Injongo Ukuvavanya iziganeko ezimbi ezinxulumene ne-fosfomycin (AEs) kunye ne-pharmacokinetics kunye notshintsho kumanqanaba e-sodium kwiintsana ezine-sepsis yeklinikhi.
Phakathi kuka-Matshi 2018 kunye noFebruwari 2019, i-120 yeentsana ezineminyaka eyi-≤28 iintsuku zafumana unyango olusemgangathweni (SOC) lwe-antibiotics ye-sepsis: i-ampicillin kunye ne-gentamicin.
Ungenelelo ngoncedo Sabela ngokungenamkhethe isiqingatha sabathathi-nxaxheba ukuba bafumane i-fosfomycin eyongezelelweyo kwi-intravenous elandelwa yi-oral fosfomycin kwidosi ye-100 mg/kg kabini yonke imihla ngeentsuku ezisi-7 (SOC-F) kwaye ilandelwe ngeentsuku ezingama-28.
Iziphumo ze-61 kunye ne-59 yeentsana ezineminyaka eyi-0-23 iintsuku zabelwa kwi-SOC-F kunye ne-SOC, ngokulandelelana.Akukho bungqina bokuba i-fosfomycin inefuthe kwi-serum.sodiumokanye imiphumo emibi yesisu.Ngexesha le-1560 kunye ne-1565 yokujonga imihla yosana, siye saqaphela i-50 AEs kwi-25 abathathi-nxaxheba be-SOC-F kunye nabathathi-nxaxheba be-SOC be-34, ngokulandelanayo (i-2.2 vs 3.2 iziganeko / iintsuku ze-100 zentsana; umehluko wezinga -0.95 kwiziganeko ze-100 / iintsana ze-100 / iintsana eziyi-100 / i-1000 ) usuku (95% CI -2.1 ukuya ku-0.20)) .I-SOC-F ezine kunye nabathathi-nxaxheba abathathu be-SOC bafa.Ukusuka kwiisampuli ze-pharmacokinetic ze-238, imodeli ibonise ukuba abaninzi abantwana bafuna umthamo we-150 mg / kg nge-intravenously kabini imihla ngemihla ukuze bafezekise iinjongo ze-pharmacodynamic, kwaye kwiintsana <iintsuku ezi-7 ubudala okanye ubunzima <1500 g imihla ngemihla Umthamo wancitshiswa ukuya kwi-100 mg / kg kabini.
Izigqibo kunye nokuBandakanya IFosfomycin inonyango olufikelelekayo njengokhetho lonyango lwe-sepsis esandul' ukuvela kunye nerejimeni yedosi elula. Ukhuseleko lwayo lufuna ukuphononongwa ngakumbi kwiqela elikhulu labantwana abasandula ukusandul' ukusekwa esibhedlele, kubandakanywa iintsana ezingekafiki ixesha okanye izigulane ezigula kakhulu. ngokuchasene nezona zidalwa zibuthathaka, ngoko kuyacetyiswa ukuba usebenzise i-fosfomycin ngokudityaniswa nenye i-antibacterial agent.
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.
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Ukunganyangeki ngamayeza okubulala iintsholongwane kubeka isoyikiso kubomi babantwana abasanda kuzalwa kwaye kukho imfuneko engxamisekileyo yonyango olutsha olufikelelekayo.
Kukho umthwalo obalulekileyo we-sodium kunye ne-intravenous fosfomycin, kunye namalungiselelo omlomo we-fosfomycin aqukethe inani elikhulu le-fructose, kodwa kukho idatha yokhuseleko oluncinci kwiintsana.
Izindululo zabantwana kunye ne-neonatal dosing ye-intravenous fosfomycin ziyahluka, kwaye azikho iirejimeni zokudosa ngomlomo ezipapashiweyo.
I-intravenous kunye ne-oral fosfomycin kwi-100 mg / kg kabini imihla ngemihla, ngokulandelanayo, ayizange ibe nefuthe kwi-serum.sodiumokanye iziphumo ebezingalindelekanga zesisu.
Uninzi lwabantwana banokufuna i-intravenous fosfomycin 150 mg/kg kabini yonke imihla ukuze bafezekise iinjongo zokusebenza, kwaye kwiintsana ezingaphantsi kweentsuku ezisi-7 ubudala okanye ezinobunzima obungaphantsi kwe-1500 g, kwi-intravenous fosfomycin 100 mg/kg kabini yonke imihla.
