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2 !" #!$% # ###" % %$ & ' " ####%%" % # %(##) * +" #!!$ # % ", $ " %#-". " $!% # #% #!$ " " $% $$,#% #%# / - #! # % 0 1 # # % # # 2 '3 #" $! $ 3 " ##!$ 4 1 ##% ## # " 5, #" # 6 % # 5!$ #%% %# % %#$ # 5 % 7 '--- $$##%%!$# $, 5 %$#33 & 89 " :; " % # % < - = >%-? $, -% #? 1 # *- -/#, * # *!$ #%%!$#, #!$%$!. AB %" %" %A-

3 The Quest for Optimal Antimicrobial Therapy Peter Mol

4 THE QUEST FOR OPTIMAL ANTIMICROBIAL THERAPY Paranimfen: Sonja Huging Prashant Nannan Panday This study was sponsored by an unconditional grant from the board of the University Medical Centre Groningen and the Health Care Insurance Board, the Netherlands. Printing of this thesis was supported by the Northern Centre of Health Care Research (NCH), the Groningen Institute of Drug Exploration (GUIDE), and Pharmacy Department of the University Medical Center Groningen. Mol, P.G.M. The Quest for Optimal Antimicrobial Therapy Dissertation University of Groningen, The Netherlands with summary in Dutch ISBN Copyright P.G.M. Mol, 2005 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronically, mechanically, by photocopying, recording, or otherwise, without the prior written permission of the author. Cover design: Jan Faber, Line Up, Groningen

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9 Editie G.A. van Es Vanden Coninc Arture Es bleven menighe avonture Die nemmer mee ne wert bescreven. Nu hebbic ene scone up heven Constics wel in twalsche vinden Ic soudse jou in dietsche ontbinden: Soe es utermaten scone! Alle die ingle vanden trone Moeten mi gheven herte ende sin De volledige tekst met verklaring is vrij toegankelijk via de website van de digitale bibliotheek voor de nederlandseletteren, De titel van dit proefschrift is ontleend aan het vroeg middelnederlandse werk dat wordt toegeschreven aan Penninc en Pieter Vostaert; De jeeste van Walewein en het schaakbord. In dit prachtige werk wordt de zoektocht van Walewein (misschien beter bekend als Gawein), één van de ronde tafelridders van koning Arthur, naar een bijzonder schaakbord verhaald. Dit soort vertellingen verhaalden van de avonturen waarmee ridders hun loyaliteit aan hun heer, hun dapperheid en in de Walewein ook het ideaalbeeld van hoofs ridderschap. In de latere middeleeuwen echter betrof de zoektocht vrijwel altijd de Heilige Graal, de beker van het laatste avondmaal, waarmee de vertellingen meer een religieuze inslag kregen. Net zoals de Jeeste van Walewein heeft de in dit proefschrift beschreven jeeste ook een meer aards doel, namelijk een optimaal antimicrobieel gebruik. Maar toch, ook het streven naar rationeel en voorzichtig voorschrijfgedrag van antimicrobiële middelen heeft in bepaalde beroepsgroepen en in het leven van deze promovendus welhaast bijbelse proporties gekregen. iii

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11 Chapter I

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38 6 0 ;%/ # $ & &!!!!$!!!$ $$! /0@!! + $ $#+!!!+ $! #!!$@!#$!!/ 7 " +! $ %&==.(('$!!!# + / $ + 7 " #+ + $"! B E0! 0* 0!0$ * 0!0! > * > * > #!* 0! > * 0! #! *! *! * 0! * #!* 0 #! * > * T * I! #!*! *! *0! *$ #!*7 $ *!#! *F 0 #$; BV!V+ / $ + 7 " #+ + $"!!B E0!!* I!!* >!* >!!*!*!! *! *!! *! *!! *! *! K * G #!!*!!*!!*!#!!*!* K! #!!*!!! *! F/ 0!!#$#+ +! ""+ 7 + E; F! C $!" #7 " * $! $ ;#+! * $$ ;#+!!*+ $ /

39 !" #7 "! $ %?5*=5%%&&=5&=*&8=.(('/ 20!! &*.((54/ 0 $ $!! * " $!2.<'3 4! + "! $!" /! $!$! *%93 %.3 $ %&==%&&($! *! # %&&()%&3.(('/! %(<%9#$!$!/ /

