Original Researcb Article
n,n
Pharmaco~'nCl
18 (6): 485-190. 1990
03! ~·596J · 90f{lOOb--{l-I85/~OJ.OO/0 () -\l)lS !'rc~s L,mllw .>..11 "ghlS rcscnw CPI(OOJCPI( ) ..
Clearance from Dial),sate and Equilibration of Intraperitoneal Vancom)'cin in Continuous Ambulator), Peritoneal Dial)'sis Deborah Neal and George R. Bailie of Manchester Ixpanmcnt of Pharmac}. Manchester. England . and Alban) College of Pharmac). Alban). Ne" York. USA Unl\"ersll~
S ummary
This anlcl" reporls on a slud) of the dISposition of loading doses (Ig and 15 mg/kg) of \ ancom)cm gl~en mtrapcfltoneali) to 6 pallenlS on conllnuous ambulalOr) pcrilOneal dlal}sls "'th Gram-poSIII\C pcmom\lS DlalyS3!e samples "rr(' colkcted e,el) 30 mlnutcs during the first d"ell. and serum samples "('rc coli("Clrd aft('r the first 5 exchanges and aflcr 7 or 1-1 da}s. The dlal)sate coneentratlon/ tlm(' data "'ere filled to a monocxpon('nhal cu"" for -I pallents and to a b,,,xponentlal cune for ~ others. 0Ial)·SI5 clearance "a~ O. 73 "!" 0.0-1 Lj h (I g dos~:) and 0. 70 !: 0.23 L/h (15 mg/~g dose). T{)1al body clcaraner "as 0. 51 ~ 0.36 L/ h Serum concentra\lons reached 14 10 18 mg/L (15 mg/kg dose) and 6. 75 to 2-1 mg/L (Ig dose) al lhl- end of the firM d"ell. The half-lIf" of equlhbrallon of 'anCOnl}cm across th(' pcmont'al membranr "as 2.5 :!: 2.3 hours. Intrapcmonralloadmg doses of ,ancomyeln produce mneomltant serum eoncentrat,ons m excess of the minImum mhlbltor) coneentrallons for susceptible organisms. Admlmstrallon on a milligram per kIlogram baSIS produces more conSistent serum concentrations lhan usmg a standard loading dose "hich is not based on bodywe.ghl.
Bactcnal peritOnitiS is thc commonest complication of continuous ambulatol) peritoneal dialysis (CA PO) [Rubin et a1. 19831. and the most common causatl\e organIsms are skin commensals. Gram-poslll\C Infections account for more than 60% of episodes and more than 40% are due to Staphylococcus l'pidl'rmldls (Bmt ct al. 1987: Swanz 1985). Vancomycin is widely used for the treatmcnt of Gram-posi tive infections, commonly via the intrapcntoneal route since it provides sustained dialysatc concentrations and is associated with less tox ici ty than intravenous administration (Bailie et al. 1987: Boyce et al. 1988: Morse et a1. 1987). The d isposition of vancomycin from serum to dialysate
has been reponed (Bunke et a1. 1983: Hanford et al. 1986). but there arc few data to determine the rate of disappearance of vancomycin from the dialysate dUring an exchange. i.e. the dialysate clearance. Gross absorption into the systemic circulation has been publiShed by Bastam ct al. (1988): Bunkc et a1. (1983): Morse et a1. (1987) and Pancorbo and Comty (1982). although others have performed a more thorough mvestigation of peritoneal vancomycin transpon ( Rogge et a1. 1985). Approximately 54 to 65% or an intraperitoneal dose is absorbed systemicall~ in 4 to 6 hours. This rapid absorptIOn rate. comparcd with the rela tively slow clearance from serum to dialysa te. can probably be explained by the dIffusion characteristics
486
of vancomycin and the differences in Ihe volumes of the peritoneal cavity and the systemic volume of distribution. The diffusion rate is a function of the concentration gradient. among olher factors. When the drug is firs t instilled intrapcriloncal1y. the dialysate concentration is high and the drug rapidly equilibrates across the membrane ;nlo the larger system ic volume ofdislribu lion. After an exchange with fresh dialysate contai ning no vancomycin, the reverse occurs, bU I the serum vancomycin concentration is considerably less and so the concentration gradient and diffusion rates are reduced. The use of a loading dose of vancomycin into the first exchange is inconsistent from centre to cen tre. The influence of an in lrapcritoncalloading dose on the disposition of vancomycin from the dialysate over the period of the dwell is unknown. This study was conducted to investigate the disposi tion of loading doses of vancomyci n during the period of the first exchange, and to quantify pharmaeokinetic parameters pertain ing to cleara nce of vancomycin from the dialysate.
