Inhloso Ukuhlola izehlakalo ezimbi ezihlobene ne-fosfomycin (AEs) kanye ne-pharmacokinetics kanye nezinguquko kumazinga e-sodium ezinganeni ezisanda kuzalwa ezine-sepsis yomtholampilo.
Phakathi kuka-March 2018 no-February 2019, izingane ezisanda kuzalwa ezingu-120 ezineminyaka engu-≤28 izinsuku zithole ama-antibiotics ajwayelekile (SOC) e-sepsis: i-ampicillin ne-gentamicin.
Ukungenelela Sabeka ngokungahleliwe ingxenye yabahlanganyeli ukuthi bathole i-fosfomycin eyengeziwe nge-intravenous elandelwa yi-oral fosfomycin ngethamo lika-100 mg/kg kabili ngosuku izinsuku eziyi-7 (SOC-F) bese ilandelwa izinsuku ezingama-28.
Imiphumela 61 kanye nezinsana ezingama-59 ezineminyaka engu-0-23 ubudala yabelwa i-SOC-F ne-SOC, ngokulandelana. Abukho ubufakazi bokuthi i-fosfomycin inomthelela ku-serum.i-sodiumnoma imiphumela engemihle yesisu.Phakathi nezikhathi zokubheka izinsuku zezingane ezingu-1560 nezingu-1565, sibheke ama-AE angu-50 kubahlanganyeli abangu-25 be-SOC-F kanye nabangu-34 babahlanganyeli be-SOC, ngokulandelanayo (imicimbi engu-2.2 vs 3.2/izinsuku ezingu-100 zosana; umehluko wezinga -0.95 izehlakalo ezingu-100 ) usuku (95% CI -2.1 kuya ku-0.20)).Abahlanganyeli abane be-SOC-F nabathathu be-SOC bafa.Kusuka kumasampula e-pharmacokinetic angu-238, ukufanisa kubonise ukuthi izingane eziningi zidinga umthamo we-150 mg / kg nge-intravenously kabili nsuku zonke ukuze ufeze imigomo ye-pharmacodynamic, futhi izingane ezisanda kuzalwa ezingaphansi kwezinsuku ezingu-7 ubudala noma ezinesisindo esingu-<1500 g ngosuku Umthamo wehliswe waba ngu-100 mg/kg kabili.
Iziphetho Nokufaneleka I-Fosfomycin inamandla okukhetha ukwelashwa okuthengekayo kwe-neonatal sepsis ngohlelo lomthamo olula. Ukuphepha kwayo kudinga ukuqhubeka kucutshungulwe eqenjini elikhulu lezingane ezisanda kuzalwa ezilaliswe esibhedlela, okuhlanganisa nezinsana ezisanda kuzalwa noma iziguli ezigula kakhulu. ngokumelene nezilwanyana ezibucayi kakhulu, ngakho-ke kunconywa ukusebenzisa i-fosfomycin ngokuhambisana nenye i-ejenti elwa namagciwane.
Data is available upon reasonable request.Trial datasets are deposited at https://dataverse.harvard.edu/dataverse/kwtrp and are available from the KEMRI/Wellcome Trust Research Program Data Governance Committee at dgc@kemri-wellcome.org.
Lesi isiqephu sendatshana esivulekile sokufinyelela esatshalaliswa ngaphansi kwelayisensi ye-Creative Commons Attribution 4.0 Unported (CC BY 4.0), evumela abanye ukuthi bakopishe, basabalalise kabusha, baxube kabusha, baguqule, bakhe lo msebenzi nganoma iyiphi injongo, inqobo nje uma ucashunwe kahle Umsebenzi wokuqala. inikeziwe, isixhumanisi selayisensi siyanikezwa, kanye nenkomba yokuthi izinguquko zenziwe yini.Bona: https://creativecommons.org/licenses/by/4.0/.
Ukumelana nemithi elwa namagciwane kubangela usongo ekuphileni kwezingane ezisanda kuzalwa futhi kunesidingo esiphuthumayo sezinketho zokwelashwa ezintsha ezithengekayo.
Kunomthwalo obalulekile we-sodium nge-intravenous fosfomycin, futhi amalungiselelo omlomo we-fosfomycin aqukethe inani elikhulu le-fructose, kodwa kunedatha yokuphepha elinganiselwe ezinganeni ezisanda kuzalwa.
