Lub Hom Phiaj Los soj ntsuam fosfomycin-related adverse events (AEs) and pharmacokinetics and change in sodium level in neonates with clinical sepsis.
Thaum Lub Peb Hlis 2018 txog Lub Ob Hlis 2019, 120 tus menyuam mos uas muaj hnub nyoog qis dua 28 hnub tau txais cov qauv kev saib xyuas (SOC) tshuaj tua kab mob rau sepsis: ampicillin thiab gentamicin.
Kev cuam tshuam Peb tau muab ib nrab ntawm cov neeg tuaj koom kom tau txais cov tshuaj fosfomycin ntxiv rau hauv qhov ncauj nrog fosfomycin ntawm qhov ncauj ntawm koob tshuaj 100 mg / kg ob zaug ib hnub rau 7 hnub (SOC-F) thiab ua raws li 28 hnub.
Cov txiaj ntsig 61 thiab 59 tus me nyuam mos hnub nyoog 0-23 hnub tau raug xa mus rau SOC-F thiab SOC, raws li.Tsis muaj pov thawj tias fosfomycin muaj kev cuam tshuam rau cov ntshav.sodiumlos yog kev mob plab hnyuv.Nyob rau lub sijhawm 1560 thiab 1565 cov menyuam mos-hnub soj ntsuam, peb pom 50 AEs hauv 25 SOC-F cov neeg koom thiab 34 SOC cov neeg koom, raws li (2.2 vs 3.2 txheej xwm / 100 hnub menyuam mos; qhov sib txawv -0.95 cov xwm txheej / 100 tus menyuam mos ) hnub (95% CI -2.1 txog 0.20)). Plaub SOC-F thiab peb tus neeg koom SOC tau tuag. Los ntawm 238 cov qauv tshuaj pharmacokinetic, kev ua qauv qhia tau hais tias feem ntau cov menyuam yaus yuav tsum tau txhaj koob tshuaj 150 mg / kg intravenously ob zaug ib hnub kom ua tiav cov hom phiaj pharmacodynamic, thiab rau cov menyuam mos uas muaj hnub nyoog qis dua 7 hnub lossis hnyav <1500 g txhua hnub Cov koob tshuaj tau txo qis rau 100 mg / kg ob zaug.
Cov Lus Qhia thiab Qhov Tseem Ceeb Fosfomycin muaj peev xwm ua tau raws li kev kho mob pheej yig rau cov menyuam mos uas muaj kab mob sepsis nrog kev siv tshuaj yooj yim.Nws txoj kev nyab xeeb yuav tsum tau kawm ntxiv nyob rau hauv ib pawg loj ntawm cov menyuam mos hauv tsev kho mob, suav nrog cov menyuam mos yug ntxov heev lossis cov neeg mob hnyav.Kev tiv thaiv tsuas yog ua tiav. tiv thaiv cov kab mob rhiab tshaj plaws, yog li nws raug pom zoo kom siv fosfomycin ua ke nrog lwm cov tshuaj tua kab mob.
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.
Nov yog ib tsab xov xwm qhib tau muab faib raws li Creative Commons Attribution 4.0 Unported (CC BY 4.0) daim ntawv tso cai, uas tso cai rau lwm tus luam tawm, rov faib dua, rov ua dua, hloov pauv, thiab tsim cov haujlwm no rau txhua lub hom phiaj, yog tias nws raug suav hais tias yog cov haujlwm qub. tau muab, ib qhov txuas mus rau daim ntawv tso cai, thiab qhia txog seb puas tau hloov pauv.Saib: https://creativecommons.org/licenses/by/4.0/.
Antimicrobial tsis kam ua rau muaj kev hem thawj rau kev ciaj sia ntawm cov menyuam yug tshiab thiab muaj kev xav tau sai rau cov kev xaiv kho tshiab pheej yig.
Muaj ib qho tseem ceeb ntawm sodium lub nra nrog fosfomycin intravenous, thiab qhov ncauj fosfomycin npaj muaj ntau ntawm fructose, tab sis muaj tsawg cov ntaub ntawv kev nyab xeeb nyob rau hauv neonates.
