the online version of this article ( doi:10.1007/s40121 - 015 - 0100-z ) contains supplementary material , which is available to authorized users .
linezolid ( lzd ) is an oxazolidinone antibiotic characterized by a wide spectrum of activity against gram - positive pathogens resistant to -lactams and glycopeptides , and its use has progressively increased in recent years [ 1 , 2 ] .
lzd clearance is mainly non - renal ( approximately 65% ) through the formation of two major inactive metabolites , the hydroxyethyl glycine metabolite ( pnu-142586 ) and the aminoethoxyacetic acid metabolite ( pnu-142300 ) , which account for 4050% and 910% of the total dose , respectively .
more recent reports have suggested that the influence of renal dysfunction on high lzd blood concentration may lead to hematological side effects such as thrombocytopenia [ 8 , 9 ] .
however , the influence of low lzd blood concentration in conjunction with high creatinine clearance ( crcl ) still remains unknown .
additionally , the pharmacokinetic / pharmacodynamic ( pk / pd ) index for the efficacy of lzd was previously shown to be a 24-h area under the plasma lzd concentration  time curve / minimum inhibitory concentration ( auc24/mic ) ratio of 100 [ 46 ] .
herein , we report the pk / pd profile of a patient with methicillin - resistant staphylococcus aureus ( mrsa ) pneumonia and bacteremia who developed diabetes insipidus ( di ) with a high level of crcl . despite the low auc24/mic of lzd in comparison with the efficacy level of auc24/mic ( 100 ) [ 46 ] ,
blood samples for the quantification of lzd in plasma were collected through an indwelling arterial catheter both before and after the morning dosing , which was administered through an intermittent intravenous infusion of 600  mg over the course of 1  h. lzd was administrated twice a day ( morning and night ) .
blood samples were taken in the morning before dosing ( trough ) and after the morning s 1-h - long lzd administration .
after centrifugation , plasma samples were separated and stored at 80  c until assayed .
blood lzd concentration was measured after the patient s transfer to the general ward . to assess renal function , creatinine concentrations in both the serum and 24-h urine samples were determined .
crcl ( ml / min ) was calculated using the formula:\documentclass[12pt]{minimal } 
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				 \begin{document}$$ { \text{crcl } } = ( c_{\text{urine } } \times v_{\text{urine } } ) /(c_{\text{serum } } ) \times ( 1.73/{\text{bsa } } ) $ $ \end{document}crcl=(curinevurine)/(cserum)(1.73/bsa)where curine ( mg / dl ) is the creatinine concentration in urine , vurine ( ml / min ) is the urine volume , cserum ( mg / dl ) is the serum creatinine concentration , and bsa ( m ) is the body surface area .
the drug concentration data were fit to a standard one - compartment model with zero - order input ( 1-h - long drug infusion ) and first - order elimination .
the pk parameters used were total clearance ( l / h ) and volume of distribution ( l ) .
a 19-year - old male was admitted to fukuoka university hospital after being involved in a traffic accident .
a neurological assessment revealed a glasgow coma scale ( gcs ) score of 3/15 . computed tomography ( ct ) of the head showed a subcutaneous and extradural hematoma .
a craniotomy was immediately performed to remove the hematoma and to attain cerebral decompression and , as a result , the gcs score recovered to 10/15 . on day  13 , he developed polyuria .
his 24-h urine volume reached 56  l / day with a urine osmolality of 159  mosm / l and a plasma osmolality of 340  mosm / l .
as a basal skull fracture was present , an intravenous vasopressin infusion was administered to treat the di .
however , it showed a poor therapeutic effect , polyuria continued , and crcl was revealed to be 180278  ml / min as a result of the di .
we were required to administer approximately 67  l / day of fluid to compensate for the high urinary fluid output . on day  50 ,
mrsa was detected in surveillance cultures of sputum and urine samples ( mic for lzd was 1 
mg / l ) . on day  55 , he developed systemic inflammatory response syndrome ( sirs ) , and pneumonia and/or a urinary tract infection was suspected based upon the results of preceding surveillance cultures
. consequently , lzd was administrated intravenously ( 600  mg every 12  h ) for 14  days . on day  57 ,
a chest x - ray and ct scan showed a consolidation in the right lung ( fig . 
