there has been an increasing interest in pharmacokinetic ( pk)/pharmacodynamic ( pd ) analyses because they are able to optimize dosing regimens , thereby improving outcomes.1 pk / pd analyses , based on the principle reported by craig2 and other researchers to optimize dose regimens for clinical applications , are now increasing in the usa and europe .
teicoplanin is a glycopeptide antibiotic that has been used to treat serious , invasive infections caused by gram - positive bacteria.3 the area under the drug concentration  time curve ( auc)/minimum inhibitory concentration ( mic ) has been identified as a pk / pd parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes.4,5 the guidelines for therapeutic drug monitoring of vancomycin suggest that an auc / mic ratio of 400 is the pk / pd parameter associated with clinical and bacteriological responses to vancomycin therapy.6,7 although optimized dosing regimens
based on pk / pd are needed , the pk / pd analysis of teicoplanin against methicillin - resistant staphylococcus aureus ( mrsa ) infections has not yet been performed .
we herein examined patients with mrsa infections who were administered with teicoplanin in order to determine the target auc / mic ratio of teicoplanin .
this study retrospectively assessed data obtained as part of our routine tdm of teicoplanin therapy in 46 patients with mrsa infections at kagoshima university hospital .
this study was approved by the ethics review board of kagoshima university hospital ( # 273 ) .
patients were excluded if they fulfilled any of the following criteria : children , lack of tdm data , teicoplanin mic data for mrsa and culture test data , and combination with other anti - mrsa agents .
teicoplanin was administered intravenously at an initial dose of 200 mg ( n=4 ) , 400 mg ( n=30 ) , 500 mg ( n=2 ) , 600 mg ( n=8 ) , and 800 mg ( n=2 ) every 12 hours for three doses .
then , teicoplanin was continued at a maintenance dose of 200 mg ( n=14 ) , 300 mg ( n=3 ) , 400 mg ( n=22 ) , 500 mg ( n=1 ) , 600 mg ( n=5 ) , and 800 mg ( n=1 ) every 24 hours .
serum samples were separated from venous blood by centrifugation at 3,000 rpm for 10 minutes , and serum concentrations of teicoplanin were determined by using a fluorescence polarization immunoassay system ( tdxflx analyzer ; abbott laboratories , abbott park , il , usa ) .
creatinine clearance ( clcr ) was estimated using the actual body weight value in the cockcroft 
gault formula.8 the serum teicoplanin concentration in each patient was used to estimate individual total clearance ( cltotal ) by using a bayesian estimation based on the population pk parameters of teicoplanin in the japanese patients.9 the mean population pk parameters were as follows : teicoplanin clearance ( l / h ) = 0.00498  clcr ( ml / min ) + 0.00426  body weight ( kg ) ; the distribution volume of the central compartment ( l ) = 10.4 ; the transfer rate constant from the central compartment to the peripheral compartment ( h ) = 0.38 ; the transfer rate constant from the peripheral compartment to the central compartment ( h ) = 0.0485 . the auc value for 24 hours under steady - state conditions was estimated as auc for 24 hours ( auc24 ; gh / ml ) = daily dose ( mg)/cltotal ( l / h).4 the mic for teicoplanin was determined using the standardized agar dilution method according to the clinical and laboratory standards institute guidelines.10 a suspension of bacteria equivalent to the 0.5 mcfarland turbidity standards was inoculated onto mueller - hinton agar plates .
the effects of teicoplanin in terms of bacteriological responses were evaluated with a quantitative and/or semi - quantitative assessment .
eradication  was defined when bacterial count was zero ,  decrease  when bacterial count was decreased by 14 levels , and 
( eradication and a decrease in mrsa ) or  failure  ( persistent mrsa ) .
a logistic regression analysis was performed to determine whether the teicoplanin auc24/mic ratio was a significant predictor of bacteriological responses ( 1 , success ; 0 , failure ) .
the time from initiation of the teicoplanin treatment to the development of microbiological efficacy was estimated using a kaplan  meier curve analysis .
all statistical analyses were performed using spss software ( version 15.0j ; spss inc . , chicago , il , usa ) .
this study retrospectively assessed data obtained as part of our routine tdm of teicoplanin therapy in 46 patients with mrsa infections at kagoshima university hospital .
this study was approved by the ethics review board of kagoshima university hospital ( # 273 ) .
patients were excluded if they fulfilled any of the following criteria : children , lack of tdm data , teicoplanin mic data for mrsa and culture test data , and combination with other anti - mrsa agents .
teicoplanin was administered intravenously at an initial dose of 200 mg ( n=4 ) , 400 mg ( n=30 ) , 500 mg ( n=2 ) , 600 mg ( n=8 ) , and 800 mg ( n=2 ) every 12 hours for three doses .
then , teicoplanin was continued at a maintenance dose of 200 mg ( n=14 ) , 300 mg ( n=3 ) , 400 mg ( n=22 ) , 500 mg ( n=1 ) , 600 mg ( n=5 ) , and 800 mg ( n=1 ) every 24 hours .
serum samples were separated from venous blood by centrifugation at 3,000 rpm for 10 minutes , and serum concentrations of teicoplanin were determined by using a fluorescence polarization immunoassay system ( tdxflx analyzer ; abbott laboratories , abbott park , il , usa ) .
creatinine clearance ( clcr ) was estimated using the actual body weight value in the cockcroft  gault formula.8
the serum teicoplanin concentration in each patient was used to estimate individual total clearance ( cltotal ) by using a bayesian estimation based on the population pk parameters of teicoplanin in the japanese patients.9 the mean population pk parameters were as follows : teicoplanin clearance ( l / h ) = 0.00498  clcr ( ml / min ) + 0.00426  body weight ( kg ) ; the distribution volume of the central compartment ( l ) = 10.4 ; the transfer rate constant from the central compartment to the peripheral compartment ( h ) = 0.38 ; the transfer rate constant from the peripheral compartment to the central compartment ( h ) = 0.0485 .
the auc value for 24 hours under steady - state conditions was estimated as auc for 24 hours ( auc24 ; gh / ml ) = daily dose ( mg)/cltotal ( l / h).4
the mic for teicoplanin was determined using the standardized agar dilution method according to the clinical and laboratory standards institute guidelines.10 a suspension of bacteria equivalent to the 0.5 mcfarland turbidity standards was inoculated onto mueller - hinton agar plates .
the effects of teicoplanin in terms of bacteriological responses were evaluated with a quantitative and/or semi - quantitative assessment .
eradication  was defined when bacterial count was zero ,  decrease  when bacterial count was decreased by 14 levels , and 
( eradication and a decrease in mrsa ) or  failure  ( persistent mrsa ) .
a logistic regression analysis was performed to determine whether the teicoplanin auc24/mic ratio was a significant predictor of bacteriological responses ( 1 , success ; 0 , failure ) .
the time from initiation of the teicoplanin treatment to the development of microbiological efficacy was estimated using a kaplan  meier curve analysis .
all statistical analyses were performed using spss software ( version 15.0j ; spss inc . ,
a total of 46 patients , 36 men and ten women , with a mean age of 73.19.4 years and body weight of 53.510.8 kg , were available for retrospective analysis .
the indications for teicoplanin treatment were as follows : wound infection ( n=17 ) , pneumonia ( n=14 ) , bacteremia ( n=6 ) , and others ( n=9 ) .
the mics and their percentages of strains were 0.38 g / ml ( 2.2% ) , 0.5 g / ml ( 6.5% ) , 0.75 g / ml ( 43.5% ) , 1.0 g / ml ( 34.8% ) , and 1.5 g / ml ( 13.0% ) .
the auc24/mic ratios with and without bacteriological responses were 926.6425.2 gh / ml ( n=34 ) and 642.2193.9 gh / ml ( n=12 ) ( p<0.05 ) , respectively .
figure 1 shows the relationship between auc24/mic ratios on day 3 and bacteriological responses ( failure , 0 ; success , 1 ) .
auc24/mic ratios of 500 , 700 , and 900 gh / ml gave probabilities of treatment success of 0.50 , 0.72 , and 0.87 , respectively .
the bacteriological treatment successes were evaluated in 15 patients with auc24/mic ratios of 900 and 31 patients with auc24/mic ratios of < 900 using the kaplan  meier curve analysis ( figure 2 ) .
patients with auc24/mic ratios of 900 had significantly stronger bacteriological responses than those with auc24/mic ratios of < 900 ( p<0.05 ) .
the trough concentrations of 1020 g / ml are needed to achieve an auc value of 400.6 if an auc / mic ratio of 400 is not achieved , even though an appropriate trough level is achieved , vancomycin treatment would not exhibit a good response .
similar to teicoplanin , previous studies have shown that teicoplanin trough concentrations of > 13 g / ml are effective for treating most infections.11 however , the teicoplanin treatment should be optimized using auc / mic ratios on the basis of pk / pd .
thus , this study examined patients with mrsa infections who were administered with teicoplanin in order to determine the target auc / mic ratio of teicoplanin .