Cov lus pom zoo rau kev siv tshuaj rau menyuam yaus thiab menyuam yug tshiab rau kev txhaj tshuaj fosfomycin sib txawv, thiab tsis muaj kev tshaj tawm kev noj tshuaj ntawm qhov ncauj.
Cov tshuaj fosfomycin hauv qhov ncauj thiab qhov ncauj ntawm 100 mg / kg ob zaug ib hnub, raws li, tsis muaj kev cuam tshuam rau cov ntshav.sodiumlos yog mob plab hnyuv.
Feem ntau cov menyuam yaus yuav tsum tau txhaj tshuaj fosfomycin 150 mg / kg ob zaug ib hnub kom ua tiav cov hom phiaj ua tau zoo, thiab rau cov menyuam yaus hnub nyoog qis dua 7 hnub lossis hnyav <1500 g, txhaj tshuaj fosfomycin 100 mg / kg ob zaug ib hnub.
Fosfomycin muaj peev xwm ua ke nrog lwm cov tshuaj tua kab mob los kho cov kab mob neonatal sepsis yam tsis tas siv cov carbapenems hauv kev teeb tsa cov tshuaj tiv thaiv kab mob ntau ntxiv.
Cov tshuaj tiv thaiv kab mob tiv thaiv kab mob (AMR) cuam tshuam tsis zoo cuam tshuam rau cov pej xeem hauv cov tebchaws tau nyiaj tsawg thiab nruab nrab (LMICs).Qhov kev txo qis hauv cov menyuam yaus hnub nyoog qis dua qis dua cov menyuam loj, nrog tsawg kawg ib feem peb ntawm cov menyuam mos tuag vim yog kis kab mob.1 AMR ua rau lub nra hnyav dua, nrog multidrug-resistant (MDR) cov kab mob suav txog kwv yees li 30% ntawm cov menyuam mos uas muaj tus mob sepsis tuag thoob ntiaj teb.2
LEEJ TWG pom zoo kom ampicillin,penicillin, los yog cloxacillin (yog S. aureus kab mob) ntxiv rau gentamicin (thawj-kab) thiab thib peb tiam cephalosporins (thib-kab) rau kev kho empirical ntawm neonatal sepsis.3 Nrog rau ncua-spectrum beta-lactamase (ESBL) thiab carbapenemase, 4 qhov chaw kho mob cais feem ntau tau tshaj tawm tias tsis hnov tsw rau qhov kev tswj hwm no.5 Kev tuav pov hwm carbapenems yog qhov tseem ceeb rau kev tswj hwm MDR, 6 thiab rov muab cov tshuaj tua kab mob tshiab tau tawm tswv yim los daws qhov tsis muaj cov tshuaj tua kab mob pheej yig tshiab.7
Fosfomycin yog cov khoom siv tsis yog phosphonic acid derivative uas tau suav tias yog "tseem ceeb" los ntawm WHO.8 Fosfomycin yog cov kab mob bactericidal9 thiab nthuav tawm cov kab mob Gram-positive thiab Gram-negative, suav nrog methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enteroc. cov neeg tsim khoom thiab tuaj yeem nkag mus rau biofilm.10 Fosfomycin tau qhia hauv vitro kev sib koom ua ke nrog aminoglycosides thiab carbapenems 11 12 thiab feem ntau siv rau cov neeg laus uas muaj MDR urinary tract infections.13
Tam sim no muaj cov lus pom zoo tsis sib haum xeeb rau kev noj cov tshuaj fosfomycin hauv cov menyuam yaus, xws li 100 txog 400 mg / kg / hnub, tsis muaj kev tshaj tawm qhov ncauj noj tshuaj.Four neonatal kev tshawb fawb kwv yees tshem tawm ib nrab-lub neej ntawm 2.4-7 teev tom qab txhaj tshuaj ntawm cov tshuaj. 25-50 mg/kg.14 15 Protein binding yog tsawg, thiab qhov siab tshaj plaws tau ua raws li cov ntaub ntawv rau cov neeg laus.16 17 Cov kab mob bactericidal raug suav hais tias muaj feem cuam tshuam nrog ob lub sij hawm siab tshaj qhov tsawg kawg nkaus inhibitory concentration (MIC) 16 lossis thaj tsam hauv qab nkhaus. (AUC): MIC ratio.18 19
Tag nrho ntawm 84 cov ntaub ntawv tshaj tawm ntawm cov menyuam mos uas tau txais fosfomycin hauv cov hlab ntshav ntawm 120-200 mg / kg / hnub qhia tias nws tau txais kev pom zoo. 330 mg sodium per gram—ib qho kev txhawj xeeb txog kev nyab xeeb rau cov menyuam mos uas nws cov sodium reabsorption inversely proportional to gestational age (GA). kev phiv thiab cuam tshuam cov kua dej.27 28
Peb tsom mus soj ntsuam cov tshuaj pharmacokinetics (PK) thiab qib sodium hloov pauv hauv cov chaw kho mob sepsis neonates, nrog rau cov xwm txheej tsis zoo (AEs) cuam tshuam nrog cov kab mob hauv lub qhov ncauj tom qab fosfomycin.