it was found that blood cultures that had been drawn before the administration of lzd developed mrsa ( mic for lzd was 1 
based upon these findings , we diagnosed mrsa pneumonia with secondary bacteremia due to pneumonia or a urinary tract infection .
blood , urine , and sputum cultures were negative on days  61 , 64 , and 68 , respectively . a chest x - ray on day  68 and ct scan on day  70 showed improvement in the consolidation ( fig . 
concomitant antibiotics were not administered because the results of the cultures showed the development of mrsa only ( fig . 
a ( chest x - ray ) and b ( chest ct scan ; day 57 ) show consolidation in right lower lung before treatment ( b , arrow ) .
c the chest x - ray ( day 68 ) and d shows the chest ct scan ( day 70 ) images after treatment , and show the improvement in the consolidationfig . 
lzd ( 600  mg ) was administrated twice a day for 1  h. the concentration of lzd was shown before the day s first administration ( trough ) and after the first 1-h lzd administration for the day .
crcl ( ml / min ) was calculated using the formula : crcl  =  ( c 
 urine    v 
 urine)/(c 
 serum )    ( 1.73/bsa ) ; where c 
 urine ( mg / dl ) is the creatinine concentration in urine , v 
 urine ( ml / min ) is the urine volume , c 
 serum ( mg / dl ) is the serum creatinine concentration , and bsa ( m ) is the body surface area .
auc 
 24 
 /mic 24-h area under the plasma linezolid concentration  time curve / minimum inhibitory concentration , crcl creatinine clearance , crp c - reactive protein , lzd linezolid , mrsa methicillin - resistant staphylococcus aureus , nd not detected , ne not examined , sirs systemic inflammatory syndrome chest imaging before and after treatment with lzd . a ( chest x - ray ) and b ( chest ct scan ; day 57 )
c the chest x - ray ( day 68 ) and d shows the chest ct scan ( day 70 ) images after treatment , and show the improvement in the consolidation clinical course and lzd blood concentration . asterisk a  +  indicates at least two sirs criteria . plus
lzd ( 600  mg ) was administrated twice a day for 1  h. the concentration of lzd was shown before the day s first administration ( trough ) and after the first 1-h lzd administration for the day .
crcl ( ml / min ) was calculated using the formula : crcl  =  ( c 
 urine    v 
 urine)/(c 
 serum )    ( 1.73/bsa ) ; where c 
 urine ( mg / dl ) is the creatinine concentration in urine , v 
 urine ( ml / min ) is the urine volume , c 
 serum ( mg / dl ) is the serum creatinine concentration , and bsa ( m ) is the body surface area .
auc 
 24 
 /mic 24-h area under the plasma linezolid concentration  time curve / minimum inhibitory concentration , crcl creatinine clearance , crp c - reactive protein , lzd linezolid , mrsa methicillin - resistant staphylococcus aureus , nd not detected , ne not examined , sirs systemic inflammatory syndrome blood concentrations of lzd from days  6068 were measured after the patient s transfer to the general ward .
the auc24/mic values over the observation period were found to be 69.3 2  days after lzd administration , and the trough levels were too low to be detected ( fig .  2 ) .
informed consent was obtained from the patient s family in relation to his being included in the study .
blood samples for the quantification of lzd in plasma were collected through an indwelling arterial catheter both before and after the morning dosing , which was administered through an intermittent intravenous infusion of 600  mg over the course of 1  h. lzd was administrated twice a day ( morning and night ) .
blood samples were taken in the morning before dosing ( trough ) and after the morning s 1-h - long lzd administration .
after centrifugation , plasma samples were separated and stored at 80  c until assayed .
to assess renal function , creatinine concentrations in both the serum and 24-h urine samples were determined .