Izincomo zomthamo wezingane kanye nezinsana ze-fosfomycin ze-intravenous ziyehluka, futhi azikho izindlela zokudosa zomlomo ezishicilelwe.
I-fosfomycin ye-intravenous ne-oral ku-100 mg/kg kabili ngosuku, ngokulandelana, ayizange ibe nomthelela ku-serum.i-sodiumnoma imiphumela emibi yesisu.
Izingane eziningi zingadinga i-intravenous fosfomycin 150 mg/kg kabili ngosuku ukuze zifinyelele imigomo yokusebenza ngempumelelo, futhi ezinganeni ezisanda kuzalwa ezingaphansi kwezinsuku ezingu-7 ubudala noma ezinesisindo esingaphansi kuka-1500 g, i-intravenous fosfomycin 100 mg/kg kabili ngosuku.
I-Fosfomycin inamandla okuhlanganiswa namanye ama-antimicrobial ukwelapha i-neonatal sepsis ngaphandle kokusebenzisa i-carbapenems esimweni sokwanda kokumelana namagciwane.
Ukumelana ne-Antimicrobial (AMR) kuthinta ngokulinganayo abantu emazweni anemali engenayo ephansi kanye nephakathi (ama-LMIC). Ukuncipha kokushona kwezinsana bekuphansi kunezingane ezindala, okungenani ingxenye yesine yokufa kwezingane ezisanda kuzalwa okubangelwa ukutheleleka. I-AMR ikhulisa lo mthwalo, enamagciwane angamelana nezidakamizwa eziningi (MDR) enza cishe u-30% wokufa kwe-neonatal sepsis emhlabeni jikelele.2
I-WHO incoma i-ampicillin,i-penicillin, noma i-cloxacillin (uma kusolwa ukutheleleka kwe-S. aureus) kanye ne-gentamicin (umugqa wokuqala) kanye ne-cephalosporins yesizukulwane sesithathu (umugqa wesibili) wokwelashwa okunamandla kwe-neonatal sepsis.3 Kanye ne-extended-spectrum beta-lactamase (ESBL) kanye i-carbapenemase, i-4 isolates emitholampilo ivame ukubikwa ukuthi ayinandaba nalolu hlobo lwemithi.5 Ukugcinwa kwe-carbapenems kubalulekile ekulawuleni i-MDR, i-6 kanye nokubuyiselwa kwama-antibiotic endabuko kukhuthazwa ukubhekana nokuntuleka kwama-antibiotic amasha athengekayo.7
I-Fosfomycin iwumphumela wokuphuma kokunye okungezona ubunikazi be-phosphonic acid okuye kwathathwa ngokuthi “ibalulekile” yi-WHO.8 I-Fosfomycin ine-bactericidal9 futhi ibonisa umsebenzi ngokumelene namagciwane e-Gram-positive kanye ne-Gram-negative, okuhlanganisa i-Staphylococcus aureus engamelana ne-methicillin, i-vancomycin-resistant, ESBL abakhiqizi futhi ingase ingene ku-biofilm.10 I-Fosfomycin ibonise i-in vitro synergy ne-aminoglycosides ne-carbapenems 11 12 futhi ivame ukusetshenziswa kubantu abadala abane-MDR ye-urinary tract infections.13
Njengamanje kunezincomo ezingqubuzanayo zokufakwa kwe-intravenous fosfomycin ezinganeni, kusukela ku-100 kuya ku-400 mg/kg/ngosuku, kungekho simiso somthamo womlomo esishicilelwe.Izifundo ezine zezingane ezisanda kuzalwa zilinganisela ukuqedwa kwesigamu sempilo yamahora angu-2.4-7 ngemva kokuphathwa kwe-intravenous 25-50 mg/kg.14 15 Ukubophezela kwamaprotheni kwakuncane, futhi ukugxila okuphezulu kwakuhambisana nedatha yabantu abadala.16 17 Imiphumela ye-bactericidal yayibhekwa njengehlotshaniswa nanoma yisiphi isikhathi esingaphezu kokuhlushwa okuphansi kwe-inhibitory (MIC) 16 noma indawo engaphansi kwejika. (AUC):Isilinganiso se-MIC.18 19
Ingqikithi yemibiko engama-84 yezingane ezisanda kuzalwa ezithola i-fosfomycin nge-intravenous ku-120-200 mg/kg/ngosuku ibonise ukuthi ibekezelelwe kahle.20-24 Ubuthi bubonakala buphansi kubantu abadala nasezinganeni ezindala.25 Nokho, i-fosfomycin yomzali iqukethe i-14.4 mmol/ I-330 mg ye-sodium ngegremu-ukukhathazeka okungase kube khona kokuphepha kwezingane ezisanda kuzalwa ezibuyisela kabusha i-sodium ngokuphambene ngokulingana nobudala bokukhulelwa (GA) .26 Ngaphezu kwalokho, i-fosfomycin yomlomo iqukethe umthwalo ophezulu we-fructose (~ 1600 mg / kg / ngosuku), okungase kubangele amathumbu imiphumela emibi futhi ithinte ibhalansi yoketshezi.27 28
Sasihlose ukuhlola i-pharmacokinetics (PK) kanye nezinguquko zeleveli ye-sodium ezinganeni ezisanda kuzalwa ze-sepsis, kanye nezehlakalo ezimbi (ama-AEs) ezihlotshaniswa ne-intravenous elandela i-oral fosfomycin.
