of the Effectiveness of an Antimicrobial Stewardship Program in Critical Care.

We evaluated the use of antimicrobials expressed as defined daily doses (DDDs) per 1,000 patient days and days of therapy (DOT) per 100 occupied bed-days in a intensive care unit (ICU) of a general hospital in Barcelona, Spain, before and after implementation of an antimicrobial stewardship (AMS) program (2007 to 2010 versus 2011 to 2015). The quarterly costs of antimicrobials used in the ICU and its weight in the overall hospital costs of antimicrobials were calculated. The effect of the applied AMS program on DDDs and DOT time series data was analyzed by means of intervention time series analysis. A total of 5,002 patients were included (1,971 for the first [before] period and 3,031 for the second [after] period). The percentage of patients treated with one or more antimicrobials decreased from 88.6 to 77.2% (P < 0.001). DDDs decreased from 246.8 to 192.3 (mean difference, -54.5; P = 0.001) and DOT from 66.7 to 54.6 (mean difference, -12.1; P = 0.066). The mean cost per trimester decreased from €115,543 to €73,477 (mean difference, -42,065.4 euros; P < 0.001), and the percentage of ICU antimicrobials cost with respect to the total cost of hospital antimicrobials decreased from 28.5 to 22.8% (mean difference, -5.59; P = 0.023). Implementation of an AMS program in the ICU was associated with a marked reduction in the use of antimicrobials, with cost savings close to one million euros since its implementation. An AMS program can have a significant impact on optimizing antimicrobial use in critical care practice.

The Not-So-Good Prognosis of Streptococcal Periprosthetic Joint Infection Managed by Implant Retention: The Results of a Large Multicenter Study.

BACKGROUND.: Streptococci are not an infrequent cause of periprosthetic joint infection (PJI). Management by debridement, antibiotics, and implant retention (DAIR) is thought to produce a good prognosis, but little is known about the real likelihood of success. METHODS.: A retrospective, observational, multicenter, international study was performed during 2003-2012. Eligible patients had a streptococcal PJI that was managed with DAIR. The primary endpoint was failure, defined as death related to infection, relapse/persistence of infection, or the need for salvage therapy. RESULTS.: Overall, 462 cases were included (median age 72 years, 50% men). The most frequent species was Streptococcus agalactiae (34%), and 52% of all cases were hematogenous. Antibiotic treatment was primarily using ß-lactams, and 37% of patients received rifampin. Outcomes were evaluable in 444 patients: failure occurred in 187 (42.1%; 95% confidence interval, 37.5%-46.7%) after a median of 62 days from debridement; patients without failure were followed up for a median of 802 days. Independent predictors (hazard ratios) of failure were rheumatoid arthritis (2.36), late post-surgical infection (2.20), and bacteremia (1.69). Independent predictors of success were exchange of removable components (0.60), early use of rifampin (0.98 per day of treatment within the first 30 days), and long treatments (≥21 days) with ß-lactams, either as monotherapy (0.48) or in combination with rifampin (0.34). CONCLUSIONS.: This is the largest series to our knowledge of streptococcal PJI managed by DAIR, showing a worse prognosis than previously reported. The beneficial effects of exchanging the removable components and of ß-lactams are confirmed and maybe also a potential benefit from adding rifampin.

Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections.

Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (Cmin ss) and at the end of the CMS infusion (Cmax ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; Cmin ss and Cmax ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.

Genomics and Susceptibility Profiles of Extensively Drug-Resistant Pseudomonas aeruginosa Isolates from Spain.