40 2

41 Chapter II! " # " $#%&"

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

45 2)%% F %& ( 0)#" FF & ( 9)FF & ( ;)! FF & ( $# A+ + "%" %! " F%%/%! /28&08%&98( FF#"&&#! /%! / 28&08&98(

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

48 # #! # "&! # # #! ) "! + #%%5<:I 8& + 5=;I 8# #"&5<=I 8#! 5<1I 8#! %)D*( 0E &!* + "!*;(73487!;* */)! 4+(! *2841 *4;2 $ - #&- #&#-!, #& #&#$! #&$ #&""! #& #&#-! #,%! $& A"#! &.&! " "."-! "& "&."&! 13.5 (12-15) &.! & &.! "& ".&! # #.#&! "" -&."! # #.#&! &.&! 0 C//D4E*F//54*+8<4:+*E*+G/8*H 8+1)+6/*/8*454:+*E*+ " $ "! "$! $ "-! $# #!, 3+216*6**4*54*/8*H 8+F//H +77;26:)23A+452H *?774*681( *9 ;+34H 1:)734;21 &I&?"-$ *168741/(+A&! J *4/4*2841(*9 12%K89 <&L8MN9!J"## n H :+*E* ( M72(4*8+&(&63*12?141A63*12? :? 272*+&!&L 8M%1;9 :*454:+*E*+H 34++8( (4*)M& <L 8MN9!239 <89 ;9 /*4/4* ( (72(4*)& C "" (%#-(#% 5! 2= # 00%" (-8) #! % +! - ( - %! %/ & ( ) * (- % # " ( #! #22%&##%"%# )$ - % %! ( & (% + % ( "#! "%(! %( #! #! % (-)D*( 0E

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

50 # '! # # "% + (+ (-#! ## "# (% + #! 51)0: 1);78) "! #! 66I <1I ) '! +! % %! %( 51)=78&!! " "! % 51);08 "! 51)298) '! (+ (-#! "# "%! "#! (-+ ## (% #! #! 51)9< 1)6<8) "! #! <0I 71I! (+ (-#! "# "&!! +! % + + :<I ""! ) '! #! % + 51)::8! % %! %( ( #!! (+ (-#! "# (%)"! #! 67I <:I ) % # # "&! "" - %- #1)<)D*( 9E *( ;%(! (+ (- %% % %%%)* +! " "! % & + + # (-! %%)#00% &2= 211I! & #- +! )! % - % + %! ( ") 3! ( -! "% " ## %! ) (-! % +!! %! "! "&%- -!! %! "") '! + #211I #(-&+ + #! 9 # ; (- & 0 # 00 %! ) 3! ("! #%5+,%/"P1)1;8& %%%%&!! #"5/"P1)178 "#"5/"P2)18&! "%! )

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

53 ! # %& #%% % ( + (% #!! $ % %! ( " %! " %! " %! ) # - (-!! -" ##%%"(! +!! " #%! %( "%" 6?=?20 26?2< )#! " # % %(," """! %( "%(() *! &(A! #"+ % - - #!! ) ##%! (+ (-#! -"# (%! % +," % % ) %& + (- + % #! % "# " ##%! - ( % ( ##% (+ - (+ "# ")*!! (! #+ #! %%! "%#% %%%&( + %%A)*##%%!,#! " %! "+ B%"" 4+ -# ( #! ) 0 '"%(A ( #! #) +! # % # "%" " %!! % ( (#%%#( " "! %)," %!! # %! ( ) ) *> &.%& *.-> #&# "+ %)

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

55 Chapter III! "##$%&#'()*+""+

56 , -!. / ! 3 /3 1 1!.!4 1!1!/ 1! 1 1 1!/3 /1 1! ! !! 4

57 !.!!1/. 0!. 2 / 1/ 1! 1!.!. & 4, 0!!. 0/1!.1!. 1 " 451!! 1 3 1'$#6 78#6 ) (2$ 4, 2! 1 -!.!.!! 0!4,!/ /023 /2 3 93!!!!/ 1 1 1!!1 + 4,! 1 / !12! 0 1.1! &2(2$ ! 2 3 1!. 1 45: /!3! 9-1! /2! 0!1 1/! 1 1 0!; 1 -!!! 82< 4 0!3 1!.! 1!!! !!!!2.01/3 "#7$+ 4,! ;.!! 23! 3! 1! /1 4!! &==+23 1&===4 1! >/0 22 0! 3!1! 1!!!. 1? /."##&4/3 3 1% / /13 1/ ! 0! 1 /3 11!4 1 1 / 3 /3 1! 9 1! &78 0!!21/1..1! 1 &"(0! 4!1! 23!!!. 1!!1! 3 /3 14!/3 3!! 11 3!! 9.3!. 1!!!1!4/ !.1/. %! !1 /3 3!!! ! 1. 14!! / /3 3!1.:

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96

97 Chapter VI! " # Journal of Antimicrobial Chemotherapy,

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101 %"'10('#/)#('0%( + *#. 0+#' 00(! (1-#'2 ##(3 +'0)#0('/%*+'0%(/#)0"#*!0*#0(# "#0(# %&' "#$! (. #0 $/. /',#- ( *#+ (%) %&' "#$! (. #0 $/. /',#- ( *#+ (%) %&' "#$!! (- )- "&%$ - # + 1 & (8555 # )# %$ - &+( %# # - %%/ 1&%, % # %$ % +.&% - - % # %$ %# # )" - )# # % + ( & - % # ) # % - % H ) % %, - )$% # %$ # & - &+ ( /=1,- &$%)# %+0

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