Drug therapy 394 2015 February 27 First Online Published 2014 September 21 Accepted 2014 September 12 Revised 2014 June 1 Received aphp.fr evelyne.jacqz-aigrain@rdb. France; 19, Cedex Paris 75935 Sérurier, Boulevard 48 Debré, Robert Hôpital INSERM, CIC1426, Center Investigation Clinical Pharmacogenetics, and Pharmacology Pediatric of Department Jacqz-Aigrain, Evelyne Dr to Correspondence article. of end af numbered For archdischild-2014-307762 ▸ Child érmexP, Bétrémieux cite: To rgnlarticle Original http://dx.doi.org/10.1136/ 2015; cnt cesmore access to Scan pnAccess Open eoxS hoW, Zhao S, Leroux recontent free 100 tal et fi :394 itossee liations . rhDis Arch – 398. oaergmn fatboiseit nFec NICUs. French in pharmacokinetic exists Developmental antibiotics of regimens dosage amikacin. and gentamicin Conclusions for and intervals vancomycin; dosing of (3) infusion continuous loading for (2) doses metronidazole; imipenem/ and amikacin, ceftazidime for cilastatin, doses daily local maintenance of (1) signi 70% had than more and in guidelines used were these 6 Among antibiotics, metronidazole). and imipenem/ clindamycin G, cilastatin, penicillin oxacillin, cloxacillin, infusion, ceftazidime, continuous as administered tobramycin, vancomycin netilmicin, gentamicin, (amikacin, antibiotics INTRODUCTION neonates. in administration for safe regimens and in dosage effective antibiotics evidence-based of establish evaluation to the order for essential are studies ii mn Knoaa nesv aeunits care intensive neonatal UK (NICUs). genta- among and vancomycin of micin regimens dosage of ineffective, ation or delayed optimal essential. antibiotics making fatal, of is rapidly use be can emer- treatment sepsis an neonatal new- is If premature therapy antibiotic gency. in empirical frequent and borns quite are infections Neonatology nnoae hudb vdnebsd French a survey evidence-based: national be should neonates antibiotics in prescribing for guidelines Therapeutic leSaliba, Elie Leroux, Stéphanie ne,i ao as fmraiyadmorbidity, neonates. and mortality premature of for cause particularly major a is onset, classi sepsis, bacterial Neonatal identi were regimens dosage 444 total, In survey. therapy. Results their antibiotic provide for to guidelines email local and/or telephone by contacted Methods (NICUs). neonatal units French care in intensive antibiotics of regimens dosage Objective ABSTRACT oe n/rdsn nevl aidsigni varied neonates. intervals full-term dosing to and/or a preterm Doses from used 9, regimens dose (mean mg/kg dosage drug intravenous unique per of 32 37% to 7.8). different 1 SD of from number varied The regimens antibiotics. dosage 41 for NICUs French eseuae httevraini h dosage the in variation the vancomycin. that and speculated aminoglycosides We as therapeutic narrow such with out- index, neonatal drug clinical for in impacts especially obviously comes, exist which may care, clinical courses treatment apeutic rvoswr eosrtdacnieal vari- considerable a demonstrated work Previous eoxS, Leroux 4(9)NCsare opriiaei this in participate to agreed NICUs (79%) 44 3 eirdcosfo 6Fec IU were NICUs French 56 from doctors Senior hsipista ihrtxco subther- or toxic either that implies This hssre ist ecieadaayethe analyse and describe to aims survey This 7 osdrbeitrcnr aiblt of variability inter-centre considerable A vln Jacqz-Aigrain, Evelyne tal et . rhDsChild Dis Arch 1,2,3 fi atvrain in variations cant e Zhao, Wei – pharmacodynamic fi 2015; da al rlate or early as ed 100 12 fi atyfr12 for cantly :394 1,2,4,5 Suspected 1,2,4 – 9.doi:10.1136/archdischild-2014-306873 398. fi din ed ireBétrémieux, Pierre nbhl fteFec oit of Society French the of