Dosage Individualization of Linezolid: Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity.

The high interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualized dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5 [±14.6] years) who underwent routine therapeutic drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-performance liquid chromatography. Population pharmacokinetic modeling was performed using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than the maximum licensed linezolid dose. The final PK model was then used to construct software for dosage individualization, and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespecified drug exposure targets. A further prospective study is needed to examine the potential clinical utility of individualized therapy.

Clinical and economic burden of community-onset multidrug-resistant infections requiring hospitalization.

OBJECTIVES: To analyze the clinical and economic burden of community-acquired (CA) or community-onset healthcare-associated (COHCA) multidrug-resistant (MDR) infections requiring hospitalization. METHODS: Case-control study. Adults admitted with CA or COHCA MDR infections were considered cases, while those admitted in the same period with non-MDR infections were controls. The matching criteria were source of infection and/or microorganism. Primary outcome was 30-day clinical failure. Secondary outcomes were 90-day and 1-year mortality, hospitalization costs and resource consumption. RESULTS: 194 patients (97 cases and 97 controls) were included. Multivariate analysis identified age (odds ratio [OR], 1.07, 95% confidence interval [CI], 1.01-1.14) and SOFA score (OR, 1.45, CI95%, 1.15-1.84) as independent predictors of 30-day clinical failure. Age (hazard ratio [HR] 1.09, 95%CI, 1.03-1.16) was the only factor associated with 90-day mortality, whereas age (HR 1.06, 95%CI, 1.03-1.09) and Charlson Index (HR 1.2, 95%CI, 1.07-1.34) were associated with 1-year mortality. MDR group showed longer hospitalization (p<0.001) and MDR hospitalization costs almost doubled those in the non-MDR group. MDR infections were associated with higher antimicrobial costs. CONCLUSIONS: Worse economic outcomes were identified with community-onset MDR infections. MDR was associated with worse clinical outcomes but mainly due to higher comorbidity of patients in MDR group, rather than multidrug resistance.

Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection.

Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ± 0.47 versus 0.15 ± 0.06 h(-1), respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of ≤0.008 mg/liter and ≤0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.

Cost-effectiveness of three echinocandins and fluconazole in the treatment of candidemia and/or invasive candidiasis in nonneutropenic adult patients.

OBJECTIVE: To estimate the cost-effectiveness of three echinocandins (anidulafungin, caspofungin, and micafungin) and generic fluconazole in the treatment of nonneutropenic adult patients with candidemia and/or invasive candidiasis in intensive care units in Spain. MATERIALS AND METHODS: A decision-tree model was applied. The success and safety (hepatic and renal adverse effects) of first-line treatments were obtained from meta-analyses and systematic reviews of clinical trials. In the case of failure, a second-line treatment (liposomal amphotericin B after the echinocandins, or one of the echinocandins after fluconazole) was administered. The duration of the treatments (14 days total) was established by a panel of clinical experts using the Delphi method and according to Infectious Diseases Society of America guidelines. The cost of the medications and renal toxicity were considered. Deterministic and probabilistic sensitivity analysis using Monte Carlo simulations were carried out. RESULTS: The total cost of the treatment of candidemia and/or invasive candidiasis with anidulafungin, caspofungin, micafungin, and fluconazole was €5,483, €5,968, €6,231, and €2,088, respectively. Anidulafungin was the dominant treatment (more effective, less expensive) compared to micafungin and caspofungin. The cost of achieving one more patient successfully treated with anidulafungin, caspofungin, and micafungin compared to fluconazole was €17,199, €23,962, and €27,339, respectively. The result remained stable, despite modification of the duration of the first-line and second-line treatments, as well as most of the dosing regimens. The probabilistic analysis also remained stable. CONCLUSION: In accordance with this economic study, anidulafungin would produce savings and would be the dominant treatment compared with micafungin and caspofungin in nonneutropenic adult patients with candidemia and/or invasive candidiasis in intensive care units in Spain.

Clinical and economic impact of urinary tract infections caused by ESBL-producing Escherichia coli requiring hospitalization: A matched cohort study.