I-Fosfomycin inamandla okudibanisa kunye nezinye ii-antimicrobials ukunyanga i-neonatal sepsis ngaphandle kokusetyenziswa kwe-carbapenems kwindawo yokunyuka kwe-antimicrobial resistance.
Ukunganyangeki kwe-Antimicrobial (AMR) kuchaphazela ngokungafaniyo abantu kumazwe anengeniso ephantsi kunye nephakathi (LMICs) .Ukuncitshiswa kokusweleka kweentsana kwakungaphantsi kubantwana abadala, kunye nekota ubuncinane yokufa kwe-neonatal okubangelwa ukusuleleka.1 I-AMR iyabandisa lo mthwalo, kunye ne-multidrug-resistant (MDR) pathogens ezibalelwa malunga ne-30% yokufa kwe-neonatal sepsis kwihlabathi jikelele.2
I-WHO icebisa ukuba i-ampicillin,ipenicillin, okanye i-cloxacillin (ukuba usulelo lwe-S. aureus lukrokrelwa) kunye ne-gentamicin (umgca wokuqala) kunye nesizukulwana sesithathu se-cephalosporins (umgca wesibini) kunyango lwe-empirical lwe-neonatal sepsis.3 Ngokuhamba kunye ne-beta-lactamase eyandisiweyo (ESBL) kunye i-carbapenemase, i-4 i-solotes yeklinikhi ivame ukuxelwa ukuba ayinandaba nale regimen.5 Ukugcinwa kwe-carbapenems kubalulekile kulawulo lwe-MDR, i-6 kunye nokubuyiselwa kwe-antibiotics yendabuko ikhuthazwa ukujongana nokungabikho kwe-antibiotics entsha efikelelekayo.7
I-Fosfomycin yi-non-proprietary phosphonic acid derivative ethathwe "ibalulekile" yi-WHO.8 I-Fosfomycin i-bactericidal9 kwaye ibonisa umsebenzi ochasene ne-Gram-positive kunye ne-Gram-negative bacteria, kubandakanywa i-methicillin-resistant Staphylococcus aureus, i-vancomycin-resistant, i-Enterococus abavelisi kwaye banokungena kwi-biofilm.10 I-Fosfomycin ibonise i-vitro synergy kunye ne-aminoglycosides kunye ne-carbapenems 11 12 kwaye isetyenziswa ngokuqhelekileyo kubantu abadala abane-MDR ye-urinary tract infections.13
Okwangoku kukho iingcebiso eziphikisanayo malunga ne-dosing ye-intravenous fosfomycin kwi-pediatrics, ukusuka kwi-100 ukuya kwi-400 mg / kg / ngosuku, kungekho mveliso yomlomo epapashiweyo. Izifundo ezine ze-neonatal ziqikelelwa ukuphelisa i-half-life ye-2.4-7 iiyure emva kokulawulwa kwe-intravenous I-25-50 mg / kg.14 I-15 i-protein ebophelelayo yayincinci, kwaye ukugxininiswa okuphezulu kwakuhambelana nedatha yabantu abadala.16 I-17 Imiphumo ye-bactericidal yayicatshangelwa ukuba idibaniswe nokuba ixesha elingaphezulu kweyona ndawo iphantsi kwe-inhibitory concentration (MIC) 16 okanye indawo ephantsi kwejika. (AUC):Umlinganiselo we-MIC.18 19
Iingxelo ze-84 ezipheleleyo ze-neonates ezifumana i-intravenous fosfomycin kwi-120-200 mg / kg / ngosuku zibonise ukuba zinyamezeleke kakuhle.20-24 I-Toxicity ibonakala iphantsi kubantu abadala kunye nabantwana abadala.25 Nangona kunjalo, i-fosfomycin yomzali iqukethe i-14.4 mmol / I-330 mg ye-sodium ngegram-inkxalabo ekhuselekileyo yokhuseleko kwiintsana ezisanda kuzalwa i-sodium reabsorption iphikisana ngokungafaniyo ne-gestational age (GA) .26 Ukongezelela, i-fosfomycin yomlomo iqulethe umthwalo ophezulu we-fructose (~ 1600 mg / kg / ngosuku), enokubangela ukuba isisu sesisu siphume. iziphumo ebezingalindelekanga kwaye zichaphazela ibhalansi yolwelo.27 28
Sijonge ukuvavanya i-pharmacokinetics (i-PK) kunye notshintsho lwezinga le-sodium kwi-clinical sepsis neonates, kunye neziganeko ezimbi (AEs) ezinxulumene ne-intravenous elandela i-fosfomycin yomlomo.