Ml!thod Prospective ethics eom millee approval was obtained. Consecutive patients of either sex presenting with the diagnosis o f CA PO-associated Grampositive peritonitis were entered into this study. Peritonitis was diagnosed by the presence of any 2 of the following: cloudy dialysate, abdominal pain or > 100 white blood cells per millilitre of dialysate. Gram-positive infect ions were identified by Gram stain prior to entry into the study, and were subsequently confirmed microbiologically. Only patients with Gram-positive infections were included. Patients were excluded if they were less than 16 or more than 80 years of age, were pregnant or lactating. or had a history of any previous adverse effect from vancomycin. They were also excluded if they had an episode of peri tonitis, an exit site or tunnel infection within the previous 4 weeks. Patients were randomly divided in to 2 groups. Group A rcreived a loading dose of intraperi toneal
Oln. Pharmacok,IIU'1. 18 (6) 199()
vancomycin Ig according to our current treatment protocol; group B received a load of IS mg/kg intraperitoneally. In all cases, patients continued maintenance doses of vancomycin 2S mg/L inlO each subsequent exchange which, according to a separate protocol, was 7 days for group Band 14 days for group A. All doses were administered in 2L of dialysate containing 1.5% dextrose ('Oianeal'. Baxter Laboratories) via Ihe indwelling peritoneal access catheter. Eaeh patient had the same dialysate schedule of three 4-hour dwells per day and one 11-hour overnight dwell. Eaeh dwell period included approximately IS minutes for drainage of spen t dialysate from the peritoneal cavity and instillation of fresh dialysate. Dialysate and serum were collected during the loading dose exchange. Dialysate samples (Sml) were obtained prior to and each 30 minutes after instillation of the dialysate into the peritoneal cavity, until the end of the dwell (4 hours). Dialysate samples were obtained by drainage of approximately 100ml into the CAPO bag under gravity in order to flush out the dead space of the peritoneal catheter. This fluid was maintained at the bollom end of the bag under gravity during sample collection. A sample offrcshly drained dialysate was then collected through the injection port on the bag. After collection of each specimen, remaining dialysate in the bag was reinstilled in to the peritoneal cavity. Blood samples (Sml) were collected prior to and at the end of the exchange. In addition, blood samples were collected at the end of the next 4 exchanges and althe end of the treatment course, i.e. 7 or 14 days. Blood samples were collected through an indwelling catheter sited in a forearm peripheral vein; the catheter was kept paten t with 2 to 3ml of normal saline injected after sample collection. Clotted blood was centrifuged and the serum separated. 24-hour urine collections were made during the first and lasl study days for those patients who had residual renal function. Serum . dialysate and urine samples were stored at -20·C until analysis. The samples were analysed for vancomycin con tent by a method of inhibition zones around 6mm antibiotic-containing discs (What man, UK) on agar plates (Walker & Kopp
487
I"'rlioncal (Icarancc of \anconl)cm In C.\ PD
19781 as moonellllal cun es and Ihe most ar· eurale cun e chosen. Ilalf·11 \ l'S of [he I anl'om~ cm remOlal from Ihe IX'Tltoneal call1~. th(' dlal~sls clcarancl' (remOlal from the (ilal~~atc). IOlal bod~ clearanc('. lolurne of dlstnbution and t of equi' l,bratlOn "erC" delertlllned. '\\onoc\poncnllal cunes I\cre described b~: C '" ('(O)c ~I
\\here C IS the concenlration at lime 1. ('(0) IS the concentratIOn at lime lero. and k IS the dcra) con· sian!. Dlal~s.1te clearance "as calculaled as: Dose
"hen.' -\UC IS Ihe area under the dial~~le con· cen!rallon/llme cUTle. calculated as .... CC '" ('(0)/ k. l 'Slllg Ihls melhod alOlded Ihl' llC"ed 10 lake 1010 conslder:lHon the Increase In d1al~sate lolume OIc"T the d\\C"l1 penod. Since the lolume of the dialysate IS small compared with the \oluml' of distribution of I ancom~cln. thIs equation IS less of an appro \Imatlon Ihan !fthesC" 101umes ,'erC" Similar 10 mag· nllude. Ble\pom'nllal cUries "ere descnbed b~'
Ta ble I. DemographiC data 01 siady patients Doses a,e sho ....n In mllhg'ams. w,th tile equivalent mlnogram per ~llo value given In parentheSes Pt no
, 2 3
Group
,
6
A B
,
A,.