this pk / pd analysis determined the auc24/mic target value of teicoplanin required to cure patients with mrsa infections .
the auc24/mic ratios of 500 , 700 , and 900 gh / ml showed probabilities of treatment success of 0.50 , 0.72 , and 0.87 , respectively .
craig previously reported that auc / mic ratios may be an important pk / pd parameter that correlates with the efficacy of vancomycin and teicoplanin.5 hagihara et al reported that the auc24 value on the third day was significantly higher in the treatment success group ( 897.671.7 gh / ml ) than that of the treatment failure group ( 652.983.4 gh / ml).12 these findings indicated that an auc24 value of at least 800 gh / ml is required to ensure bacteriological responses ( mic of 1.0 g / ml for all isolates).12 kanazawa et al also showed that an increase in the probability of treatment success was dependent on auc24 values and that the target that gave a probability of 0.9 was 750 gh / ml ( mic of < 2.0 g / ml for all isolates).13 they could not estimate auc24/mic , because exact mics were not measured .
on the other hand , ogawa et al indicated that a log[cmax , unbound / mic ] of 0.30 on day 3 of teicoplanin therapy was the threshold for achieving treatment success14 ; however , they did not evaluate auc24/mic ratios .
the mics of teicoplanin for a total of 46 mrsa strains were determined in the present study by the e - test method .
auc24/mic ratios were significantly higher in the treatment success group ( 926.6425.2 gh / ml ) than in the treatment failure group ( 642.2193.9 ) .
an auc24/mic ratio of 900 gh / ml showed a probability of treatment success of 0.87 ( figure 1 ) .
meier curve analysis , an auc24/mic ratio of 900 exhibited a significantly stronger bacteriological response than that of an auc24/mic ratio of < 900 ( figure 2 ) .
these results suggested that an auc24/mic ratio of 900 gh / ml may be required to ensure bacteriological responses .
therefore , not only trough concentrations but also auc / mic ratios should be monitored for teicoplanin tdm .
this study focused on bacteriological responses because clinical outcomes , such as relief from symptoms , reduced white blood cell count , and decrease in body temperature , are dependent on many factors.12,13,15 however , clinical outcomes are also important for the interpretation and clinical applicability of the current results .
additionally , in this retrospective study , each patient was different in teicoplanin dose , duration of therapy , severity of illness , and type of infections .
therefore , well - designed prospective studies for various types of infection in a larger number of patients are needed to validate the current findings .
this pk / pd analysis revealed the target auc24/mic ratios of teicoplanin in patients with mrsa infections on the basis of pk / pd analyses .
these results indicated that an auc24/mic ratio of 900 gh / ml is required to ensure bacteriological responses .
however , further studies are needed to confirm these results and clarify their therapeutic implications .
 backgroundteicoplanin is a glycopeptide antibiotic that has been used to treat serious , invasive infections caused by gram - positive bacteria . 
 the area under the drug concentration  time curve ( auc)/minimum inhibitory concentration ( mic ) was identified as a pharmacokinetic  pharmacodynamic ( pk  pd ) parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes . although optimized dosing regimens based on pk  pd are needed , a pk  
 pd analysis of teicoplanin against methicillin - resistant staphylococcus aureus ( mrsa ) infections has not yet been performed . 
 thus , this study examined patients with mrsa infections , who were administered with teicoplanin in order to determine the target auc / mic ratio.methodsthis study retrospectively assessed data obtained as part of our routine therapeutic drug monitoring ( tdm ) of teicoplanin therapy in 46 patients with mrsa infections at kagoshima university hospital . 
 serum concentrations of teicoplanin were determined using a fluorescence polarization immunoassay system and used for a bayesian pk estimation to estimate auc for 24 hours ( auc24 ) . 
 the mic value for teicoplanin was determined using a standardized agar dilution method . 
 the effects of teicoplanin were evaluated in terms of bacteriological responses by a quantitative assessment.resultsthe estimated auc24/mic ratios with and without bacteriological responses were 926.6425.2 gh / ml ( n=34 ) and 642.2193.9 gh / ml , respectively ( n=12 ; p<0.05 ) . on the basis of a logistic regression analysis , auc24/mic ratios of 500 gh / ml , 700 gh / ml , and 900 gh / ml gave probabilities of treatment success of 0.50 , 0.72 , and 0.87 , respectively . 
 furthermore , using the kaplan  
 meier curve analysis , an auc24/mic ratio of 900 led to a significantly stronger bacteriological response than an auc24/mic ratio of < 900.conclusionthese results suggest that an auc24/mic ratio of 900 gh / ml is required to ensure a sufficient bacteriological response . 