behalf on ie:()du ae 2 oe n pe bound upper and lower (2) guide- name; all drug in (1) antibiotic each lines: following for The extracted function. were renal data and/or weight age, different patients as on with primarily based them interval, de of regimen included each dosage typically antibiotics, guidelines various therapeutic local extractionAll data and guidelines Therapeutic identi were NICUs 3 level 56 of total A collection Data METHODS atdb hn n/realbtenMyand May survey. con- this between in was email participate NICU to and/or 2013 each June phone from by doctor tacted senior A seas. care intensive Pédiatriques Urgences paediatric ( French network of directory the eiesi omnpolmfrantibiotic pharmacokinetic of for number quality limited problem of because high common neonates in a therapy is regimens hrp nalFec IU oeaut h current the recommendations. evaluate dosage to local NICUs antibiotic French all for in guidelines therapy local surveyed We studies. ▸ ▸ ▸ ▸ ▸ hti led nw nti topic? this on known already is What htti td adds? study this What n etmcnaogU entlintensive units. neonatal care UK among vancomycin gentamicin of and regimens dosage of variation considerable a demonstrated work Previous neonates. in manage therapy to antimicrobial variable neonates. is in practice off-label Local used are antibiotics Most h ai fdvlpetlpharmacokinetics pharmacodynamics. developmental of on treatment basis neonatal the for validated be antibiotics should of regimens dosage Evidence-based units. care French intensive in neonatal exists antibiotics dosage of of regimens variability inter-centre considerable A rueFacpoed enmto et Reanimation de Francophone Groupe 3 arc Pladys, Patrick fi e yads n dosing a and dose a by ned :5 erpltnad2over- 2 and metropolitan 54 ): – pharmacodynamic 3,6 ’ aibe such variables fi dfrom ed

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Arch Dis Child: first published as 10.1136/archdischild-2014-306873 on 27 January 2015. Downloaded from from Downloaded 2015. January 27 on 10.1136/archdischild-2014-306873 as published first Child: Dis Arch http://adc.bmj.com/ on September 23, 2021 by guest. Protected by copyright. by Protected guest. by 2021 23, September on Arch Dis Child: first published as 10.1136/archdischild-2014-306873 on 27 January 2015.Drug Downloaded therapy from http://adc.bmj.com/ on September 23, 2021 by guest. Protected by copyright. Table 1 . 20 mg/kg). – table 1 Original article cantly different among fi cantly different for 5 antibio- fi cantly different for continuous infu- cantly different among NICUs for 9 fi fi cant inter-centre variability in median fi ). . table 1 gure 1 fi 42 h) ( – Maintenance daily doses were signi Loading doses were signi tics: gentamicin(p<0.001), (p<0.001), tobramycin (p<0.001) amikacin andGentamicin clindamycin (p<0.001), and (p=0.023). amikacin netilmicin local were included guidelines in and more(12 median than dosing 70% of intervals varied 3.5Dosage times individualisation A total of 444were used dosage in regimens French (407 NICUs intravenous for and 41 37 antibiotics. oral) The number of Inter-centre variability in dailyAntibiotics dose and with dosing intervals daily signi doses and dosing intervals are presented in Daily dose The daily doses wereantibiotics, signi administrated intravenously. NICUs for 8 antibioticstatin, (amikacin, netilmicin, penicillin G, cloxacillin, imipenem/cilas- dime); oxacilline, 4 of metronidazole, them ceftazi- ceftazidime) (amikacin, were imipenem/cilastatin, included metronidazole, in moreand than their 70% median of local daily guidelines doses varied from 2 to 5 times. sion vancomycin (p<0.001),local which guidelines. The was loading dose included varied in 3 times 78.4% (7 of Dosing intervals The dosing intervals were signi compared their dosesmended by in Neofax and local Redbook. guidelines with doses recom- sources from which thestrated local in guidelines were developed are illu- 4 uoroqui- fl ed, including 19 fi Wallis (n>2 medians) or – 398. doi:10.1136/archdischild-2014-306873 395 – :394 cant. 100 fi 2015; Arch Dis Child . Sources for local guidelines. et al Whitney-Wilcoxon (n=2 medians). Statistical analyses – 24). A total of 41 antibiotics were identi Each local guideline included a mean of 16 antibiotics (range – Figure 1 Leroux S, 5 RESULTS All 56 Frenchlocal level antibiotic 3 guidelines44 NICUs and (79%) were agreed 9 to contacted: participate. declined 3 participation. declared Thus, no Mann Data analysis The number ofof antibiotics in dosage each regimensmaximum) local of and guideline, the the the lowerand number bound distribution dosing and interval (minimum, uppereach in bound median, antibiotic. each of Median local daily ofall dose guideline daily were doses the described andInter-centre for dosing variability intervals was guidelines for assessedof the by were daily comparing doseparametric the and calculated medians statistical dosing test interval among of for NICUs Kruskal using non- each antibiotic. or (2) therapeutic guidelines for meningitis. were conducted using R softwareconsidered (V.3.0).A statistically value signi of p<0.05 was values for the dailyand doses (3) (mg/kg/day) variables andage for dosing or dosage intervals weight). individualisation, (h); mendations Exclusion when for criteria used infants with included: (i.e., a (1) postmenstrual dosage age over recom- 44 weeks beta-lactams, 4 aminoglycosides,nolones, 2 6 glycopeptides, macrolides, 2 3 antibacterial imidazoles, 1 sulfonamide agents. and(n=31), 4 orally other (n=3) They orwas both (n=7). are either Intravenous intermittent administration tinuous administered (n=37) (n=1), or with intravenously bothnidazole, a loading intermittent ornidazole, dose and teicoplanin, strategy con- in vancomycin). 4 The cases (metro- different Drug therapy ism re ooti aktn uhrsto o entlueand use off-label. neonatal used for are authorisation them marketing of most a obtain to order ain eedn.Teeoe prpit entldosing neonatal appropriate Therefore, dependant. patient niirba ucpiiiyTesting of Susceptibility breakpoints resistance by Antimicrobial and sensitivity provided on microorganisms based is MIC ratio, ‘ inwsae hc perdi 8 fidvdaie dosage individualised of 88% in appeared regimens. which individualisa- patients age, dosage any of was account covariate tion used into used regimens most taking dosage The without oral characteristics. dose, of mg/kg In 87% unique 32. and a to intravenous 1 of from 37% ranged all, antibiotic per regimens dosage different 396 under area AUC the the by (i.e., determined AUIC curve ultimately inhibitory epidemiology, be will the bacterial therapy will local and dosing antibiotic context while of upon clinical merely choice the and on initial possible depend as The early suspicion. as started clinical be to has treatment and morbidity of risk high a with associated mortality. and frequent are therapeutic evidence-based developing data. available already and from prescrip- consensus neonates dosing antibiotic optimise in doses, to need tions daily These urgent 32 individualisation. the in to dosage highlighted 1 for data differences from used covariates regimens important and dosage intervals with of number drug, the varied and per guideline 24 local to per inter-centre 5 antibiotics considerable from a of show number with data the guidelines Our as 44 variability anti- antibiotics. included prescribe 41 and of to NICUS total used French guidelines the in local biotics the analysed study This DISCUSSION niitcae ne h concentration the under area antibiotic lnclLbrtr tnad Institute Standards Laboratory Clinical rgnlarticle Original Antibiotic 1 Table Tobramycin Gentamicin Netilmicin Amikacin Antibiotic Ceftazidime Metronidazole 20.0 Oxacillin Cloxacillin Netilmicin Imipenem/cilastatin G Penicillin Amikacin Clindamycin smcoilgclyeautdifcini aei neonates, in rare is infection evaluated microbiologically As niitc r xesvl rsrbdi entsa infections as neonates in prescribed extensively are Antibiotics A o available. not NA, ’ iiu niioyconcentration). inhibitory minimum s 56 h al oe n oigitraso niitc ihsgiiatitrcnr aiblt:cmaio ihNoa n RedBook and Neofax with comparison variability: inter-centre significant with antibiotics of intervals dosing and doses daily The oee,fwatboishv eneautdin evaluated been have antibiotics few However, 8 8 8 25.0 3.75 25.0 50.0 2.0 50.0 iia al oe aia al doses daily Maximal (Min (mg/kg/day) results Survey doses daily Minimal 8 6 (Min (h) results Survey 4.0 iia oigintervals dosing Minimal – – – – – 24 48 24 24 8866 – – – – – – – – 15.0 6.0 – – 200.0 30.0 180.0 180.0 75.0 200.0 max) max) ‘ 78 h uoenCmiteon Committee European The — – iecret h organ- the to curve time EUCAST 24 ’ 10 11 oMCrtoo the of ratio MIC to – odtriesuch determine To (mg/kg/day) Neofax 24 24 24 24 (h) Neofax 60.0 3.75 50.0 NA 40.0 30.0 9.0 2.5 13 hl U is AUC while ‘ rb the by or 9 ’ eoxS, Leroux (mg/kg/day) RedBook 12 12 12 NA (h) RedBook 100.0 3.75 50.0 NA 40.0 30.0 7.5 NA ition. vlaino h rpsdrgmnb rsetv ef prospective clinical a also study. by but regimen safety validation) proposed and external the of and be evaluation only internal be model can both to pharmacokinetic dosing validated regimen (with neonatal a dosage on requires optimal consensus and the evidence-based A on neonates. resulting consensus in validated of used clinically lack were the them in of None study. present ed oitgaeterpddvlpetlcagso h neo- the of re changes as developmental period, rapid natal the integrate to needs tde ihalmtdnme fnoae n3)hv been have (n=32) neonates of number limited published, a with studies oiei ifrne ndu ipsto,apeeust o clin- for ef prerequisite of a evaluation disposition, ical pharma- drug study-related in differences of cokinetic understanding thorough ensure might n diinlvralsmyb etd ies,associated disease, tested: be support. may ventilatory and cardiovascular variables so drugs, and tests Additional function liver on. post- concentration postnatal, creatine gestational, age, include menstrual may and maturation and size lutae ytetoeteeeape faiai and literature amikacin the of in proposed examples extreme two as the metronidazole. neonates, in by antibiotics all illustrated almost for lacking are the prescriptions underlying studies. antibiotics, pharmacokinetic designed of well of recommendation importance neo- establish dosage to approaches natal simulation and modelling cokinetic tso rgcnetain. a aea motn impact important set- clinical an different to have tings. results may published the concentrations.) extrapolating when many covari- drug biological in or measure neo- to included ates the methods of patients analytical characteristics included, of as nates (such number factors limited study-related centres, a have usually 2 o erndzl,ol ouainpharmacokinetic population 2 only metronidazole, For (2) codnl,rgltr guidelines regulatory Accordingly, 1 o mkcn 9dfeetnoaa oigrgmn are regimens dosing neonatal different 19 amikacin, For (1) optimal support to regimens dosing evidence-based However, tal et 14 34 . rhDsChild Dis Arch eedn ntedu,teecvrae r akr of markers are covariates these drug, the on Depending nsc ae,pplto hraoiei meta-analysis pharmacokinetic population cases, such In 536 35 aia oigintervals dosing Maximal (Min (mg/kg/day) results Survey 18 24 12 18 (Min (h) results Survey 50.0 15.0 75.0 75.0 40.0 150.0 13.3 4.0 – – – – – 12 vntog h rghsbe sdfrmany for used been has drug the though even – 72 60 48 48 – – – – – – 7.5 – – 33 – 200.0 40.0 300.0 180.0 100.0 27.5 2015; fl max) max) 300.0 fi ce ycvrae in covariates by ected ayadsafety. and cacy spamckntcsuisi neonates in studies pharmacokinetic As 100 :394 18 – – 32 9.doi:10.1136/archdischild-2014-306873 398. n 1wr identi were 31 and 48 48 48 48 12 90.0 15.0 75.0 NA 50.0 90.0 15.0 4.0 (mg/kg/day) Neofax (h) Neofax 15 – 17 fl eomn pharma- recommend ecn rgdispos- drug uencing 48 48 48 NA 12 150.0 30.0 100.0 NA 75.0 90.0 30.0 NA (mg/kg/day) RedBook (h) RedBook fi di the in ed

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Arch Dis Child: first published as 10.1136/archdischild-2014-306873 on 27 January 2015. Downloaded from from Downloaded 2015. January 27 on 10.1136/archdischild-2014-306873 as published first Child: Dis Arch http://adc.bmj.com/ on September 23, 2021 by guest. Protected by copyright. by Protected guest. by 2021 23, September on Arch Dis Child: first published as 10.1136/archdischild-2014-306873 on 27 January 2015.Drug Downloaded therapy from http://adc.bmj.com/ on September 23, 2021 by guest. Protected by copyright. 4. – ” Curr Drug Eur J Clin 3. – uf, V. Poirier), 2004;114:1362 Network of œ — 70. – Pediatrics off-label use. Original article Pediatrics — 2013;2013:586076. 2011;87:S31 . Neonatal sepsis due to J Antimicrob Chemother 2011;30:365 . Recent advances in prevention of sepsis . Secular trends in antibiotic use among et al . Variation in gentamicin and vancomycin et al et al . Reported medication use in the neonatal et al Treat Infections in NeoNates network Early Hum Dev “ Clin Dev Immunol et al ned the study. SL contacted the NICUs with the . Drug utilisation on a preterm and neonatal fi Not commissioned; externally peer reviewed. et al rst draft of the manuscript. WZ and EJ-A reviewed the 95. Pediatr Infect Dis J fi – 92. – None. We acknowledge all neonatologists from paediatric and 87. 2008. 50. – – – ster R, Posfay-Barbe KM, Societé Française de Neonatologie (http://sdp.perinat-france.org/SFN). 2010;66:87 fi This is an Open Access article distributed in accordance with the SL, ZW and EJ-A de 2012;13:885 Hôpital Hasenrain ( J. Nakhleh), Nantes Hôpital Mère-Enfant (JC. Rozé), This work was supported by — CH Intercommunal (C. Danan, X. Durrmeyer), Grenoble CHU Hôpital Couple — intensive care unit in Germany:Pharmacol a prospective, cohort-based analysis. Targets neonates: 2001 coagulase-negative staphylococci. intensive care unit: data from2006;117:1979 a large national data set. in the premature neonates in NICU. dosage and monitoring in2011;66:2647 UK neonatal units. 8 Neubert A, Lukas K, Leis T, 7 Zingg W, Posfay-Barbe KM. Antibiotic use in children 1 Marchant EA, Boyce GK, Sadarangani M, 6 Zingg W, P 4 Engle WA. Age terminology during the perinatal period. 2 Manzoni P, Rizzollo S, Decembrino3 L, Kadambari S, Heath PT, Sharland M, 5 Clark RH, Bloom BT, Spitzer AR, Division of Neonatology, Department of Child and AdolescentClinical Medicine, Investigation CHU Center de CIC1426, INSERM,Department Paris, of France Clinical Pharmacy, School of Pharmaceutical Sciences,INSERM Shandong U1099, Institut desPaediatric Neurosciences and Cliniques Neonatal de Intensive Rennes, Care Rennes, Unit, France CHRU Tours, Tours, France Rennes, Rennes, France University, Jinan, China Acknowledgements neonatal intensive care network (listedsurvey (CH: in centre alphabetic hospitalier): order) Amiens(S. who CHU Le participated (G. bouedec, in Kongolo), B. this la Angers Leboucher), Côte CHU Arras Basque CH Hôtel (P. (B. Dieu CHRU Jouvencel), Theret, Morvan Bicêtre L. Brest Hôpital Desnoulez), (A. Bicètre Bayonne(B. (D. Garenne, CH Guillois, JM. Devictor, de A. Roue), L. Ceneric), Caen, Chevret),Antoine Calais Hôpital Brest Béclère CH Côte (O. (MJ. de Romain), Thieuleux, Nacre Cotentin Chambery L. (S. CH Egreteau), Saumureau), (M. Clamart Clermont-Ferrand Deiber), Hôpital Hôpital Cherbourg Estaing CH (B. public B du REFERENCES 3 4 5 6 7 Creteil Enfant (T. Debillon, L.S. Marcus, Klosowski), F. Lille Audeoud), Hôpital LensFemme Jeanne CH Mère de Docteur Enfant Flandre Schaffner (O. (L. (C.I. Claris, Storme, Morisot, Jordan), F. A. Marseille Plaisant), Fily), Hôpital Lyon LyonConception Hôpital Nord Hôpital (U. Croix (U. Simeoni, Rousse Simeoni, I. ( S. JC.(G. Ligi), Hassid), Picaud, Cambonie, Montpellier Marseille R. hôpital Hôpital Mesnage), Arnaud deMulhouse Montreuil de la Hôpital Villeneuve André GrégoireNice (P. Hôpital Daoud), Archet 2Hôpital (C. Magenta Dageville), (L. Nimes Tauzin), CHUEnfants-Malades Paris Caremeau (P. Hôpital ( JB. Hubert, Cochin Mariette), M. (PH. Noumea V Nicloux), Jarreau), Paris Biran); Paris Paris Hôpital Hôpital Hôpital Robert Necker Jean Trousseau Debré (D. (P. (O. Thevenot, Mitanchez, Baud, R. F. Kieffer), Mesnage),Pontoise Hôpital Perpignan Poissy CH Hôpital René Intercommunal Saint Dubos (P.A. (P. Boileau, Boize), David), G. Reims, Rouen Ciarlo), Hôpital HôpitalBretagne Maison Charles (P. Blanche Nicolle Pladys, (P. (S. P. Morville, Marret), Betremieux),Saint Rennes Saint Denis Hôpital Brieux La sud Hôpital Reunion Anne YvesHôpital CHU de Le Hautepierre Felix Foll (D. Guyon (E. Astruc, (S. Boutaric), A. L. Samperiz, Bouissou), Palpacuer), D. Tours Troyes Ramful), CH Hôpital Strasbourg (I.Vannes Clocheville CH Arnault), (E. Bretagne Valenciennes Saliba, Atlantique CH (H. (F. Lapeyre, Journel,Collaborators M. H. Hassan), Bourdial). Contributors participation of PB, PPthe and analysis ES. and SL, wrote ZW the and EJ-A planned the analysis. SL performed manuscript; the last version was validatedFunding by all authors. (TINN1 and TINN2, EU-fundedTINN1; FP7 no projects, 260908 Grant TINN2) Agreement numbers and no Global 223614 Research in Paediatrics Excellence (GRIP, EU-funded FP7 project, GrantCompeting Agreement interests number 261060). Provenance and peer review Open Access Creative Commons Attribution Non Commercialpermits (CC others BY-NC to 4.0) distribute, license,and remix, which adapt, license build their upon derivativeproperly works this cited on work and different non-commercially, the terms,licenses/by-nc/4.0/ use provided the is original non-commercial. work See: is http://creativecommons.org/ - fi cacy), (2) the fi 9 as they are 40 41 who reported wide pharmacodynamics. 39 45 46 et al 398. doi:10.1136/archdischild-2014-306873 397 – s hospitals in the type and dose Several factors may explain this ’ The National Institute of Health :394 37 44 100 cult to obtain. 2015; however, the current clinical practice is fi oxacin. fl ects more common situations encountered 38 ndings by Porta c and antibiotic treatment has to be started fl fi despite regulatory initiatives that encourage fi or cipro 42 43 Arch Dis Child . 3 liations fi et al t ratio than the currently used antibiotics; and (4) in such fi cacy and safety in older paediatric patients or even adults fre- Such variability in local guidelines, along with the paucity and We further compared the doses in local guidelines with The French inter-NICU variability reported in this survey In conclusion, this survey analysed the multiple dosage regi- fi EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert frequentlyInconsistencies used were highlighted,recommends e.g. 30 reference mg/kg for perpostmenstrual ceftazidime, dose age Neofax books every andmends 8 postnatal 50 or mg/kg age, 12 by per hweight while dose according and RedBook every to postnataltherapy neonatologists. recom- 8 age. in or neonates Reaching is 12 a urgentlylaboration h required, consensus according but will on to needneonatologists. antibiotic body close between col- paediatricpoor quality of randomised controlledculties trials, pharmacologists in highlights conducting the dif in studies assessing neonates, and the effects of antibiotics empirical treatment varies betweenepidemiology units, and as it clinical dependsef context; on (3) local antibioticsquently with enter neonatal proven carehave because a clinicians more adapted perceivebene spectrum them of to activityemergency and/or situations, better risks and to cokinetics whatever and the safety study or randomised design controlled (pharma- trial for ef Debré, APHP, Paris, France variation between four children of antibiotic useddata. in paediatrics based ondosages recommended daily by Neofax prescription and Redbook, and Care Excellence guidancestarting recommends a dose unique gentamicin ofinfection 5 treatment; mg/kg every 36 h for early onset neonatal 2 Leroux S, Author af 1 drug studies insituation: neonatology. (1) signs ofsepsis) neonatal are sepsis unspeci (eitheras early early or as late possible onset and merely upon clinical suspicion; almost certainly re in European countries orheterogeneity at the in international clinical level. practicedata Indeed, evaluating is such the in dosage agreement recommendationsgentamicin of with vancomycin previous and years for treating complicatedAdditional abdominal infections data in are neonates. highly obviously required variable asneonates. from treated patients extremely are low birth weight to term mens to beNICUs. A followed wide toof inter-centre daily variability prescribe doses, was antibioticsindividualisation. dosing evidenced Obviously, intervals in evidence-based in and dosage terms antibiotics the regimens covariates of used should French for bebasis dosage of validated developmental for– pharmacokinetics neonatal treatment on the variable for gentamicin therapy. Inbinations UK of survey, 24 dose differentmarkedly were com- from revealed 12 and to theferent 48 h. dosing combinations In interval a of varied from French survey, 8 we doses found to and 25 48variable dif- h. in the For France, vancomycin, dosing astent clinical both infusion interval of practice were continuous is routinely varied infusion used.with even Our and more the results intermit- previous are also consistent informed consent is dif Drug therapy 5AlgetK osyV eerA, Debeer V, Cossey K, Allegaert 25 8StauyR uet ,RnjnL, Rundjan R, Suwento R, Setiabudy 18 Agency. Medicines European 17 and pharmacokinetics on consider to Points Agency. Medicines European 16 A, Canut A, Isla E, Asín http://www.clsi.org13 12 http://www.eucast.org in pharmacodynamics pharmacokinetics 11 Understanding T. Metsvaht I, Lutsar 10 3SewnCT vh ,VndrLne A, Linden der Van S, Svahn CMT, Sherwin 23 4AlgetK nesnB,vndnAkrJN, Anker den van BJ, Anderson K, Allegaert 24 398 2SdiiA hnD,Ka FA, Khan DA, Khan A, Siddiqi 22 A, Bökenkamp AJ, Wilhelm MF, Schreuder 21 M, Hedaya M, Hamamsy El E, Abdel-Hady 20 MF, Schreuder K, Allegaert RFW, Cock De 19 exposure– industry: for Guidance neonates: in practice clinical 15 and disposition Drug K. Allegaert P, Annaert A, Smits 14 6Téue M el ,TneirS, Tonnelier Y, Merlé JM, Tréluyer 26 7LbueJ,BezcN ar P, Maire N, Bleyzac JM, Labaune 27 dodK ad .Nwapoce opeetn,dansn,adtreating and diagnosing, preventing, to approaches New A. Zaidi K, Edmond 9 rgnlarticle Original 2009;65:705 analysis. pharmacokinetic/pharmacodynamic a neonates: in ents eaint rntlgrowth. prenatal to relation neonates: egto mkcncerneo a flife. of 1 day 2009;4:1774 on clearance amikacin on weight 2012;51:105 neonates. in Ther ototoxicity and aminoglycosides of concentration 1) rev (CPMP/EWP/558/95 infections http://www.ema.europa.eu bacterial of treatment for indicated Ref. products. medicinal http://www.ema.europa.eu antibacterial CPMP/EWP/2655/99). of development the in pharmacodynamics http://www.fda.gov/downloads/Drugs applications. regulatory and analysis, for breakpoints clinical bacteria. CLSI Gram-positive and EUCAST with breakpoints pharmacodynamic sepsis. neonatal managing rtr n eminfants. term and preterm npeemifnsi needn ftegsainlage. gestational the of 2005;20:740 independent is infants preterm in oigrgmn faiai nnoae ihsepsis. with 2011;36:45 neonates in amikacin of dosing-regimens fi pharmacology. and 2013;16:8 physiology developmental between talk cross nlsso mkcni ents nat,adchildren. and infants, Chemother neonates, in amikacin of analysis o upce neto tbrhbsdo ouainpamckntcmodels. pharmacokinetic population on Neonate based Biol birth at infection suspected for entlsepsis. neonatal tainrt nnoae,a refl as neonates, in rate ltration 2013;51:401 – 2002;46:1381 – 13. – – – – 52. 2001;80:142 13. 8. 17. 3. LSMed PLoS – 6. n niirbAgents Antimicrob J Int tal et – igpr e J Med Singapore – urOi netDis Infect Opin Curr 2010;7:e1000213. 7. 7. oprsno niirba pharmacokinetic/ antimicrobial of Comparison . oefrgiac neauto fmdcnlproducts medicinal of evaluation on guidance for Note tal et ce yaiai clearance. amikacin by ected epnerelationships response Teipc fiurfno ea clearance renal on ibuprofen of impact The tal et tal et tal et hrpui rgmntrn faiai in amikacin of monitoring drug Therapeutic . tal et . neadyidvdaie mkcndosing amikacin individualized Once-a-day . hrDu Monit Drug Ther oprmti ouainpharmacokinetic population Nonparametric . ako eainhpbtenteserum the between relationship a of Lack . tal et tal et tal et tal et 2009;50:486 tal et auaino h glomerular the of Maturation . lnJA o Nephrol Soc Am J Clin mato ettoa g n birth and age gestational of Impact . niiulsddsn famikacin of dosing Individualised . h ef The . 2012;40:313 2010;23:201 ea rgcernei preterm in clearance drug Renal . lnPamTher Pharm Clin J — fi niirbAgents Antimicrob 2007;29:284 ayadtxct ftwo of toxicity and cacy – eit Nephrol Pediatr td ein data design, study 9. u lnPharmacol Clin J Eur – – lnPharmacokinet Clin n lnPharmacol Clin J Int 22. 7. n Pharm J Int – 91. . eoxS, Leroux 6AilP oeuD icn-eo C, Vincent-Genod D, Moreau P, Amiel 46 9PraA saY orotK, 2012. Doerholt infection. Y, neonatal Hsia early-onset A, for Porta Antibiotics Guidence: Clinical 39 NICE 38 2Kgeio ,Tre A hoaaI, Choonara MA, Turner F, 2013. Kaguelidou Pediatrics. of 2011. Academy Staff. American Editorial 42 RedBook. Clinical Reuters Thomson 41 Neofax. 40 4Bnai KJ,SihP,Mrh MD, Murphy PB, Smith Jr, DK Benjamin 44 5NclnS pne A erimn alr nerynoaa research. neonatal early in failure Recruitment SA. Spencer S, Nicklin 45 1Ptre O el G ersG.Aiai oigi ents vlaino a of evaluation neonates: in dosing Amikacin GL. 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