" "" "
F F
B B B A
5..
79
M
F F
"
M
Weight lkg~
VancomycIn (lose
69
1035 (\5)
60
900 (15) 800 (15)
""
62 63
1000 (24 4) 1000 (16 1) 950 (15)
Aoo'eV'BllOns PI .. patient F • lemale. loA • male
"hcrc),1 and;"l arc the deca} constants of the m· Itla) and term Ina! phases oflhe cUTle. and C! and C2 arc the Intercepts on the ,.·a:\ls of the II1ll1al and terminal phases of the CUTI es. Dialysate clearance \I, as calculaled from thc AUC as before, where Ihe an'a under the CUTI I..' "as caleulated as: (I C2 AUC", - - + - ;"1
;.,~
The 'olume of dlstnbution lias calculated from dal3 obtall1cd dunng the loadtng dose e~change. assuming thai distnbullon cqulllbrium lias reached dunng the d"dl period. The amount absorbed " as first calculated: -\mount absorbed'" VIOl x ('(0) - V{ t) x CO) "here VIO) IS Ihe volume of dlal)sate tnstll1ed at the start of Ihe d\l,cl1. V(t) IS the volume remo' ed at the end of the dllcl1. GO) 1S the I ancomycln concenlrall0n tn the dial)sate at the start of the dllcll and CIt) is the concentration tn the dial~sate at the end of the d"ell. The amount eliminated b~ reSidual renal funCllon was approx1mated from unne data: dwell Ilme
..... t· '"
-'-c----x V ur X Cur 24h
"here -\e '" amount elimtnated. Vur = volume of unne and Cur = unne \ancom~nn concentration.
488
Om P/wrIl1UwJ..llwf {,Ii (6) 1'1'1(1
T.W. II. PharmacolunetIC parametflfs Irom monoexponential ~,
'" ~.
,-, C(O)
,,
• ' SO
(11- ')
588.'
0.385
424.0
0.318 0.102 0.406 0.468 3: 0 .151
1061.•
5
Mlln
k
51".1 422 .1 :!: \86 .•
YO
""J
AUC
"I"J
0.579
1529 3
08"
11216 1511.
0.671 080' 066'
l · h)
rallOil it.~'
Patlt!nt
r100
CL iml/m,nl
,, ,•
Mean • SO
1043
'"
0075 1462
""
'"
. 608
'1'1 ." '" 025
".
. ''''
490
elm. Phormacol./fI('1 . 18 (6) IWI)
T.bIot VI. Unne datl lrom patoenlS Wltl'l reSIdual renal tuncuon '" M .
Flrstday
""one YOIume
, 2 •
Last Gay
v.ncomycin concenlr .1ion
'''
,-,
BOO
81'
'"
N'
'25
tot,l amount
,-'" '''''' ". ". N•
malcly I an d 19 ho urs after instillation of the di· alysate, for thc 3 patients for whom it was possi ble to perform the calculation. The results demonstrate that intraperitoneal loading doses of vancom ycin produce acceptable serum concentrations fo r susceptible organisms. Thus. it sho uld tx possible 10 reat t a concomitant bacteraemia wi th intraperito neal vancom ycin, which is consistent with the find ings o f Rogge CI al. (1 985). The adm inistration o f va ncomyci n on a milligram per kilogram basis produces more consistent serum concentrations. the practice o r giving a ll patien ts a tsandard loading dose irrespecti ve of their bodyweight. Ack ll ow/~dg~m~nt
The au thors are grateful 10 ProftSSOr Malcolm Row-
land , Uni versity of Manchester, for hiS adY lce on data analYSIS.