Senze isilingo esilawulwa ngokungahleliwe esinelebula evulekile eqhathanisa izinga lokunakekelwa (i-SOC) imithi elwa namagciwane iyodwa nge-SOC kanye ne-IV elandelwa yi-oral fosfomycin ezinganeni ezisanda kuzalwa ezine-sepsis yomtholampilo e-Kilifi County Hospital (KCH), Kenya.
Zonke izingane ezisanda kuzalwa ezingeniswe ku-KCH zahlolwa.Imibandela yokufaka yayiyilokhu: ubudala ≤ izinsuku ezingu-28, isisindo somzimba > 1500 g, ukukhulelwa > amasonto angu-34, kanye nemibandela ye-intravenous antibiotics kuzinkombandlela ze-WHO3 kanye ne-Kenya29. Uma i-CPR idinga, i-Grade 3 hypoxic-ischemic encephalopathy, I-30 sodium ≥150 mmol/L, i-creatinine ≥150 µmol/L, i-jaundice edinga ukushintshwa, ukungezwani komzimba noma ukuphikisana ne-fosfomycin, inkomba ethile yesinye isigaba sesifo esibulala ama-antibiotics, umntwana osanda kuzalwa akafakwanga kwesinye isibhedlela noma cha e-Kilifi County (Umfanekiso 1 ).
Zama i-flowchart.Lesi sibalo sokuqala sidalwe yi-CWO kulo mbhalo wesandla.CPR, ukuvuselelwa kwenhliziyo;I-HIE, i-hypoxic-ischemic encephalopathy;IV, ukufakwa emthanjeni;I-SOC, izinga lokunakekelwa;I-SOC-F, izinga lokunakekelwa kanye ne-fosfomycin.*Izimbangela zihlanganisa umama (46) noma ukugula kakhulu (6) ngemva kokuhlinzwa, ukukhishwa esibhedlela (3), ukukhishwa ngaphandle kokunconywa (3), ukushiywa ngumama (1) nokuhlanganyela ekukhulelweni. olunye ucwaningo (1).†Omunye umhlanganyeli we-SOC-F ushone ngemva kokuqeda ukulandelela (Usuku 106).
Ababambiqhaza babhaliswe phakathi kwamahora angu-4 wedosi yokuqala yemithi elwa namagciwane e-SOC kuze kube uSepthemba 2018, lapho izichibiyelo zephrothokholi zandisa lokhu kungakapheli amahora angama-24 ukuze kufakwe nokungeniswa ebusuku.
Abahlanganyeli babelwa (1:1) ukuthi baqhubeke nama-antibiotic e-SOC kuphela noma bathole i-SOC plus (kufika) ezinsukwini ezingu-7 ze-fosfomycin (SOC-F) besebenzisa ishejuli ye-randomization enosayizi wokuvimba okungahleliwe (Umfanekiso Owengeziwe S1 ku-inthanethi). Kufihlwe ngokulandelana ngokulandelana. izimvilophu ezivaliwe ezinezinombolo.
Ngokusho kwe-WHO kanye neziqondiso zezingane zaseKenya, ama-SOC afaka i-ampicillin noma i-cloxacillin (uma kusolwa ukutheleleka kwe-staphylococcal) kanye ne-gentamicin njengama-antibiotic omugqa wokuqala, noma ama-cephalosporin esizukulwane sesithathu (isb, i-ceftriaxone) njengama-antibiotic omugqa wesibili.3 29 Abahlanganyeli bahlelwe ngokungahleliwe ku-SOC -F iphinde yathola i-intravenous fosfomycin okungenani amahora angu-48, ishintshela emlonyeni lapho ukudla okwanele kwabekezelelwa ukuze kuthathwe ukumuncwa okwanele komuthi ophathwayo.I-Fosfomycin (efakwa emthanjeni noma ngomlomo) yasetshenziswa izinsuku ezingu-7 noma kuze kube yilapho ikhishwa, kuye ngokuthi yikuphi okwenzeka kuqala.Fomicyt 40 mg/mL isixazululo se-fosfomycin sodium sokufakwa emthanjeni (Infectopharm, Germany) kanye ne-Fosfocin 250 mg/5 mL fosfomycin calcium suspension for theoral administration (Laboratorios ERN, Spain) kabili ngosuku kusetshenziswa i-100 mg/kg/dose.
Abahlanganyeli balandelwa izinsuku ze-28. Bonke abahlanganyeli banakekelwa kuyunithi efanayo encike kakhulu yokulawula ukuqapha kwe-AE. Izibalo zegazi ezigcwele kanye ne-biochemistry (kuhlanganise ne-sodium) zenziwa ekungeneni, izinsuku ze-2, ne-7, futhi ziphindaphindiwe uma kuboniswe emtholampilo.AEs zikhokhwa ngokwe-MedDRA V.22.0.Ukuqina kwahlukaniswa ngokwe-DAIDS V.2.1.AEs kwalandelwa kuze kube yilapho isixazululo somtholampilo noma kwahlulelwa ukuthi yizifo ezingelapheki nezizinzile ngesikhathi sokwelashwa. kulesi sibalo sabantu, okuhlanganisa ukuwohloka okungenzeka ngesikhathi sokuzalwa (iphrothokholi kufayela Lokwengeza 1 ku-inthanethi).
Ngemuva kwe-IV yokuqala kanye ne-fosfomycin yokuqala yomlomo, iziguli ezabelwe i-SOC-F zahlelwa ngokungahleliwe zibe yinye ngaphambi kwesikhathi (imizuzu engu-5, 30, noma engu-60) kanye nesampula se-PK esisodwa sekwephuzile (2, 4, noma ihora lesi-8) isampula ye-PK. kubabambiqhaza abasangeniswe esibhedlela ngosuku lwe-7. Amasampula e-cerebrospinal fluid (CSF) aqoqwe kusukela ekubhobhozweni kwe-lumbar (LP) okuboniswe emtholampilo).Ukucubungula isampula kanye nezilinganiso ze-fosfomycin kuchazwe kufayela le-Supplementary 2 ku-intanethi.
Sibuyekeze idatha yokwamukelwa phakathi kuka-2015 no-2016 futhi sabala ukuthi isilinganiso se-sodium yezingane ezingu-1785 ezinesisindo esingu->1500 g sasingu-139 mmol/L (SD 7.6, ububanzi obungu-106-198). Ngaphandle kwezingane ezingu-132 ezine-serum sodium>150 mmol/L (yethu indlela yokukhishwa), izingane ezisanda kuzalwa eziyi-1653 ezisele zinesilinganiso se-sodium engu-137 mmol/L (SD 5.2) . kunqunywa ngamandla angu- >85% ngokusekelwe kudatha yendawo yangaphambilini yokusabalalisa isodium.
Ku-PK, usayizi wesampula wama-45 uhlinzekwe >85% wamandla okulinganisa amapharamitha e-PK ukuze kugunyazwe, umthamo wokusabalalisa, nokuba khona kwe-bioavailability, nama-CI angu-95% alinganiselwe kusetshenziswa ukulingisa ngokunemba okungu-≥20%.Kuze kube manje, imodeli yesimo sabantu abadala. kwasetshenziswa, ukukala ubudala nosayizi ezinganeni ezisanda kuzalwa, kwenezela ukumuncwa oda lokuqala kanye nokucatshangwa ukuthi i-bioavailability.31 Ukuvumela amasampula alahlekile, sasihlose ukuqasha izingane ezisanda kuzalwa ezingama-60 iqembu ngalinye.
Umehluko kumapharamitha ayisisekelo ahlolwe kusetshenziswa ukuhlolwa kwe-χ2, ukuhlolwa kwe-t yoMfundi, noma ukuhlolwa kwe-rank-sum ka-Wilcoxon. Umehluko osukwini lwe-2 nosuku lwe-7 ye-sodium, i-potassium, i-creatinine, ne-alanine aminotransferase ihlolwe kusetshenziswa ukuhlaziywa kwe-covariance elungiselelwe amanani ayisisekelo. Kuma-AEs, izehlakalo ezimbi kakhulu (ama-SAE), kanye nokusabela okubi kwezidakamizwa, sisebenzise i-STATA V.15.1 (StataCorp, College Station, Texas, USA).
Izilinganiso ezisekelwe kumodeli zamapharamitha we-PK zenziwe ku-NONMEM V.7.4.32 kusetshenziswa izilinganiso ezinemibandela ze-oda lokuqala nokusebenzisana, imininingwane egcwele yokuthuthukiswa kwemodeli ye-PK kanye nokulingiswa kunikezwa kwenye indawo.32
Ukuqapha esizeni kwenziwa yi-DNDi/GARDP, ngokugada okuhlinzekwe yikomiti elizimele lokuvikela nokuqapha idatha.
Phakathi kukaMashi 19, 2018, kanye noFebhuwari 6, 2019, izingane ezisanda kuzalwa eziyi-120 (61 SOC-F, 59 SOC) zabhaliswa (Umfanekiso 1), kuzo ezingama-42 (35%) zabhaliswa ngaphambi kokubuyekezwa kwephrothokholi.Iminyaka yeqembu.Median (IQR), isisindo kanye ne-GA bekuwusuku olungu-1 (IQR 0-3), 2750 g (2370-3215) namaviki angama-39 (38-40), ngokulandelana. Ithebula le-inthanethi Lokwengeza S1.
I-bacterium itholwe ezinganeni ezimbili ezisanda kuzalwa (Ithebula Le-Supplementary S2 ku-inthanethi) .2 kwezinsana ezingu-55 ezithole i-LP zine-meningitis eqinisekiswe ilabhorethri (i-Streptococcus agalactiae bacteremia ne-CSF leukocyte ≥20 cells/µL (SOC-F); i-positive Streptococcus antibrospinal fluide kanye namaleukocyte e-CSF ≥ amaseli angu-20/µL (SOC)).
Olunye usana olusanda kuzalwa lwe-SOC-F lwathola ngokungalungile kuphela ama-antimicrobial e-SOC futhi alufakwanga ekuhlaziyweni kwe-PK. Ama-SOC-F amabili kanye ne-SOC Neonatal eyodwa ahoxile imvume - okuhlanganisa idatha yokuhoxiswa kwangaphambili. Bonke ngaphandle kwabahlanganyeli be-SOC ababili (i-cloxacillin kanye ne-gentamicin (n=1 ) kanye ne-ceftriaxone (n=1)) bathole i-ampicillin kanye ne-gentamicin ekungenweni. ekwelapheni komugqa wesibili ngenxa yokuwohloka komtholampilo noma i-meningitis, abahlanu kubo ababengaphambi kwesampula yesine ye-PK (Ithebula Lesengezo S3 ku-inthanethi). Sekukonke, ababambiqhaza abangama-60 bathole okungenani umthamo owodwa womjovo we-fosfomycin kwathi abangama-58 bathola okungenani umthamo womlomo owodwa.
Abayisithupha (abane be-SOC-F, ababili be-SOC) bashonele esibhedlela (Umfanekiso 1). Umhlanganyeli oyedwa we-SOC ushone ezinsukwini ezi-3 ngemuva kokukhishwa (usuku lwama-22). 106 (ngaphandle kokulandelelwa kocwaningo);idatha yafakwa phakathi nosuku lwama-28. Izingane ezintathu ze-SOC-F zalahleka ukuze zilandelelwe. Ingqikithi yezingane/izinsuku zokubhekwa ze-SOC-F ne-SOC zaziyi-1560 kanye ne-1565, ngokulandelana, lapho ama-422 kanye nama-314 alaliswa esibhedlela.
Ngosuku lwe-2, isilinganiso (i-SD) se-sodium ye-plasma yabahlanganyeli be-SOC-F sasingu-137 mmol/L (4.6) ngokuqhathaniswa ne-136 mmol/L (3.7) kubahlanganyeli be-SOC;umehluko wesilinganiso +0.7 mmol/L (95% CI) -1.0 kuya +2.4) .Ngosuku 7, isilinganiso (SD) amanani sodium kwaba 136 mmol/L (4.2) kanye 139 mmol/L (3.3);umehluko wesilinganiso -2.9 mmol/L (95% CI -7.5 kuya +1.8) (Ithebula 2).