crcl ( ml / min ) was calculated using the formula:\documentclass[12pt]{minimal } 
				 \usepackage{amsmath } 
				 \usepackage{wasysym } 
				 \usepackage{amsfonts } 
				 \usepackage{amssymb } 
				 \usepackage{amsbsy } 
				 \usepackage{mathrsfs } 
				 \usepackage{upgreek } 
				 \setlength{\oddsidemargin}{-69pt } 
				 \begin{document}$$ { \text{crcl } } = ( c_{\text{urine } } \times v_{\text{urine } } ) /(c_{\text{serum } } ) \times ( 1.73/{\text{bsa } } ) $ $ \end{document}crcl=(curinevurine)/(cserum)(1.73/bsa)where curine ( mg / dl ) is the creatinine concentration in urine , vurine ( ml / min ) is the urine volume , cserum ( mg / dl ) is the serum creatinine concentration , and bsa ( m ) is the body surface area .
the drug concentration data were fit to a standard one - compartment model with zero - order input ( 1-h - long drug infusion ) and first - order elimination .
the pk parameters used were total clearance ( l / h ) and volume of distribution ( l ) .
a 19-year - old male was admitted to fukuoka university hospital after being involved in a traffic accident .
a neurological assessment revealed a glasgow coma scale ( gcs ) score of 3/15 . computed tomography ( ct ) of the head showed a subcutaneous and extradural hematoma .
a craniotomy was immediately performed to remove the hematoma and to attain cerebral decompression and , as a result , the gcs score recovered to 10/15 . on day  13 , he developed polyuria .
his 24-h urine volume reached 56  l / day with a urine osmolality of 159  mosm / l and a plasma osmolality of 340  mosm / l .
as a basal skull fracture was present , an intravenous vasopressin infusion was administered to treat the di .
however , it showed a poor therapeutic effect , polyuria continued , and crcl was revealed to be 180278  ml / min as a result of the di .
we were required to administer approximately 67  l / day of fluid to compensate for the high urinary fluid output . on day  50 , mrsa was detected in surveillance cultures of sputum and urine samples ( mic for lzd was 1 
mg / l ) . on day  55 , he developed systemic inflammatory response syndrome ( sirs ) , and pneumonia and/or a urinary tract infection was suspected based upon the results of preceding surveillance cultures
. consequently , lzd was administrated intravenously ( 600  mg every 12  h ) for 14  days . on day  57 ,
a chest x - ray and ct scan showed a consolidation in the right lung ( fig . 
it was found that blood cultures that had been drawn before the administration of lzd developed mrsa ( mic for lzd was 1 
based upon these findings , we diagnosed mrsa pneumonia with secondary bacteremia due to pneumonia or a urinary tract infection .
blood , urine , and sputum cultures were negative on days  61 , 64 , and 68 , respectively . a chest x - ray on day  68 and ct scan on day  70 showed improvement in the consolidation ( fig . 
concomitant antibiotics were not administered because the results of the cultures showed the development of mrsa only ( fig . 
a ( chest x - ray ) and b ( chest ct scan ; day 57 ) show consolidation in right lower lung before treatment ( b , arrow ) .
c the chest x - ray ( day 68 ) and d shows the chest ct scan ( day 70 ) images after treatment , and show the improvement in the consolidationfig . 
( 600  mg ) was administrated twice a day for 1  h. the concentration of lzd was shown before the day s first administration ( trough ) and after the first 1-h lzd administration for the day .
crcl ( ml / min ) was calculated using the formula : crcl  =  ( c 
 urine    v 
 urine)/(c 
 serum )    ( 1.73/bsa ) ; where c 
 urine ( mg / dl ) is the creatinine concentration in urine , v 
 urine ( ml / min ) is the urine volume , c 
 serum ( mg / dl ) is the serum creatinine concentration , and bsa ( m ) is the body surface area .
auc 
 24 
 /mic 24-h area under the plasma linezolid concentration  time curve / minimum inhibitory concentration , crcl creatinine clearance , crp c - reactive protein , lzd linezolid , mrsa methicillin - resistant staphylococcus aureus , nd not detected , ne not examined , sirs systemic inflammatory syndrome chest imaging before and after treatment with lzd .
a ( chest x - ray ) and b ( chest ct scan ; day 57 ) show consolidation in right lower lung before treatment ( b , arrow ) .