OBJECTIVE: To analyze the clinical and economic impact of urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli requiring hospitalization. METHODS: Matched cohort study including adults with UTI caused by ESBL-producing E. coli admitted to a tertiary care hospital in Barcelona, Spain, between August 2010 and July 2013. Demographic, clinical and economic data were analyzed. RESULTS: One hundred and twenty episodes of UTI were studied: 60 due to ESBL-producing E. coli and 60 due to non-ESBL-producing E. coli. Bivariate analysis showed that prior antimicrobial treatment (p = 0.007) and ESBL production (p < 0.001) were related to clinical failure during the first 7 days. Multivariate analysis selected ESBL as the sole risk factor for clinical failure (p = 0.002). Regarding the economic impact of infections caused by ESBL-producing E. coli, an ESBL-producing infection cost more than a non-ESBL-producing E. coli infection (mean €4980 vs. €2612). Looking at hospital expenses separately, the total pharmacy costs and antibiotic costs of ESBL infections were considerably higher than for non-ESBL infections (p < 0.001), as was the need for outpatient parenteral antibiotic therapy (OPAT) and its related costs. Multivariate analysis performed for the higher costs of UTI episodes found statistically significant differences for males (p = 0.004), chronic renal failure (p = 0.025), ESBL production (p = 0.008) and OPAT (p = 0.009). CONCLUSION: UTIs caused by EBSL-producing E. coli requiring hospital admission are associated with worse clinical and economic outcomes.

Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis.

OBJECTIVES: Limited information about the pharmacokinetics of micafungin in the peritoneal cavity is available. The aim of this study was to explore the pharmacokinetics/pharmacodynamics of micafungin in plasma and peritoneal fluid in post-surgical critically ill patients with proven or suspected intra-abdominal fungal infection. METHODS: Patients were administered 100 mg/day micafungin. Serial blood and peritoneal fluid samples were collected on day 1 and day 3 (steady-state) of treatment. Concentrations were determined by validated chromatography and were subject to a population pharmacokinetic analysis with Pmetrics(®). Monte Carlo simulations were performed for AUC0-24/MIC ratios in plasma. The PTA was calculated using AUC0-24/MIC cut-offs: 285 for Candida parapsilosis and 3000 for non-parapsilosis Candida spp. RESULTS: Ten patients were included; six were male. The median (range) age, APACHE II score and Mannheim peritonitis index were 72 (43-85) years, 15 (11-36) and 26 (8-37), respectively. On day 1, median (SD) penetration of micafungin into the peritoneal cavity was 30% (30%-40%). A three-compartment model adequately described the data. The mean (SD) estimates for clearance and volume of distribution of the central compartment were 1.27 (0.75) L/h and 9.26 (1.11) L, respectively. In most patients, the PTA in plasma was ≥ 90% for MICs of 0.008-0.016 mg/L for Candida spp. and 0.125-0.25 mg/L for C. parapsilosis. CONCLUSIONS: After the first dose, micafungin at 100 mg/day achieves pharmacokinetic/pharmacodynamic targets in plasma for Candida spp. and C. parapsilosis MICs of 0.008-0.016 and 0.125-0.25 mg/L, respectively.

Cost-effectiveness of anidulafungin in confirmed candidaemia and other invasive Candida infections in Spain.

BACKGROUND: Candidaemia and invasive Candida infections can cause patient death and are expensive. Anidulafungin, a newly-licensed candin, has proven effective in treating candidaemia. Our study evaluates the cost-effectiveness of anidulafungin compared with fluconazole, the current standard of care, for treating invasive candidiasis and candidaemia in Spain. METHODS: A decision tree model from the hospital perspective was constructed to examine the cost-effectiveness of anidulafungin compared with fluconazole in treating confirmed candidaemia. Treatment success, patient treatment patterns, and patient survival were based on the results from a randomised, double-blind multicentre trial (Reboli et al., 2007 [41]). Only in-hospital (2011 €) direct costs per-patient obtained from a Spanish national database were considered. Renal toxicity probabilities and costs were extracted from the published literature. The incremental cost per successfully treated patient was calculated. One-way sensitivity analyses were performed to test model robustness. RESULTS: The percentage of successfully treated patients was higher with anidulafungin than with fluconazole (74% versus 57%). Treatment with anidulafungin resulted in higher antifungal drug costs (5991€ versus 3149€) but lower overall costs (40047€ versus 41350€) due to reductions in other medical costs. Univariate sensitivity analyses showed that anidulafungin was the most cost-effective. CONCLUSIONS: Anidulafungin demonstrated improved clinical efficacy versus fluconazole in treating confirmed candidaemia. Despite increased drug costs, treating confirmed candidaemia with anidulafungin is a cost-effective strategy.

