staphylococcus aureus may cause community - acquired and nosocomial bacterial meningitis and is associated with significant mortality .
it is usually associated with neurosurgical interventions ( including csf shunts ) , staphylococcal bacteriemia or a parameningeal focus .
methicillin - resistant s. aureus ( mrsa ) is an important cause of hospital - acquired central nervous system infections [ 17 ] . over the last decade ,
since the available treatment options are limited , treatment of infections , particularly meningitis , is problematic .
however , glycopeptides achieve relatively low cerebrospinal fluid ( csf ) concentrations and treatment failure is not rare .
there are a few case reports in which teicoplanin , fucidic acid and daptomycin have been used successfully . to date ,
experience with linezolid for the treatment of meningitis is anecdotal and limited to case reports or series .
the aim of this study was to compare the efficacy of vancomycin and linezolid in a mrsa rabbit meningitis model .
s. aureus atcc 43300 ( vancomycin mic : 1 mg / l , linezolid mic : 0.025 mg / l measured in duplicate using the etest ; ab biodisk , solna , sweden ) was used as the infecting bacteria .
this solution was further diluted 1/300 to achieve a concentration of 10 colony - forming units ( cfu)/ml .
drugs used were vancomycin ( lilly , indianapolis , usa ) and linezolid ( pfizer pharmaceuticals group , new york , usa ) . new zealand white rabbits weighing 22.5 kg were anaesthetized by intramuscular injections of ketamine ( 35 mg / kg ) and xylazine ( 5 mg / kg ) before each intraventricular intervention including induction of meningitis and csf sampling [ 911 ] .
then 0.5 ml of the bacterial solution of mrsa was injected directly into the cisterna magna of each rabbit using a 22 g spinal needle ( hayat ticaret , istanbul , turkey ) .
csf white cell count more than 1000/mm ( counted by thoma slide ) and a bacterial count greater than 10 cfu / ml were accepted as the indications of meningitis .
the linezolid-10 group received 10 mg / kg linezolid every 12 h ( q12h ) similar with normal human dosage ( at 16 h and 28 h after the induction of meningitis ) .
the linezolid-20 group received 20 mg / kg linezolid every 12 h ( q12h ) ( at 16 h and 28 h after the induction of meningitis ) .
the vancomycin group received 20 mg / kg vancomycin every 12 h ( q12h ) ( at 16 h and 28 h after the induction of meningitis ) .
vancomycin and linezolid were administered through a peripheral ear vein . at the end of the study period ( 24 h after the end of incubation period or
start of treatment , 40 h after bacterial inoculation ) , animals were humanely killed by intravenous infusion of high dose nembutal .
bacterial concentrations in csf were measured at the end of the 16 h ( end of incubation period and before the first dosage of vancomycin or linezolid ) and the 40 h of the study ( end of treatment ) by plating undiluted and serial 10-fold and 100-fold dilutions of csf ( 10 l ) on 5% sheep blood agar and incubated at 37c for 24 h. bacterial response was evaluated in 3 categories  full response , sterilization of csf ; partial response , any decrease in bacterial count ; and bacteriological failure , an increased bacterial count .
data were evaluated by spss 11.0 package program using mann - whitney u test , kruskal wallis test and fisher s  test . a p - value less than 0.05 was considered significant .
the study was approved by the local ethics committee on animal studies ( approval no : 2005 - 23 ) .
s. aureus atcc 43300 ( vancomycin mic : 1 mg / l , linezolid mic : 0.025 mg / l measured in duplicate using the etest ; ab biodisk , solna , sweden ) was used as the infecting bacteria .
this solution was further diluted 1/300 to achieve a concentration of 10 colony - forming units ( cfu)/ml .
drugs used were vancomycin ( lilly , indianapolis , usa ) and linezolid ( pfizer pharmaceuticals group , new york , usa ) .
new zealand white rabbits weighing 22.5 kg were anaesthetized by intramuscular injections of ketamine ( 35 mg / kg ) and xylazine ( 5 mg / kg ) before each intraventricular intervention including induction of meningitis and csf sampling [ 911 ] .
then 0.5 ml of the bacterial solution of mrsa was injected directly into the cisterna magna of each rabbit using a 22 g spinal needle ( hayat ticaret , istanbul , turkey ) .
csf white cell count more than 1000/mm ( counted by thoma slide ) and a bacterial count greater than 10 cfu / ml were accepted as the indications of meningitis .
the linezolid-10 group received 10 mg / kg linezolid every 12 h ( q12h ) similar with normal human dosage ( at 16 h and 28 h after the induction of meningitis ) .
the linezolid-20 group received 20 mg / kg linezolid every 12 h ( q12h ) ( at 16 h and 28 h after the induction of meningitis ) .
the vancomycin group received 20 mg / kg vancomycin every 12 h ( q12h ) ( at 16 h and 28 h after the induction of meningitis ) .
vancomycin and linezolid were administered through a peripheral ear vein . at the end of the study period ( 24 h after the end of incubation period or
start of treatment , 40 h after bacterial inoculation ) , animals were humanely killed by intravenous infusion of high dose nembutal .
