Chinangwa Kuongorora zviitiko zvakashata zvine chekuita nefosfomycin (AEs) uye pharmacokinetics uye shanduko mumazinga e sodium muvacheche vane kliniki sepsis.
Pakati paKurume 2018 naKukadzi 2019, vacheche zana nemakumi maviri vane makore ≤28 mazuva vakagamuchira mwero wekutarisira (SOC) mishonga inorwisa mabhakitiriya ye sepsis: ampicillin uye gentamicin.
Kupindira Isu takapa hafu yevatori vechikamu kuti vawane mamwe intravenous fosfomycin inoteverwa nemuromo fosfomycin pachiyero che 100 mg / kg kaviri zuva nezuva kwemazuva manomwe (SOC-F) uye yakatevera kwemazuva makumi maviri nemasere.
Zviwanikwa 61 uye 59 vacheche vane makore 0-23 mazuva vakaiswa kuSOC-F neSOC, zvichiteerana.Hapana humbowo hunoratidza kuti fosfomycin ine simba paserum.sodiumkana gastrointestinal side effects.Mukati me1560 uye 1565 nguva yekucherechedza kwemazuva echeche, takacherechedza 50 AEs mu25 vatori vechikamu SOC-F uye 34 SOC vatori vechikamu, maererano (2.2 vs 3.2 zviitiko / 100 mazuva echeche; chiyero chekusiyana -0.95 mucheche zviitiko / 195 zviitiko ) zuva (95% CI -2.1 kusvika 0.20)) .Vana veSOC-F uye vatatu veSOC vatori vechikamu vakafa.Kubva ku238 pharmacokinetic samples, muenzaniso wakaratidza kuti vana vakawanda vaida chirwere che150 mg / kg intravenously kaviri zuva nezuva kuti vawane zvinangwa zve pharmacodynamic, uye kune vacheche <mazuva manomwe ekuberekwa kana kurema <1500 g zuva nezuva Muyero wakaderedzwa kusvika 100 mg/kg kaviri.
Mhedziso uye Kukosheswa Fosfomycin ine mukana wekurapa kweanonatal sepsis ine mukana wekurapa neonatal sepsis ine nyore dosing regimen.Kuchengetedzeka kwayo kunoda kuongororwazve muboka rakakura revana vachangobva muchipatara, kusanganisira vanozvarwa vasati vazvarwa kana varwere vanorwara zvakanyanya. kurwisa zvipenyu zvakanyanya, saka zvinokurudzirwa kushandisa fosfomycin pamwe chete neimwe 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.
Ichi chinyorwa chakavhurika chekupinda chakagoverwa pasi peCreative Commons Attribution 4.0 Unported (CC BY 4.0) rezinesi, iyo inobvumira vamwe kukopa, kugoverazve, remix, kushandura, uye kuvaka basa iri kune chero chinangwa, kunze kwekunge rakanyorwa nemazvo Basa rekutanga. rakapihwa, chinongedzo cherezinesi chinopiwa, uye chiratidzo chekuti shanduko yaitwa.Ona: https://creativecommons.org/licenses/by/4.0/.
Mishonga inorwisa utachiona inoisa njodzi kukurarama kwevachangobva kuzvarwa uye pane kudiwa kwekukurumidzira kwemaitiro matsva ekurapa anokwanisika.
Pane mutoro wakakosha wesodium ine intravenous fosfomycin, uye oral fosfomycin magadzirirwo ane yakawanda yefructose, asi kune mashoma kuchengetedza data muvacheche.
Kurudziro yevana uye neonatal dosing ye intravenous fosfomycin inosiyana, uye hapana akaburitswa emuromo dosing regimens.
Intravenous uye yemuromo fosfomycin pa100 mg/kg kaviri pazuva, zvichiteerana, haina mhedzisiro paserum.sodiumkana gastrointestinal side effects.
Vana vazhinji vanogona kuda intravenous fosfomycin 150 mg/kg kaviri pazuva kuti vabudirire kuita zvinangwa, uye kune vacheche vane mazuva manomwe ekuberekwa kana kurema <1500 g, intravenous fosfomycin 100 mg/kg kaviri pazuva.
Fosfomycin ine mukana wekubatanidzwa nemamwe maantimicrobial kurapa neonatal sepsis pasina kushandisa carbapenems mukugadzirisa kwekuwedzera antimicrobial resistance.