[Pharmacoeconomic assessment of daptomycin as first-line therapy for bacteraemia and complicated skin and skin structure infections caused by gram-positive pathogens in Spain]. / Evaluación farmacoeconómica de daptomicina como terapia de primera línea en el tratamiento de bacteriemia e infecciones complicadas de piel y tejidos blandos causadas por microorganismos grampositivos en España.

OBJECTIVE: To assess the efficiency of daptomycin as firstline therapy (D) versus daptomycin as salvage therapy after vancomycin (V→D ) or linezolid (L→D) failure in gram-positive bacteraemia and complicated skin and skin-structure infections (cSSTIs). METHODS: Cost-effectiveness analysis of 161 bacteraemia and 84 cSSTIs patients comparing the above mentioned therapeutic alternatives was performed using the data from 27 Spanish hospitals involved in the EUCORE study. Direct medical costs were considered. Patients were observed from the first antibiotic dose for infection until either the end of daptomycin therapy or exitus. A multivariate Monte Carlo probabilistic sensitivity analysis was applied for costs (lognormal distribution) and effectiveness (normal distribution). RESULTS: In terms of effectiveness there were no statistical differences between groups but referring total costs per patient, there were significant differences. Sensitivity analysis confirmed that D dominates over L→D between 44.2%-62.1% of simulations in bacteraemia and between 48.2%-67.5% in cSSTIs. In comparison to V→D, D dominance was detected in 29.2%-33.2% of simulations in bacteraemia and between 48.2%-59.3% in cSSTIs. CONCLUSIONS: Daptomycin as first-line therapy dominates over daptomycin as salvage therapy after linezolid failure both in bacteraemia and cSSTIs. Comparing daptomycin as first-line therapy with its use after vancomycin failure, in cSSTIs the former is dominant. In bacteremia daptomycin as first line therapy is as effective as daptomycin as salvage therapy after vancomycin failure and implies lower costs.

Cost of bacteraemia caused by methicillin-resistant vs. methicillin-susceptible Staphylococcus aureus in Spain: a retrospective cohort study.

The aim of this study was to determine the impact on healthcare resource utilization and associated costs of bacteraemia due to methicillin-resistant Staphylococcus aureus (MRSA) vs. methicillin-susceptible S. aureus (MSSA) strains in Spain. An observational, retrospective, cohort multicentre study was conducted during 2005. The target population comprised Spanish patients with S. aureus bacteraemia (five and ten cases per hospital for resistant and susceptible strains, respectively). The resources used were obtained from the hospital patient records. The unit costs were obtained from the participating hospitals and from Spanish databases; the costs of a bacteraemic episode were estimated from resource utilization results and expressed in euros (euro). Univariate sensitivity analyses were performed. The clinical records of 366 valid patients with S. aureus bacteraemia (121 MRSA and 245 MSSA) from 27 Spanish hospitals were reviewed. Resource use per bacteraemic episode was higher for MRSA cases than for MSSA cases, with longer antibiotic treatment (3.1 additional days) and greater length of hospital stay (LOS) (2.2 additional days), more diagnostic tests, and higher rates of admission to the intensive-care unit (ICU) (7.6%). As a consequence, a higher cost per episode was incurred, with an additional euro1205 in episodes of MRSA infections (1.12-fold increase). The main drivers of the cost difference were the higher rates of ICU admission and hospital re-admission and increased LOS. The analysis confirmed that there were additional costs due to resistant strains, ranging from euro293 to euro5188. Overall, MRSA was associated with higher costs in bacteraemic patients, and this was attributable mainly to the greater rate of ICU admissions and increased LOS.

Economic evaluation of posaconazole vs fluconazole in the prevention of invasive fungal infections in patients with GVHD following haematopoietic SCT.

