Publications by authors named "Santiago Grau"

138 Publications

Nebulized micafungin treatment for / tracheobronchitis in lung transplant recipients.

Antimicrob Agents Chemother 2021 Mar 15. Epub 2021 Mar 15.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

cause infections with high mortality in lung transplant recipients. Treatment is challenging due to antimicrobial resistance. We describe two cases of tracheobronchitis in lung transplant recipients successfully treated with nebulized micafungin. This antifungal was well tolerated and achieved high concentrations in epithelial lining fluid up to 14 hours after nebulization without significant plasma concentrations. Nebulized micafungin could be a safe and effective option for the treatment of fungal tracheobronchitis.
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http://dx.doi.org/10.1128/AAC.02174-20DOI Listing
March 2021

Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole.

Infect Drug Resist 2021 24;14:719-722. Epub 2021 Feb 24.

Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain.

Background: Skeletal involvement of is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient.

Case Presentation: We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations.

Conclusion: To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.
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http://dx.doi.org/10.2147/IDR.S294299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917311PMC
February 2021

Evolution of Antimicrobial Consumption During the First Wave of COVID-19 Pandemic.

Antibiotics (Basel) 2021 Jan 29;10(2). Epub 2021 Jan 29.

Pharmacy Department, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Hospital del Mar, Parc de Salut Mar, Passeig Maritim 25-29, 08003 Barcelona, Spain.

The first wave of COVID-19 pandemic may have significantly impacted antimicrobial consumption in hospitals. The objective of this study was to assess the evolution of antimicrobial consumption during this period: A retrospective quasi-experimental before-after study was conducted in a Spanish tertiary care hospital. The study compared two periods: pre-pandemic, from January 2018 to February 2020, and during the COVID-19 pandemic from March to June 2020. Antimicrobial consumption was analyzed monthly as defined daily doses (DDD)/100 bed-days and overall hospital and ICU consumption were evaluated. An increase in the hospital consumption was noticed. Although only ceftaroline achieved statistical significance ( = 0.014), a rise was observed in most of the studied antimicrobials. A clear temporal pattern was detected. While an increase in ceftriaxone and azithromycin was observed during March, an increment in the consumption of daptomycin, carbapenems, linezolid, ceftaroline, novel cephalosporin/β-lactamase inhibitors or triazoles during April-May was noticed. In the ICU, these findings were more evident, namely ceftriaxone ( = 0.029), carbapenems ( = 0.002), daptomycin ( = 0.002), azithromycin ( = 0.030), and linezolid ( = 0.011) but followed a similar temporal pattern. : An increase in the antimicrobial consumption during the first wave of COVID-19 pandemic was noticed, especially in the ICU. Availability of updated protocols and antimicrobial stewardship programs are essential to optimize these outcomes.
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http://dx.doi.org/10.3390/antibiotics10020132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911440PMC
January 2021

A Loading Micafungin Dose in Critically Ill Patients Undergoing Continuous Veno-Venous Hemofiltration or Continuous Veno-Venous Hemodiafiltration: A Population Pharmacokinetic Analysis.

Ther Drug Monit 2021 Feb 8. Epub 2021 Feb 8.

Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, Centre Hospitalier Universitaire (CHU) Nîmes, Nîmes, France Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Univ Montpellier, Montpellier, France Equipe d'accueil 2992 Caractéristiques Féminines des Interfaces Vasculaires (IMAGINE), Faculté de médecine, Univ Montpellier, Montpellier, France Laboratoire de Biochimie, CHU Nîmes, Hôpital Carémeau, Nîmes, France Department of Anesthesia and Surgical Intensive Care, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain Universidad Autónoma de Madrid, Madrid, Spain Pharmacy Department. Hospital del Mar, Parc de Salut Mar, Barcelona, Spain. Infectious Pathology and Antimicrobials Research Group (IPAR). Institut Hospital del Mar d'Investigacions Mèdiques (IMIM). Pharmacy Department. Hospital del Mar, Parc de Salut Mar, Barcelona, Spain. Universitat Auto[Combining Grave Accent]noma de Barcelona, Barcelona, Spain. UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Background: In the present study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous veno-venous hemofiltration (CVVH, 30 mL/kg/h) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h) and determine the optimal dosing regimen using the developed model.

Methods: Patients with septic shock undergoing continuous renal replacement therapy (CRRT) and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from eight CVVH sessions and eight CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 h to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma.

Results: The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a two-compartmental PK model. No covariates, including CRRT modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (standard deviation) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis.

Conclusions: No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.
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http://dx.doi.org/10.1097/FTD.0000000000000874DOI Listing
February 2021

Finding the Dose for Ceftolozane-Tazobactam in Critically Ill Children with and without Acute Kidney Injury.

Antibiotics (Basel) 2020 Dec 10;9(12). Epub 2020 Dec 10.

Pediatric Intensive Care Unit, Hospital General Universitario Gregorio Marañón, 28009 Madrid, Spain.