bacterial concentrations in csf were measured at the end of the 16 h ( end of incubation period and before the first dosage of vancomycin or linezolid ) and the 40 h of the study ( end of treatment ) by plating undiluted and serial 10-fold and 100-fold dilutions of csf ( 10 l ) on 5% sheep blood agar and incubated at 37c for 24 h. bacterial response was evaluated in 3 categories  full response , sterilization of csf ; partial response , any decrease in bacterial count ; and bacteriological failure , an increased bacterial count .
data were evaluated by spss 11.0 package program using mann - whitney u test , kruskal wallis test and fisher s  test . a p - value less than 0.05 was considered significant .
the study was approved by the local ethics committee on animal studies ( approval no : 2005 - 23 ) .
at the beginning of the study , 60 rabbits were inoculated with bacteria , of which 47 were alive and had developed meningitis at the end of 16 h incubation time .
mean bacterial concentrations of these 4 groups were similar as log10 cfu / ml at 16 h ( table 1 , p>0.05 ) .
although at 40 h the differences in mean csf bacterial counts were significant between vancomycin and control groups ( p=0.037 ) and between linezolid 10 or 20 and control groups ( p=0.01 ) , the mean cfu / ml in both vancomycin and linezolid-10 or -20 groups was similar ( p=0.71 and 0.54 ) ( table 1 ) . at the end of treatment
the decrease in bacterial counts in the vancomycin group was approximately 2 logs higher than the linezolid-20 group ( p>0.05 ) and approximately 4 logs higher than in the linezolid-10 group ( p : 0.037 ) ( vancomycin group : 2.8604.495 vs. linezolid-20 : 0.7244.360 , vs. linezolid-10 : 1.393.37 ) . during the study mortality was relatively higher in the linezolid-20 group ( 2/11 in vancomycin , 6/11 in linezolid-20 , 3/14 in linezolid-10 and 5/11 in control group , p>0.05 ) , but this difference was not statistically significant . at the end of the study ,
rates of full ( 2/9 in vancomycin group , 0/11 in linezolid-10 and 2/5 in linezolid-20 group , p>0.05 ) and partial success rates were similar ( 5/9 in the vancomycin group , 1/5 in the linezolid-20 and 3/14 in the linezolid-10 group , p > 0.05 ) . full or partial bacteriological response was higher in vancomycin vs. linezolid-10 ( p : 0.01 ) but not vancomycin vs. linezolid-20 or linezolid-10 vs. linezolid-20 groups ( 7/9 in vancomycin group , 3/5 in linezolid-20 and 3/11 in linezolid-10 group ) .
despite developments in intensive care facilities and antibiotic agents , meningitis is still associated with significant mortality and morbidity .
s. aureus is an important pathogen , causing both community - acquired and hospital - acquired meningitis .
the main option for the treatment of mrsa meningitis is vancomycin , but teicoplanin , linezolid , fucidic acid and daptomycin may be used as salvage therapy .
this decision is based primarily on published series , but not controlled human studies . despite available treatment modalities , prognosis of mrsa meningitis
recent guidelines for treatment of meningitis from the european federation of neurological sciences suggest linezolid as the main therapy option for methicillin - resistant staphylococcal meningitis .
recently , sipahi et al . reported microbiological eradication of mrsa in 7 of 8 mrsa meningitis cases .
however , to our knowledge , there is no human or animal study comparing vancomycin and linezolid in the treatment of mrsa meningitis .
this study was performed to compare antibacterial activity of vancomycin ( 20 mg / kg ) and linezolid ( 10 or 20 mg / kg ) against mrsa in a rabbit meningitis model .
the vancomycin dosage of the study was adopted from previous meningitis studies in rabbit models .
there was only 1 meningitis study related to linezolid in a rabbit model using 20 mg / kg .
hence , we used 2 different dosages of linezolid  10 mg / kg q 12 h ( the usual dosage in humans )   and 20 mg / kg q 12 h. our findings showed that linezolid was not statistically inferior to vancomycin in the treatment of mrsa meningitis at 20 mg / kg dosage , but was inferior at 10 mg / kg .
however , the rate of full bacteriological response was very low in each treatment group .
the low full bacteriological success with vancomycin is probably due to the low csf penetration of the drug and is in concordance with previous published data .
sipahi et al   compared vancomycin ( 20 mg / kg - same dosage used in this study ) and teicoplanin ( 6 mg / kg ) in a mrsa ( the same strain used in this study ) rabbit meningitis model .
although they found teicoplanin as effective as vancomycin , the rates of full ( 2 in 11 rabbits ) or partial ( 2 in 11 rabbits ) bacteriological response rates were very low , in concordance with the present study .
they analyzed trough antibiotic levels and reported that only 4 rabbits in the teicoplanin group and 2 rabbits in the vancomycin group had antibiotic levels higher than the lowest drug detection limit of the bioassay ( > 1 mg / l ) .
also analyzed the vancomycin levels in the rabbit csf after the same vancomycin dosage used in our study .
