An optimised dosing regimen versus a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in neonates and infants aged less than 90 days (NeoVanc): study protocol for a randomised controlled trial

Louise F Hill, Mark A Turner, Irja Lutsar, Paul T Heath, Pollyanna Hardy, Louise Linsell, Evelyne Jacqz-Aigrain, Emmanuel Roilides, Mike Sharland, NeoVanc Consortium, Carlo Giaquinto, Davide Bilardi, Mike Sharland, Paul T Heath, Louise F Hill, Timothy Planche, Tatiana Munera Huertas, Mark A Turner, William Hope, Irja Lutsar, Emmanuel Roilides, Evelyne Jacqz-Aigrain, Wei Zhao, Louise Linsell, Peter Ghazal, Andrea Dotta, Javier de la Cruz, Clara Alonso Díaz, Susan Conroy, Louise Rawcliffe, Donato Bonifazi, Cristina Manfredi, Mariagrazia Felisi, Louise F Hill, Mark A Turner, Irja Lutsar, Paul T Heath, Pollyanna Hardy, Louise Linsell, Evelyne Jacqz-Aigrain, Emmanuel Roilides, Mike Sharland, NeoVanc Consortium, Carlo Giaquinto, Davide Bilardi, Mike Sharland, Paul T Heath, Louise F Hill, Timothy Planche, Tatiana Munera Huertas, Mark A Turner, William Hope, Irja Lutsar, Emmanuel Roilides, Evelyne Jacqz-Aigrain, Wei Zhao, Louise Linsell, Peter Ghazal, Andrea Dotta, Javier de la Cruz, Clara Alonso Díaz, Susan Conroy, Louise Rawcliffe, Donato Bonifazi, Cristina Manfredi, Mariagrazia Felisi

Abstract

Background: Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin's continued efficacy.

Methods: NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy.

Discussion: Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS.

Trial registration: ClinicalTrials.gov, NCT02790996. Registered on 7 April 2016. EudraCT, 2015-000203-89. Entered on 18 July 2016.

Keywords: Late-onset sepsis; Loading dose; Neonate; Non-inferiority; Randomised controlled trial; Vancomycin, coagulase negative staphylococci.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
NeoVanc flow chart demonstrating how the pre-clinical studies, NeoVanc-1 (hollow fibre infection and rabbit models) and NeoVanc-2 (population pharmacokinetics meta-analysis) advised the dosing for the optimised arm of the NeoVanc Clinical Trial (NeoVanc-3)

