senior citizens aged 75 years and older represent the largest and most frequent users of health care facilities such as hospitals and long - term skilled nursing and residential homes . since immune systems are often affected by aging and underlying diseases , incidences of hospital - acquired pneumonia ( hap ) induced by methicillin - resistant staphylococcus aureus ( mrsa ) are more frequent in the elderly . 1 improving treatment outcomes for elderly patients with mrsa infections will therefore increase survival and quality of life , and reduce health care expenditure burdens.2 mrsa hap is primarily treated via the intravenous administration of vancomycin ( vcm ) , and the dosage is determined by pharmacokinetic / pharmacodynamic ( pk / pd ) parameters . however , a previous study involving adult patients with mrsa pneumonia or sepsis failed to show an association between the pk / pd parameters for vcm and treatment outcome.3 martin et al4 recommend a target area under the concentration curve ( auc)/minimum inhibitory concentration ( mic ) for vcm of > 400 g  h / ml , while we previously reported that auc / mic values of 250450 g  h / ml were acceptable for elderly patients.5 the reason for this discrepancy is currently unclear . 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.6 hayashi et al7 reported that hypoalbuminemia was a risk factor with the long - term administration of vcm . however , the reason that hypoalbuminemia has an influence on the treatment outcome of vcm remains unknown . since the potency of vcm is dependent on the free unbound form , albumin levels may have an influence on vcm treatment outcomes . in addition , body fluid volume and renal function are frequently decreased in elderly patients , and such patients show large individual differences in pk / pd parameters . nevertheless , these parameters in elderly patients with hypoalbuminemia have not been clarified . to elucidate the association between severe hypoalbuminemia and vcm treatment outcomes the study was conducted at the national center for geriatrics and gerontology hospital , obu , japan . this 320-bed hospital oversees general ( including emergency ) services , except pediatrics , and admits approximately 5,000 patients per year ( more than 50% of whom are aged over 75 years ) . mrsa is endemic in this hospital , and the ratio of mrsa isolates per total s. aureus isolates is approximately 70% . over a 7-year period ( from january 2006 through december 2012 ) , all hospitalized patients aged 75 years or older with mrsa pneumonia that had been microbiologically confirmed by sputum or blood cultures , and who had been treated with vcm therapy , were identified using the clinical pharmacokinetics department computer database . we conducted a retrospective observational study with 28-day mortality as the primary outcome for 94 elderly patients with mrsa pneumonia who had been treated with vcm during the 7-year study period . the baseline characteristics of the study patients were age , gender , body weight , serum creatinine level , charlson comorbidity index , albumin level , combination antibiotic therapy , diagnosis of pneumonia , and infection severity . in addition , we assessed the relationship between the effect of vcm pk indices , including serum peak and trough concentrations , auc / mic values , volume of distribution , half - life , clearance of vcm , single and daily dose of vcm , and dose interval of vcm . the clinical characteristics of the study patients were retrieved from the hospital medical records . for patients with multiple episodes , this study was approved by the ethics committee of the national center for geriatrics and gerontology hospital . the definition of hap was based on american thoracic society guidelines for the management of adults with hospital - acquired , ventilator - associated , and health care - associated pneumonia.2 for the purposes of this study , hap was defined as pneumonia that occurred 48 hours or more after hospitalzation for an acute lung infection characterized by a cough , fever , purulent sputum , and an abnormal chest x - ray that was not deemed to be incubating at the time of admission . among the hap cases , those with mrsa isolated from blood cultures or sputum that showed no signs of improvement after treatment with broad - spectrum antibiotics , such as carbapenem , for more than 3 days severe hypoalbuminemia was defined as a serum albumin level of < 2.5 g / dl . the severity rating of pneumonia was defined according to the japanese respiratory society guidelines for the management of hap8 and was used to allocate the patients into severe , moderate , and mild groups . the severe group was defined as patients with three or more of the following risk factors or conditions : malignancy or immunocompromized status , impaired consciousness , requiring a fraction of inspired oxygen ( fio2 ) > 35% to maintain a saturated oxygen ( sao2 ) level > 90% , men aged 70 years or older , or women aged 75 years or older , and oliguria or dehydration . the moderate group was defined as patients with any two of the above risk factors , and in addition , at least one of the following secondary risk factors : c - reactive protein ( crp ) 20.0 mg / l or extent of infiltration on a chest x - ray ( cxr ) covering at least two - thirds of one lung . the mild group was defined as all other patients who did not fit the severe or moderate criteria . the patients were divided into a severe hypoalbuminemia and a non - severe hypoalbuminemia group before vcm administration . nephrotoxicity to vcm was defined as an increase in serum creatinine of 0.5 g / dl or a 50% increase over pretreatment levels.2 liver dysfunction was defined according to international consensus meeting criteria.9 the initial treatment schedule