Ngosuku 2, ukugxila kwe-potassium yesilinganiso (SD) ku-SOC-F bekungaphansi kancane kunezingane ezisanda kuzalwa ze-SOC-F: 3.5 mmol/L (0.7) vs 3.9 mmol/L (0.7), umehluko -0.4 mmol/L ( 95% CI -0.7 kuya ku -0.1).Kwakungekho bufakazi bokuthi ezinye izilinganiso zaselabhorethri zihlukile phakathi kwamaqembu amabili (Ithebula 2).
Siqaphele ama-AE angama-35 kubahlanganyeli be-SOC-F abangama-25 kanye nama-AE angama-50 kubahlanganyeli abangama-SOC abangama-34;Imicimbi engu-2.2/izinsuku eziyi-100 zosana kanye nemicimbi engu-3.2/izinsuku eziyi-100 zosana, ngokulandelana: IRR 0.7 (95% CI 0.4 kuya ku-1.1), imicimbi ye-IRD -0.9/izinsuku eziyi-100 zosana (95% CI -2.1 kuya ku-+0.2, p=0.11).
Ama-SAE ayishumi nambili enzeka kubahlanganyeli be-SOC-F abangu-11 kanye nama-SAE angu-14 kubahlanganyeli be-SOC abangu-12 (imicimbi ye-SOC 0.8/100 yezinsuku zosana iqhathaniswa nemicimbi engu-1.0/izinsuku zosana eziyi-100; IRR 0.8 (95% CI 0.4 kuya ku-1.8) , IRnt/100 emicimbini engu-2. izinsuku (95% CI -0.9 kuya +0.5, p=0.59). I-Hypoglycemia kwakuyi-AE evame kakhulu (5 SOC-F kanye ne-6 SOC); 3 kwangu-4 eqenjini ngalinye 3 SOC-F kanye 4 ababambiqhaza babene-SOC emaphakathi noma enzima i-thrombocytopenia futhi bebeqhuba kahle ngaphandle kokumpontshelwa kwe-platelet ngosuku lwama-28. Abahlanganyeli abangu-13 be-SOC-F kanye ne-13 be-SOC babene-AE echazwe ngokuthi “okulindelekile” (Ithebula Lesengezo S5 ku-inthanethi) Abahlanganyeli abangu-3 be-SOC bavunyelwe kabusha (inyumoniya (n=2) nesifo se-febrile imvelaphi engaziwa (n=1)) Bonke bakhishwe ekhaya bephila Omunye umhlanganyeli we-SOC-F ube nokuqubuka okuncane kwe-perineal kanti omunye umhlanganyeli we-SOC-F waba nesifo sohudo esimaphakathi ezinsukwini eziyi-13 ngemuva kokukhishwa, kokubili kuxazululwe ngaphandle kokulandelana. Ama-AE axazululiwe futhi angu-27 axazululwa ngaphandle koshintsho noma ukulandelana okuxazululiwe (Ithebula Le-inthanethi Le-Supplementary S6). Awekho ama-AE ayehlobene nesidakamizwa socwaningo.
Okungenani isampula ye-PK ye-intravenous yaqoqwa kubahlanganyeli be-60. Abahlanganyeli abangamashumi amahlanu nanhlanu banikeze amasethi amasampula amane aphelele, futhi ababambiqhaza abangu-5 banikeze amasampula ayingxenye. 119 ye-fosfomycin yomlomo) kanye namasampula e-CSF angu-15 ahlaziywa.Awekho amasampula anamazinga e-fosfomycin angaphansi komkhawulo we-quantitation.32
Ukuthuthukiswa kwemodeli ye-PK yabantu kanye nemiphumela yokulingisa ichazwa ngokuningiliziwe kwenye indawo.32 Kafushane, imodeli ye-PK enamagumbi amabili enendawo eyengeziwe ye-CSF inikeze ukulingana okuhle kwedatha, ngokuvunyelwa kanye nevolumu endaweni enganyakazi kubahlanganyeli abajwayelekile (isisindo somzimba (isisindo somzimba) WT) 2805 g, iminyaka yangemva kokubeletha (PNA) usuku olungu-1, iminyaka yokuya esikhathini (PMA) amasonto angama-40) yayiyi-0.14 L/ihora (0.05 L/ihora/kg) kanye ne-1.07 L (0.38 L/kg), ngokulandelana. ukukhula kwe-allometric kanye nokuvuthwa kwe-PMA okulindelekile okusekelwe ekusebenzeni kwezinso31, i-PNA ihlotshaniswa nokukhuphuka kwemvume phakathi neviki lokuqala lokubeletha.Isilinganiso esisekelwe kumodeli se-oral bioavailability sasingu-0.48 (95% CI 0.35 kuya ku-0.78) kanti isilinganiso se-cerebrospinal fluid/plasma sasingu-0.32 (95% CI 0.27 kuya ku-0.41).