Peb tau ua qhov qhib-label randomized tswj kev sim piv cov qauv ntawm kev saib xyuas (SOC) tshuaj tua kab mob ib leeg nrog SOC ntxiv rau IV ua raws li qhov ncauj fosfomycin hauv cov menyuam mos uas muaj kev kuaj mob sepsis ntawm Kilifi County Tsev Kho Mob (KCH), Kenya.
Txhua tus menyuam mos yug tshiab tau txais KCH raug kuaj xyuas.Cov txheej txheem suav nrog: hnub nyoog ≤28 hnub, lub cev hnyav> 1500 g, cev xeeb tub> 34 lub lis piam, thiab cov txheej txheem rau cov tshuaj tua kab mob hauv WHO3 thiab Kenya29 cov lus qhia.Yog xav tau CPR, Qib 3 hypoxic-ischemic encephalopathy, 30 sodium ≥150 mmol/L, creatinine ≥150 µmol/L, jaundice yuav tsum tau hloov pauv hloov pauv, ua xua lossis contraindication rau fosfomycin, qhia tshwj xeeb ntawm lwm hom kab mob tshuaj tua kab mob, tus menyuam yug tshiab tsis suav nrog lwm lub tsev kho mob lossis tsis nyob hauv Kilifi County (Daim duab 1 ).
Sim tawm cov flowchart.Cov duab qub no yog tsim los ntawm CWO rau daim ntawv no.CPR, cardiopulmonary resuscitation;HIE, hypoxic-ischemic encephalopathy;IV, tso zis;SOC, qauv kev saib xyuas;SOC-F, tus qauv kev saib xyuas ntxiv rau fosfomycin.* Ua rau muaj xws li niam (46) lossis mob hnyav (6) tom qab kev phais mob, tawm hauv tsev kho mob (3), tawm tawm tsis pom zoo (3), tso tseg los ntawm leej niam (1) thiab kev koom tes hauv Lwm txoj kev tshawb fawb (1).†Ib tus neeg koom nrog SOC-F tuag tom qab ua tiav kev soj ntsuam (Hnub 106).
Cov neeg koom nrog tau cuv npe hauv 4 teev ntawm thawj koob tshuaj SOC tshuaj tua kab mob kom txog rau thaum lub Cuaj Hlis 2018, thaum cov txheej txheem hloov kho txuas ntxiv mus rau hauv 24 teev kom suav nrog kev nkag mus rau hmo ntuj.
Cov neeg koom nrog tau raug xaiv (1: 1) mus txuas ntxiv rau SOC tshuaj tua kab mob ib leeg lossis tau txais SOC ntxiv (txog) 7 hnub ntawm fosfomycin (SOC-F) siv lub sijhawm randomization nrog random block loj (Cov duab ntxiv S1 online). zais los ntawm ntu ntu numbered opaque ntim hnab ntawv.
Raws li WHO thiab Kenyan cov lus qhia rau menyuam yaus, SOCs suav nrog ampicillin lossis cloxacillin (yog tias xav tias muaj tus kab mob staphylococcal) ntxiv rau gentamicin ua cov tshuaj tua kab mob thawj zaug, lossis thib peb tiam cephalosporins (xws li ceftriaxone) ua cov tshuaj tua kab mob thib ob.3 29 Cov neeg koom nrog randomized rau SOC -F kuj tau txais cov tshuaj fosfomycin rau hauv cov hlab ntsha tsawg kawg yog 48 teev, hloov mus rau qhov ncauj thaum pub noj txaus kom pom tau tias kev nqus ntawm lub qhov ncauj txaus. mg/mL fosfomycin sodium tov rau intravenous infusion (Infectopharm, Lub teb chaws Yelemees) thiab Fosfocin 250 mg / 5 mL fosfomycin calcium suspension rau kev tswj qhov ncauj (Laboratorios ERN, Spain) ob zaug ib hnub twg nrog 100 mg / kg / koob tshuaj.