This study assessed the molecular epidemiology, resistance mechanisms, and susceptibility profiles of a collection of 150 extensively drug-resistant (XDR) Pseudomonas aeruginosa clinical isolates obtained from a 2015 Spanish multicenter study, with a particular focus on resistome analysis in relation to ceftolozane-tazobactam susceptibility. Broth microdilution MICs revealed that nearly all (>95%) of the isolates were nonsusceptible to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem, and ciprofloxacin. Most of them were also resistant to tobramycin (77%), whereas nonsusceptibility rates were lower for ceftolozane-tazobactam (31%), amikacin (7%), and colistin (2%). Pulsed-field gel electrophoresis-multilocus sequence typing (PFGE-MLST) analysis revealed that nearly all of the isolates belonged to previously described high-risk clones. Sequence type 175 (ST175) was detected in all 9 participating hospitals and accounted for 68% (n = 101) of the XDR isolates, distantly followed by ST244 (n = 16), ST253 (n = 12), ST235 (n = 8), and ST111 (n = 2), which were detected only in 1 to 2 hospitals. Through phenotypic and molecular methods, the presence of horizontally acquired carbapenemases was detected in 21% of the isolates, mostly VIM (17%) and GES enzymes (4%). At least two representative isolates from each clone and hospital (n = 44) were fully sequenced on an Illumina MiSeq. Classical mutational mechanisms, such as those leading to the overexpression of the ß-lactamase AmpC or efflux pumps, OprD inactivation, and/or quinolone resistance-determining regions (QRDR) mutations, were confirmed in most isolates and correlated well with the resistance phenotypes in the absence of horizontally acquired determinants. Ceftolozane-tazobactam resistance was not detected in carbapenemase-negative isolates, in agreement with sequencing data showing the absence of ampC mutations. The unique set of mutations responsible for the XDR phenotype of ST175 clone documented 7 years earlier were found to be conserved, denoting the long-term persistence of this specific XDR lineage in Spanish hospitals. Finally, other potentially relevant mutations were evidenced, including those in penicillin-binding protein 3 (PBP3), which is involved in ß-lactam (including ceftolozane-tazobactam) resistance, and FusA1, which is linked to aminoglycoside resistance.

Impact of colistin plasma levels on the clinical outcome of patients with infections caused by extremely drug-resistant Pseudomonas aeruginosa.

BACKGROUND: Colistin has a narrow therapeutic window with nephrotoxicity being the major dose-limiting adverse effect. Currently, the optimal doses and therapeutic plasma levels are unknown. METHODS: Prospective observational cohort study, including patients infected by colistin-susceptible P. aeruginosa treated with intravenous colistimethate sodium (CMS). Clinical data and colistin plasma levels at steady-state (Css) were recorded. The primary and secondary end points were clinical cure and 30-day all-cause mortality. RESULTS: Ninety-one patients were included. Clinical cure was observed in 72 (79%) patients. The mean (SD) Css was 1.49 (1.4) mg/L and 2.42 (1.5) mg/L (p = 0.01) in patients who achieved clinical cure and those who not, respectively. Independent risk factors for clinical failure were male sex (OR 5.88; 95% CI 1.09-31.63), APACHE II score (OR 1.15; 95% CI 1.03-1.27) and nephrotoxicity at the EOT (OR 9.13; 95% CI 95% 2.06-40.5). The 30-day mortality rate was 30.8%. Risk factors for 30-day mortality included the APACHE II score (OR 1.98; 95% CI 1-1.20), the McCabe score (OR 2.49; 95% CI 1.14-5.43) and the presence of nephrotoxicity at the end of treatment (EOT) (OR 3.8; 95% CI 1.26-11.47). CONCLUSION: In this series of patients with infections caused by XDR P. aeruginosa infections, Css is not observed to be related to clinical outcome.

Characterization and rapid control of a vancomycin-resistant Enterococcus faecium (VREF) outbreak in a renal transplant unit in Spain: The environment matters.

OBJECTIVE: To describe a clonal outbreak due to vancomycin-resistant Enterococcus faecium (VREF) in the nephrology and renal transplant unit of a tertiary teaching hospital in Barcelona, Spain, and to highlight how active patient and environment surveillance cultures, as well as prompt and directed intervention strategies, mainly environmental, helped to successfully bring it under control. PATIENTS AND METHODS: A study was conducted on patients admitted to the nephrology ward with any culture positive for VREF over a 6-month period (August 2012-January 2013). Based on the identification of a clonal link between the isolates, weekly rectal screening using swabs was implemented for all patients, as well as environmental cultures and cleaning of medical equipment and the ward. VREF isolates were identified by MicroScan and confirmed by Etest. Bacterial identification was confirmed by MALDI-TOF MS. The presence of van genes, and esp and hyl virulence genes was determined using PCR. The clonal relationship between the isolates was studied first with DiversiLab (bioMérieux), and then by PFGE-Smal and MLST. A two-tier sequence of infection control measures was implemented. RESULTS: During the study period, VREF was isolated from 13 patients. All cases were colonized with no criteria for infection. VREF isolates were also extensively recovered from the environment and medical equipment. Isolates carried the vanA gene, and were multidrug-resistant, including high-level resistance (MIC >16mg/L) to vancomycin and teicoplanin. Molecular analysis showed that all VREF isolates belonged to sequence type 17 (ST17) carrying hyl virulence genes. After implementing infection control measures in a two-tier sequence, and reinforcing particularly environmental and medical equipment cleaning, no further cases were detected in the follow-up year. CONCLUSION: A clonal outbreak of VREF-ST17 involving only colonization is reported. The prompt implementation of aggressive infection control measures in patients and the environment was effective in controlling the outbreak and avoided the potential emergence of infection among patients.