Ceftolozane-tazobactam is a new antibiotic against multidrug-resistant pathogens such as . Ceftolozane-tazobactam dosage is still uncertain in children, especially in those with renal impairment or undergoing continuous renal replacement therapy (CRRT). Evaluation of different ceftolozane-tazobactam dosing regimens in three critically ill children. Ceftolozane pharmacokinetics (PK) were characterized by obtaining the patient's specific parameters by Bayesian estimation based on a population PK model. The clearance (CL) in patient C undergoing CRRT was estimated using the prefilter, postfilter, and ultrafiltrate concentrations simultaneously. Variables such as blood, dialysate, replacement, and ultrafiltrate flow rates, and hematocrit were integrated in the model. All PK analyses were performed using NONMEM v.7.4. Patient A (8 months of age, 8.7 kg) with normal renal function received 40 mg/kg every 6 h: renal clearance (CL) was 0.88 L/h; volume of distribution (Vd) Vd = 3.45 L, Vd = 0.942 L; terminal halflife (t) = 3.51 h, dosing interval area under the drug concentration vs. time curve at steady-state (AUC) 397.73 mg × h × L. Patient B (19 months of age, 11 kg) with eGFR of 22 mL/min/1.73 m received 36 mg/kg every 8 h: CL = 0.27 L/h; Vd = 1.13 L; Vd = 1.36; t = 6.62 h; AUC 1481.48 mg × h × L. Patient C (9 months of age, 5.8 kg), with severe renal impairment undergoing CRRT received 30 mg/kg every 8 h: renal replacement therapy clearance (CL) 0.39 L/h; Vd 0.74 L; Vd 1.17; t 3.51 h; AUC 448.72 mg × h × L. No adverse effects attributable to antibiotic treatment were observed. Our results suggest that a dose of 35 mg/kg every 8 h can be appropriate in critically ill septic children with multi-drug resistance infections. A lower dose of 10 mg/kg every 8 h could be considered for children with severe AKI. For patients with CRRT and a high effluent rate, a dose of 30 mg/kg every 8 h can be considered.
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http://dx.doi.org/10.3390/antibiotics9120887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763445PMC
December 2020

Impact of non-formulary drugs on pharmacological prescription in hospitalised patients.

Eur J Hosp Pharm 2020 Oct 8. Epub 2020 Oct 8.

Pharmacy Department, Hospital del Mar, Barcelona, Spain.

Objectives: The growing number of drugs on the market makes it necessary to adapt hospital formularies in order to ensure consistent drug coverage. The aim of this study was to evaluate the impact of the prescription of non-formulary drugs (NFD) on the therapeutic management of admitted patients.

Methods: This retrospective observational study included NFD prescriptions in patients hospitalised in a tertiary university hospital during the period 2012-2015. NFD prescriptions are displayed on the computerised medical order as a pending alert to be reviewed by the clinical pharmacists, who make a notation to the clinical course that includes a recommendation for an available therapeutic alternative when available in the hospital formulary. The degree of acceptance of the recommendation by physicians is recorded.

Results: Approximately 0.5% of patients hospitalised during the study period were affected by an NFD prescription. A total of 52 (9.5%) NFD were of doubtful therapeutic efficacy, five (0.9%) were non-replaceable drugs and 490 (89.4%) were prescriptions for drugs with an alternative available in the hospital formulary. The acceptance rate for the recommended alternative was 34.9% in the evaluable NFD prescriptions. No correlation was observed between the number of NFD prescriptions or the number of NFD and the availability index (drugs included in the hospital formulary in relation to the total number of drugs marketed).

Conclusions: The number of patients with a NFD prescription was very low. The lack of correlation between the number of NFD or NFD prescriptions and the availability index demonstrated that the hospital formulary covers practically all therapeutic needs.
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http://dx.doi.org/10.1136/ejhpharm-2020-002204DOI Listing
October 2020

The cost-effectiveness of isavuconazole compared to voriconazole, the standard of care in the treatment of patients with invasive mould diseases, prior to differential pathogen diagnosis in Spain.

Mycoses 2021 Jan 30;64(1):66-77. Epub 2020 Oct 30.

Medical Department, Pfizer, Madrid, Spain.

Background: Invasive mould diseases are associated with high morbidity, mortality and economic impact. Its treatment is often started prior to differential pathogen diagnosis. Isavuconazole is approved for treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) when amphotericin-B is not indicated.

Objectives: To estimate the cost-effectiveness of isavuconazole vs voriconazole for the treatment of adult patients with possible IA prior to differential pathogen diagnosis, in Spain.

Methods: A decision tree analysis was performed using the Spanish Healthcare System perspective. Among all patients with possible IA, it was considered that 7.81% actually had IM. Costs for laboratory analysis, management of adverse events, hospitalisation and drugs per patient, deaths and long-term effects in life years (LYs) and quality-adjusted LYs (QALYs) were considered. Efficacy data were obtained from clinical trials and utilities from the literature. Deterministic and probabilistic sensitivity analyses (PSA) were conducted.

Results: In patients with possible IA and when compared to voricanozole, isavuconazole showed an incremental cost of 4758.53€, besides an incremental effectiveness of +0.49 LYs and +0.41 QALYs per patient. The Incremental Cost Effectiveness Ratio was 9622.52€ per LY gained and 11,734.79€ per QALY gained. The higher cost of isavuconazole was due to drug acquisition. Main parameters influencing results were mortality, treatment duration and hospitalisation days. The PSA results showed that isavuconazole has a probability of being cost-effective of 67.34%, being dominant in 24.00% of cases.

Conclusions: Isavuconazole is a cost-effective treatment compared to voriconazole for patients with possible IA for a willingness to pay threshold of 25,000€ per additional QALY.
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http://dx.doi.org/10.1111/myc.13189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894146PMC
January 2021

Azithromycin in the treatment of COVID-19: a review.

Expert Rev Anti Infect Ther 2021 02 6;19(2):147-163. Epub 2020 Oct 6.

Service of Pharmacy, Hospital Del Mar, Hospital Del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital Del Mar d'Investigacions Mèdiques (IMIM) , Barcelona, Spain.

Introduction: SARS-CoV-2 is a novel virus that causes coronavirus disease-19 (COVID-19). Antiviral and immunomodulatory agents have been proposed as potential treatments. Azithromycin exhibits both properties and therefore may play a role.

Areas Covered: This article reviews the pharmacology, pharmacokinetics, clinical efficacy, and safety of azithromycin in viral infections, with emphasis on COVID-19. A literature search of PUBMED was conducted on May 30 and updated on July 28.

Expert Opinion: Azithromycin presents activity against SARS-CoV-2 and could act in different points of the viral cycle. Its immunomodulatory properties include the ability to downregulate cytokine production, maintain epithelial cell integrity or prevent lung fibrosis. Azithromycin use was associated with a reduction in mortality and ventilation days in other viral infections. These properties could be beneficial throughout the COVID-19. However, the evidence of its use is scarce and of low quality. Azithromycin has been assessed in retrospective observational studies mainly in combination with hydroxychloroquine, which has shown to provide no benefit. This macrolide presents a well-known safety profile. Upcoming clinical trials will determine the role of azithromycin in the COVID-19 (including the stage of the disease where it offers the greatest benefits and the effect of its combination with other drugs).
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http://dx.doi.org/10.1080/14787210.2020.1813024DOI Listing
February 2021

Antibiotic consumption trends among acute care hospitals in Catalonia (2008-2016): impact of different adjustments on the results.

Expert Rev Anti Infect Ther 2021 Feb 30;19(2):245-251. Epub 2020 Sep 30.

Department of Health, Director of VINCat Program (2006-2018) , Catalonia, Spain.

Objectives: Hospital antibiotic consumption is measured using defined-daily-doses (DDD) divided by bed days. However,other denominators as discharges could provide a more accurate interpretation of consumption. The main objective was to analyze trends of antibiotic consumption among hospitals in Catalonia during the period 2008-2016, using both DDD/100 bed days and DDD/100 discharges.

Methods: Retrospective, descriptive, and longitudinal study performed among acute care hospitals affiliated to VINCat Program. Antibiotic consumption was expressed using the Anatomical Therapeutic Chemical/DDD classification and trends with a mixed linear model. Trends after using both DDD/100 bed days and DDD/100 discharges were determined and compared.

Results: Overall antibiotic consumption from 2008 to 2016 increased by 10.24% ( < 0.001) DDD/100 bed days, but remained stable (-0.87%, = 0.051) in DDD/100 discharges. Although DDD and discharges remained unchanged, a significant reduction in bed days (-9.63%) and length of stay (-8.19%) was observed. A worrisome increase in the consumption of carbapenems and anti-MRSA drugs was noticed.

Conclusion: Whereas a significant upward trend in antibiotic consumption in DDD/100 bed days was noticed, DDD/100 discharges remained stable. The description of both indicators seems therefore essential for a correct interpretation of data.
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http://dx.doi.org/10.1080/14787210.2020.1814142DOI Listing
February 2021

Impact of HCV cure with drug-acting antivirals in the use of concomitant medication and lipid profile: follow-up data 2 years after the sustained virological response.

Eur J Gastroenterol Hepatol 2021 Feb;32(2):214-222

Liver Section, Gastroenterology Department, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Background And Aim: Patients with chronic hepatitis C (CHC) frequently associated comorbidities and concomitant medication. Sustained virological response (SVR12) has been related to an increase in cholesterol serum levels and in peripheral vascular resistance. Our aim was to evaluate the impact of SVR12 on the use of concomitant medication and serum lipid profile.

Methods: Prospective study including patients treated with direct-acting antivirals who had achieved the SVR12. Clinical data and concomitant drugs were analysed at baseline and at least 1 year after SVR12. Differences from baseline to follow-up in the concomitant medication were evaluated by Stuart-Maxwell test and lipid profile by Wilcoxon signed-rank test. Patients were categorized according to the increase/decrease in the number of drugs included in each class (Anatomical Therapeutic Chemical classification system).

Results: Two hundred twenty-six patients with SVR12 were included, 73.5% were receiving concomitant drugs (49.6% with antihypertensive effect, 30.5% antacids, 16.4% anti-diabetic drugs, and 7.1% lipid-lowering agents). One year after SVR12, total cholesterol serum levels increased from 161 to 179 mg/dl (P < 0.001) and, after a median time of 25.7 months, the use of lipid-lowering drugs increased from 7.8 to 11.5% (P = 0.009). In addition, we observed a trend to use more antihypertensive drugs in older patients (P = 0.06), especially in those with cirrhosis. Anxiolytics decreased after SVR12 from 13.7 to 10.6% (P = 0.035).

Conclusion: CHC cure is associated with a significant increase in cholesterol serum levels and the use of lipid-lowering agents, as well as the use of drugs with antihypertensive effect in older patients.
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http://dx.doi.org/10.1097/MEG.0000000000001714DOI Listing
February 2021

Strong opioid consumption and its correlation with pain intensity and inpatient complexity. A 6-year analysis in a tertiary hospital.

Eur J Pain 2020 07 4;24(6):1151-1159. Epub 2020 Apr 4.

Department of Pharmacy, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain.

Background: An increasing trend in opioid consumption has been observed worldwide in last decades. However, data related to opioid utilization in hospital settings are scarce. The aim of this study was to determine the evolution of use of strong opioids and pain intensity in a tertiary hospital during 6 years.

Methods: Consumption of strong opioid analgesics used at the hospital at any time between 2012 and 2017 was collected. Data were expressed on oral morphine equivalents (OMEs) per 100 bed-days. Pain intensity was measured by the numerical rating scale (NRS) and the percentage of patients who experienced a NRS value ≥3 and ≥7 were calculated. Case mix index (CMI) was also collected. Data were quantified in medical and surgical area separately.

Results: Consumption of opioids varied from 812.4 to 1,038.8 OMEs/100 bed-days and from 967.3 to 1,023.7 in medical and surgical area. The percentage of patients that experienced a value of NRS ≥ 3 and ≥7 in medical area increased from 24.2% and 5.5% to 31.7% and 7.5%, (p = .038, p = .040). It was observed a correlation between the percentage of patients that experienced a NRS ≥ 7 in two consecutive determinations and opioid prescription in medical area (p = .039).The CMI increased from 1.05 and 0.91 to 1.18 and 1.04 in medical and surgical area (p = .020, p = .004).

Conclusions: Consumption of strong opioids has remained stable, both in medical and surgical area, during last years. A correlation between prescription of opioids and pain intensity is observed in case of repeated and severe pain in medical departments.

Significance: This study shows a stable consumption of strong opioid analgesics in a hospital setting in contrast to what appears to be the extrahospitalary trend during last years. The association between consumption of opioids and pain intensity seems to indicate a good control of pain in the clinical setting, showing a significant correlation between the consumption of opioids and repeated and severe pain in medical departments.
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http://dx.doi.org/10.1002/ejp.1560DOI Listing
July 2020

Comparison of the Safety and Tolerance Profile of Micafungin with that of Other Echinocandins and Azoles in Patients with Pre-existing Child-Pugh B or C Liver Disease: A Case-Control Retrospective Study.

Infect Dis Ther 2020 Mar 21;9(1):151-163. Epub 2020 Feb 21.

Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Introduction: To assess the association between exposure to micafungin, other echinocandins, or azoles and the development of short-term liver injury (STLI) or long-term liver injury (LTLI) in patients with Child-Pugh B or C liver disease.

Methods: Multicenter case-control study of patients with Child-Pugh B or C liver disease who received antifungals (AF) for ≥ 72 h (May 2009-May 2015) in six Spanish and Italian hospitals. All micafungin patients were randomly matched with one patient who received another echinocandin and with one patient who received azole treatment. Primary outcome was development of STLI or LTLI (development of any type of liver tumor during the follow-up period).

Results: Of 2335 patients with chronic liver disease admitted to the six centers, 20 (0.85%) were found to have Child-Pugh B or C liver disease and received micafungin for ≥ 72 h. During AF treatment, the frequency of STLI was 10% in each group. Most cases of STLI were asymptomatic, and AFs had to be switched to another class of AF in only two patients (one micafungin and one azole). No patients developed acute liver insufficiency, were admitted to the ICU, or had to undergo transplantation. Follow-up data (median of 1.3 years) were available for 30 patients. LTLI was observed in only one patient, who had previously received treatment with azoles.

Conclusions: Our study suggests that the administration of micafungin to patients with end-stage liver disease does not imply a higher risk of developing STLI or LTLI.
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http://dx.doi.org/10.1007/s40121-020-00282-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054556PMC
March 2020

Risk Factors for Mortality among Patients with Bloodstream Infections: What Is the Influence of XDR Phenotype on Outcomes?

J Clin Med 2020 Feb 14;9(2). Epub 2020 Feb 14.

Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Spanish Network for Research in Infectious Diseases (REIPI), 08003 Barcelona, Spain.

This study aimed to assess the impact of extensively drug-resistant (XDR) phenotype on mortality in bacteremia. A retrospective cohort study was performed in a tertiary hospital from January 2000 to December 2018. All consecutive prospectively recorded bacteremia in adult patients were assessed. In this study, 382 patients were included, of which 122 (31.9%) due to XDR . Independent factors associated with 14-day mortality were as follows: high-risk source of bacteremia (hazard ratio (HR) 3.07, 95% confidence interval (CI), 1.73-5.46), septic shock (HR 1.75, 95% CI, 1.12-2.75), and higher Pitt scores (one-point increments; HR 1.25, 95% CI, 1.12-1.38). Otherwise, the appropriateness of definitive antibiotic therapy was a protective factor (HR 0.39, 95% CI, 0.24-0.62). The same variables were also associated with 30-day mortality. XDR phenotype was not associated with 14- or 30-day mortality. In a subanalysis considering only high-risk source cases, combined antimicrobial therapy was independently associated with 14-day favorable outcome (HR 0.56, 95% CI, 0.33-0.93). In conclusion, XDR phenotype was not associated with poor prognosis in patients with bacteremia in our cohort. However, source of infection, clinical severity, and inappropriate definitive antibiotic therapy were risk factors for mortality. Combined antimicrobial therapy should be considered for high-risk sources.
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http://dx.doi.org/10.3390/jcm9020514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074151PMC
February 2020

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial.

Crit Care 2020 02 17;24(1):55. Epub 2020 Feb 17.

Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.

Background: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia.

Methods: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia.

Results: The median (IQR) of meropenem AUC in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L.

Conclusions: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected.

Trial Registration: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.
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http://dx.doi.org/10.1186/s13054-020-2763-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026992PMC
February 2020

Efficacy of Ceftolozane-Tazobactam in Combination with Colistin against Extensively Drug-Resistant Pseudomonas aeruginosa, Including High-Risk Clones, in an Pharmacodynamic Model.

Antimicrob Agents Chemother 2020 03 24;64(4). Epub 2020 Mar 24.

Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain

Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) infections. Colistin has been the only treatment available for these infections for many years, but its results are suboptimal. Ceftolozane-tazobactam (C/T) is a newly available therapeutic option that has shown good antipseudomonal activity, even against a number of XDR strains. However, data about combinations containing C/T are scarce. The aim of this study was to analyze the activity of C/T and colistin alone and in combination against a collection of XDR strains containing 24 representative clinical isolates from a multicentre Spanish study. Twenty-four time-kill experiments performed over 24 h were conducted in duplicate to determine the effects of colistin and C/T alone and combined. An pharmacodynamic chemostat model then was used to validate this combination against three selected XDR ST175 isolates with different susceptibility levels to C/T. Static time-kill assays demonstrated superior synergistic or additive effect for C/T plus colistin against 21 of the 24 isolates studied. In the dynamic pharmacokinetic/pharmacodynamic (PK/PD) model, the C/T regimen of 2/1 g every 8 h with a steady-state concentration of 2 mg/liter colistin effectively suppressed the bacterial growth at 24 h. Additive or synergistic interactions were observed for C/T plus colistin against XDR strains and particularly against C/T-resistant strains. C/T plus colistin may be a useful treatment for XDR infections, including those caused by high risk-clones resistant to C/T.
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http://dx.doi.org/10.1128/AAC.02542-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179322PMC
March 2020

Which type of bone releases the most vancomycin? Comparison of spongious bone, cortical powder and cortico-spongious bone.

Cell Tissue Bank 2020 Mar 21;21(1):131-137. Epub 2019 Dec 21.

Barcelona Tissue Bank, Banc de Sang I Teixits, Barcelona, Spain.

Bone infections can be challenging to treat and can lead to several surgeries and relapses. When a graft is needed, cavitary bone loss can be grafted with cancellous or cortical bone. Both can be used for grafting. However, the antibiotic releasing capacity of these grafts has not been compared. Which type of bone is best at releasing the most antibiotic has not been well established. The aim of this study was to determine which type of bone is best for antibiotic release when the bone is suffused with antibiotics by the surgeon. The hypothesis is that there would be a difference between the type of bone tested due to different release capacities of cortical and cancellous bone. This was an experimental study. Cortical spongy bone in chips, Spongy bone in chips and demineralized cortical bone powder were compared. For each type of bone, 5 samples were tested. Processed and decontaminated grafts were freeze-dried to be kept at room temperature. The primary endpoint was the amount of vancomycin released by the graft as it affects the concentration of antibiotic around the graft in clinical practice. The procedure for the study consisted of full graft immersion in a vancomycin solution. Then, the liquid was removed with aspiration. In order to measure the quantity of antibiotic released, the bone was put into distilled water in agitation in a heated rocker at 37 °C. After 30 min of soaking, 1 mL of the liquid was removed. The same extraction process was also carried out after 60 min soaking, 2 h, 3 h, 24 h, and 48 h. No differences were found between each type of bone relative to the concentration of vancomycin released at each time of the assessment. There was a significant difference in the weight of the bone with a higher weight for the cortical powder (1.793 g) versus cortical spongy bone and spongy bone (1.154 g and 1.013 g) with a p value < 0.0001. A significant difference was seen in the weight of the bone with vancomycin after the aspiration of the liquid with 3.026 g for cortical powder, 2.140 g and 2.049 g for the cortical spongy bone and the spongy bone with a p value < 0.0001. In daily clinical practice, one can use cancellous bone, cortico-cancellous bone or cortical powder in order to add vancomycin to a bone graft. Our results show the release kinetics of the soaked allografts. With a maximum of 14 mg/mL in the first minutes and a rapid decrease it shows a pattern comparable to antibiotic loaded bone cement. The method used appears favourable for prophylactic use, protecting the graft against contamination at implantation, but is not sufficient for treating chronic bone infection. LEVEL OF EVIDENCE: V.
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http://dx.doi.org/10.1007/s10561-019-09806-2DOI Listing
March 2020

Economic analysis of ceftaroline fosamil for treating community-acquired pneumonia in Spain.

J Med Econ 2020 Feb 26;23(2):148-155. Epub 2019 Nov 26.

Hospital del Mar Universitat Autònoma de Barcelona, Barcelona, Spain.

Adults admitted to hospital with community-acquired pneumonia (CAP) impose significant burden upon limited hospital resources. To achieve early response and possibly early discharge, thus reducing hospital expenditure, the choice of initial antibiotic therapy is pivotal. A cost-consequences model was developed to evaluate ceftaroline fosamil (CFT) as an alternative to other antibiotic therapies (ceftriaxone, co-amoxiclav, moxifloxacin, levofloxacin) for the empiric treatment of hospitalized adults with moderate/severe CAP (PORT score III-IV) from the perspective of the Spanish National Health System (NHS). Compared with ceftriaxone, the model predicted an increase in the number of CFT-treated patients discharged early (PDE) (30.6% vs. 26.1%) while decreasing initial antibiotic failures (3.8% vs. 7.6%). For patients with pneumococcal pneumonia, CFT was cost-saving vs. ceftriaxone (by 1.2%) and significantly increased PDE (32.1% vs. 24.6%). CFT resulted in cost-saving vs. levofloxacin, due lower initial antibiotic therapy costs and increased PDE (30.6% vs. 14.9%). Moxifloxacin and co-amoxiclav early response rate of 53.63% and 54.24% resulted in cost neutrality vs. CFT, with direct comparison hampered by the significantly different early response criteria utilized in the literature. Despite a higher unit cost, CFT is a reasonable alternative to other agents for adults hospitalized with moderate/severe CAP, given the projected higher PDE achieved with similar or lower total costs.
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http://dx.doi.org/10.1080/13696998.2019.1688819DOI Listing
February 2020

Organisational and financial consequences of the early discharge of patients treated for acute bacterial skin and skin structure infection and osteomyelitis in infectious disease departments in Greece, Italy and Spain: a scenario analysis.

BMJ Open 2019 09 12;9(9):e031356. Epub 2019 Sep 12.

Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Objective: The aim of the analysis is to assess the organisational and economic consequences of adopting an early discharge strategy for the treatment of acute bacterial skin and skin structure infection (ABSSSI) and osteomyelitis within infectious disease departments.

Setting: Infectious disease departments in Greece, Italy and Spain.

Participants: No patients were involved in the analysis performed.

Interventions: An analytic framework was developed to consider two alternative scenarios: standard hospitalisation care or an early discharge strategy for patients hospitalised due to ABSSSI and osteomyelitis, from the perspective of the National Health Services of Greece, Italy and Spain. The variables considered were: the number of annual hospitalisations eligible for early discharge, the antibiotic treatments considered (ie, oral antibiotics and intravenous long-acting antibiotics), diagnosis-related group (DRG) reimbursements, number of days of hospitalisation, incidence and costs of hospital-acquired infections, additional follow-up visits and intravenous administrations. Data were based on published literature and expert opinions.

Primary And Secondary Outcome Measures: Number of days of hospitalisation avoided and direct medical costs avoided.

Results: The total number of days of hospitalisation avoided on a yearly basis would be between 2216 and 5595 in Greece (-8/-21 hospital beds), between 15 848 and 38 444 in Italy (-57/-135 hospital beds) and between 7529 and 23 520 in Spain (-27/-85 hospital beds). From an economic perspective, the impact of the early discharge scenario is a reduction between €45 036 and €149 552 in Greece, a reduction between €182 132 and €437 990 in Italy and a reduction between €292 284 and €884 035 in Spain.

Conclusions: The early discharge strategy presented would have a positive organisational impact on National Health Services, leading to potential savings in beds, and to a reduction of hospital-acquired infections and costs.
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http://dx.doi.org/10.1136/bmjopen-2019-031356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747647PMC
September 2019

Systemic pharmacokinetics and safety of high doses of nebulized colistimethate sodium in critically ill patients with hospital-acquired and ventilator-associated pneumonia.

J Antimicrob Chemother 2019 11;74(11):3268-3273

Department of Pharmacy, Hospital del Mar, IMIM (Hospital del Mar Research Institute), Universitat Autònoma de Barcelona, Paseo Marítimo 25-29, Barcelona, Spain.

Objectives: To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP).

Patients And Methods: Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded.

Results: Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12-0.33), 0.20 (0.11-0.24), 0.17 (0.12-0.23) and 0.17 (0.11-0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11-0.35), 0.24 (0.12-0.44), 0.24 (0.10-0.49) and 0.23 (0.11-0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group, but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated and no bronchospasms or neurotoxicity events were observed.

Conclusions: In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.
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http://dx.doi.org/10.1093/jac/dkz356DOI Listing
November 2019

Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections.

Clin Microbiol Rev 2019 09 28;32(4). Epub 2019 Aug 28.

Service of Pharmacy, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain.

In recent years, the worldwide spread of the so-called high-risk clones of multidrug-resistant or extensively drug-resistant (MDR/XDR) has become a public health threat. This article reviews their mechanisms of resistance, epidemiology, and clinical impact and current and upcoming therapeutic options. and treatment studies and pharmacokinetic and pharmacodynamic (PK/PD) models are discussed. Polymyxins are reviewed as an important therapeutic option, outlining dosage, pharmacokinetics and pharmacodynamics, and their clinical efficacy against MDR/XDR infections. Their narrow therapeutic window and potential for combination therapy are also discussed. Other "old" antimicrobials, such as certain β-lactams, aminoglycosides, and fosfomycin, are reviewed here. New antipseudomonals, as well as those in the pipeline, are also reviewed. Ceftolozane-tazobactam has clinical activity against a significant percentage of MDR/XDR strains, and its microbiological and clinical data, as well as recommendations for improving its use against these bacteria, are described, as are those for ceftazidime-avibactam, which has better activity against MDR/XDR , especially strains with certain specific mechanisms of resistance. A section is devoted to reviewing upcoming active drugs such as imipenem-relebactam, cefepime-zidebactam, cefiderocol, and murepavadin. Finally, other therapeutic strategies, such as use of vaccines, antibodies, bacteriocins, anti-quorum sensing, and bacteriophages, are described as future options.
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http://dx.doi.org/10.1128/CMR.00031-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730496PMC
September 2019

Effects of the extracorporeal membrane oxygenation circuit on plasma levels of ceftolozane.

Perfusion 2020 04 7;35(3):267-270. Epub 2019 Aug 7.

Intensive Care Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Introduction: New antibiotics with bactericidal activity against multi-drug-resistant bacteria are increasingly used in the intensive care units. Here, we aimed to evaluate the influence of the extracorporeal membrane oxygenation on plasma levels of ceftolozane.

Case Report: A 34-year-old female was admitted to the intensive care unit after bilateral lung transplantation, complicated by primary graft dysfunction and cardiogenic shock needing venoarterial extracorporeal membrane oxygenation. Ceftolozane/tazobactam was started. Plasma ceftolozane levels were monitored on the first and third days of antibiotic treatment. A non-compartment pharmacokinetic analysis was performed and the extraction rate through the oxygenator was calculated.

Discussion: The extracorporeal circuit of extracorporeal membrane oxygenation may alter the pharmacokinetics of antibiotics, to varying degrees due to drug sequestration and increased distribution volume. In this case, the extracorporeal membrane oxygenation circuit had little impact on the ceftolozane plasma concentration.

Conclusion: Plasma levels of ceftolozane are stable in the extracorporeal membrane oxygenation circuit, suggesting that adjustment of standard doses of ceftolozane in patients with extracorporeal membrane oxygenation support may not be needed.
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http://dx.doi.org/10.1177/0267659119864813DOI Listing
April 2020

Colistin for the treatment of urinary tract infections caused by extremely drug-resistant Pseudomonas aeruginosa: Dose is critical.