Posaconazole has been proven to be as effective as fluconazole in the prevention of invasive fungal infections (IFI) in allogeneic haematopoietic SCT patients with GVHD. We assessed, from the perspective of the Spanish National Health Service, the cost-effectiveness of posaconazole vs fluconazole in preventing IFI. A decision-analytic model was developed to assess the average per patient treatment costs, IFIs avoided, life-years gained (LYG) and incremental cost per LYG for each prophylactic treatment used (in euros at 2007 prices). Patients are assumed to have received either posaconazole or fluconazole. The probabilities of IFI, IFI-related death and death from other causes were obtained from a single clinical trial. Long-term mortality and costs were estimated from secondary sources. Posaconazole was associated with fewer IFIs (5.3 vs 9%), increased LYG (8.01 vs 7.78) and higher IFI-related costs ([euro]11 585 vs [euro]6 959) per patient compared with fluconazole. The incremental cost-effectiveness of posaconazole vs fluconazole was estimated at [euro]20 246 per LYG. There was a 70% probability that posaconazole is cost-effective at a [euro]30 000 per LYG threshold. In conclusion, compared with fluconazole, posaconazole prophylaxis is a cost-effective strategy for the prevention of IFI in patients with GVHD.

[Pharmacoeconomics of infection in the intensive care unit]. / Farmacoeconomía de la infección en la Unidad de Cuidados Intensivos.

The intensive care unit (ICU) services are areas that have a need for greater use of economic resources, including the frequent use of higher priced drugs, standing out among them those corresponding to antimicrobial agents. This situation has led many hospital sites to include the ICU within those units needing special monitoring in regards to the use of drugs and the introduction of cost-containment programs in the ICU. It is possible that indiscriminate restriction in the financial cost section aimed at antimicrobial agents may mean that these drugs may be prescribed more inappropriately, a practice that has been related with greater mortality of patients with severe infections. Thus, the pharmacoeconomics of infection in the ICU should be analyzed through the study of different aspects and not only from the strict analysis of direct cost of the antimicrobial agents. In the present review, the cost of infection in the ICU has been analyzed, contemplating a series of perspectives that are considered essential and demonstrating, at all times, that evaluation of the cost of acquiring the antimicrobial agent as the only element for its choice should be avoided. The analysis was made by evaluating cost of infection in the ICU, the strategies for the control of use and cost of antibiotics in the ICU, importance of adequate early empiric treatment, the costs associated with the development of bacterial resistances and pharmacoeconomic studies.

[Patients at risk of malnutrition: assessment of 11 cases of severe malnutrition with individualised total parenteral nutrition]. / Pacientes con riesgo de desnutrición: valoración de 11 casos gravemente desnutridos con nutrición parenteral total individualizada.

OBJECTIVE: To describe and assess the efficacy and safety of individualised nutritional support during the first week of total parenteral nutrition in moderately to severely malnourished patients who are susceptible to the refeeding syndrome. METHOD: Retrospective observational study carried out between January 2003 and June 2006, including adult patients with moderate to severe malnutrition who received = 5 days total parenteral nutrition. The nutritional support was described and the appearance of severe hydroelectrolytic and metabolic disturbances were assessed during the first week of nutrition. RESULTS: The study included 11 patients with a mean body mass index of 15.4 kg/m2. These patients received an average of 23 Kcal/kg/day. They did not show any signs of severe hydroelectrolytic or metabolic disturbances. Three patients presented with hypophosphataemia, five with hypokalaemia and four with hypomagnesaemia, all of which were mild to moderate and with the exception of two cases, all were corrected within one week of feeding. CONCLUSIONS: Individualised nutritional support in moderately to severely malnourished patients does not produce refeeding syndrome. Individualised nutrition is an essential strategy for avoiding complications associated with overfeeding.

Economic evaluation of linezolid versus teicoplanin for the treatment of infections caused by gram-positive microorganisms in Spain.