Antimicrobial resistance (AMR) inokanganisa vanhu vari munyika dzine mari yakaderera nepakati (LMICs).Kudzikiswa kwekufa kwevacheche kwaive kwakaderera pane kuvana vakura, paine chikamu chimwe muzvina chenzufu dzinokonzerwa nehutachiona.1 AMR inowedzera mutoro uyu. ine utachiona husingaurayiwi nemishonga yakawanda (MDR) hunoverengera kunosvika 30% yekufa kwevacheche pasi rose.2
WHO inokurudzira ampicillin,penicillin, kana cloxacillin (kana chirwere cheS. aureus chichifungidzirwa) pamwe nejentamicin (mutsara wekutanga) uye chizvarwa chechitatu cephalosporins (mutsara wechipiri) wehutano hwehutachiona hwehutachiona hwehutachiona. carbapenemase, 4 kliniki isolates inowanzonzi hainzwisisi kune chirongwa ichi.5 Kuchengetwa kwecarbapenems kwakakosha kuti MDR itonge, 6 uye kudzorerwa kwemishonga inorwisa mabhakitiriya inokurudzirwa kugadzirisa kushayikwa kwemishonga inorwisa mabhakitiriya.7
Fosfomycin is non-proprietary phosphonic acid derivative yakanzi "yakakosha" neWHO.8 Fosfomycin ine bactericidal9 uye inoratidza basa rekurwisa mabhakitiriya eGram-positive neGram-negative, kusanganisira methicillin-resistant Staphylococcus aureus, vancomycin-resistant, ESBL vanogadzira uye inogona kupinda mubiofilm.10 Fosfomycin yakaratidza in vitro synergy neaminoglycosides uye carbapenems 11 12 uye inowanzoshandiswa kune vanhu vakuru vane MDR urinary tract infections.13
Parizvino pane zvinopokana zvinokurudzira zvedosing ye intravenous fosfomycin muvana, kubva ku100 kusvika 400 mg/kg/zuva, pasina yakabudiswa oral dosing regimen. Zvidzidzo zvina zvevana neonatal zvinofungidzira kubviswa kwehafu yehupenyu hwemaawa 2.4-7 mushure mekutonga kwe intravenous. 25-50 mg / kg.14 15 Kusungirirwa kweprotein kwakanga kuduku, uye kuwanda kwakanyanya kwaienderana nemashoko evanhu vakuru.16 17 Bactericidal madhara yaifungidzirwa kuti yakabatanidzwa kana imwe nguva iri pamusoro pehuwandu hwekudzivirira inhibitory concentration (MIC) 16 kana nzvimbo iri pasi pevhavha. (AUC):MIC ratio.18 19
Zvose makumi masere nemana ezvinyorwa zvevacheche vanogamuchira intravenous fosfomycin pa 120-200 mg / kg / zuva zvakaratidza kuti zvakabvumirwa zvakanaka.20-24 Toxicity inoratidzika yakaderera kune vanhu vakuru nevana vakwegura.25 Zvisinei, parenteral fosfomycin ine 14.4 mmol/ 330 mg sodium per gram-anogona kuchengetedza kunetseka kune vacheche avo sodium reabsorption inopesana nekuenzanisa nezera rekudzivirira (GA) .26 Mukuwedzera, oral fosfomycin ine high fructose load (~ 1600 mg / kg / zuva), iyo inogona kukonzera gastrointestinal. zvinokanganisa uye zvinokanganisa zvikero zvemvura.27 28
Isu takavavarira kuongorora pharmacokinetics (PK) uye sodium level shanduko mukiriniki sepsis neonates, pamwe neakaipa zviitiko (AEs) zvine chekuita neintravenous inotevera oral fosfomycin.
Takaita yakavhurika-randomized controlled muyedzo tichienzanisa mwero wekutarisira (SOC) mishonga inorwisa mabhakitiriya chete neSOC pamwe neIV ichiteverwa neoral fosfomycin muvacheche vane kliniki sepsis paKilifi County Hospital (KCH), Kenya.
Vose vachangoberekwa vakabvumirwa kuKCH vakaongororwa.Kubatanidzwa kwemaitiro aiva: makore ≤28 mazuva, uremu hwemuviri > 1500 g, gestation > mavhiki e34, uye maitiro emishonga inorwisa mabhakitiriya mu WHO3 uye Kenya29 mirayiridzo. 30 sodium ≥150 mmol/L, creatinine ≥150 µmol/L, jaundice inoda kuchinjanisa kuwedzerwa, allergy kana contraindication kune fosfomycin, chiratidzo cheimwe kirasi yechirwere chemishonga, mwana achangoberekwa akadzingwa kubva kune chimwe chipatara kana kwete muKilifi County (Mufananidzo 1 )
Edzai flowchart.Iyi yepakutanga nhamba yakagadzirwa neCWO yeichi chinyorwa.CPR, cardiopulmonary resuscitation;HIE, hypoxic-ischemic encephalopathy;IV, intravenous;SOC, mwero wekuchengeta;SOC-F, mwero wekuchengeta pamwe nefosfomycin.*Zvikonzero zvinosanganisira amai (46) kana kurwara zvakanyanya (6) mushure mekuvhiyiwa, kubuda muchipatara (3), kuburitswa pasina kurudziro (3), kusiiwa naamai (1) uye kupinda muchirongwa. chimwe chidzidzo (1) † Mumwe mubatanidzwa weSOC-F akafa mushure mekupedza kutevera (Zuva 106).
Vatori vechikamu vakanyoreswa mukati memaawa mana ekutanga dosi reSOC mishonga inorwisa mabhakitiriya kusvika munaGunyana 2018, apo magadzirirwo eprotocol akawedzera izvi kusvika mukati memaawa makumi maviri nemana kuti ubatanidze kubvumidzwa kwehusiku humwe.
Vatori vechikamu vakagoverwa (1: 1) kuti vaenderere mberi paSOC antibiotics chete kana kugamuchira SOC plus (kusvika) 7 mazuva e fosfomycin (SOC-F) vachishandisa purogiramu ye randomisation ine random block size (Supplementary Figure S1 online). Yakavanzwa ne sequentially mahamvuropu akavharidzirwa ane nhamba.
Maererano neWHO uye Kenyan nhungamiro yevana, maSOC anosanganisira ampicillin kana cloxacillin (kana chirwere che staphylococcal chichifungidzirwa) pamwe nejentamicin semishonga inorwisa mabhakitiriya, kana cephalosporins yechizvarwa chechitatu (semuenzaniso, ceftriaxone) semishonga inorwisa mabhakitiriya.3 29 Vatori vechikamu vakarongerwa kuSOC. -F yakagamuchirawo intravenous fosfomycin kwemaawa angangoita 48, ichishandura kumuromo kana chikafu chakakwana chakabvumirwa kutora kubatwa kwakakwana kwemishonga yemuromo.Fosfomycin (intravenous kana muromo) yakashandiswa kwemazuva manomwe kana kusvika pakubuda, chero ipi zvayo yakaitika pakutanga.Fomicyt 40 mg/mL fosfomycin sodium solution ye intravenous infusion (Infectopharm, Germany) uye Fosfocin 250 mg/5 mL fosfomycin calcium suspension for oral administration (Laboratorios ERN, Spain) kaviri zuva nezuva ne 100 mg / kg / dose inoshandiswa.
Vatori vechikamu vakateverwa kwemazuva 28. Vose vatori vechikamu vaitarisirwa mune imwechete yakanyatsoenderana nechikwata chekugadzirisa kutarisa kweAE.Kukwana kweropa uye biochemistry (kusanganisira sodium) yakaitwa pakugamuchira, mazuva 2, uye 7, uye yakadzokororwa kana kliniki yakaratidza.AEs zvinoiswa coded maererano neMedDRA V.22.0.Severity yakarongedzerwa maererano neDAIDS V.2.1.AEs yakateverwa kusvika kugadziriswa kwekliniki kana kuti kutongerwa kusingagumi uye kugadzikana panguva yekurapwa. muhuwandu uhu, kusanganisira kukanganisa kunobvira pakuzvarwa (protocol in Supplementary file 1 online).
Mushure mekutanga IV uye yekutanga oral fosfomycin, varwere vakagoverwa kuSOC-F vakashandurwa kune imwe yekutanga (5, 30, kana maminitsi 60) uye imwe yakanonoka (2, 4, kana 8 awa) PK sampu. kune vatori vechikamu vakanga vachiri muchipatara pazuva 7. Opportunistic cerebrospinal fluid (CSF) samples dzakaunganidzwa kubva kuchipatara chakaratidza lumbar puncture (LP) .Sample processing uye fosfomycin zviyero zvinotsanangurwa muSupplementary file 2 paIndaneti.
Takaongorora dhata rekubvumidzwa pakati pa2015 na2016 tikaverenga kuti sodium yemukati yevachangozvarwa 1785 inorema >1500 g yaive 139 mmol/L (SD 7.6, range 106-198).Tisingasanganisire 132 neonates ine serum sodium>150 mmol/L (yedu nzira yekuregererwa), vakasara ve1653 neonates vaiva nehuwandu hwe sodium ye 137 mmol / L (SD 5.2) . yakatemerwa ne> 85% simba rinobva pane yemuno yekutanga sodium yekugovera data.
Kune PK, saizi yemakumi mana neshanu yakapihwa > 85% simba rekufungidzira PK parameters yemvumo, vhoriyamu yekugovera, uye bioavailability, ine 95% CIs inofungidzirwa kushandisa simulations nekururama kwe ≥20%.Kusvika izvi, munhu mukuru maitiro yakashandiswa, kuwedzera zera uye ukuru kune vacheche, kuwedzera kutorwa kwekutanga uye kunofungidzirwa kuti bioavailability.31 Kuti tibvumire kushayikwa kwemasampuli, taiva nechinangwa chekutora 60 vacheche paboka.
Kusiyana kwezvikamu zvekutanga kwakaedzwa uchishandisa χ2 test, Student's t-test, kana Wilcoxon's rank-sum test.Kusiyana kwezuva 2 uye zuva 7 sodium, potassium, creatinine, uye alanine aminotransferase yakaedzwa kushandiswa kwekuongorora covariance yakagadziridzwa kune yekutanga tsika. Kune maAEs, zviitiko zvakakomba zvakashata (SAEs), uye maitiro asina kunaka ezvinodhaka, takashandisa STATA V.15.1 (StataCorp, College Station, Texas, USA).
Muenzaniso-based estimates yePK parameters yakaitwa muNONMEM V.7.4.32 uchishandisa yekutanga-yakarongeka mamiriro ekuenzanisa nekubatana, zvizere zvePK model yekuvandudza uye kuenzanisa kunopiwa kune imwe nzvimbo.32
Kutariswa kwepa-saiti kwakaitwa neDNDi/GARDP, nekutarisisa kwakapihwa neyakazvimiririra yekuchengetedza data uye komiti yekutarisa.
Pakati paKurume 19, 2018, naKukadzi 6, 2019, vacheche zana nemakumi maviri (61 SOC-F, 59 SOC) vakanyoreswa (Mufananidzo 1), avo makumi mana nevaviri (35%) vakanyoreswa isati yadzokororwa.Boka.Median (IQR) zera, uremu uye GA vaive zuva rimwe (IQR 0-3), 2750 g (2370-3215) uye mavhiki makumi matatu nemapfumbamwe (38-40), zvichiteerana.Baseline maitiro uye marabhoritari parameters anoratidzwa muTebhura 1 uye online Supplementary Tafura S1.
Bacteremia yakaonekwa muvacheche vaviri (Supplementary Table S2 online) 2 yevane 55 vacheche vakagamuchira LP vaiva ne laboratory-confirmed meningitis (Streptococcus agalactiae bacteremia ne CSF leukocytes ≥20 masero / µL (SOC-F); positive Streptococcus anti pneumoniae fluide uye CSF leukocytes ≥ 20 masero / µL (SOC)).
Mumwe mwana weSOC-F mucheche akagamuchira zvisizvo chete maSOC antimicrobials uye haana kuverengerwa kubva mukuongorora kwePK. MaSOC-F maviri uye imwe SOC Neonatal aramba mvumo - kusanganisira pre-withdrawal data. Vese kunze kwevaviri veSOC vatori vechikamu (cloxacillin plus gentamicin (n=1 ) neceftriaxone (n=1)) yakagamuchira ampicillin plus gentamicin pakupinzwa.Online Supplementary Table S3 inoratidza misanganiswa yemishonga inorwisa mabhakitiriya yakashandiswa kune vatori vechikamu vakagamuchira maantibioti kunze kweampicillin plus gentamicin pakuiswa kana kuti mushure mekuchinja kurapwa.Vatori vechikamu gumi veSOC-F vakashandurwa. kusvika kumutsara wechipiri wekurapa nekuda kwekliniki yekuwedzera kana meningitis, vashanu vavo vakanga vari pamberi pechina PK sampu (Supplementary Table S3 online) .Pazhinji, vatori vechikamu 60 vakagamuchira kanenge kamwe intravenous dose ye fosfomycin uye 58 vakagamuchira kanenge kamwe chete nemuromo.
Vatanhatu (vana veSOC-F, vaviri veSOC) vatori vechikamu vakafira muchipatara (Mufananidzo 1) .Mumwe mubatanidzwa weSOC akafa mazuva 3 mushure mekusunungurwa (zuva 22) .Mumwe weSOC-F akapinda akashaya kutevera uye akazoonekwa kuti akafa pazuva 106 (kunze kwekutevera kwekudzidza);data yakabatanidzwa kuburikidza nezuva 28. Vatatu veSOC-F vacheche vakarasika kutevera.Total vacheche / mazuva ekucherechedza kweSOC-F neSOC vaiva 1560 uye 1565, maererano, iyo 422 uye 314 vakaiswa muchipatara.
PaZuva 2, zvinoreva (SD) plasma sodium value yeSOC-F vatori vechikamu yaiva 137 mmol / L (4.6) inopesana ne136 mmol / L (3.7) yevatori veSOC;zvinoreva musiyano + 0.7 mmol / L (95% CI) -1.0 kusvika +2.4) .Pazuva rechinomwe, chiyero che (SD) che sodium chaive 136 mmol / L (4.2) uye 139 mmol / L (3.3);zvinoreva musiyano -2.9 mmol/L (95% CI -7.5 kusvika +1.8) (Tafura 2).
Pazuva rechipiri, zvinoreva (SD) potassium concentrations muSOC-F yakanga yakaderera zvishoma pane yeSOC-F vacheche: 3.5 mmol/L (0.7) vs 3.9 mmol/L (0.7), musiyano -0.4 mmol/L (95% CI -0.7 kusvika -0.1) .Pakanga pasina humbowo hwekuti mamwe maparameter emurabhoritari akasiyana pakati pemapoka maviri (Table 2).
Takacherechedza 35 AEs mu25 vatori vechikamu SOC-F uye 50 AEs mu34 vatori vechikamu SOC;2.2 zviitiko / 100 mazuva echeche uye 3.2 zviitiko / 100 mazuva echeche, maererano: IRR 0.7 (95% CI 0.4 kusvika 1.1), IRD -0.9 zviitiko / 100 mazuva echeche (95% CI -2.1 kusvika +0.2, p = 0.11).
Gumi nembiri SAEs zvakaitika mu11 vatori vechikamu SOC-F uye gumi nemana SAEs mune gumi nevaviri SOC vatori vechikamu (SOC 0.8 zviitiko / 100 mucheche mazuva vs 1.0 zviitiko / 100 mazuva emucheche; IRR 0.8 (95% CI 0.4 kusvika 1.8) , IRD / 100 mu2 zviitiko. mazuva (95% CI -0.9 kusvika +0.5, p=0.59) Hypoglycemia ndiyo yainyanyozivikanwa AE (5 SOC-F uye 6 SOC); 3 ye4 muboka rega rega 3 SOC-F uye 4 vatori vechikamu veSOC vaive nepakati kana kuomarara. thrombocytopenia uye vakanga vachiita zvakanaka pasina kuwedzerwa kweplatelet pazuva 28. 13 SOC-F uye 13 vatori vechikamu SOC vaiva neAE yakarongerwa se "inotarisirwa" (Supplementary Table S5 online) Vatori ve3 SOC vakadzorerwa (pneumonia (n = 2) uye chirwere chefebrile (n=1)) Vese vakaburitswa kumba vari vapenyu.Mumwe vatori vechikamu cheSOC-F aive nekapundu kadiki uye mumwe aive neSOC-F aive aine manyoka ari pakati nepakati mazuva gumi nematatu abuda muropa; zvese zvakagadziriswa pasina kutevedzana. MaAE akagadziriswa uye makumi maviri nenomwe akagadziriswa pasina shanduko kana kuteedzera kwakagadziriswa (online Supplementary Table S6)..
Inenge imwe intravenous PK sampu yakaunganidzwa kubva kune vatori vechikamu 60. Vatori makumi mashanu nevashanu vakapa zvikamu zvina zvizere zvemuenzaniso, uye vatori vechikamu 5 vakapa zvikamu zvishoma. 119 yeoral fosfomycin) uye 15 CSF samples dzakaongororwa.Hapana sampuli dzine fosfomycin mazinga ari pasi pemuganhu wehuwandu.32
Population PK modhi yekusimudzira uye mhedzisiro yekuenzanisa inotsanangurwa zvakadzama kune imwe nzvimbo.32 Muchidimbu, maviri-compartment PK disposition model ine imwezve CSF compartment yakapa kuenderana kwakanaka kune data, nemvumo uye vhoriyamu pakugadzikana kwevanowanzo vatori vechikamu (huremu hwemuviri) WT) 2805 g, zera rekuberekwa (PNA) 1 zuva, postmenstrual age (PMA) 40 mavhiki) aiva 0.14 L / awa (0.05 L / awa / kg) uye 1.07 L (0.38 L / kg), pamwe chete. allometric kukura uye zvinotarisirwa PMA maturation zvichienderana nerenal function31, PNA inobatanidza nekuwedzera kubvumirwa mukati mevhiki yekutanga yekuberekwa.Muenzaniso-based estimate ye oral bioavailability yaiva 0.48 (95% CI 0.35 kusvika 0.78) uye cerebrospinal fluid / plasma ratio yaiva 0.32 (95% CI 0.27 kusvika 0.41).
Online Supplementary Figure S2 inofananidzira yakateedzerwa yakatsiga-state plasma concentration-time profiles.Figus 2 and 3 present the AUC Probability of Target Attainment (PTA) yehuwandu hwechidzidzo (huremu hwemuviri>1500 g): MIC thresholds for bacteriostasis, 1-log. kuuraya, uye kudzivirira kudzivirira, uchishandisa MIC zvikumbaridzo kubva kune vadiki vacheche.data to infer.Zvichipa kukurumidza kuwedzera kwemvumo mukati mevhiki yekutanga yehupenyu, mafananidziro akawedzera stratified nePNA (Supplementary Table S7 online).
Zvinangwa zvingangoitwa ne intravenous fosfomycin.Neonatal subpopulations.Boka 1: WT >1.5 kg +PNA ≤7 mazuva (n=4391), Boka 2: WT >1.5 kg +PNA>7 mazuva (n=2798), Boka 3: WT ≤1.5 kg + PNA ≤7 Mazuva (n = 1534), Boka 4: WT ≤1.5 kg + PNA > 7 mazuva (n = 1277) .Mapoka 1 uye 2 aimiririra varwere vakafanana nevaya vakasangana nemaitiro edu ekubatanidzwa. Mapoka 3 uye 4 inomiririra extrapolations kune vasina kudzidza preterm neonates muhuwandu hwedu.Ichi chimiro chepakutanga chakasikwa neZK chezvinyorwa izvi.BID, kaviri pazuva;IV, jekiseni remutsinga;MIC, shoma inhibitory concentration;PNA, zera rekuberekwa;WT, uremu.
Probabilistic target yakaitwa neoral fosfomycin doses.Neonatal subpopulations.Boka 1: WT >1.5 kg +PNA ≤7 mazuva (n=4391), Boka 2: WT >1.5 kg +PNA >7 mazuva (n=2798), Boka 3: WT ≤1.5 kg + PNA ≤7 Mazuva (n = 1534), Boka 4: WT ≤1.5 kg + PNA > 7 mazuva (n = 1277) .Mapoka 1 uye 2 aimiririra varwere vakafanana nevaya vakasangana nemaitiro edu ekubatanidzwa. Mapoka 3 uye 4 inomiririra extrapolation yevacheche vasati vasvika vachishandisa data rekunze risina kudzidzwa muhuwandu hwedu.Ichi chimiro chepakutanga chakasikwa neZK yezvinyorwa izvi.BID, kaviri pazuva;MIC, shoma inhibitory concentration;PNA, zera rekuberekwa;PO, oral;WT, uremu.
Kune zvipenyu zvine MIC> 0.5 mg/L, kudzvinyirirwa kwekudzivirira hakuna kuwanikwa nguva dzose nemhando ipi zvayo yekunyomba dosing regimens (Figures 2 uye 3) .Ku 100 mg / kg iv kaviri pazuva, bacteriostasis yakawanikwa neMIC ye32 mg / L. ye100% PTA muzvikamu zvina zvekuseka (Mufananidzo 2) .Nezve 1-log kuuraya, kumapoka 1 uye 3 ane PNA ≤7 mazuva, PTA yaiva 0.84 uye 0.96 ne 100 mg / kg iv kaviri zuva nezuva uye MIC yaiva 32 mg / L, asi boka racho raiva nePTA yakaderera, 0.19 uye 0.60 ye2 uye 4 PNA> mazuva 7, maererano.Pa 150 uye 200 mg / kg kaviri zuva nezuva intravenously, 1-log inouraya PTA yaiva 0.64 uye 0.90 yeboka 2 uye 0.91 uye 0.98 yeboka 4, zvichiteerana.
Huwandu hwePTA hwemapoka 2 uye 4 pa100 mg/kg nemuromo kaviri pazuva hwaive 0.85 uye 0.96, zvichiteerana (Mufananidzo 3), uye PTA tsika dzemapoka 1-4 dzaive 0.15, 0.004, 0.41, uye 0.05 pa 32 mg / L, zvichiteerana.Uraya 1-log pasi peMIC.
Takapa uchapupu hwe fosfomycin pa 100 mg / kg / dose kaviri zuva nezuva mucheche pasina uchapupu hweplasma sodium disturbance (intravenous) kana osmotic diarrhea (muromo) kana ichienzaniswa neSOC. Chinangwa chedu chekutanga chekuchengetedza, kuona kusiyana kwemazinga e plasma sodium pakati pe mapoka maviri ekurapa pazuva 2, akanga ane simba rakakwana.Kunyange zvazvo saizi yedu yemuenzaniso yakanga iri duku zvikuru kuti ione kusiyana kweboka mune zvimwe zviitiko zvekuchengetedza, vechidiki vose vacheche vainyatsoongororwa uye zviitiko zvakashumwa zvinobatsira kupa uchapupu hunotsigira kushandiswa kwefosfomycin mune izvi. vanhu vanobatwa vane sepsis alternative empiric therapy.Zvisinei, kusimbiswa kweizvi zvinoguma mumapoka makuru uye akaoma zvikuru achave akakosha.
Takanga tine chinangwa chekutora vacheche ≤28 mazuva ezera uye hatina kusarudza kubatanidza kufungidzirwa kwekutanga-kutanga sepsis.Zvisinei, 86% yevacheche vakaiswa muchipatara mukati mevhiki yekutanga yehupenyu, vachisimbisa mutoro mukuru wehutano hwepakutanga hwemwana huchangobva kutaurwa muLMICs dzakafanana.33. -36 Zvirwere zvinokonzera kutanga-kutanga uye kunonoka-kutanga sepsis (kusanganisira ESBL E. coli uye Klebsiella pneumoniae zvakaonekwa) kune empirical antimicrobials, 37-39 inogona kuwanikwa mukudzivirira. sekutanga-mutsara kurapwa kunogona kuvandudza mhedzisiro uye kudzivirira carbapenem kushandiswa.
Sezvinoita maantimicrobial akawanda, 40 PNA ndiyo yakakosha covariate inotsanangura fosfomycin clearance.Ichi chiitiko, chakasiyana neGA uye uremu hwemuviri, chinomiririra kukurumidza kupedzwa kweglomerular filtration mushure mekuzvarwa.Munzvimbo, 90% yeEnterobacteriaceae inoparadza ine fosfomycin MIC yeg3 /mL15, uye basa rekuuraya utachiona hungada >100 mg/kg/dose uchipinzwa mutsinga muvacheche > mazuva manomwe (Mufananidzo 2) Kurapa kwe intravenous.Kana yadzikamiswa, kana shanduko yeoral fosfomycin ichidiwa, muyero unogona kusarudzwa zvichienderana neonatal WT, PMA, PNA, uye pamwe pathogen MIC, asi bioavailability yakataurwa pano inofanira kufungwa.Zvidzidzo zvinodiwa kuti uwedzere kuongorora chirwere chacho. kuchengetedzeka uye kushanda kweiyi yepamusoro dosi inokurudzirwa neyedu PK modhi.
Nguva yekutumira: Mar-16-2022