Umdwebo we-Online Supplementary Figure S2 ukhombisa amaphrofayili wesikhathi sokugxilisa wesimo se-plasma alingisiwe.Amanani 2 kanye no-3 athula Amathuba e-AUC of Target Attainment (PTA) wesibalo socwaningo (isisindo somzimba>1500 g): Imikhawulo ye-MIC ye-bacteriostasis, ilogi elingu-1 bulala, kanye nokuvimbela ukumelana, kusetshenziswa imingcele ye-MIC evela ezinganeni ezisanda kuzalwa ezincane.uma kucatshangelwa ukwanda okusheshayo kokuvunyelwa phakathi nesonto lokuqala lokuphila, ukulingisa kwaphinde kwahlukaniswa yi-PNA (Ithebula Le-Supplementary S7 ku-inthanethi).
Amathuba amagoli afinyelelwa nge-intravenous fosfomycin.Neonatal subpopulations.Iqembu 1: WT >1.5 kg +PNA ≤7 izinsuku (n=4391), Iqembu 2: WT >1.5 kg +PNA >7 days (n=2798), Group 3: WT ≤1.5 kg +PNA ≤7 Izinsuku (n=1534), Iqembu 4: WT ≤1.5 kg + PNA > izinsuku ezingu-7 (n=1277).Amaqembu 1 kanye ne-2 amele iziguli ezifanayo nalabo abahlangabezana nemibandela yethu yokufakwa.Amaqembu 3 kanye 4 simelela ukungezwani kwezingane ezisanda kuzalwa ezingakafundiwe emphakathini wethu.Lesi sibalo sangempela sadalwa ngu-ZK kulo mbhalo wesandla.BID, kabili nsuku zonke;IV, umjovo ngomjovo;I-MIC, ukugxila okuncane kokuvimbela;I-PNA, iminyaka yangemva kokubeletha;WT, isisindo.
Ithagethi engenzeka izuzwe ngemithamo ye-fosfomycin yomlomo.Ukwanda kwezingane ezisanda kuzalwa.Iqembu 1: WT >1.5 kg +PNA ≤7 izinsuku (n=4391), Iqembu 2: WT >1.5 kg +PNA > izinsuku ezingu-7 (n=2798), Iqembu 3: I-WT ≤1.5 kg +PNA ≤7 Izinsuku (n=1534), Iqembu 4: WT ≤1.5 kg + PNA > izinsuku ezingu-7 (n=1277).Amaqembu 1 kanye ne-2 amele iziguli ezifanayo nalabo abahlangabezana nemibandela yethu yokufakwa.Amaqembu 3 futhi u-4 umele ukukhishwa kwezingane ezisanda kuzalwa ngaphambi kwesikhathi kusetshenziswa idatha yangaphandle engafundwanga kubantu bakithi.Lesi sibalo sokuqala sadalwa ngu-ZK kulo mbhalo wesandla.BID, kabili nsuku zonke;I-MIC, ukugxila okuncane kokuvimbela;I-PNA, iminyaka yangemva kokubeletha;PO, ngomlomo;WT, isisindo.
Ezilwaneni ezine-MIC> 0.5 mg/L, ukucindezelwa kokumelana akuzange kufinyelelwe ngokuqhubekayo nanoma yiziphi izinhlobo zemithi yokudosa mbumbulu (Izibalo 2 kanye no-3). Ngo-100 mg/kg iv kabili ngosuku, i-bacteriostasis yatholwa nge-MIC engu-32 mg/L ye-100% PTA kuzo zonke izingqimba ezine zokuhlekisa (Umfanekiso 2) .Mayelana nokubulawa kwelogi ye-1, amaqembu 1 kanye ne-3 ene-PNA ≤7 izinsuku, i-PTA yayingu-0.84 kanye ne-0.96 ne-100 mg / kg iv kabili nsuku zonke futhi i-MIC yayiyi-32 mg/L, kodwa iqembu libe ne-PTA ephansi, i-0.19 kanye ne-0.60 ye-2 ne-4 PNA> izinsuku ezingu-7, ngokulandelana.Ku-150 no-200 mg / kg kabili ngosuku nge-intravenously, i-1-log kill PTA yayingu-0.64 kanye ne-0.90 yeqembu le-2 kanye no-0.91 kanye no-0.98 weqembu lesi-4, ngokulandelanayo.