Ref erellces Ba llII' G R. Mon on R. Ga nsuh L Keanl'y M. Waldc~ S. InlravcnO!J$ or InUlIpc:n lonnl vanrom~cln for IIII' lrealmenl of CA PD-aWlClaled &rim pas", ve pc:rnom1lS' Nl'pllron 46: 31&318.1987
u.runl II. Spyker DA. Westcrvcll FB. Pentoni'l l Ib!.orJHlOfI of "neomyc,n dun"llnd aft"" ~UIIO" ofpcTltonnll In CIIPH pllIent$.. PerItoneal o.aly:lols Intcrnatlonal 8 OS-OO. 198& B,n i A. FIIIC"II R. Go~al R. Goldsmith 111. Junor B. clll. o.a,. 1IOSl$ and ml,..",.,n, of pc:fllonnll In CAPO, report of a wor. ,n, Piny oflilC" Bnhsh SocK"y for Anllml(robIll C1>cmollK'1llpy. lanttt I' 84S-849. 1987
Boya NW. Wood C Thomwn NM. Kcrr P. AtkIns RC 1011"11-
unn. vOlume
.mount
'''
v.ncomycln concentration
,-",
(moll)
,mOl
N.
'"
N.
...
,
"
15.3
101,1
1092 , "3
pc:nlonnl ~anrom)cln liIC"l"1IPY for CA PO pc:fI1onlll) _ a proSpeCtive. I"1Indomlled romPl"!iOn of Inlerml1lenl H'Bus con_ l1ll00uS thtnpy. Amencan JO!J~I of Kidney I),~a!on 12 J().I.. lO6, 1988
Bl)'an CS. Whlll WL Safely ofo.. 1 >ancomYCln In funCllonally anephrlC" plllI'nts, AntlmlCroboal "&tnt) and CiIC"mOlherap)' 14: 6J4-fJJ5. 1918
Bunke CM. AronofTGM . 8rll'r ME. Sloan ItS. Luft F("". VancomYCin ~IIIC"IK"S dun", CA PO ClinICal Pharmaroio&) Ind Tl!C"raptullC'$)4 631-6J7. 1983 llafford AM . SICI DA. Tarta&llOlIC" T . Polk 1tE. Dahon HP. c, at Vanrom)'(ln ~rmacollnctK"S In CAPO Plllen!! " '1111 pc:nlonlhS. Nephron 43 211.222. 1986 Matlkc G M. MtOory RW. Iblslcnwn CE. KeallC" WF Phar. mKOk'llC"lK"S of "lnrom)\'ln In PI"en!) "'''h "aflO!J) do:tn:n or renal function AnllmK"TOblaIA~nlSandClll'mOIMf1Ip)~' 433-437 . 1984
Mone GO. Flrohno OF. Apl«lIa MA. WaisM JJ Comp;lral"e ~Iudy of Inlf1lpc:rnoncal and Inlf1l"l'nous pharmaco~ lnchcS of vancomycIn dunn& CAP O. Anllmlnob,al A~nl$ and ChcmoliIC"rapy 31 : 173-177. 1987 PaIlOOl'bo S. Comly C Ptm oncaJ If1I n~pOr1 of "aneOm)Cln In " palll'n!S undelJOln, CA PO. Nephron 31: 37_19. 1982 ROllI' MC Johnwn CA. Zl m ~an SW. Welh", PG VancomYCin dl~1I10n dunn, ronhnoous ambulalory pc:mollC"al dlll):IoI$ (CAPO): a pllarmaroklncllC" a","I)':IoI~ of pc:nloneal dru, !l"1InlPOfl. An!lm.crob!.ll Altnli Ind C1>cmolilC"raPl 27. 578~82.
1985
Rotsclt.afcr JC Crm$ley K. as~c DE. Mead K. Sawthu ~ RJ. ct aI. PharmacolullC"llCS ofnncom),(",:obscrvIIIOllS In 28 pallenlS and ~ rttOmmendallon$.. AnllmlCt'Oblal Aaenes and ChC"molilC"f1IPY 22. 391.J94. 1982 Rub", J. Ray R. Barnes T. Tnl N. Hdlems E. CI al I'cn lonllls In CAPI) palll'nl~ Amencan Journal of K ld n~) o.sca!oC~ I I 602-609. 1983
Swanl R D. ChronIC pc:rI1oonl dlaly .. ~ mechan.cal and ,nfl'\" uou~ compllClhon •. Nephron 40: 29.J7. 1985 Wal ker C. Kopp 8. SensitIve blDass.ay for vlnromyc,n Anllml' (roboa] A&tn" and o.e,mOlilC"rapy 13; )()'33. 1978
COI'lt'ij'lOndclll'\' and I"l:prlntl: I; R IIDII... IIUOCIaIC Prorc..~or. Alban y CoIk'IC of Pharmacy. 106 No- Srotland ,\ > en"",. Alban). NY 12208. USA
n,n
Pharmaco~'nCl
18 (6): 485-190. 1990
03! ~·596J · 90f{lOOb--{l-I85/~OJ.OO/0 () -\l)lS !'rc~s L,mllw .>..11 "ghlS rcscnw CPI(OOJCPI( ) ..