c the chest x - ray ( day 68 ) and d shows the chest ct scan ( day 70 ) images after treatment , and show the improvement in the consolidation clinical course and lzd blood concentration . asterisk a  +  indicates at least two sirs criteria . plus
lzd ( 600  mg ) was administrated twice a day for 1  h. the concentration of lzd was shown before the day s first administration ( trough ) and after the first 1-h lzd administration for the day .
crcl ( ml / min ) was calculated using the formula : crcl  =  ( c 
 urine    v 
 urine)/(c 
 serum )    ( 1.73/bsa ) ; where c 
 urine ( mg / dl ) is the creatinine concentration in urine , v 
 urine ( ml / min ) is the urine volume , c 
 serum ( mg / dl ) is the serum creatinine concentration , and bsa ( m ) is the body surface area .
auc 
 24 
 /mic 24-h area under the plasma linezolid concentration  time curve / minimum inhibitory concentration , crcl creatinine clearance , crp c - reactive protein , lzd linezolid , mrsa methicillin - resistant staphylococcus aureus , nd not detected , ne not examined , sirs systemic inflammatory syndrome blood concentrations of lzd from days  6068 were measured after the patient s transfer to the general ward .
the auc24/mic values over the observation period were found to be 69.3 2  days after lzd administration , and the trough levels were too low to be detected ( fig .  2 ) .
informed consent was obtained from the patient s family in relation to his being included in the study .
to the best of our knowledge , this is the first case to report a pk profile of lzd in a patient with di with high crcl . in this case ,
crcl was 180278  ml / min as a result of di . in regard to patients with a high level of crcl in the intensive care unit
, it was reported that blood lzd concentrations were variable , showing trough concentrations from 0.13 to 14.49  mg / l ( median 2.06  mg / l ) . in the current case , blood lzd trough levels were lower than the detection limit ( < 0.5  mg / l ) and the auc24/mic ( 69.3 ) was also remarkably low compared with those provided in previous reports concerning 20 critically ill patients ( median  248  mg / l , interquartile range 144347  mg
/ l ) . since the lzd trough levels were lower than the detection limit ( 0.5  mg / l ) , the actual auc24/mic may have been lower than that in our calculated auc24/mic levels .
the precise mechanism of the decreased lzd auc24/mic and blood trough levels in this case is unknown ; however , lzd pk might be altered by high crcl and a large volume of fluid administration . in the current case , we diagnosed mrsa pneumonia for the following reasons .
first , the precedent surveillance culture of sputum only developed mrsa and no other significant microorganisms ; second , the chest ct scan showed a consolidation in the right lower lung , which suggested a transbronchial route of infection ; and third , the pneumonia was successfully treated with lzd only , not with any other antimicrobials .
an american consensus review   recommended vancomycin for the treatment of mrsa infections ; however , in a randomized - controlled study for mrsa nosocomial pneumonia , lzd showed better clinical efficacy and microbiological responses than vancomycin .
rayner et al .   reported that higher success rates for lzd may occur at auc24/mic values of 80120 for bacteremia , skin and skin structure infections , and lower respiratory tract infections .
in this case , on day  50 , the urine culture developed mrsa 10/colony - forming units / ml . it is unclear whether the patient had a urinary tract infection or if the observed mrsa in the urine had simply passed into the urine from the blood .
additionally , on day  64 , mrsa was not detected in the urine culture . to the best of our knowledge
, little investigation has been conducted into the usefulness of lzd for the treatment of urinary tract infections .
approximately 35% of lzd is excreted in urine . in this case , a high level of urine output was observed because of di and , consequently , the high doses of lzd may be passed though the urinary tract . therefore , despite low plasma lzd auc , the urine culture may become negative .
interestingly , in spite of the remarkably low level of the auc24/mic in this case , mrsa pneumonia bacteremia was treated successfully after lzd administration . in lzd , the level of plasma protein binding is 31% and the volume of distribution approximates the total water content of the body ( 4050  l ) [ 15 , 16 ] . in lung tissues , it was reported that lzd concentrations in the epithelial lining fluid ( 64.3    33.1  g / ml ) were much higher than those in the blood ( 7.3    4.9  g / ml ) and alveolar cells ( 2.2    0.6  g / ml ) .