Executive summary of management of prosthetic joint infections. Clinical practice guidelines by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC).

The incidence of prosthetic joint infection (PJI) is expected to increase in the coming years. PJI has serious consequences for patients, and high costs for the health system. The complexity of these infections makes it necessary to organize the vast quantity of information published in the last several years. The indications for the choice of a given surgical strategy and the corresponding antimicrobial therapy are specifically reviewed. The authors selected clinically relevant questions and then reviewed the available literature in order to give recommendations according to a pre-determined level of scientific evidence. The more controversial aspects were debated, and the final composition was agreed at an ad hoc meeting. Before its final publication, the manuscript was made available online in order that all SEIMC members were able to read it and make comments and suggestions.

CTX-M-15-H30Rx-ST131 subclone is one of the main causes of healthcare-associated ESBL-producing Escherichia coli bacteraemia of urinary origin in Spain.

OBJECTIVES: The objective of this study was to assess the prevalence and molecular epidemiology of ESBL-producing Escherichia coli causing healthcare-associated (HCA) and community-associated (CA) bacteraemia of urinary origin (BUO) in Spain. METHODS: An observational cohort study was conducted at eight hospitals from different Spanish geographical areas (2010-11). BUO episodes (n = 425) were classified as HCA (n = 215) and CA (n = 210), and one blood isolate per episode was collected. Susceptibility testing was performed, ESBLs were screened by double-disc diffusion test and ESBL and OXA-1 genes were characterized (PCR and sequencing). Population structure (phylogenetic groups, XbaI-PFGE and MLST) and ST131 subtyping (PCR) were determined. Virulence genes were detected by PCR and virulence score, profiles and extraintestinal pathogenic E. coli (ExPEC) status calculated. RESULTS: ESBL-producing E. coli prevalence was 9.2% (39/425). ESBL-producing E. coli episodes were significantly associated with HCA-BUO episodes [14% (30/215) versus 4.3% (9/210); P = 0.001]. The highest non-susceptibility proportions corresponded to ciprofloxacin (97.4%), amoxicillin/clavulanate (74.4%), co-trimoxazole (69.2%) and tobramycin (61.5%). Of the 39 ESBL-producing E. coli isolates, 34 produced CTX-M enzymes (21 CTX-M-15, 11 CTX-M-14 and 2 CTX-M-1). Fifteen STs were identified, the B2-ST131 clone being the most prevalent (54%; 21/39). All ST131 isolates were ExPEC and had the highest virulence scores, but they showed less diversity in virulence profiles than other STs. The H30Rx subclone accounted for most ST131 isolates (20/21), co-produced CTX-M-15 (20/20) and OXA-1 (19/20) enzymes and was associated with HCA episodes (16/20). CONCLUSIONS: The CTX-M-15-ST131-H30Rx subclone is a relevant MDR pathogen causing BUO, mainly HCA episodes. The dominance of this subclone with comparatively less diversity of virulence profiles reflects the spread of a successful and MDR ESBL ST131 lineage in Spain.

Pharmacokinetics of micafungin in patients with pre-existing liver dysfunction: A safe option for treating invasive fungal infections.

In this prospective observational study performed in 12 hospitalized patients with proven or suspected invasive fungal infection treated for a mean of 14 days with micafungin (MCF), 8 of whom with pre-existing liver function impairment, plasma levels of MCF at steady state were not correlated with liver function tests at the beginning of treatment. Liver function remained stable or even improved in all patients, except in one in which MCF was discontinued due to liver toxicity.