for vcm was simulated to achieve a trough concentration 1015 g / ml , with therapeutic drug monitoring ( tdm ) software using patient characteristics , including age , body weight and serum creatinine ( vcm - tdm microsoft excel version 3.0 , shionogi and co , ltd , osaka , japan ) . the serum concentrations of vcm were determined from samples collected during the fifth day from the start of administration . the blood samples were obtained twice : before vcm administration ( trough ) and 1 hour after vcm administration ( peak ) . the predicted 24-hour auc values for vcm were calculated using the tdm software based on peak and trough concentrations . continuous variables were compared using the student s t - test for normally distributed variables and the welch test for non - normally distributed variables . categorical variables were compared with the chi - square (  ) test . in these tests , a two - sided p - value of < 0.05 was considered to be significant . the study was conducted at the national center for geriatrics and gerontology hospital , obu , japan . this 320-bed hospital oversees general ( including emergency ) services , except pediatrics , and admits approximately 5,000 patients per year ( more than 50% of whom are aged over 75 years ) . mrsa is endemic in this hospital , and the ratio of mrsa isolates per total s. aureus isolates is approximately 70% . over a 7-year period ( from january 2006 through december 2012 ) , all hospitalized patients aged 75 years or older with mrsa pneumonia that had been microbiologically confirmed by sputum or blood cultures , and who had been treated with vcm therapy , were identified using the clinical pharmacokinetics department computer database . we conducted a retrospective observational study with 28-day mortality as the primary outcome for 94 elderly patients with mrsa pneumonia who had been treated with vcm during the 7-year study period . the baseline characteristics of the study patients were age , gender , body weight , serum creatinine level , charlson comorbidity index , albumin level , combination antibiotic therapy , diagnosis of pneumonia , and infection severity . in addition , we assessed the relationship between the effect of vcm pk indices , including serum peak and trough concentrations , auc / mic values , volume of distribution , half - life , clearance of vcm , single and daily dose of vcm , and dose interval of vcm . the clinical characteristics of the study patients were retrieved from the hospital medical records . for patients with multiple episodes , this study was approved by the ethics committee of the national center for geriatrics and gerontology hospital . the definition of hap was based on american thoracic society guidelines for the management of adults with hospital - acquired , ventilator - associated , and health care - associated pneumonia.2 for the purposes of this study , hap was defined as pneumonia that occurred 48 hours or more after hospitalzation for an acute lung infection characterized by a cough , fever , purulent sputum , and an abnormal chest x - ray that was not deemed to be incubating at the time of admission . among the hap cases , those with mrsa isolated from blood cultures or sputum that showed no signs of improvement after treatment with broad - spectrum antibiotics , such as carbapenem , for more than 3 days were defined as mrsa hap . severe hypoalbuminemia was defined as a serum albumin level of < 2.5 g / dl . the severity rating of pneumonia was defined according to the japanese respiratory society guidelines for the management of hap8 and was used to allocate the patients into severe , moderate , and mild groups . the severe group was defined as patients with three or more of the following risk factors or conditions : malignancy or immunocompromized status , impaired consciousness , requiring a fraction of inspired oxygen ( fio2 ) > 35% to maintain a saturated oxygen ( sao2 ) level > 90% , men aged 70 years or older , or women aged 75 years or older , and oliguria or dehydration . the moderate group was defined as patients with any two of the above risk factors , and in addition , at least one of the following secondary risk factors : c - reactive protein ( crp ) 20.0 mg / l or extent of infiltration on a chest x - ray ( cxr ) covering at least two - thirds of one lung . the mild group was defined as all other patients who did not fit the severe or moderate criteria . the patients were divided into a severe hypoalbuminemia and a non - severe hypoalbuminemia group before vcm administration . nephrotoxicity to vcm was defined as an increase in serum creatinine of 0.5 g / dl or a 50% increase over pretreatment levels.2 liver dysfunction was defined according to international consensus meeting criteria.9 the initial treatment schedule for vcm was simulated to achieve a trough concentration 1015 g / ml , with therapeutic drug monitoring ( tdm ) software using patient characteristics , including age , body weight and serum creatinine ( vcm - tdm microsoft excel version 3.0 , shionogi and co , ltd , osaka , japan ) . the serum concentrations of vcm were determined from samples collected during the fifth day from the start of administration . the blood samples were obtained twice : before vcm administration ( trough ) and 1 hour after vcm administration ( peak ) . the predicted 24-hour auc values for vcm were calculated using the tdm software based on peak and trough concentrations . continuous variables were compared using the student s t - test for normally distributed variables and the welch test for non - normally distributed variables . categorical variables were compared with the chi - square (  ) test . in these tests , a two - sided p - value of < 0.05 was considered to be significant . the 94 patients were divided into severe