Cov neeg koom nrog tau ua raws li 28 hnub.Txhua tus neeg koom tau raug saib xyuas nyob rau hauv tib lub tsev uas muaj kev vam meej heev los tswj AE kev saib xyuas.Ua tiav cov ntshav suav thiab biochemistry (xws li sodium) tau ua tiav rau kev nkag, hnub 2, thiab 7, thiab rov hais dua yog tias kuaj pom.AEs yog coded raws li MedDRA V.22.0.Severity tau muab cais raws li DAIDS V.2.1.AEs tau ua raws li kom txog thaum kev kho mob los yog txiav txim ntev thiab ruaj khov thaum lub sij hawm kho. nyob rau hauv cov pej xeem no, suav nrog tej zaum yuav deterioration thaum yug los (txoj cai nyob rau hauv Ntxiv cov ntaub ntawv 1 online).
Tom qab thawj IV thiab thawj qhov ncauj fosfomycin, cov neeg mob muab rau SOC-F tau randomized rau ib qho ntxov (5, 30, lossis 60 feeb) thiab ib qho lig (2, 4, lossis 8 teev) PK qauv.Ib qho piv txwv thib tsib uas tsis zoo tau sau. rau cov neeg koom nrog uas tseem tau mus pw hauv tsev kho mob hnub 7. Cov qauv kuaj mob cerebrospinal fluid (CSF) tau sau los ntawm cov kws kho mob qhia txog lumbar puncture (LP).Sample processing and fosfomycin measurements are description in Supplementary file 2 online.
Peb tau tshuaj xyuas cov ntaub ntawv nkag ntawm xyoo 2015 thiab 2016 thiab suav tias qhov nruab nrab sodium cov ntsiab lus ntawm 1785 neonates hnyav> 1500 g yog 139 mmol / L (SD 7.6, thaj tsam 106-198). Tsis suav nrog 132 neonates nrog serum sodium> 150 mmol / L (peb. Cov txheej txheem tsis suav nrog), qhov seem 1653 cov menyuam yaus muaj cov ntsiab lus sodium ntawm 137 mmol / L (SD 5.2).Ib qho piv txwv loj ntawm 45 rau ib pab pawg tau muab xam kom ntseeg tau tias qhov sib txawv ntawm 5 mmol / L hauv ntshav plasma sodium hnub 2 tuaj yeem ua tau. txiav txim siab nrog> 85% lub zog raws li cov ntaub ntawv xa tawm hauv zos ua ntej sodium.
Rau PK, tus qauv loj ntawm 45 tau muab> 85% lub zog los kwv yees PK tsis txwv rau kev tshem tawm, ntim ntawm kev faib tawm, thiab bioavailability, nrog 95% CIs kwv yees siv simulations nrog qhov tseeb ntawm ≥20% rau qhov kawg no, tus qauv coj tus neeg laus. tau siv, scaling hnub nyoog thiab loj rau neonates, ntxiv thawj-order absorption thiab presumed bioavailability.31 Txhawm rau tso cai rau cov qauv uas ploj lawm, peb tsom mus nrhiav 60 neonates ib pab pawg.
Qhov sib txawv ntawm cov kab hauv qab tau sim siv qhov kev xeem χ2, Cov Tub Ntxhais Kawm T-test, lossis Wilcoxon's rank-sum test.Differences nyob rau hnub 2 thiab hnub 7 sodium, potassium, creatinine, thiab alanine aminotransferase tau sim siv kev soj ntsuam ntawm cov sib txawv hloov kho rau cov nqi hauv paus. Rau AEs, cov xwm txheej tsis zoo (SAEs), thiab cov tshuaj tsis zoo, peb siv STATA V.15.1 (StataCorp, College Station, Texas, USA).
Qauv-raws li kev kwv yees ntawm PK tsis tau ua nyob rau hauv NONMEM V.7.4.32 siv thawj-order conditional kwv yees nrog kev sib cuam tshuam, tag nrho cov ntsiab lus ntawm PK qauv tsim thiab simulation yog muab rau lwm qhov.32
Kev saib xyuas ntawm qhov chaw tau ua los ntawm DNDi/GARDP, nrog kev saib xyuas los ntawm pawg neeg saib xyuas kev ruaj ntseg thiab cov ntaub ntawv ywj pheej.
Nyob nruab nrab ntawm Lub Peb Hlis 19, 2018, thiab Lub Ob Hlis 6, 2019, 120 neonates (61 SOC-F, 59 SOC) tau cuv npe (Daim duab 1), ntawm 42 (35%) tau tso npe ua ntej kev hloov kho raws tu qauv.Group.Median (IQR) hnub nyoog, qhov hnyav thiab GA yog 1 hnub (IQR 0-3), 2750 g (2370-3215) thiab 39 lub lis piam (38-40), raws li.Baseline yam ntxwv thiab kev kuaj tsis tau muaj nyob rau hauv Table 1 thiab Online Table Ntxiv S1.
Cov kab mob Bacteremia tau kuaj pom hauv ob tus menyuam mos (Sab Ntxiv Table S2 online).2 ntawm 55 tus menyuam mos uas tau txais LP tau kuaj pom tus mob meningitis (Streptococcus agalactiae bacteremia nrog CSF leukocytes ≥20 hlwb / µL (SOC-F); zoo Streptococcus pneumpinoniae cereboniae thiab CSF leukocytes ≥ 20 cells/µL (SOC)).
Ib qho SOC-F neonate tsis raug tau txais SOC cov tshuaj tua kab mob nkaus xwb thiab tsis suav nrog PK tsom xam.Ob lub SOC-Fs thiab ib qho SOC Neonatal tau txais kev pom zoo - suav nrog cov ntaub ntawv rho tawm ua ntej.Txhua tus neeg koom nrog SOC (cloxacillin ntxiv rau gentamicin (n= 1). ) thiab ceftriaxone (n=1)) tau txais ampicillin ntxiv rau gentamicin ntawm kev nkag mus.Online Cov Table Ntxiv S3 qhia cov tshuaj tua kab mob sib xyaw ua ke siv rau cov neeg koom nrog uas tau txais cov tshuaj tua kab mob uas tsis yog ampicillin ntxiv rau gentamicin thaum nkag los yog tom qab kev kho mob hloov.Ten SOC-F cov neeg koom tau hloov dua siab tshiab mus rau txoj kab thib ob vim kev kho mob hnyav lossis mob meningitis, tsib tus ntawm lawv tau ua ntej tus qauv PK thib plaub (Sab Ntxiv Table S3 online).Txhua, 60 tus neeg koom tau txais tsawg kawg ib koob tshuaj fosfomycin thiab 58 tau txais tsawg kawg ib koob tshuaj ntawm qhov ncauj.
Rau (plaub SOC-F, ob tug SOC) cov neeg koom tau tuag hauv tsev kho mob (Daim duab 1).Ib tug neeg koom nrog SOC tuag 3 hnub tom qab tso tawm (hnub 22).Ib tug neeg koom nrog SOC-F tsis tuaj yeem taug qab thiab tom qab ntawd pom tias tau tuag rau hnub 106 (tawm ntawm kev soj ntsuam kev kawm);Cov ntaub ntawv tau suav nrog rau hnub 28.Peb tus menyuam mos SOC-F tau ploj mus rau kev soj ntsuam.Tag nrho cov menyuam mos / hnub ntawm kev soj ntsuam rau SOC-F thiab SOC yog 1560 thiab 1565, raws li, ntawm 422 thiab 314 tau pw hauv tsev kho mob.
Hnub 2, qhov nruab nrab (SD) plasma sodium tus nqi rau SOC-F cov neeg koom yog 137 mmol / L (4.6) piv rau 136 mmol / L (3.7) rau SOC cov neeg koom;Piv txwv li, qhov sib txawv ntawm +0.7 mmol/L (95% CI) -1.0 txog +2.4).Hnub 7, qhov nruab nrab (SD) sodium qhov tseem ceeb yog 136 mmol/L (4.2) thiab 139 mmol/L (3.3);Qhov sib txawv nruab nrab -2.9 mmol / L (95% CI -7.5 txog +1.8) (Table 2).