Senze uvavanyo oluvulekileyo olulawulwa ngokungahleliwe ngokuthelekisa umgangatho wokunyamekela (i-SOC) i-antibiotics yodwa kunye ne-SOC kunye ne-IV elandelwa yi-fosfomycin yomlomo kwiintsana ezine-sepsis yekliniki kwiSibhedlele sase-Kilifi County (KCH), eKenya.
Zonke iintsana ezisanda kuzalwa ezingeniswe kwi-KCH zihlolwe.Iinqobo zokufakwa kwezi zilandelayo: ubudala ≤28 iintsuku, ubunzima bomzimba> 1500 g, ukukhulelwa> iiveki ze-34, kunye nemilinganiselo ye-antibiotics ye-intravenous kwi-WHO3 kunye nezikhokelo zaseKenya29. Ukuba i-CPR ifunekayo, iBanga lesi-3 le-hypoxic-ischemic encephalopathy, I-30 ye-sodium ≥150 mmol / L, i-creatinine ≥150 µmol / L, i-jaundice efuna utshintshiselwano, i-allergies okanye i-contraindication kwi-fosfomycin, isibonakaliso esithile solunye udidi lwe-antibiotics isifo, umntwana osanda kuzalwa akazange afakwe kwesinye isibhedlele okanye kungekhona kwi-Kilifi County (Umfanekiso 1). ).
Zama i-flowchart.Lo mzobo wokuqala wenziwa yi-CWO kulo mbhalo-ngqangi.CPR, ukuvuselela i-cardiopulmonary;I-HIE, i-hypoxic-ischemic encephalopathy;IV, ngokufakwa emithanjeni;I-SOC, umgangatho wokhathalelo;I-SOC-F, umgangatho wokhathalelo kunye nefosfomycin.*Oonobangela baquka umama (46) okanye ukugula kakhulu (6) emva kotyando, ukukhutshwa esibhedlele (3), ukukhutshwa ngokuchasene nengcebiso (3), ukulahlwa ngumama (1) kunye nokuthatha inxaxheba olunye uphononongo (1).†Omnye umthathi-nxaxheba we-SOC-F usweleke emva kokugqiba ukulandelelwa (uSuku lwe-106).
Abathathi-nxaxheba babhaliswe kwiiyure ze-4 zedosi yokuqala ye-antibiotics ye-SOC kude kube ngoSeptemba 2018, xa izilungiso zeprotocol zandisa oku kwiiyure ze-24 ukubandakanya ukungeniswa ebusuku.
Abathathi-nxaxheba babelwa (1: 1) ukuba baqhubeke kwi-SOC antibiotics yedwa okanye ukufumana i-SOC kunye (ukuya kuthi ga) iintsuku ze-7 ze-fosfomycin (SOC-F) usebenzisa ishedyuli ye-randomization kunye nobukhulu obungahleliweyo bebhloko (i-Supplementary Figure S1 kwi-intanethi) .Ifihliwe ngokulandelelana iimvulophu ezinenombolo ezivaliweyo ezivaliweyo.
Ngokwe-WHO kunye nezikhokelo zabantwana baseKenya, ii-SOCs ziquka i-ampicillin okanye i-cloxacillin (ukuba kukrokrelwa ukuba usulelo lwe-staphylococcal) kunye ne-gentamicin njengamayeza onyango lokuqala, okanye i-cephalosporins yesizukulwana sesithathu (umzekelo, i-ceftriaxone) njengezibulala-ntsholongwane zodidi lwesibini.3 29 -F nayo ifumene i-intravenous fosfomycin ubuncinane ubuncinane iiyure ze-48, ukutshintshela emlonyeni xa ukutya okwaneleyo kunyamezelwa ukuba kuthathwe ngokufanelekileyo kweyeza lomlomo.I-Fosfomycin (i-intravenous okanye yomlomo) yayilawulwa ngeentsuku ze-7 okanye ide ikhuphe, nayiphi na into eyenzekayo kuqala.Fomicyt 40 mg / mL i-fosfomycin isisombululo se-sodium ye-intravenous infusion (i-Infectopharm, eJamani) kunye ne-Fosfocin 250 mg / 5 mL i-fosfomycin yokumisa i-calcium yokulawula ngomlomo (i-Laboratorios ERN, eSpain) kabini imihla ngemihla kunye ne-100 mg / kg / idosi elawulwayo.
Abathathi-nxaxheba balandelwa iintsuku ze-28. Bonke abathathi-nxaxheba babenyamekelwa kwiyunithi efanayo exhomekeke kakhulu ukulawula ukubekwa esweni kwe-AE. Ubalo olupheleleyo lwegazi kunye ne-biochemistry (kubandakanywa ne-sodium) zenziwa ekungenweni, iintsuku ze-2, kunye ne-7, kwaye ziphinda ziphindwe ukuba zibonakaliswe yiklinikhi.AEs zikhowudwa ngokwe-MedDRA V.22.0.Ubunzima bahlelwa ngokwe-DAIDS V.2.1.AEs zalandelwa de kwathathwa isigqibo seklinikhi okanye kujongwa ukuba zingapheliyo kwaye zizinzile ngexesha lonyango. kolu luntu, kubandakanywa ukuwohloka okunokwenzeka ekuzalweni (iprotocol kwifayile eyoNgezelelweyo 1 kwi-intanethi).
Emva kwe-IV yokuqala kunye ne-fosfomycin yokuqala yomlomo, izigulane ezabelwe i-SOC-F zaye zahlelwa ngokukhawuleza (5, 30, okanye imizuzu engama-60) kunye nenye emva kwexesha (i-2, i-4, okanye i-8 iyure) isampuli ye-PK.Isampuli yesihlanu engabonakaliyo yaqokelelwa. kubathathi-nxaxheba ababesesibhedlele ngosuku lwe-7.Iisampulu ze-cerebrospinal fluid (CSF) ezikhethiweyo ziqokelelwe kwi-kliniki ebonakaliswe kwi-lumbar puncture (LP) .Isampula yokucubungula kunye nemilinganiselo ye-fosfomycin ichazwe kwifayile ye-Supplementary 2 kwi-intanethi.
Sihlolisise idatha yokungeniswa phakathi kwe-2015 kunye ne-2016 kwaye sibale ukuba umxholo we-sodium ophakathi kwe-1785 yeentsana ezinobunzima> 1500 g yayingu-139 mmol / L (SD 7.6, uluhlu lwe-106-198) .Ngaphandle kwe-132 yeentsana ezine-serum sodium> 150 mmol / L (yethu imilinganiselo yokukhutshwa), i-1653 eseleyo ye-neonates inomlinganiselo we-sodium ye-137 mmol / L (SD 5.2) .Isampuli yesampula ye-45 kwiqela ngalinye yabalwa ukuze kuqinisekiswe ukuba umehluko we-5 mmol / L kwi-sodium ye-plasma ngosuku lwe-2 ingabalwa. inqunywe nge> 85% amandla asekelwe kwidatha yendawo yangaphambili yokusabalalisa isodium.
Kwi-PK, ubungakanani besampula ye-45 enikeziweyo> i-85% amandla okuqikelela iiparitha ze-PK zokucoca, umthamo wokusabalalisa, kunye ne-bioavailability, kunye ne-95% ye-CIs eqikelelwa ngokusebenzisa ukulinganisa ngokuchaneka kwe-≥20%. isetyenzisiwe, ukulinganisa ubudala kunye nobukhulu kubantwana abasandul 'ukuzalwa, ukongeza i-odolo yokuqala kunye ne-bioavailability ecingelwa ukuba i-bioavailability.31 Ukuvumela iisampulu ezilahlekileyo, sijolise ekufuneni abantwana abangama-60 kwiqela ngalinye.
Ukwahluka kwimilinganiselo yesiseko kuhlolwe kusetyenziswa uvavanyo lwe-χ2, uvavanyo lwe-t-test yoMfundi, okanye uvavanyo lwe-Wilcoxon lwe-rank-sum.Ukwahluka kweentsuku ze-2 kunye nosuku lwe-7 ye-sodium, i-potassium, i-creatinine, kunye ne-alanine aminotransferase yavavanywa ngokusebenzisa uhlalutyo lwe-covariance ehlengahlengisiweyo kwimilinganiselo yesiseko. Kwii-AEs, iziganeko ezibi kakhulu (ii-SAEs), kunye nokuchasana kweziyobisi, sasebenzisa i-STATA V.15.1 (i-StataCorp, iSikhululo seKholeji, eTexas, eU.SA).
Uqikelelo olusekelwe kwimodeli yee-parameters ze-PK zenziwa kwi-NONMEM V.7.4.32 usebenzisa uqikelelo lwemiqathango yokuqala kunye nokusebenzisana, iinkcukacha ezipheleleyo zophuhliso lwemodeli ye-PK kunye nokulinganisa kunikwe kwenye indawo.32
Ukuhlolwa kwendawo kwenziwa yi-DNDi/GARDP, ngokongamela okubonelelwa yikomiti ezimeleyo yokhuseleko lwedatha kunye nekomiti yokubeka iliso.
Phakathi kwe-19 kaMatshi ngo-2018, kunye noFebruwari 6, 2019, kwabhaliswa abantwana abasanda kuzalwa abayi-120 (61 SOC-F, 59 SOC) (umzobo 1), kubo abangama-42 (35%) babhaliswa phambi kohlaziyo lweprotocol.Iqela.Median (IQR) ubudala, ubunzima kunye ne-GA yayiyi-1 imini (IQR 0-3), 2750 g (2370-3215) kunye neeveki ezingama-39 (38-40), ngokulandelanayo.Iimpawu zesiseko kunye neeparamitha zebhubhoratri zichazwe kwiThebhile 1 kwaye Itheyibhile eyoNgezelelweyo ye-intanethi ye-S1.
I-Bacteremia yafunyanwa kwiintsana ezimbini (i-Supplementary Table S2 kwi-intanethi) .2 ye-55 yeentsana ezifumene i-LP zine-meningitis eqinisekisiwe yasebhubhoratri (i-Streptococcus agalactiae bacteremia kunye ne-CSF leukocytes ≥20 iiseli / µL (SOC-F); i-positive Streptococcus anti pneumoniae kunye ne-CSF leukocytes ≥ iiseli ze-20 / µL (SOC)).
Omnye umntwana osanda kuzalwa we-SOC-F wafumana ngokungalunganga kuphela ii-antimicrobial ze-SOC kwaye akazange afakwe kuhlalutyo lwe-PK. Ii-SOC-F ezimbini kunye ne-SOC Neonatal enye irhoxise imvume - kubandakanywa idatha yokurhoxiswa kwangaphambili. Bonke kodwa abathathi-nxaxheba ababini be-SOC (i-cloxacillin kunye ne-gentamicin ) kunye ne-ceftriaxone (n=1)) ifumene i-ampicillin kunye ne-gentamicin ekumkelwe. ukuya kunyango lodidi lwesibini ngenxa yokwanda kweklinikhi okanye i-meningitis, abahlanu kubo babephambi kwesampulu yesine ye-PK (iTheyibhile eyoNgezelelweyo ye-S3 kwi-intanethi). Lilonke, abathathi-nxaxheba be-60 bafumana ubuncinane idosi ye-intravenous ye-fosfomycin kwaye i-58 yafumana ubuncinane idosi yomlomo.
Abathandathu (abane be-SOC-F, ababini be-SOC) abathathi-nxaxheba bafa esibhedlele (Umfanekiso 1) . Omnye umthathi-nxaxheba we-SOC wafa emva kweentsuku ze-3 emva kokukhutshwa (usuku lwe-22) . I-106 (ngaphandle kokulandelwa kwezifundo);idatha ifakwe ngosuku lwe-28. Iintsana ezintathu ze-SOC-F zalahleka ukuba zilandelele. Iintsana ezipheleleyo / iintsuku zokuqwalaselwa kwe-SOC-F kunye ne-SOC ziyi-1560 kunye ne-1565, ngokulandelanayo, apho i-422 kunye ne-314 yalala esibhedlele.
Ngomhla we-2, i-SD (i-SD) ixabiso le-sodium ye-plasma kubathathi-nxaxheba be-SOC-F ngu-137 mmol / L (4.6) ngokubhekiselele kwi-136 mmol / L (3.7) kubathathi-nxaxheba be-SOC;Umehluko ophakathi + 0.7 mmol / L (95% CI) -1.0 ukuya + 2.4) .Ngomhla we-7, ixabiso le-sodium eliphakathi (SD) laliyi-136 mmol / L (4.2) kunye ne-139 mmol / L (3.3);umahluko ophakathi -2.9 mmol / L (95% CI -7.5 ukuya +1.8) (Itheyibhile 2).
Ngomhla we-2, intsingiselo (SD) i-potassium igxininise kwi-SOC-F yayingaphantsi kancinci kuneentsana 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 ukuya -0.1).Kwakungekho bungqina bokuba ezinye iiparamitha zebhubhoratri zahluke phakathi kwamaqela amabini (Itheyibhile 2).
Siqaphele ii-35 ze-AEs kwi-25 abathathi-nxaxheba be-SOC-F kunye ne-50 AEs kubathathi-nxaxheba be-SOC be-34;Iziganeko ze-2.2 / iintsuku ze-100 zentsana kunye neziganeko ze-3.2 / iintsuku ze-100 zentsana, ngokulandelanayo: IRR 0.7 (95% CI 0.4 ukuya ku-1.1), iziganeko ze-IRD -0.9 / iintsuku ze-100 zentsana (95% CI -2.1 ukuya +0.2, p = 0.11).
I-SAEs ezilishumi elinesibini zenzeke kubathathi-nxaxheba be-SOC-F abali-11 kunye ne-14 SAEs kubathathi-nxaxheba be-SOC be-12 (iziganeko ze-SOC 0.8 / iintsuku ze-100 zentsana vs iziganeko ze-1.0 / iintsuku ze-100 zentsana; IRR 0.8 (95% CI 0.4 ukuya ku-1.8) , i-IRnt / 100 iziganeko. iintsuku (95% CI -0.9 ukuya +0.5, p=0.59).I-Hypoglycemia yayiyeyona ixhaphakileyo i-AE (5 SOC-F kunye ne-6 SOC);I-3 ye-4 kwiqela ngalinye i-3 SOC-F kunye ne-4 abathathi-nxaxheba be-SOC babenomlinganiselo ophakathi okanye onzima. I-thrombocytopenia kwaye babeqhuba kakuhle ngaphandle kokutofelwa kweplatelet ngosuku lwe-28. I-13 ye-SOC-F kunye ne-13 abathathi-nxaxheba be-SOC babene-AE echazwe "njengokulindelekileyo" (iTheyibhile eyoNgezelelweyo ye-S5 kwi-intanethi) Abathathi-nxaxheba be-SOC be-3 baphinda bamkelwa (inyumoniya (n = 2) kunye nesifo se-febrile engaziwayo imvelaphi (n=1)) Bonke baye bakhululwa ekhaya bephila Omnye umthathi-nxaxheba we-SOC-F wayenerhashalala ephakathi kunye nomnye umthathi-nxaxheba we-SOC-F wayenorhudo oluphakathi kwiintsuku ezili-13 emva kokuphuma komchamo, zombini zisonjululwe ngaphandle kokulandelelana. Ii-AEs zasonjululwa kwaye ezingama-27 zasonjululwa kungekho tshintsho okanye ulandelelwano lwasonjululwa (kwi-intanethi eyoNgezelelweyo kwiTheyibhile S6)..
Ubuncinci isampula ye-PK ye-intravenous iqokelelwe kubathathi-nxaxheba be-60. Abathathi-nxaxheba abangamashumi amahlanu anesihlanu banikezela iiseti ezine zesampula ezipheleleyo, kwaye abathathi-nxaxheba be-5 banikezela ngeesampuli eziyingxenye. I-119 ye-fosfomycin yomlomo) kunye neesampuli ze-CSF ze-15 zahlaziywa.Akukho sampuli zinezinga le-fosfomycin elingaphantsi komda wobungakanani.32
Uphuhliso lwemodeli ye-PK yabemi kunye neziphumo zokulinganisa zichazwe ngokweenkcukacha kwenye indawo.32 Ngokufutshane, imodeli ye-PK ye-compartment ezimbini kunye ne-CSF compartment eyongezelelweyo inikezela ngokufanelekileyo kwidatha, kunye nokukhutshwa kunye nomthamo kwimeko ezinzileyo kubathathi-nxaxheba abaqhelekileyo (ubunzima bomzimba (ubunzima bomzimba) I-WT) i-2805 g, ubudala bokuzala (i-PNA) usuku lwe-1, ubudala be-postmenstrual (PMA) iiveki ze-40) zaziyi-0.14 L / iyure (0.05 L / iyure / kg) kunye ne-1.07 L (0.38 L / kg), ngokulandelanayo.Ngaphezu kokusisigxina. ukukhula kwe-allometric kunye nokulindeleka kokuvuthwa kwe-PMA esekelwe kwi-renal function31, i-PNA ihambelana nokunyuka kwemvume ngexesha leveki yokuqala yokubeleka.Uqikelelo olusekelwe kumzekelo we-bioavailability yomlomo ngu-0.48 (95% CI 0.35 ukuya kwi-0.78) kunye ne-cerebrospinal fluid / plasma ratio yi-0.32 (95% CI 0.27 ukuba 0.41).