hypoalbuminemia ( n = 23 ) and non - severe hypoalbuminemia ( n = 71 ) groups . the pk / pd parameters for vcm in the severe hypoalbuminemia and non - severe hypoalbuminemia groups are also summarized in table 2 . notably , no significant difference was found between the two groups for the mean trough and peak concentrations , clearance of vcm , and whether a single and daily dose of vcm was administered ( table 2 ) . the percentage of auc values of > 450 g  h / ml in the severe hypoalbuminemia group was significantly higher than in the non - severe hypoalbuminemia group ( 9 of 23 patients [ 39% ] vs 6 of 71 patients [ 9% ] ; p < 0.001 ) . the half - life of vcm in the severe hypoalbuminemia group was significantly longer than in the non - severe hypoalbuminemia group ( 33.2  5.4 hours [ 15135 ] vs 24.9  1.6 hours [ 1068 ] ; p = 0.049 ) . auc / mic values of 250450 and > 450 g  h / ml were significantly associated with 28-day mortality as a primary outcome in the severe hypoalbuminemia patients ( p < 0.001 , figure 1 ) ; statistical power was 0.968 and 0.778 , respectively . auc / mic values of < 250 g  h / ml were not associated ( p = 0.143 , figure 1 ) . we also examined the adverse effects of vcm treatment among the elderly patients and found that 12 of 94 ( 13% ) developed nephrotoxicity after vcm administration . we detected a significant difference in increasing the 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 ) ( table 3 ) . in patients with auc / mic values of > 450 g  h / ml , the percentage of nephrotoxicity after vcm administration was significantly higher in the severe hypoalbuminemia group than in the non - severe hypoalbuminemia group ( 67% vs 33% ; p < 0.001 ) ( figure 2 ) , whereas the percentage of nephrotoxicity in the non - severe hypoalbuminemia group was significantly higher than in the severe hypoalbuminemia group for auc / mic values of < 250 g  h / ml . this is the first study to have shown that severe hypoalbuminemia influences the half - life of vcm and treatment outcome . furthermore , patients with severe hypoalbuminemia with auc / mic values of > 450 g  h / ml showed evidence of nephrotoxicity . the volume of distribution and clearance of other highly protein - bound antibacterials , such as teicoplanin , aztreonam , fusidic acid , or daptomycin , were increased in critically ill patients with hypoalbuminaemia.10 since the protein - binding rate of vcm is lower than that of teicoplanin,11 few studies have investigated whether severe hypoalbuminemia influences the pk / pd parameters of vcm in elderly patients . in the present study , the half - life of vcm was longer in elderly patients with severe hypoalbuminemia than in the patients with non - severe hypoalbuminemia . furthermore , the percentage of auc / mic values of > 450 g  h / ml was increased in the patients with severe hypoalbuminemia ( table 2 ) . although vcm has a relatively low protein - binding rate , these results indicate that severe hypoalbuminemia might affect the concentration of the free form , and prolong the half - life of vcm in elderly patients . vcm therapeutic guidelines recommend a target auc / mic for vcm of > 400 g  h / ml;3 however , our previous report suggested that auc / mic values of 250450 g  h / ml were suitable for the treatment of mrsa pneumonia with vcm in elderly patients.4 the reason for this discrepancy is currently unclear . in the present study , the half - life of vcm was extended in the patients with severe hypoalbuminemia , and the auc / mic values of vcm were also higher . moreover , with an increase in auc / mic values , the percentage of nephrotoxicity was also increased in patients with severe hypoalbuminemia ( figure 2 ) . interestingly , auc / mic values of < 250 g  h / ml did not influence 28-day mortality in patients with severe hypoalbuminemia , whereas the mortality rate was high in patients with severe hypoalbuminemia with auc / mic values of 250 g  h / ml ( figure 1 ) . these results suggest that elderly patients with severe hypoalbuminemia had a high risk of developing nephrotoxicity and 28-day mortality in the case of target auc / mic values of > 400 g  h / ml . elderly patients with infectious diseases are associated with a high incidence of severe hypoalbuminemia , moreover , hypoalbuminemia can be acute in severely infected patients , and can be entirely independent of baseline nutritional state . since malnutrition leads to poor outcomes for therapy with vcm , although we did not recommend a target auc / mic in patients with severe hypoalbuminemia , we consider that elderly patients with low body weight and severe hypoalbuminemia should have their doses individually adjusted by the pharmacist according to those parameters . first , the targeted vcm trough concentration in this study is about 10 g / ml , which is lower than the guidelines recommended by the infectious diseases society of america / american society of health - system pharmacists : 1520 g / ml.12 moreover , the average weight of patients in the present study was very low . it was necessary to limit the dosage , because study patients had disuse syndrome or low muscle tone . we consider that elderly patients with low body weight and severe hypoalbuminemia should have their dose individually adjusted by the pharmacist according to those parameters . second , a relatively small number of patients with mrsa pneumonia were enrolled in this study . new , large prospective studies are needed to investigate whether nutritional treatment might be useful for vcm therapy in elderly patients . this is the first study to indicate that severe hypoalbuminemia influences the half - life of vcm and vcm - related treatment outcomes in patients aged 75 years or older with mrsa pneumonia . to establish more effective and safer treatments ,