Clearance from Dial),sate and Equilibration of Intraperitoneal Vancom)'cin in Continuous Ambulator), Peritoneal Dial)'sis Deborah Neal and George R. Bailie of Manchester Ixpanmcnt of Pharmac}. Manchester. England . and Alban) College of Pharmac). Alban). Ne" York. USA Unl\"ersll~
S ummary
This anlcl" reporls on a slud) of the dISposition of loading doses (Ig and 15 mg/kg) of \ ancom)cm gl~en mtrapcfltoneali) to 6 pallenlS on conllnuous ambulalOr) pcrilOneal dlal}sls "'th Gram-poSIII\C pcmom\lS DlalyS3!e samples "rr(' colkcted e,el) 30 mlnutcs during the first d"ell. and serum samples "('rc coli("Clrd aft('r the first 5 exchanges and aflcr 7 or 1-1 da}s. The dlal)sate coneentratlon/ tlm(' data "'ere filled to a monocxpon('nhal cu"" for -I pallents and to a b,,,xponentlal cune for ~ others. 0Ial)·SI5 clearance "a~ O. 73 "!" 0.0-1 Lj h (I g dos~:) and 0. 70 !: 0.23 L/h (15 mg/~g dose). T{)1al body clcaraner "as 0. 51 ~ 0.36 L/ h Serum concentra\lons reached 14 10 18 mg/L (15 mg/kg dose) and 6. 75 to 2-1 mg/L (Ig dose) al lhl- end of the firM d"ell. The half-lIf" of equlhbrallon of 'anCOnl}cm across th(' pcmont'al membranr "as 2.5 :!: 2.3 hours. Intrapcmonralloadmg doses of ,ancomyeln produce mneomltant serum eoncentrat,ons m excess of the minImum mhlbltor) coneentrallons for susceptible organisms. Admlmstrallon on a milligram per kIlogram baSIS produces more conSistent serum concentrations lhan usmg a standard loading dose "hich is not based on bodywe.ghl.
Bactcnal peritOnitiS is thc commonest complication of continuous ambulatol) peritoneal dialysis (CA PO) [Rubin et a1. 19831. and the most common causatl\e organIsms are skin commensals. Gram-poslll\C Infections account for more than 60% of episodes and more than 40% are due to Staphylococcus l'pidl'rmldls (Bmt ct al. 1987: Swanz 1985). Vancomycin is widely used for the treatmcnt of Gram-posi tive infections, commonly via the intrapcntoneal route since it provides sustained dialysatc concentrations and is associated with less tox ici ty than intravenous administration (Bailie et al. 1987: Boyce et al. 1988: Morse et a1. 1987). The d isposition of vancomycin from serum to dialysate
has been reponed (Bunke et a1. 1983: Hanford et al. 1986). but there arc few data to determine the rate of disappearance of vancomycin from the dialysate dUring an exchange. i.e. the dialysate clearance. Gross absorption into the systemic circulation has been publiShed by Bastam ct al. (1988): Bunkc et a1. (1983): Morse et a1. (1987) and Pancorbo and Comty (1982). although others have performed a more thorough mvestigation of peritoneal vancomycin transpon ( Rogge et a1. 1985). Approximately 54 to 65% or an intraperitoneal dose is absorbed systemicall~ in 4 to 6 hours. This rapid absorptIOn rate. comparcd with the rela tively slow clearance from serum to dialysa te. can probably be explained by the dIffusion characteristics
486
of vancomycin and the differences in Ihe volumes of the peritoneal cavity and the systemic volume of distribution. The diffusion rate is a function of the concentration gradient. among olher factors. When the drug is firs t instilled intrapcriloncal1y. the dialysate concentration is high and the drug rapidly equilibrates across the membrane ;nlo the larger system ic volume ofdislribu lion. After an exchange with fresh dialysate contai ning no vancomycin, the reverse occurs, bU I the serum vancomycin concentration is considerably less and so the concentration gradient and diffusion rates are reduced. The use of a loading dose of vancomycin into the first exchange is inconsistent from centre to cen tre. The influence of an in lrapcritoncalloading dose on the disposition of vancomycin from the dialysate over the period of the dwell is unknown. This study was conducted to investigate the disposi tion of loading doses of vancomyci n during the period of the first exchange, and to quantify pharmaeokinetic parameters pertain ing to cleara nce of vancomycin from the dialysate.
Ml!thod Prospective ethics eom millee approval was obtained. Consecutive patients of either sex presenting with the diagnosis o f CA PO-associated Grampositive peritonitis were entered into this study. Peritonitis was diagnosed by the presence of any 2 of the following: cloudy dialysate, abdominal pain or > 100 white blood cells per millilitre of dialysate. Gram-positive infect ions were identified by Gram stain prior to entry into the study, and were subsequently confirmed microbiologically. Only patients with Gram-positive infections were included. Patients were excluded if they were less than 16 or more than 80 years of age, were pregnant or lactating. or had a history of any previous adverse effect from vancomycin. They were also excluded if they had an episode of peri tonitis, an exit site or tunnel infection within the previous 4 weeks. Patients were randomly divided in to 2 groups. Group A rcreived a loading dose of intraperi toneal
Oln. Pharmacok,IIU'1. 18 (6) 199()
vancomycin Ig according to our current treatment protocol; group B received a load of IS mg/kg intraperitoneally. In all cases, patients continued maintenance doses of vancomycin 2S mg/L inlO each subsequent exchange which, according to a separate protocol, was 7 days for group Band 14 days for group A. All doses were administered in 2L of dialysate containing 1.5% dextrose ('Oianeal'. Baxter Laboratories) via Ihe indwelling peritoneal access catheter. Eaeh patient had the same dialysate schedule of three 4-hour dwells per day and one 11-hour overnight dwell. Eaeh dwell period included approximately IS minutes for drainage of spen t dialysate from the peritoneal cavity and instillation of fresh dialysate. Dialysate and serum were collected during the loading dose exchange. Dialysate samples (Sml) were obtained prior to and each 30 minutes after instillation of the dialysate into the peritoneal cavity, until the end of the dwell (4 hours). Dialysate samples were obtained by drainage of approximately 100ml into the CAPO bag under gravity in order to flush out the dead space of the peritoneal catheter. This fluid was maintained at the bollom end of the bag under gravity during sample collection. A sample offrcshly drained dialysate was then collected through the injection port on the bag. After collection of each specimen, remaining dialysate in the bag was reinstilled in to the peritoneal cavity. Blood samples (Sml) were collected prior to and at the end of the exchange. In addition, blood samples were collected at the end of the next 4 exchanges and althe end of the treatment course, i.e. 7 or 14 days. Blood samples were collected through an indwelling catheter sited in a forearm peripheral vein; the catheter was kept paten t with 2 to 3ml of normal saline injected after sample collection. Clotted blood was centrifuged and the serum separated. 24-hour urine collections were made during the first and lasl study days for those patients who had residual renal function. Serum . dialysate and urine samples were stored at -20·C until analysis. The samples were analysed for vancomycin con tent by a method of inhibition zones around 6mm antibiotic-containing discs (What man, UK) on agar plates (Walker & Kopp
487
I"'rlioncal (Icarancc of \anconl)cm In C.\ PD
19781 as moonellllal cun es and Ihe most ar· eurale cun e chosen. Ilalf·11 \ l'S of [he I anl'om~ cm remOlal from Ihe IX'Tltoneal call1~. th(' dlal~sls clcarancl' (remOlal from the (ilal~~atc). IOlal bod~ clearanc('. lolurne of dlstnbution and t of equi' l,bratlOn "erC" delertlllned. '\\onoc\poncnllal cunes I\cre described b~: C '" ('(O)c ~I
\\here C IS the concenlration at lime 1. ('(0) IS the concentratIOn at lime lero. and k IS the dcra) con· sian!. Dlal~s.1te clearance "as calculaled as: Dose
"hen.' -\UC IS Ihe area under the dial~~le con· cen!rallon/llme cUTle. calculated as .... CC '" ('(0)/ k. l 'Slllg Ihls melhod alOlded Ihl' llC"ed 10 lake 1010 conslder:lHon the Increase In d1al~sate lolume OIc"T the d\\C"l1 penod. Since the lolume of the dialysate IS small compared with the \oluml' of distribution of I ancom~cln. thIs equation IS less of an appro \Imatlon Ihan !fthesC" 101umes ,'erC" Similar 10 mag· nllude. Ble\pom'nllal cUries "ere descnbed b~'
Ta ble I. DemographiC data 01 siady patients Doses a,e sho ....n In mllhg'ams. w,th tile equivalent mlnogram per ~llo value given In parentheSes Pt no
, 2 3
Group
,
6
A B
,
A,.