Umzobo owoNgezelelweyo kwi-Intanethi u-S2 ubonisa iprofayili yexesha loxinaniso lwe-plasma elinganisiweyo ezinzileyo. Umfanekiso wesi-2 kunye no-3 ubonisa i-AUC enokwenzeka yokuFumaneka ekujoliswe kuyo (PTA) kuluntu lophononongo (ubunzima bomzimba> 1500 g): imiqobo ye-MIC ye-bacteriostasis, i-1-log ukubulala, kunye nokuthintela ukuxhathisa, usebenzisa i-MIC thresholds ukusuka kwiintsana ezincinci.idatha ukuba infer.Ngenxa yokunyuka okukhawulezayo kokucocwa kwiveki yokuqala yobomi, ukulinganisa kwagqitywa ngakumbi yi-PNA (i-Supplementary Table S7 online).
Iinjongo ezinokwenzeka eziphunyeziweyo nge-intravenous fosfomycin.Neonatal subpopulations.Iqela 1: WT >1.5 kg +PNA ≤7 iintsuku (n=4391), Iqela 2: WT >1.5 kg +PNA>7 iintsuku (n=2798), Iqela 3: WT ≤1.5 kg + PNA ≤7 Iintsuku (n = 1534), Iqela 4: WT ≤1.5 kg + PNA > iintsuku ezi-7 (n = 1277) .Amaqela e-1 kunye ne-2 amele izigulane ezifanayo nezo zidibene nemigaqo yethu yokubandakanywa. Amaqela 3 kunye I-4 imele i-extrapolations kwiintsana ezingafundiweyo zangaphambi kwexesha kuluntu lwethu.Lo mzobo wokuqala wenziwa ngu-ZK kulo mbhalo-ngqangi.BID, kabini yonke imihla;IV, inaliti emithanjeni;I-MIC, i-concentration encinci ye-inhibitory;I-PNA, iminyaka yasemva kokubeleka;WT, ubunzima.
Ithagethi enokwenzeka iphunyeziwe ngeedosi zomlomo zefosfomycin.Ukwanda kwabantwana abasandul’ ukusekwa.Iqela 1: WT >1.5 kg +PNA ≤7 iintsuku (n=4391), Iqela 2: WT >1.5 kg +PNA>7 iintsuku (n=2798), Iqela 3: I-WT ≤1.5 kg + PNA ≤7 Iintsuku (n = 1534), Iqela le-4: WT ≤1.5 kg + PNA > iintsuku ezi-7 (n = 1277) kwaye i-4 imele i-extrapolation ye-preterm neonates usebenzisa idatha yangaphandle engafundwanga kuluntu lwethu.Lo mzobo wokuqala wenziwa ngu-ZK kulo mbhalo wesandla.BID, kabini imihla ngemihla;I-MIC, i-concentration encinci ye-inhibitory;I-PNA, iminyaka yasemva kokubeleka;PO, ngomlomo;WT, ubunzima.
Kwizinto eziphilayo ezine-MIC> 0.5 mg / L, ukunyanzeliswa kokuxhatshazwa akuzange kuphunyezwe ngokuqhubekayo kunye naluphi na uhlobo lwe-dosing dosing regimens (Amanani 2 kunye ne-3) . Nge-100 mg / kg iv kabini imihla ngemihla, i-bacteriostasis yafunyanwa nge-MIC ye-32 mg / L. ye-100% ye-PTA kuzo zonke iileyile ezine ezihlekisayo (Umfanekiso 2) . Ngokumalunga ne-1-log yokubulala, kumaqela e-1 kunye ne-3 kunye ne-PNA ≤7 iintsuku, i-PTA yayiyi-0.84 kunye ne-0.96 kunye ne-100 mg / kg iv kabini imihla ngemihla kwaye i-MIC yayiyi-32 mg / L, kodwa iqela libe ne-PTA ephantsi, i-0.19 kunye ne-0.60 ye-2 kunye ne-4 PNA> iintsuku ze-7, ngokulandelanayo. Kwi-150 kunye ne-200 mg / kg kabini imihla ngemihla nge-intravenously, i-1-log yokubulala i-PTA yayingu-0.64 kunye ne-0.90 yeqela le-2 kunye no-0.91 kunye no-0.98 kwiqela lesi-4, ngokulandelelanayo.