Hnub 2, qhov nruab nrab (SD) cov ntsiab lus ntawm cov poov tshuaj hauv SOC-F tau qis dua me ntsis hauv cov menyuam mos SOC-F: 3.5 mmol / L (0.7) vs 3.9 mmol / L (0.7), qhov sib txawv -0.4 mmol / L (95% CI. -0.7 txog -0.1).Tsis muaj pov thawj tias lwm qhov chaw kuaj mob txawv ntawm ob pawg (Table 2).
Peb tau pom 35 AEs hauv 25 SOC-F cov neeg koom thiab 50 AEs hauv 34 SOC cov neeg koom;2.2 txheej xwm / 100 hnub menyuam mos thiab 3.2 txheej xwm / 100 hnub menyuam mos, raws li: IRR 0.7 (95% CI 0.4 txog 1.1), IRD -0.9 cov xwm txheej / 100 hnub menyuam mos (95% CI -2.1 txog +0.2, p = 0.11).
Kaum ob SAEs tshwm sim hauv 11 SOC-F cov neeg koom thiab 14 SAEs hauv 12 SOC cov neeg koom (SOC 0.8 txheej xwm / 100 hnub me nyuam mos vs 1.0 txheej xwm / 100 hnub menyuam mos; IRR 0.8 (95% CI 0.4 txog 1.8), IRD -0.2 txheej xwm / 100 inf hnub (95% CI -0.9 txog +0.5, p = 0.59). Hypoglycemia yog feem ntau AE (5 SOC-F thiab 6 SOC); 3 ntawm 4 hauv txhua pab pawg 3 SOC-F thiab 4 SOC cov neeg koom nrog muaj mob hnyav lossis hnyav. thrombocytopenia thiab ua tau zoo yam tsis muaj kev txhaj tshuaj platelet rau hnub 28. 13 SOC-F thiab 13 SOC cov neeg koom tau muaj AE cais raws li "xav tau" (Sab Ntxiv Table S5 online). Tsis paub keeb kwm (n=1)) Txhua tus raug tso tawm hauv tsev ciaj sia. Ib tus neeg koom nrog SOC-F muaj cov pob khaus me me thiab lwm tus neeg koom nrog SOC-F tau mob raws plab 13 hnub tom qab tso tawm; ob qho tib si daws tsis muaj qhov tshwm sim tom qab tshem tawm ntawm kev tuag, Tsib caug AEs daws tau thiab 27 daws tsis muaj kev hloov pauv lossis kev daws teeb meem (online Supplementary Table S6) Tsis muaj AEs cuam tshuam txog kev kawm tshuaj.
Tsawg kawg ib tus qauv PK tau sau los ntawm 60 tus neeg koom nrog.Tsib caug-tsib tus neeg koom tau muab tag nrho plaub tus qauv, thiab 5 tus neeg koom tau muab cov qauv ib nrab. Rau cov neeg koom nrog cov qauv sau rau hnub 7.A tag nrho ntawm 238 cov qauv ntshav (119 rau IV thiab 119 rau qhov ncauj fosfomycin) thiab 15 CSF cov qauv raug tshuaj xyuas.Tsis muaj cov qauv uas muaj fosfomycin qis dua qhov kev txwv ntawm quantitation.32
Population PK qauv kev txhim kho thiab simulation cov txiaj ntsig tau piav qhia meej nyob rau lwm qhov.32 Luv luv, ob chav PK qauv qauv nrog ib qho ntxiv CSF compartment muab qhov haum rau cov ntaub ntawv, nrog kev tshem tawm thiab ntim ntawm lub xeev khov kho rau cov neeg koom nrog (lub cev hnyav ( WT) 2805 g, hnub nyoog postnatal (PNA) 1 hnub, hnub nyoog postmenstrual (PMA) 40 lub lis piam) yog 0.14 L / teev (0.05 L / teev / kg) thiab 1.07 L (0.38 L / kg), feem. Kev loj hlob ntawm allometric thiab xav tias PMA maturation raws li lub raum kev ua haujlwm 31, PNA cuam tshuam nrog kev tshem tawm ntau ntxiv thaum thawj lub lim tiam tom qab yug menyuam.Cov qauv kev kwv yees ntawm qhov ncauj bioavailability yog 0.48 (95% CI 0.35 rau 0.78) thiab cerebrospinal fluid/plasma ratio yog 0.32 (95% CI 0.27 txog 0.41).