/ l , respectively , while peak serum concentration was 36.88.0 mg / l and trough serum concentration was 4.21.0
both studies confirm that penetration of vancomycin in the csf is very poor . in the present study ,
at the end of treatment bacterial counts were significantly lower linezolid group in comparison to untreated controls .
however , although not statistically significant , the mean decrease in bacterial counts in the vancomycin group was approximately 2 log cfu / ml more than in the linezolid-20 group and approximately 4 log cfu / ml more than linezolid-10 group ( p<0.05 ) . in the linezolid-10 group there was partial bacterial response in only 3 of 14 rabbits at 24 h. our data are in concordance with the study of cottagnoud et al .  
in which they compared linezolid with ceftriaxone in penicillin - susceptible streptococcus pneumoniae and with ceftriaxone+vancomycin in penicillin - resistant s. pneumoniae meningitis of rabbits , and reported that linezolid had lower anti - bacterial activity ( more than 2 log 10 cfu difference at 8 h ) than both comparators .
the relatively low full bacteriological response rate with linezolid in both studies is probably due to the fact that it is mainly a bacteriostatic agent [ 1517 ] .
although mortality was somewhat higher in the linezolid-20 group , the difference was not statistically significant .
linezolid shows good penetration into the cns , achieving levels in csf 30% to 70% of those present of serum in humans .
the only study that analyzed penetration of linezolid into rabbit csf was by cottognaud et al , who reported that linezolid showed 384% csf penetration with a dosage 20 mg / kg via high performance liquid chromatography technique .
linezolid csf levels peaked at 9.5 mg / l and troughed to 1.8 mg / l . in the present study ,
a total of 13 rabbits ( 21.6% of total ) died during the incubation period .
this rate is somewhat higher than the 13.3% mortality in a previous study performed with the same bacteria and inoculum , possibly due to inadequate surgical intervention . in previous studies ,
main limitation of our study is the lack of pharmacokinetic data , which were not analyzed since the main aim was to compare antibacterial efficacy of the drugs , the presence already existing data related to the distribution of vancomycin and linezolid in rabbits ( which are summarized above ) , and economic reasons .
are rather time dependent and linezolid s efficacy is slow , it would have been of major interest to have examined antibiotic efficacy over a longer period of time and to have tested different dosages , but this was not possible because of economic reasons .
in addition , previous studies that analyzed antibacterial efficacy in a rabbit meningitis model lasted only 24 h or less [ 911 ] .
we did not evaluate efficacy of vancomycin+linezolid combination , but previous reports of this combination was reported as indifferent or slightly antagonistic .
finally , the fact that animal experiments , in particular with rabbits , do not permit large cohorts , limits the power of statistical analysis .
according to the us food and drug administration , linezolid is not yet indicated for the treatment of meningitis . experience with linezolid is limited to single case reports or small series for the treatment of meningitis caused by gram - positive pathogens [ 2,3,57 ] .
our results suggest that linezolid is not statistically inferior to vancomycin in the treatment of mrsa meningitis in an experimental rabbit model in 20 mg / kg q12 h dosage , but it is inferior in 10 mg / kg q12 h dosage .
additional data should be gathered to confirm these findings in advance of clinical trials to assess efficacy in humans .
 summarybackgroundthe aim of this study was to compare the antibacterial efficacy of vancomycin and linezolid in a rabbit model of methicillin - resistant staphylococcus aureus ( mrsa ) meningitis.material/methodsmeningitis was induced by intracisternal inoculation of atcc 43300 strain . 
 after 16 h incubation time and development of meningitis , the vancomycin group received vancomycin 20 mg / kg every 12 h. the linezolid-10 and linezolid-20 groups received linezolid in 10 and 20 mg / kg dosages every 12 h , respectively . 
 the control group did not receive any antibiotics . 
 cerebrospinal fluid bacterial counts were measured at the end of 16-h incubation time and at the end of 24-h treatment.resultsbacterial counts were similar in all groups at 16 h. at the end of treatment the decrease in bacterial counts in the vancomycin group was approximately 2 logs higher than the linezolid-20 group ( p>0.05 ) and approximately 4 logs higher than in the linezolid-10 group ( p : 0.037 ) ( vancomycin group : 2.8604.495 versus linezolid-20 : 0.7244.360 , versus linezolid-10 : 1.393.37 ) . 
 full or partial bacteriological response was higher in vancomycin versus linezolid-10 ( p : 0.01 ) , but not vancomycin versus linezolid-20 or linezolid-10 versus - linezolid-20 groups.conclusionsour results suggest that linezolid is not statistically inferior to vancomycin in the treatment of mrsa meningitis in an experimental rabbit model in 20 mg / kg q12 h dosage ; however , it is inferior in 10 mg / kg q12 h dosage . 
 additional data should gathered to confirm these findings in advance of clinical trials to assess efficacy in humans . 
Background
Material and Methods
Bacterial strain
Antimicrobial agents
Rabbit meningitis model
Measurement of bacterial concentrations
Statistical analysis
Ethics
Results
Discussion
Conclusions