Amaxabiso e-PTA kumaqela 2 kunye ne-4 kwi-100 mg / kg ngomlomo kabini imihla ngemihla yayiyi-0.85 kunye ne-0.96, ngokulandelanayo (Umfanekiso 3), kunye nexabiso le-PTA kumaqela 1-4 yayiyi-0.15, 0.004, 0.41, kunye ne-0.05 32 mg / L, ngokulandelanayo.Bulala i-1-log phantsi kwe-MIC.
Sinike ubungqina be-fosfomycin kwi-100 mg / kg / i-dose kabini imihla ngemihla kwiintsana ezingenabo ubungqina be-plasma ye-sodium disturbance (intravenous) okanye i-osmotic diarrhea (ngomlomo) xa kuthelekiswa ne-SOC.Injongo yethu ephambili yokhuseleko, ukufumanisa umehluko kumanqanaba e-sodium ye-plasma phakathi Amaqela amabini onyango ngosuku lwe-2, anikwe amandla ngokwaneleyo.Nangona ubungakanani bethu besampulu babuncinci kakhulu ukumisela ukuhlukana phakathi kweqela kwezinye iziganeko zokhuseleko, zonke iintsana zibekwe iliso elibukhali kwaye iziganeko ezixeliweyo zinceda ukunika ubungqina bokuxhasa ukusetyenziswa kwefosfomycin kule nto. Inani labantu abanokuchaphazeleka kunye ne-sepsis yonyango olulolunye lwe-empiric. Nangona kunjalo, ukuqinisekiswa kwezi ziphumo kumaqela amakhulu kunye nobunzima kakhulu kuya kubaluleka.
Sijolise ekufuneni abantwana abasandul 'ukuzalwa ≤28 iintsuku zeminyaka kwaye asizange sikhethe ukukrokrelwa ekuqaleni kwe-sepsis.Nangona kunjalo, i-86% yeentsana zalaliswa esibhedlele kwiveki yokuqala yobomi, eqinisekisa umthwalo ophezulu wokugula kwangaphambi komntwana ochazwe kwi-LMICs efanayo.33 -I-36 Pathogens ezibangela ukuqala kwangaphambili kunye ne-sepsis yokuqala emva kwexesha (kubandakanywa ne-ESBL E. coli kunye ne-Klebsiella pneumoniae ziye zabonwa) kwii-antimicrobials ezinobungqina, i-37-39 inokufumaneka kwi-obstetrics. njengoko unyango lokuqala lunokuphucula iziphumo kwaye lugweme ukusetyenziswa kwe-carbapenem.
Njengamachiza amaninzi okulwa neentsholongwane, i-40 PNA yi-covariate engundoqo echaza ukukhutshwa kwe-fosfomycin. Esi siphumo, esahlukileyo kwi-GA kunye nobunzima bomzimba, simele ukuvuthwa ngokukhawuleza kwe-glomerular filtration emva kokuzalwa.Ekuhlaleni, i-90% ye-Enterobacteriaceae ehlaselayo ine-fosfomycin MIC ye-g3 /mL15, kunye nomsebenzi we-bactericidal unokufuna >100 mg/kg/dose emithanjeni kubantwana abasanda kuzalwa>iintsuku ezisi-7 (Figure 2) Unyango lwe-intravenous.Xa uzinzisiwe, ukuba kufuneka kutshintshelwe kwi-fosfomycin yomlomo, umthamo unokukhethwa ngokusekelwe kwi-WT yosana, i-PMA, i-PNA, kunye ne-MIC ye-pathogen enokwenzeka, kodwa i-bioavailability echazwe apha kufuneka ithathelwe ingqalelo.Izifundo ziyafuneka ukuvavanya ngakumbi ukhuseleko kunye nokusebenza kakuhle kweli thamo liphezulu elicetyiswa yimodeli yethu ye-PK.
Ixesha lokuposa: Mar-16-2022