Online Supplementary Figure S2 qhia txog qhov simulated steady-state plasma concentration-time profiles.Daim duab 2 thiab 3 nthuav qhia AUC Qhov Ua Tau Zoo ntawm Lub Hom Phiaj Tau Txais (PTA) rau cov neeg kawm (lub cev hnyav> 1500 g): MIC qhov pib rau bacteriostasis, 1-log tua, thiab tiv thaiv kev tiv thaiv, siv MIC qhov pib los ntawm me me neonates.Cov ntaub ntawv rau infer.Muab qhov kev tshem tawm sai sai thaum thawj lub limtiam ntawm lub neej, cov kev simulation tau ntxiv stratified los ntawm PNA (Table Ntxiv S7 online).
Cov hom phiaj muaj peev xwm ua tiav nrog cov kab mob fosfomycin.Neonatal subpopulations.Pab 1: WT > 1.5 kg +PNA ≤7 hnub (n=4391), Pawg 2: WT > 1.5 kg +PNA > 7 hnub (n=2798), Pawg 3: WT ≤1.5 kg +PNA ≤7 Hnub (n=1534), Pab Pawg 4: WT ≤1.5 kg + PNA > 7 hnub (n=1277).Pom 1 thiab 2 sawv cev rau cov neeg mob zoo ib yam li cov uas tau ua raws li peb cov txheej txheem suav nrog.Groups 3 thiab 4 sawv cev extrapolations rau unstudied preterm neonates nyob rau hauv peb cov pejxeem.Cov thawj daim duab no yog tsim los ntawm ZK rau daim ntawv no.BID, ob zaug ib hnub twg;IV, txhaj tshuaj;MIC, yam tsawg kawg nkaus inhibitory concentration;PNA, hnub nyoog postnatal;WT, pes.
Lub hom phiaj probabilistic ua tiav nrog qhov ncauj fosfomycin koob tshuaj.Neonatal subpopulations.Pab 1: WT > 1.5 kg +PNA ≤7 hnub (n=4391), Pawg 2: WT > 1.5 kg +PNA > 7 hnub (n=2798), Pawg 3: WT ≤1.5 kg +PNA ≤7 Hnub (n=1534), Pab Pawg 4: WT ≤1.5 kg + PNA > 7 hnub (n=1277).Pom 1 thiab 2 sawv cev rau cov neeg mob zoo ib yam li cov uas tau ua raws li peb cov txheej txheem suav nrog.Pom 3 thiab 4 sawv cev extrapolation ntawm preterm neonates siv lwm cov ntaub ntawv uas tsis tau kawm nyob rau hauv peb cov pejxeem.Cov thawj daim duab no yog tsim los ntawm ZK rau daim ntawv no.BID, ob zaug ib hnub twg;MIC, yam tsawg kawg nkaus inhibitory concentration;PNA, hnub nyoog postnatal;PO, qhov ncauj;WT, pes.
Rau cov kab mob uas muaj MIC > 0.5 mg / L, kev tiv thaiv kev tiv thaiv tsis tau ua tiav nrog ib qho ntawm cov kev coj noj coj ua (Daim duab 2 thiab 3).Rau 100 mg / kg iv ob zaug ib hnub, bacteriostasis tau ua tiav nrog MIC ntawm 32 mg / L. ntawm 100% PTA nyob rau hauv tag nrho plaub txheej mock (Daim duab 2).Hais txog 1-log tua, rau pawg 1 thiab 3 nrog PNA ≤7 hnub, PTA yog 0.84 thiab 0.96 nrog 100 mg / kg iv ob zaug ib hnub thiab MIC yog 32 mg / L, tab sis cov pab pawg muaj qis dua PTA, 0.19 thiab 0.60 rau 2 thiab 4 PNA> 7 hnub, raws li 150 thiab 200 mg / kg ob zaug hauv ib hnub, intravenously, 1-log tua PTA yog 0.64 thiab 0.90 rau pawg 2. thiab 0.91 thiab 0.98 rau pawg 4, feem.
Cov txiaj ntsig ntawm PTA rau pawg 2 thiab 4 ntawm 100 mg / kg ntawm qhov ncauj ob zaug ib hnub yog 0.85 thiab 0.96, raws li (Daim duab 3), thiab PTA tus nqi rau pawg 1-4 yog 0.15, 0.004, 0.41, thiab 0.05 ntawm 32 mg / L, raws.Tua 1-log hauv MIC.
Peb tau muab pov thawj ntawm fosfomycin ntawm 100 mg / kg / koob tshuaj ob zaug ib hnub rau cov menyuam mos uas tsis muaj pov thawj ntawm plasma sodium cuam tshuam (txo hauv cov hlab ntsha) lossis osmotic diarrhea (qhov ncauj) piv nrog SOC.Peb lub hom phiaj tseem ceeb ntawm kev nyab xeeb, kuaj pom qhov sib txawv ntawm cov ntshav plasma sodium theem ntawm cov ob pab pawg kho mob nyob rau hnub 2, tau muaj zog txaus.Txawm tias peb cov qauv me me dhau los txiav txim siab ntawm pawg sib txawv hauv lwm cov xwm txheej kev nyab xeeb, txhua tus menyuam mos tau raug saib xyuas zoo thiab cov xwm txheej qhia tau pab muab pov thawj los txhawb kev siv fosfomycin hauv qhov no. Cov neeg raug tsim txom nrog sepsis lwm txoj kev kho mob empiric.Txawm li cas los xij, kev lees paub ntawm cov txiaj ntsig no hauv pawg neeg loj thiab hnyav dua yuav yog qhov tseem ceeb.
Peb tsom mus nrhiav cov menyuam yaus hnub nyoog qis dua ≤28 hnub thiab tsis tau xaiv suav nrog qhov xav tias yuav pib ntxov ntxov sepsis.Txawm li cas los xij, 86% ntawm cov menyuam mos yug tshiab tau mus pw hauv tsev kho mob thawj lub limtiam ntawm lub neej, lees paub lub nra hnyav ntawm kev mob menyuam yaus thaum ntxov tau tshaj tawm hauv LMICs zoo sib xws.33 -36 Cov kab mob uas ua rau ntxov ntxov thiab lig-pib pib sepsis (xws li ESBL E. coli thiab Klebsiella pneumoniae tau pom) rau cov tshuaj tiv thaiv kab mob, 37-39 tej zaum yuav kis tau rau hauv obstetrics.In xws li cov chaw, broad-spectrum antimicrobial coverage. raws li kev kho thawj kab tuaj yeem txhim kho cov txiaj ntsig thiab zam kev siv carbapenem.
Raws li nrog ntau cov tshuaj tua kab mob, 40 PNA yog ib qho tseem ceeb covariate piav qhia txog fosfomycin clearance.Cov nyhuv no, txawv ntawm GA thiab lub cev hnyav, sawv cev rau kev loj hlob sai ntawm glomerular filtration tom qab yug me nyuam. Hauv zos, 90% ntawm cov kab mob Enterobacteriaceae muaj fosfomycin MIC ntawm ≤32. /mL15, thiab cov kab mob bactericidal yuav xav tau> 100 mg / kg / koob tshuaj txhaj rau hauv cov menyuam mos > 7 hnub (Daim duab 2).Rau lub hom phiaj ntawm 32 µg / mL, yog tias PNA > 7 hnub, 150 mg / kg ob zaug ib hnub yog pom zoo rau Kev kho cov kab mob hauv cov hlab ntsha.Ib zaug ruaj khov, yog tias yuav tsum tau hloov mus rau qhov ncauj fosfomycin, cov koob tshuaj tuaj yeem raug xaiv raws li cov menyuam yaus WT, PMA, PNA, thiab cov kab mob MIC, tab sis cov bioavailability qhia ntawm no yuav tsum tau txiav txim siab. kev nyab xeeb thiab kev ua tau zoo ntawm qhov koob tshuaj ntau dua pom zoo los ntawm peb tus qauv PK.
Post lub sij hawm: Mar-16-2022