Amanani we-PTA wamaqembu 2 no-4 ku-100 mg/kg ngomlomo kabili ngosuku ayengu-0.85 no-0.96, ngokulandelana (Umfanekiso 3), futhi amanani e-PTA kumaqembu 1-4 ayengu-0.15, 0.004, 0.41, kanye no-0.05 32 mg/L, ngokulandelana.Bulala ilogi elingu-1 ngaphansi kwe-MIC.
Sinikeze ubufakazi be-fosfomycin ku-100 mg/kg/dose kabili nsuku zonke ezinsaneni ezingenabo ubufakazi bokuphazamiseka kwe-plasma sodium (intravenous) noma isifo sohudo se-osmotic (ngomlomo) uma kuqhathaniswa ne-SOC.Inhloso yethu eyinhloko yokuphepha, ukuthola umehluko kumazinga e-sodium e-plasma phakathi amaqembu amabili okwelapha ngosuku lwe-2, ayenamandla anele ngokwanele.Nakuba usayizi wethu wesampula wawumncane kakhulu ukunquma umehluko phakathi kweqembu kwezinye izenzakalo zokuphepha, zonke izingane ezisanda kuzalwa zaziqashwe ngokucophelela futhi izenzakalo ezibikiwe zisiza ukunikeza ubufakazi bokusekela ukusetshenziswa okungenzeka kwe-fosfomycin kulokhu. inani labantu abathintekayo abane-sepsis ehlukile yokwelashwa kwe-empiric.Nokho, ukuqinisekiswa kwale miphumela kumaqoqo amakhulu futhi aqine kakhulu kuzobaluleka.
Sasihlose ukuqasha izingane ezisanda kuzalwa ≤ izinsuku ezingu-28 ubudala futhi asizange sikhethe ngokukhethayo okusolakala ukuthi i-sepsis esanda kuqala. Nokho, u-86% wezingane ezisanda kuzalwa walaliswa esibhedlela phakathi nesonto lokuqala lokuphila, okuqinisekisa umthwalo omkhulu wokugula kwengane yokuqala okubikwe kuma-LMIC afanayo.33 -36 Amagciwane abangela i-sepsis eqala ekuqaleni kanye nesephuzile (kuhlanganise ne-ESBL E. coli kanye ne-Klebsiella pneumoniae aye abonwa) kuma-empirical antimicrobials,37-39 angase atholakale ekubelethweni. njengoba ukwelashwa komugqa wokuqala kungathuthukisa imiphumela futhi kugweme ukusetshenziswa kwe-carbapenem.
Njengama-antimicrobial amaningi, i-40 PNA iyi-covariate eyinhloko echaza imvume ye-fosfomycin. Lo mphumela, ohlukile ku-GA nesisindo somzimba, umele ukuvuthwa okusheshayo kokuhlunga kwe-glomerular ngemva kokuzalwa. Endaweni, u-90% we-Enterobacteriaceae ehlaselayo ine-fosfomycin MIC ye-g3 /mL15, kanye nomsebenzi wokubulala amagciwane ungase udinge >100 mg/kg/dose emthanjeni ezinganeni ezisanda kuzalwa > izinsuku ezingu-7 (Umfanekiso 2). Okuhlosiwe okungu-32 µg/mL, uma i-PNA > izinsuku ezingu-7, kunconywa 150 mg/kg kabili ngosuku Uma isizinzile, uma kudingeka ukushintshelwa ku-fosfomycin yomlomo, umthamo ungakhethwa ngokusekelwe ku-WT esanda kuzalwa, i-PMA, i-PNA, kanye ne-pathogen MIC okungenzeka ukuthi iyi-pathogen, kodwa i-bioavailability ebikwe lapha kufanele icatshangelwe.Kudingeka ucwaningo ukuze kuqhutshekwe nokuhlolwa ukuphepha nokusebenza ngempumelelo kwalo mthamo ophezulu onconywe imodeli yethu ye-PK.
Isikhathi sokuthumela: Mar-16-2022