" "" "
F F
B B B A
5..
79
M
F F
"
M
Weight lkg~
VancomycIn (lose
69
1035 (\5)
60
900 (15) 800 (15)
""
62 63
1000 (24 4) 1000 (16 1) 950 (15)
Aoo'eV'BllOns PI .. patient F • lemale. loA • male
"hcrc),1 and;"l arc the deca} constants of the m· Itla) and term Ina! phases oflhe cUTle. and C! and C2 arc the Intercepts on the ,.·a:\ls of the II1ll1al and terminal phases of the CUTI es. Dialysate clearance \I, as calculaled from thc AUC as before, where Ihe an'a under the CUTI I..' "as caleulated as: (I C2 AUC", - - + - ;"1
;.,~
The 'olume of dlstnbution lias calculated from dal3 obtall1cd dunng the loadtng dose e~change. assuming thai distnbullon cqulllbrium lias reached dunng the d"dl period. The amount absorbed " as first calculated: -\mount absorbed'" VIOl x ('(0) - V{ t) x CO) "here VIO) IS Ihe volume of dlal)sate tnstll1ed at the start of Ihe d\l,cl1. V(t) IS the volume remo' ed at the end of the dllcl1. GO) 1S the I ancomycln concenlrall0n tn the dial)sate at the start of the dllcll and CIt) is the concentration tn the dial~sate at the end of the d"ell. The amount eliminated b~ reSidual renal funCllon was approx1mated from unne data: dwell Ilme
..... t· '"
-'-c----x V ur X Cur 24h
"here -\e '" amount elimtnated. Vur = volume of unne and Cur = unne \ancom~nn concentration.
488
Om P/wrIl1UwJ..llwf {,Ii (6) 1'1'1(1
T.W. II. PharmacolunetIC parametflfs Irom monoexponential ~,
'" ~.
,-, C(O)
,,
• ' SO
(11- ')
588.'
0.385
424.0
0.318 0.102 0.406 0.468 3: 0 .151
1061.•
5
Mlln
k
51".1 422 .1 :!: \86 .•
YO
""J
AUC
"I"J
0.579
1529 3
08"
11216 1511.
0.671 080' 066'
l · h)
rallOil it.~'
Patlt!nt
r100
CL iml/m,nl
,, ,•
Mean • SO
1043
'"
0075 1462
""
'"
. 608
'1'1 ." '" 025
".
. ''''
490
elm. Phormacol./fI('1 . 18 (6) IWI)
T.bIot VI. Unne datl lrom patoenlS Wltl'l reSIdual renal tuncuon '" M .
Flrstday
""one YOIume
, 2 •
Last Gay
v.ncomycin concenlr .1ion
'''
,-,
BOO
81'
'"
N'
'25
tot,l amount
,-'" '''''' ". ". N•
malcly I an d 19 ho urs after instillation of the di· alysate, for thc 3 patients for whom it was possi ble to perform the calculation. The results demonstrate that intraperitoneal loading doses of vancom ycin produce acceptable serum concentrations fo r susceptible organisms. Thus. it sho uld tx possible 10 reat t a concomitant bacteraemia wi th intraperito neal vancom ycin, which is consistent with the find ings o f Rogge CI al. (1 985). The adm inistration o f va ncomyci n on a milligram per kilogram basis produces more consistent serum concentrations. the practice o r giving a ll patien ts a tsandard loading dose irrespecti ve of their bodyweight. Ack ll ow/~dg~m~nt
The au thors are grateful 10 ProftSSOr Malcolm Row-
land , Uni versity of Manchester, for hiS adY lce on data analYSIS.
