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      Clinical Interventions in Aging (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on prevention and treatment of diseases in people over 65 years of age. Sign up for email alerts here.

      36,334 Monthly downloads/views I 3.829 Impact Factor I 7.4 CiteScore I 1.83 Source Normalized Impact per Paper (SNIP) I 1.044 Scimago Journal & Country Rank (SJR)

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      The influence of severe hypoalbuminemia on the half-life of vancomycin in elderly patients with methicillin-resistant Staphylococcus aureus hospital-acquired pneumonia

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          Abstract

          Background

          Vancomycin (VCM) treatment outcomes depend on the characteristics of the patient, and it is well known that hypoalbuminemia is a risk factor for poor treatment outcomes, as reported in a previous study. However, the reason that severe hypoalbuminemia has an influence on the treatment outcome of VCM remains unknown.

          Objective

          To elucidate the association between severe hypoalbuminemia and VCM treatment outcomes, we examined pharmacokinetic/pharmacodynamic (PK/PD) parameters in elderly patients with severe hypoalbuminemia.

          Methods

          We conducted a retrospective observational study of 94 patients with methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired pneumonia who had been treated with VCM between January 2006 and December 2012. The 94 patients were divided into severe hypoalbuminemia and non-severe hypoalbuminemia groups. The PK/PD parameters and treatment outcomes of VCM were compared between the two groups.

          Results

          The half-life of VCM in the severe hypoalbuminemia group was significantly longer than in the non-severe hypoalbuminemia group (33.2 + 5.4 vs 24.9 + 1.6; P = 0.049). Area under the concentration curve (AUC)/minimum inhibitory concentration (MIC) values of 250–450 and >450 μg × h/mL were significantly associated with 28-day mortality in the severe hypoalbuminemia group ( P < 0.001), whereas AUC/MIC values of <250 μg × h/mL were not associated. We also detected a significant difference in the increased percentage of nephrotoxicity in the severe hypoalbuminemia group (6 of 23 patients [26%]) compared with the non-severe hypoalbuminemia group (6 of 71 patients [8%]; P < 0.001).

          Conclusion

          These findings indicate that severe hypoalbuminemia influences the half-life of VCM and treatment outcomes in elderly patients (≥75 years of age). To establish a more effective and safer treatment protocol, the issue of malnutrition in elderly patients needs to be addressed and improved.

          Most cited references9

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          The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients.

          Lara N Roberts, Marta Ulldemolins, Jordi Rello … (2011)
          Low serum albumin levels are very common in critically ill patients, with reported incidences as high as 40-50%. This condition appears to be associated with alterations in the degree of protein binding of many highly protein-bound antibacterials, which lead to altered pharmacokinetics and pharmacodynamics, although this topic is infrequently considered in daily clinical practice. The effects of hypoalbuminaemia on pharmacokinetics are driven by the decrease in the extent of antibacterial bound to albumin, which increases the unbound fraction of the drug. Unlike the fraction bound to plasma proteins, the unbound fraction is the only fraction available for distribution and clearance from the plasma (central compartment). Hence, hypoalbuminaemia is likely to increase the apparent total volume of distribution (V(d)) and clearance (CL) of a drug, which would translate to lower antibacterial exposures that might compromise the attainment of pharmacodynamic targets, especially for time-dependent antibacterials. The effect of hypoalbuminaemia on unbound concentrations is also likely to have an important impact on pharmacodynamics, but there is very little information available on this area. The objectives of this review were to identify the original research papers that report variations in the highly protein-bound antibacterial pharmacokinetics (mainly V(d) and CL) in critically ill patients with hypoalbuminaemia and without renal failure, and subsequently to interpret the consequences for antibacterial dosing. All relevant articles that described the pharmacokinetics and/or pharmacodynamics of highly protein-bound antibacterials in critically ill patients with hypoalbuminaemia and conserved renal function were reviewed. We found that decreases in the protein binding of antibacterials in the presence of hypoalbuminaemia are frequently observed in critically ill patients. For example, the V(d) and CL of ceftriaxone (85-95% protein binding) in hypoalbuminaemic critically ill patients were increased 2-fold. A similar phenomenon was reported with ertapenem (85-95% protein binding), which led to failure to attain pharmacodynamic targets (40% time for which the concentration of unbound [free] antibacterial was maintained above the minimal inhibitory concentration [fT>MIC] of the bacteria throughout the dosing interval). The V(d) and CL of other highly protein-bound antibacterials such as teicoplanin, aztreonam, fusidic acid or daptomycin among others were significantly increased in critically ill patients with hypoalbuminaemia compared with healthy subjects. Increased antibacterial V(d) appeared to be the most significant pharmacokinetic effect of decreased albumin binding, together with increased CL. These pharmacokinetic changes may result in decreased achievement of pharmacodynamic targets especially for time-dependent antibacterials, resulting in sub-optimal treatment. The effects on concentration-dependent antibacterial pharmacodynamics are more controversial due to the lack of data on this topic. In conclusion, altered antibacterial-albumin binding in the presence of hypoalbuminaemia is likely to produce significant variations in the pharmacokinetics of many highly protein-bound antibacterials. Dose adjustments of these antibacterials in critically ill patients with hypoalbuminaemia should be regarded as another step for antibacterial dosing optimization. Moreover, some of the new antibacterials in development exhibit a high level of protein binding although hypoalbuminaemia is rarely considered in clinical trials in critically ill patients. Further research that defines dosing regimens that account for such altered pharmacokinetics is recommended.
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            Pneumonia caused by methicillin-resistant Staphylococcus aureus.

            Ethan Rubinstein, Marin H. Kollef, Dilip Nathwani (2008)
            A recent increase in staphylococcal infections caused by methicillin-resistant Staphylococcus aureus (MRSA), combined with frequent, prolonged ventilatory support of an aging, often chronically ill population, has resulted in a large increase in cases of MRSA pneumonia in the health care setting. In addition, community-acquired MRSA pneumonia has become more prevalent. This type of pneumonia historically affects younger patients, follows infection with influenza virus, and is often severe, requiring hospitalization and causing the death of a significant proportion of those affected. Ultimately, hospital-acquired MRSA and community-acquired MRSA are important causes of pneumonia and present diagnostic and therapeutic challenges. Rapid institution of appropriate antibiotic therapy, including linezolid as an alternative to vancomycin, is crucial. Respiratory infection-control measures and de-escalation of initial broad-spectrum antibiotic regimens to avoid emergence of resistant organisms are also important. This article reviews the clinical features of, diagnosis of, and therapies for MRSA pneumonia.
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              Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices.

              Meghan Jeffres, Warren Isakow, Joshua A Doherty … (2006)
              The goal of this investigation was to determine whether vancomycin pharmacokinetic indexes (eg, serum trough concentrations or area under the concentration curve [AUC] values) were associated with mortality for patients with health-care-associated pneumonia (HCAP) attributed to methicillin-resistant Staphylococcus aureus (MRSA). A retrospective, single-center, observational cohort study. Barnes-Jewish Hospital, a 1,200-bed urban teaching facility. Adult patients requiring hospitalization who were identified as having HCAP attributed to MRSA by BAL semi-quantitative cultures. Retrospective data collection from automated hospital, microbiology, and pharmacy databases. One hundred two patients with MRSA HCAP were identified over a 6.5-year period. Thirty-two patients (31.4%) died during their hospitalization. The mean (+/- SD) vancomycin trough concentrations (13.6 +/- 5.9 vs 13.9 +/- 6.7 microg/mL, respectively; p = 0.866) and AUC values (351 +/- 143 vs 354 +/- 109 microg/h/mL, respectively; p = 0.941) did not differ between survivors and nonsurvivors. The stratification of the vancomycin trough concentrations and AUC values yielded no relationship with hospital mortality. We found no evidence that greater vancomycin trough concentrations or AUC values correlated with hospital outcome. Based on these results, aggressive dosing strategies for vancomycin (eg, trough concentrations of > 15 microg/mL) may not offer any advantage over traditional dose targets (range, 5 to 15 microg/mL).
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                Author and article information

                Journal
                Journal ID (nlm-ta): Clin Interv Aging
                Journal ID (iso-abbrev): Clin Interv Aging
                Title: Clinical Interventions in Aging
                Publisher: Dove Medical Press
                ISSN (Print): 1176-9092
                ISSN (Electronic): 1178-1998
                Publication date Collection: 2013
                Publication date (Print): 2013
                Publication date (Electronic): 30 September 2013
                Volume: 8
                Pages: 1323-1328
                Affiliations
                [1 ]Department of Analytical Pharmacology, Meijo University Graduate School of Pharmacy, Nagoya, Japan
                [2 ]Department of Pharmacy, National Center for Geriatrics and Gerontology
                [3 ]Department of Respiratory Medicine, National Center for Geriatrics and Gerontology
                [4 ]Department of Clinical Research and Development, National Center for Geriatrics and Gerontology, Obu, Japan
                Author notes

                *These authors contributed equally to this work

                Correspondence: Fumihiro Mizokami, Department of Pharmacy, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka, Obu, Aichi 474-8511, Japan, Tel +81 562 46 2311, Fax +81 562 48 8895, Email mizokami@ 123456ncgg.go.jp
                Article
                Publisher ID: cia-8-1323
                DOI: 10.2147/CIA.S52259
                PMC ID: 3793010
                SO-VID: bcebb203-97a2-4f6c-9cdf-4384ddd7ef35
                Copyright © © 2013 Mizuno et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License
                License:

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Health & Social care
                Keywords: methicillin-resistant staphylococcus aureus,elderly patients,vancomycin,severe hypoalbuminemia,pharmacokinetics,pharmacodynamics
                Data availability:
                ScienceOpen disciplines: Health & Social care
                Keywords: methicillin-resistant staphylococcus aureus, elderly patients, vancomycin, severe hypoalbuminemia, pharmacokinetics, pharmacodynamics

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