J Infect 2019 09 29;79(3):253-261. Epub 2019 Jun 29.

Infectious Diseases Department, Parc de Salut Mar, Passeig Marítim 25-29, E-08003 Barcelona, Spain; Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain; CEXS-Universitat Pompeu Fabra (UPF), Barcelona, Spain; Spanish Network for Research in Infectious Diseases (REIPI RD 16/0016/0015), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Objectives: Optimal dosage regimens of colistin for the treatment of urinary tract infections (UTI) are unknown. Colistimethate sodium (CMS), the inactive prodrug of colistin, is mainly excreted in urine and converts to colistin after filtration by glomeruli, suggesting that concentrations of colistin in urine could be much higher than in plasma. Therefore, there is a need to optimize dosage regimens of intravenous CMS for UTI. The aim of this study was to examine the relationship between AUC/MIC of formed colistin and clinical outcomes in patients with UTI caused by extremely drug resistant (XDR) Pseudomonas aeruginosa.

Methods: This prospective, observational cohort study involved patients with UTI caused by XDR P. aeruginosa. Clinical cure, bacteriological clearance and acute kidney injury (AKI) were analyzed. Steady-state colistin plasma concentrations (C) were measured using HPLC. Based on the PK/PD of colistin in neutropenic mouse thigh infection models with P. aeruginosa, the optimal AUC/MIC should be ≥60 mg·h/L. According to the pharmacokinetics (PK) in critically-ill patients, the C target of formed colistin in plasma was 2.5 mg/L.

Results: Thirty-three patients were included (24 lower UTI and 9 pyelonephritis). The MIC and MIC values for colistin were 0.5 and 2 mg/L respectively. Nineteen patients (57.6%) received colistin monotherapy (84.2% lower UTI and 15.8% pyelonephritis). Of these, clinical cure was achieved in 89.5% of cases. Among patients with clinical cure and monotherapy, only 5 (29.4%) attained an optimal plasma AUC/MIC and only 1 (5.9%) the therapeutic level of formed colistin (2.5 mg/L). However, 10 (58.8%) patients showed colistin plasma concentrations above the MIC of the isolated P. aeruginosa. Microbiological eradication was achieved in 76.9% of patients. AKI at the end of treatment was present in 29.4% of patients.

Conclusions: The currently recommended dosage regimens of CMS showed high efficacy for the treatment of lower complicated UTI caused by XDR P. aeruginosa in non-critically ill patients and in the case of low MIC values, but also a considerable nephrotoxicity rate. Our data suggest that the use of lower CMS doses for lower UTI should be investigated in future studies to minimize the unnecessary nephrotoxicity.
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http://dx.doi.org/10.1016/j.jinf.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265153PMC
September 2019

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

Ther Drug Monit 2019 12;41(6):732-739

Departments of Intensive Care and Pharmacy, Royal Brisbane and Women's Hospital.

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.
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http://dx.doi.org/10.1097/FTD.0000000000000665DOI Listing
December 2019

Colistin plus meropenem combination is synergistic in vitro against extensively drug-resistant Pseudomonas aeruginosa, including high-risk clones.

J Glob Antimicrob Resist 2019 09 30;18:37-44. Epub 2019 May 30.

Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra Barcelona, Spain. Electronic address:

Background: Extensively drug-resistant (XDR) Pseudomonas aeruginosa (P. aeruginosa) and particularly P. aeruginosa high-risk clones, are of growing concern because treatment options are limited. For years, colistin monotherapy has been the only available treatment, but is well known that is not an optimal treatment. A combination of colistin with another antibiotic could be a possible therapeutic option.

Objectives: This study aimed to investigate effective antibiotic combinations against 20 XDR P. aeruginosa isolates obtained in a Spanish multicentre study (2015).

Methods: Forty-five checkerboards with six antipseudomonal antibiotics (amikacin, aztreonam, ceftazidime, meropenem, colistin, and ceftolozane/tazobactam) were performed to determine whether combinations were synergic or additive by fractional inhibitory concentration indices. On average, 15 different regimens were evaluated in duplicate against the three most prevalent high-risk clones (ST175, ST235, ST111) by time-kill analyses over 24h. The combination showing synergism in the three high-risk clones was validated in all studied XDR isolates.

Results: In time-kill curves, the untreated control failed, as did each study regimen when administered alone. Two combinations were synergistic in the three high-risk clones that were initially studied: amikacin plus ceftazidime and colistin plus meropenem, with the second being the most effective combination. The efficacy of colistin plus meropenem was then tested in all 20 isolates. A synergistic bacterial density reduction for the duration of the study occurred in 80% of the entire XDR collection.

Conclusions: These data suggest that colistin plus meropenem may be a useful combination for the treatment of infections due to XDR P. aeruginosa, including high-risk clones, which warrants evaluation in a clinical trial.
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http://dx.doi.org/10.1016/j.jgar.2019.04.012DOI Listing
September 2019

Extended-pulsed fidaxomicin versus vancomycin in patients 60 years and older with Clostridium difficile infection: cost-effectiveness analysis in Spain.

Eur J Clin Microbiol Infect Dis 2019 Jun 13;38(6):1105-1111. Epub 2019 Apr 13.

Health Value, C/ Virgen de Aránzazu, 21. 5° B, 28034, Madrid, Spain.