Ref erellces Ba llII' G R. Mon on R. Ga nsuh L Keanl'y M. Waldc~ S. InlravcnO!J$ or InUlIpc:n lonnl vanrom~cln for IIII' lrealmenl of CA PD-aWlClaled &rim pas", ve pc:rnom1lS' Nl'pllron 46: 31&318.1987
u.runl II. Spyker DA. Westcrvcll FB. Pentoni'l l Ib!.orJHlOfI of "neomyc,n dun"llnd aft"" ~UIIO" ofpcTltonnll In CIIPH pllIent$.. PerItoneal o.aly:lols Intcrnatlonal 8 OS-OO. 198& B,n i A. FIIIC"II R. Go~al R. Goldsmith 111. Junor B. clll. o.a,. 1IOSl$ and ml,..",.,n, of pc:fllonnll In CAPO, report of a wor. ,n, Piny oflilC" Bnhsh SocK"y for Anllml(robIll C1>cmollK'1llpy. lanttt I' 84S-849. 1987
Boya NW. Wood C Thomwn NM. Kcrr P. AtkIns RC 1011"11-
unn. vOlume
.mount
'''
v.ncomycln concentration
,-",
(moll)
,mOl
N.
'"
N.
...
,
"
15.3
101,1
1092 , "3
pc:nlonnl ~anrom)cln liIC"l"1IPY for CA PO pc:fI1onlll) _ a proSpeCtive. I"1Indomlled romPl"!iOn of Inlerml1lenl H'Bus con_ l1ll00uS thtnpy. Amencan JO!J~I of Kidney I),~a!on 12 J().I.. lO6, 1988
Bl)'an CS. Whlll WL Safely ofo.. 1 >ancomYCln In funCllonally anephrlC" plllI'nts, AntlmlCroboal "&tnt) and CiIC"mOlherap)' 14: 6J4-fJJ5. 1918
Bunke CM. AronofTGM . 8rll'r ME. Sloan ItS. Luft F("". VancomYCin ~IIIC"IK"S dun", CA PO ClinICal Pharmaroio&) Ind Tl!C"raptullC'$)4 631-6J7. 1983 llafford AM . SICI DA. Tarta&llOlIC" T . Polk 1tE. Dahon HP. c, at Vanrom)'(ln ~rmacollnctK"S In CAPO Plllen!! " '1111 pc:nlonlhS. Nephron 43 211.222. 1986 Matlkc G M. MtOory RW. Iblslcnwn CE. KeallC" WF Phar. mKOk'llC"lK"S of "lnrom)\'ln In PI"en!) "'''h "aflO!J) do:tn:n or renal function AnllmK"TOblaIA~nlSandClll'mOIMf1Ip)~' 433-437 . 1984
Mone GO. Flrohno OF. Apl«lIa MA. WaisM JJ Comp;lral"e ~Iudy of Inlf1lpc:rnoncal and Inlf1l"l'nous pharmaco~ lnchcS of vancomycIn dunn& CAP O. Anllmlnob,al A~nl$ and ChcmoliIC"rapy 31 : 173-177. 1987 PaIlOOl'bo S. Comly C Ptm oncaJ If1I n~pOr1 of "aneOm)Cln In " palll'n!S undelJOln, CA PO. Nephron 31: 37_19. 1982 ROllI' MC Johnwn CA. Zl m ~an SW. Welh", PG VancomYCin dl~1I10n dunn, ronhnoous ambulalory pc:mollC"al dlll):IoI$ (CAPO): a pllarmaroklncllC" a","I)':IoI~ of pc:nloneal dru, !l"1InlPOfl. An!lm.crob!.ll Altnli Ind C1>cmolilC"raPl 27. 578~82.
1985
Rotsclt.afcr JC Crm$ley K. as~c DE. Mead K. Sawthu ~ RJ. ct aI. PharmacolullC"llCS ofnncom),(",:obscrvIIIOllS In 28 pallenlS and ~ rttOmmendallon$.. AnllmlCt'Oblal Aaenes and ChC"molilC"f1IPY 22. 391.J94. 1982 Rub", J. Ray R. Barnes T. Tnl N. Hdlems E. CI al I'cn lonllls In CAPI) palll'nl~ Amencan Journal of K ld n~) o.sca!oC~ I I 602-609. 1983
Swanl R D. ChronIC pc:rI1oonl dlaly .. ~ mechan.cal and ,nfl'\" uou~ compllClhon •. Nephron 40: 29.J7. 1985 Wal ker C. Kopp 8. SensitIve blDass.ay for vlnromyc,n Anllml' (roboa] A&tn" and o.e,mOlilC"rapy 13; )()'33. 1978
COI'lt'ij'lOndclll'\' and I"l:prlntl: I; R IIDII... IIUOCIaIC Prorc..~or. Alban y CoIk'IC of Pharmacy. 106 No- Srotland ,\ > en"",. Alban). NY 12208. USA