these findings suggest that lzd is excluded or rapidly removed from the blood to the lung compartment . as this was a retrospective study
for this reason we could not take cultures and blood samples every day . to our knowledge , this is the first report showing the successful treatment of mrsa pneumonia with bacteremia despite very low lzd auc24/mic .
localized higher concentrations of lzd in the lung might have been sufficiently effective in treating the pneumonia and the secondary bacteremia as a result of the sites of these infections ; however , the precise mechanism of low lzd auc24/mic and successful treatment of mrsa infection in these cases remains generally unknown .
in conclusion , sub - therapeutic levels of lzd blood concentrations may be caused by uncontrolled di with high crcl and a high level of fluid administration . in spite of the low level of auc24/mic , mrsa pneumonia and bacteremia
were successfully treated with lzd . as this was a retrospective study , we were unable to evaluate the concentration of lzd on days  6068 after the 1-h lzd administration for the pk assessment .
we must further study the actual pk assessment of lzd in patients with high crcl caused by di .
further investigation is required into the mechanisms of low lzd auc24/mic and the successful treatment of these mrsa infections . 

below is the link to the electronic supplementary material . 
 supplementary material 1 ( pdf 243  kb ) supplementary material 1 ( pdf 243  kb )
yoshihiko nakamura , masanobu uchiyama , shuuji hara , mariko mizunuma , takafumi nakano , hiroyasu ishikura , kota hoshino , yasumasa kawano , and tohru takata have nothing to disclose .
informed consent was obtained from the patient s family in relation to his being included in the study .
this article is distributed under the terms of the creative commons attribution - noncommercial 4.0 international license ( http://creativecommons.org/licenses/by-nc/4.0/ ) , which permits any noncommercial use , distribution , and reproduction in any medium , provided you give appropriate credit to the original author(s ) and the source , provide a link to the creative commons license , and indicate if changes were made .
 introductionfew studies have investigated the effect of increased creatinine clearance ( crcl ) on linezolid ( lzd ) concentration . 
 herein , we report the pharmacokinetic / pharmacodynamic ( pk / pd ) profile of lzd used in the management of methicillin - resistant staphylococcus aureus ( mrsa ) pneumonia with concomitant bacteremia in a patient with high crcl caused by diabetes insipidus ( di).case reporta 19-year - old man was admitted to the intensive care unit following a traumatic brain injury . after admission , he underwent a craniotomy for the severe brain injury . 
 however , he developed di after the operation . despite treatment with vasopressin , 
 his urine output reached 56  l / day as a result of the di , and his crcl increased to 180278  ml / min . 
 we were required to administer 67  l of fluid a day to compensate for the high urinary fluid output . on day 55 , 
 mrsa pneumonia with sepsis was suspected and , consequently , lzd was administrated intravenously ( 600  mg every 12  h ) . 
 he was treated with lzd for 14  days . 
 the patient has since successfully recovered from mrsa pneumonia with concomitant bacteremia , and was transferred to the general ward on day 82 . 
 blood lzd levels from days 6068 , which were measured after the patient s transfer to the general ward , showed that the trough levels were lower than the threshold level of detection . 
 the blood 24-h area under the plasma lzd concentration  time curve ( auc)24/minimum inhibitory concentration ( mic ) was 69.3.conclusionin spite of the low level of lzd auc24/mic caused by the high crcl with di , mrsa pneumonia with concomitant bacteremia was successfully treated with lzd.electronic supplementary materialthe online version of this article ( doi:10.1007/s40121 - 015 - 0100-z ) contains supplementary material , which is available to authorized users . 
Electronic supplementary material
Introduction
Case Report
Sampling and Drug Administration
Creatinine Clearance
LZD Assay
Pharmacokinetic Assessment
Case
Discussion
Conclusions
Electronic supplementary material
Disclosures
Compliance with ethics guidelines
Open Access