The aim of this study was to perform a comparative cost-effectiveness analysis of linezolid vs teicoplanin (i.v., switching to oral/i.m. respectively) in Spain. A decision tree model was used with the results of a randomized, comparative, controlled clinical trial with linezolid vs teicoplanin in the treatment of infections caused by Gram-positive microorganisms, with a timeline of 31 days. The efficacy endpoint was the percentage of patients with clinical healing or improvement in their infection. Direct medical costs were included using Spanish 2005 prices. Average cost per patient, average cost-effectiveness ratio and several sensitivity analyses were carried out. In the intent-to-treat (ITT) analysis linezolid obtained a higher percentage of therapeutic success than teicoplanin (95.5% vs 87.6% respectively, p = 0.005), both with similar tolerability. The average cost per treated patient was euro 8,064.76 for linezolid vs euro 8,727.36 for teicoplanin, with an incremental cost of euro 622.59 (-7,6%). Linezolid yielded a lower average cost-effectiveness ratio, euro 8,444.78 (8,195.90 - 8,709.25) than teicoplanin, euro 9,962.74 (9,465.68 - 10,502.23), with a slight reduction in average cost per successfully treated patient of 15.2% ( euro 1,517.96). The results were robust to the sensitivity analysis. In conclusion, linezolid is a more cost-effective option than teicoplanin in the treatment of infections caused by Gram-positive microorganisms, since it offers superior clinical benefits with a lower use of associated resources.

Cost-effectiveness analysis of the treatment of ventilator-associated pneumonia with linezolid or vancomycin in Spain.

UNLABELLED: The aim of this study was to assess the cost-effectiveness of linezolid (LIN) versus vancomycin (VAN) for the treatment of ventilator-associated pneumonia (VAP) using a decision model analysis from the National Health System perspective. Patients and participants comprising four subgroups were analyzed: all, Gram-positive (GP), Staphylococcus aureus (SA), methicillin-resistant SA (MRSA). The treatments were LIN 600 mg i.v., every 12 hours, 10 days and VAN 1,000 mg i.v., every 12 hours 10 days. The primary outcome was the incremental cost-effectiveness of LIN in terms of cost per added quality-adjusted life year (QALY) gained. The secondary outcome was the marginal cost per year of life saved (LYS) generated by using LIN. Clinical cure and survival rates estimates were derived from a retrospective analysis of two trials comparing LIN with VAN. QALY was based on time-trade off study. Resource use and unit costs (Euros 2003) were obtained from Spanish VAP treatment and health cost databases. The additional QALY and LYS per LIN patients were 0.392; 0.688; 0.606; 1.805 and 0.471; 0.829; 0.729; 2.175 respectively, compared with those of VAN in the patients with VAP (all, GP, SA, and MRSA, respectively). The additional costs for LYS with LIN, as compared to VAN were 1,501.31; 827.63; 955.13 and 289.51 Euros, respectively. The additional cost per QALY with LIN was 1,803.87; 997.25; 1,149.00 and 348.85 Euros, respectively. CONCLUSIONS: LIN was more cost-effective than VAN in the treatment of VAP in Spain, with an additional cost per QALY/LYS gained below the acceptable threshold in Spain of Euros 30,000 for new therapies.

Monitoring of antimicrobial therapy by an integrated computer program.

OBJECTIVE: To assess the impact of the setting-up of a computer program designed by the Hospital Pharmacy Department as a tool that provides information for the antimicrobial therapy monitoring. To assess its influence on pharmaceutical costs. MATERIAL AND METHOD: The computer application for the follow-up of antimicrobial treatments integrates information from the Pharmacy Department and the Microbiology Laboratory and selects all patients to whom some controlled antibiotic has been prescribed. The pharmacist reviews all the controlled antibiotic treatments, suggests any change to the physician if needed and quantifies the economic impact of the accepted interventions. RESULTS: On average, 12.5% of controlled antibiotic treatments warranted a pharmaceutical intervention, and 92% of them were accepted. The most frequent interventions related to prescriptions were change of dosage and administration route and related to the disease were in respiratory and urinary tract infections. From the economic point of view, the accepted interventions represented a saving of 12,087,029 pesetas (83,359 $)/year, on average. CONCLUSION: The applied computer program resulted a useful tool for a clinical pharmacist to reach more correct antibiotical therapeutics and better cost-effectiveness relation. It also helped to achieve favorable clinical outcomes.