The cost of treating Clostridium difficile infection (CDI) in Spain is substantial. Findings from the randomised, controlled, open-label, phase 3b/4 EXTEND study showed that an extended-pulsed fidaxomicin (EPFX) regimen was associated with improved sustained clinical cure and reduced recurrence of CDI versus vancomycin in patients aged 60 years and older. We assessed the cost-effectiveness of EPFX versus vancomycin for the treatment of CDI in patients aged 60 years and older from the perspective of the National Health System (NHS) in Spain. We used a Markov model with six health states and 1-year time horizon. Health resources, their unit costs and utilities were based on published sources. Key efficacy data and transition probabilities were obtained from the EXTEND study and published sources. A panel of Spanish clinical experts validated all model assumptions. In the analysis, 0.638 and 0.594 quality-adjusted life years (QALYs) per patient were obtained with EPFX and vancomycin, respectively, with a gain of 0.044 QALYs with EPFX. The cost per patient treated with EPFX and vancomycin was estimated to be €10,046 and €10,693, respectively, with a saving of €647 per patient treated with EPFX. For willingness-to-pay thresholds of €20,000, €25,000 and €30,000 per QALY gained, the probability that EPFX was the most cost-effective treatment was 99.3%, 99.5% and 99.9%, respectively. According to our economic model and the assumptions based on the Spanish NHS, EPFX is cost-effective compared with vancomycin for the first-line treatment of CDI in patients aged 60 years and older.
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http://dx.doi.org/10.1007/s10096-019-03503-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520320PMC
June 2019

Successful ceftolozane-tazobactam rescue therapy in a child with endocarditis caused by multidrug-resistant Pseudomonas aeruginosa.

J Paediatr Child Health 2019 Aug 8;55(8):985-987. Epub 2019 Feb 8.

Department of Pediatrics, Complutense University of Madrid, Madrid, Spain.

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http://dx.doi.org/10.1111/jpc.14388DOI Listing
August 2019

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

Molecules 2019 Feb 1;24(3). Epub 2019 Feb 1.

Infectious Diseases Department, Hospital del Mar, Infectious Pathology and Antimicrobial Research Group (IPAR), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, 08003 Barcelona, Spain.

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m² for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (C) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45⁻95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; < 0.001). Mean C was 0.9 (0.2⁻2.9) mg/L, and C was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved C were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.
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http://dx.doi.org/10.3390/molecules24030530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384574PMC
February 2019

Pharmacokinetics of Micafungin in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis With High Cutoff Membranes.

Ther Drug Monit 2019 06;41(3):376-382

Faculty of Medicine, School of Pharmacy, the University of Queensland.

Background: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO).

Methods: Prospective observational study performed in critically ill patients treated with 100 mg/d of micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and micafungin concentrations were determined using HPLC-UV.

Results: Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of micafungin concentrations in the effluent were <0.2 (<0.2-0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model.

Conclusions: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of micafungin, and that standard doses of this antifungal can be used.
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http://dx.doi.org/10.1097/FTD.0000000000000595DOI Listing
June 2019

Cost-Effectiveness Analysis of Bezlotoxumab Added to Standard of Care Versus Standard of Care Alone for the Prevention of Recurrent Clostridium difficile Infection in High-Risk Patients in Spain.

Adv Ther 2018 11 16;35(11):1920-1934. Epub 2018 Oct 16.

Pharmacy Department, Hospital del Mar, Universidad Autónoma de Barcelona, Barcelona, Spain.

Introduction: Clostridium difficile infection (CDI) is the major cause of infectious nosocomial diarrhoea and is associated with considerable morbidity, mortality and economic impact. Bezlotoxumab administered in combination with standard of care (SoC) antibiotic therapy prevents recurrent CDI. This study assessed the cost-effectiveness of bezlotoxumab added to SoC, compared to SoC alone, to prevent the recurrence of CDI in high-risk patients from the Spanish National Health System perspective.

Methods: A Markov model was used to simulate the natural history of CDI over a lifetime horizon in five populations of patients at high risk of CDI recurrence according to MODIFY trials: (1) ≥ 65 years old; (2) severe CDI; (3) immunocompromised; (4) ≥ 1 CDI episode in the previous 6 months; and (5) ≥ 65 years old and with ≥ 1 CDI episode in the previous 6 months. The incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed.

Results: In all patient populations (from 1 to 5), bezlotoxumab added to SoC reduced CDI recurrence compared to SoC alone by 26.4, 19.5, 21.2, 26.6 and 39.7%, respectively. The resulting ICERs for the respective subgroups were €12,724, €17,495, €9545, €7386, and €4378. The model parameters with highest impact on the ICER were recurrence rate (first), mortality, and utility values. The probability that bezlotoxumab was cost-effective at a willingness-to-pay threshold of €21,000/QALY was 85.5%, 54.1%, 86.0%, 94.5%, 99.6%, respectively.

Conclusion: The results suggest that bezlotoxumab added to SoC compared to SoC alone is a cost-effective treatment to prevent the recurrence of CDI in high-risk patients. The influence of changes in model parameters on DSA results was higher in patients  ≥ 65 years old, with severe CDI and immunocompromised. Additionally, PSA estimated that the probability of cost-effectiveness exceeded 85% in most subgroups.

Funding: Merck Sharp & Dohme Corp.
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http://dx.doi.org/10.1007/s12325-018-0813-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223985PMC
November 2018

Antimicrobial stewardship in Spain: Programs for Optimizing the use of Antibiotics (PROA) in Spanish hospitals.

Germs 2018 Sep 3;8(3):109-112. Epub 2018 Sep 3.

MD, PhD, Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Avda. Dr. Fedriani nº 3, Sevilla, 41009, Spain.

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http://dx.doi.org/10.18683/germs.2018.1137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141224PMC
September 2018