References

    1. Isaacs D. A ten year, multicentre study of coagulase negative staphylococcal infections in Australasian neonatal units. Arch Dis Child Fetal Neonatal Ed. 2003;88(2):F89–F93. doi: 10.1136/fn.88.2.F89.
    1. Makhoul IR, Sujov P, Smolkin T, Lusky A, Reichman B. Epidemiological, clinical, and microbiological characteristics of late-onset sepsis among very low birth weight infants in Israel: a national survey. Pediatrics. 2002;109(1):34–39. doi: 10.1542/peds.109.1.34.
    1. Cantey JB, Wozniak PS, Pruszynski JE, Sánchez PJ. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): A prospective interrupted time-series study. Lancet Infect Dis. 2016;16:1178–1184. doi: 10.1016/S1473-3099(16)30205-5.
    1. Benjamin DK, DeLong E, Cotten CM, Garges HP, Steinbach WJ, Clark RH. Mortality following blood culture in premature infants: increased with Gram-negative bacteremia and candidemia, but not Gram-positive bacteremia. J Perinatol. 2004;24(3):175–180. doi: 10.1038/sj.jp.7211068.
    1. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110(2):285–291. doi: 10.1542/peds.110.2.285.
    1. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff A. a, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292(19):2357–2365. doi: 10.1001/jama.292.19.2357.
    1. Wheater M, Rennie JM. Perinatal infection is an important risk factor for cerebral palsy in very-low-birthweight infants. Dev Med Child Neurol. 2000;42(6):364–367. doi: 10.1017/S0012162200000670.
    1. Gray JE, Richardson DK, McCormick MC, Goldmann DA. Coagulase-negative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome. Pediatrics. 1995;95(2):225–230.
    1. Seale AC, Blencowe H, Manu AA, Nair H, Bahl R, Qazi SA, et al. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14:731–741. doi: 10.1016/S1473-3099(14)70804-7.
    1. Kellogg JA, Ferrentino FL, Goodstein MH, Liss J, Shapiro SL, Bankert DA. Frequency of low level bacteremia in infants from birth to two months of age. Pediatr Infect Dis J. 1997;16(4):381–385. doi: 10.1097/00006454-199704000-00009.
    1. Dritsakou K, Liosis G, Gioni M, Glynou E, Avdeliodi K, Papagaroufalis K. CRP levels in extremely low birth weight (ELBW) septic infants. J Matern Neonatal Med. 2015;28(2):237–239. doi: 10.3109/14767058.2014.908842.
    1. Lai M-Y, Tsai M-H, Lee C-W, Chiang M-C, Lien R, Fu R-H, et al. Characteristics of neonates with culture-proven bloodstream infection who have low levels of C-reactive protein (≦10 mg/L) BMC Infect Dis. 2015;15(1):320. doi: 10.1186/s12879-015-1069-7.
    1. Smith CL, Dickinson P, Forster T, Craigon M, Ross A, Khondoker MR, et al. Identification of a human neonatal immune-metabolic network associated with bacterial infection. Nat Commun. 2014;5:1–15.
    1. Dickinson P, Smith C, Forster T, Craigon M, Ross A, Khondoker M, et al. Whole blood gene expression profiling of neonates with confirmed bacterial sepsis. Genomics Data. 2015;3:41–48. doi: 10.1016/j.gdata.2014.11.003.
    1. Hira V, Sluijter M, Estevao S, Horst-Kreft D, Ott A, de Groot R, et al. Clinical and molecular epidemiologic characteristics of coagulase-negative staphylococcal bloodstream infections in intensive care neonates. Pediatr Infect Dis J. 2007;26(7):607–612. doi: 10.1097/INF.0b013e318060cc03.
    1. Brilene T, Soeorg H, Kiis M, Sepp E, Kõljalg S, Lõivukene K, et al. In vitro synergy of oxacillin and gentamicin against coagulase-negative staphylococci from blood cultures of neonates with late-onset sepsis. APMIS. 2013;121(9):859–864. doi: 10.1111/apm.12048.
    1. Klingenberg C, Sundsfjord A, Rønnestad A, Mikalsen J, Gaustad P, Flægstad T. Phenotypic and genotypic aminoglycoside resistance in blood culture isolates of coagulase-negative staphylococci from a single neonatal intensive care unit, 1989-2000. J Antimicrob Chemother. 2004;54(5):889–896. doi: 10.1093/jac/dkh453.
    1. Neumeister B, Kastner S, Bartmann P, Trautmann M, Marre R. Interpretive criteria for susceptibility testing of coagulase-negative staphylococci with special reference to netilmicin. Infection. 1997;25(3):175–177. doi: 10.1007/BF02113608.
    1. Versporten A, Bielicki J, Drapier N, Sharland M, Goossens H. ARPEC project group. The worldwide antibiotic resistance and prescribing in european children (ARPEC) point prevalence survey: Developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother. 2016;71(4):1106–1117. doi: 10.1093/jac/dkv418.
    1. Lee VC. The antibiotic resistance crisis: Part 1: Causes and threats. Pharm Ther. 2015;40(4):277–283.
    1. Meyer E, Gastmeier P, Deja M, Schwab F. Antibiotic consumption and resistance: Data from Europe and Germany. Int J Med Microbiol. 2013;303:388–395. doi: 10.1016/j.ijmm.2013.04.004.
    1. Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M. A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis. 2014;14:13. doi: 10.1186/1471-2334-14-13.
    1. Metsvaht T, Nellis G, Varendi H, Nunn AJ, Graham S, Rieutord A, et al. High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination. BMC Pediatr. 2015;15:41. doi: 10.1186/s12887-015-0359-y.
    1. Leroux S, Zhao W, Bétrémieux P, Pladys P, Saliba E, Jacqz-Aigrain E. Therapeutic guidelines for prescribing antibiotics in neonates should be evidence-based: A French national survey. Arch Dis Child. 2015;100(4):394–398. doi: 10.1136/archdischild-2014-306873.
    1. Kadambari S, Heath PT, Sharland M, Lewis S, Nichols A, Turner MA. Variation in gentamicin and vancomycin dosage and monitoring in UK neonatal units. J Antimicrob Chemother. 2011;66(11):2647–2650. doi: 10.1093/jac/dkr351.
    1. Sharland M. Manual of Childhood Infections - the Blue Book. 4. Oxford: Oxford University Press; 2016. Blue Book Antimicrobial Dosing Guide; p. 965.
    1. Paediatric Formulary Committee . British National Formulary for Children. London: BMJ Group; 2017.
    1. de Hoog M, Mouton JW, van den Anker JN. Vancomycin: pharmacokinetics and administration regimens in neonates. Clin Pharmacokinet. 2004;43(7):417–440. doi: 10.2165/00003088-200443070-00001.
    1. Rafii F, Sutherland JB, Cerniglia CE. Effects of treatment with antimicrobial agents on the human colonic microflora. Ther Clin Risk Manag. 2008;4:1343–1358. doi: 10.2147/TCRM.S4328.
    1. Antachopoulos C, Patel K, Sprague B, Short B, Campos J, Singh N. European Society of Clinical Microbiology and Infectious Diseases Conference. 2004. Risk factors for candidiasis in the neonatal unit: a matched case-control study; p. 362.
    1. Yüce A, Karaman M, Gülay Z, Yulug N. Vancomycin-resistant Enterococci in neonates. Scand J Infect Dis. 2001;33(11):803–805. doi: 10.1080/00365540110027295.
    1. Benjamin DK, Garges H, Steinbach WJ. Candida bloodstream infection in neonates. Semin Perinatol. 2003;27(5):375–383. doi: 10.1016/S0146-0005(03)00061-2.
    1. European Medicines Agency. Revised priority list for studies on off-patent paediatric medicinal products [Internet], vol. 44: Human Medicines Development and Evaluation; 2012. p. 1–12. .
    1. Sertkaya A, Birkenbach A, Berlind A, Eyraud J. Examination of clinical trial costs and barriers for drug development. US Department of Health & Human Services - Office of the Assistant Secretary for Planning and Evaluation. 2014.
    1. Ramos-Martin V, Johnson A, Livermore J, McEntee L, Goodwin J, Whalley S, et al. Pharmacodynamics of vancomycin for CoNS infection: Experimental basis for optimal use of vancomycin in neonates. J Antimicrob Chemother. 2016;71(4):992–1002. doi: 10.1093/jac/dkv451.
    1. Simitsopoulou M, Kadiltzoglou P, Kyrpitzi D, Roilides E. Differential susceptibility of staphylococcus epidermidis biofilms to vancomycin, daptomycin and linezolid between clinical isolates from neonates and adults. Int J Biol Med Res. 2019;10(1):6591–6596.
    1. Jacqz-Aigrain E, Leroux S, Thomson A, Allegaert K, Capparelli E, Biran V, et al. Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young Infants. J Antimicrob Chemother. 2019;74(8):2128–2138. doi: 10.1093/jac/dkz158.
    1. European Medicines Agency . Report on the Expert Meeting on Neonatal and Paediatric Sepsis [Internet] 2010. pp. 1–6.
    1. Committee for Medicinal Products for Human Use and Paediatric Committee . Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate [Internet] 2010. pp. 1–20.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever