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Beta-lactams and Aminoglycosides in Neonates at the University Hospital of Cocody in . ß-lactamines et Aminosides utilisés en Néonatalogie au Centre Hospitalier Universitaire de Cocody en Côte d’Ivoire.

Geneviève N’guessan-Irié 1,2* , Madeleine Amorissani-Folquet 3,4 , Gisèle Siransy-Kouakou 1,5 , Cyprien Kouakou 3,4 , Landry Kouakou 1 1Département de Pharmacologie, UFR Sciences Pharmaceutiques et Biologiques, Université Félix Houphouët-Boigny, email : [email protected], [email protected], [email protected] ; 2Service de Pharmacie, Centre Hospitalier et Universitaire de Cocody ; 3Service de Pédiatrie, Centre Hospitalier et Universitaire de Cocody, email : [email protected], [email protected] ; 4Département de Pédiatrie, UFR Sciences Médicales d’, Université Félix Houphouët-Boigny ; 5Service de Pharmacologie Clinique, Centre Hospitalier et Universitaire de Cocody. *Author for correspondence: [email protected] Postal address: 08 BP 3163 Abidjan 08; Phone: +225 07 98 81 57

Abstract RESUME Aim : In Ivory Coast, neonatal infections are very Objectif : en Côte d’Ivoire, les infections néonatales frequent. However the antibacterial therapy of these sont très fréquentes. Cependant leur prise en charge ne diseases is not still the object of a national consensus. fait pas encore l’objet de consensus national. Il paraît Then it seems important to make the current situation of alors judicieux de faire l’état des lieux de antibacterial therapy in neonates in reference Hospitals l’antibiothérapie en Néonatalogie dans les hôpitaux de like the University Hospital of Cocody. The aim of this référence comme le centre hospitalier et universitaire study was to analyze the practice of antibacterial care in (CHU) de Cocody. L’objectif de cette étude était neonatal infections there with regard to international d’analyser l’antibiothérapie néonatale au CHU de recommendations, if need be, to make propositions for Cocody au regard des recommandations internationales improvement. Methods : Two hundred and fourteen en vue de faire des propositions pour l’améliorer. neonates hospitalized for infection except parasitic or Méthode : 214 nouveau-nés hospitalisés pour infection, viral disorders were recruited for seven-month excepté les parasitoses et viroses, ont été recrutés pour transversal study. Hospital practices were observed and une étude transversale de sept mois. Les pratiques detailed antibacterial therapy was noted. Results : hospitalières et le détail des antibiothérapies ont été Antibacterial therapy was dominated by double- notés. Résultats : le traitement a été dominé par la bi- antibacterial therapy (98.13%). This concerned in first antibiothérapie (98,13%). En première intention : intention Amoxicillin 100 Mg/Kg twice a day or Amoxicilline 100 mg/kg deux fois par jour ou Ceftriaxone 100 Mg/Kg once a day in direct intravenous Ceftriaxone 100 mg/kg une fois par jour en injection injection + Netilmicin or Gentamycin 5 Mg/Kg once a intraveineuse directe + Nétilmicine ou Gentamycine 5 day in intramuscular injection; in second intention mg/kg une fois par jour en injection intramusculaire ; en (sepsis or altered general state): Cefotaxim 50-75 deuxième intention (sepsis ou état général altéré) : Mg/Kg twice a day in direct intravenous injection + Céfotaxime 50-75 mg/kg deux fois par jour en injection Netilmicin or Gentamycin 5 Mg/Kg once a day in intraveineuse directe + Nétilmicine ou Gentamycine 5 intramuscular injection. Third-generation mg/kg une fois par jour en injection intramusculaire. cephalosporins were more prescribed at forward Les céphalosporines de troisième génération ont été plus neonates than at the premature ones ( χ2 = 5.58); prescrites aux nouveau-nés à terme qu’aux prématurés antibacterial therapy was generally driven hanging three (χ2 = 5,58) ; l’antibiothérapie a généralement duré trois in ten days (90.19%); 77.1% of neonates presented a à dix jours (90,19%); 77,1% des nouveau-nés ont regularity in therapy administrations. bénéficié d’une régularité d’administration des Conclusions : Intramuscular injections of antibiotiques. Conclusion : l’injection intramusculaire aminoglycosides and irregularities in some therapy des aminosides et les irrégularités d’administration des administrations must be corrected to promote an optimal antibiotiques doivent être corrigées pour optimiser la pharmacotherapeutics. pharmacothérapeutique.

Key-words : Antibacterial therapy, Ivory Coast, Mots-clés : Antibiothérapie, Côte d’Ivoire, Infections Neonatal infections. néonatales.

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INTRODUCTION the French recommendations? If not, what In neonatal pathology, infection constitutes a propositions could help improving the situation, not only frequent, but also serious. antibiotic coverage of the neonates? Such were Its incidence is from 0.5 to 1% of the births in the objectives assigned to this study. industrialized countries with approximately 5 million deaths a year (Aujard, 2011), I- METHODS corresponding to mortality from 6 to 10% at a- Population of study the forward neonates and of 30% at the The neonates, hospitalized in the neonatal premature neonates (Arsac, 2007). In block of the Pediatrics department of the developing countries, the situation is more University Hospital of Cocody for neonatal worrisome: indeed, the incidence is higher, infection, constituted our population of study. that is 3 in 5% (Aujard, 2011). In Ivory Coast, We adopted the mode of sampling by infections had 27.5% prevalence in neonates at convenience, and so recruited for the period of the University Hospital of Yopougon with our study 214 neonates (a very representative 24.6% mortality (Akaffou et al, 1998). More sample). than ten years later, prevalence and mortality b- Frame of study rates are still high. Indeed further studies Investigations were led in the neonatal block showed that neonatal infections represent of the Pediatrics department of the University 22.7% prevalence at the University Hospital of Hospital of Cocody in Abidjan (Ivory Coast’s Cocody with 15.5% mortality. All this economic capital). The University Hospital of epidemiological information shows the scale Cocody belongs to the highest level of the of neonatal infections in Ivory Coast, requiring national sanitary pyramid. The neonatal block optimal therapeutic coverage for reaching the includes a room of systematic screening of fourth Millennium Development Goal, namely HIV, a resuscitation room, a room of "to reduce childhood mortality". However the hospitalization for the forward neonates, a care of neonatal infections is not still the room of hospitalization for the premature object of a national consensus. International neonates, a room for kangaroo care and a room recommendations, in particular the French for dietetics. ones, remain reference tables. Does the driving The unit of care in neonatology is equipped of the antibacterial therapy in neonatal with fifteen cradles, fourteen incubators, four infections at the University Hospital of tables of resuscitation, three devices of Cocody follow good therapeutic approach? Is phototherapy, four heaters, two vacuum this antibacterial therapy in compliance with cleaners, a mobile trolley for the care, an

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, N° 5, Vol. 1: 20-27 N’guessan-Irié et al., 2016 electric baby scales, and thirteen sources of antibacterial therapy, the beginning and the oxygen end of the therapy. c- Type of study e- Statistical Analyses It was about a transverse study with Discrete data are presented as absolute and descriptive and analytical aim over a period of relative values (n [%]).We used the Chi -square seven months going from September, 2013 till test (degree of freedom = 1) to analyze the link March, 2014. between the gestational age and the used d- Study selection antibiotic molecules. Two -tailed p-values < Inclusion criteria included: 0.05 were considered to indicate statistical 1) Neonates from 0 to 28 days of life; significance in all tests. 2) Hospitalized in the neonatal block from September 1st, 2013 till March 31st, 2014; II- RESULTS 3) With neonatal infection; Antibacterial prescription 4) Followed therapeutically until their release Over the 214 newborn children, 210 received a of hospitalization. double-antibiotic treatment and 3 received a Non-inclusion criteria included: triple-antibiotic treatment. We noted a case 1) Neonates admitted in the department during where the regimen was neither a double - the same period but who presented a parasitic antibacterial therapy, nor a triple -antibacterial infection with a positive thick drop; and/or therapy: this only case was classified other. 2) Arisen from mother known HIV positive. Progress of the study We obtained an authorizati on of investigation with the Pediatrics department head. Besides, data were collected taken in any anonymity and confidentiality, according to ethical and business ethical considerations. Observation of hospital practices and interviews of the health worke rs and the mothers allowed filling investigation forms to supply the following Figure 1: distribution of the neonates according to the regimen of antibacterial information: clinical signs of the neonate at therapy entry, biological and radiological realized analyses, the clinical diagnosis, the detailed

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In regimen of double-antibacterial therapy, the Molecules used in triple -antibacterial therapy most prescribed association was Ceftriaxone + regimen were the associations of Amoxicillin Netilmicin. + Netilmicin + Metronidazole or Ceftriaxone + Netilmicin + Metronidazole. The only case neither double -antibacterial therapy, nor triple -antibacterial therapy, consisted in the association of Amoxicillin + Netilmicin, then Ceftriaxone alone, then Cefotaxim alone, and finally Imipenem alone. Besides, we noted a statistical link between the prescription of beta -lactams and the gestational age: third -generation cephalosporins were more prescribed at Figure 2: distribution of the neonates according to the molecules used in double - forward neonates than at the premature ones. antibactérial therapy

Table I: relationship between beta -lactams prescription and gestational age Antibiotics 3rd CG Amoxycillin Premature neonates 37 32 Forward neonates 101 43 χ2 = 5.58 χ2 0.05 = 3.84 3 rd CG: third cephalosporins generation

Antibacterial dosage Netilmicin or Gentamycin 5 Mg/Kg once a day Antibacterial dosage, whatever the gestational in intramuscular injection. age, was: Amoxicillin 100 Mg/Kg twice a day in direct Duration of therapy intravenous injection; The antibacterial therapy was generally driven Cefotaxim 50-75 Mg/Kg twice a day in direct hanging three in ten days, except two cases of intravenous injection; two-day therapy and nineteen cases of therapy Ceftriaxone 100 Mg/Kg once a day in direct above ten days. intravenous injection;

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Ceftriaxone was removed from the therapeutic plan, certa inly because of its strong binding in albumin, susceptible to move free bilirubin of its site of binding in albumin, causing erythroblastosis fetalis. However, it is advisable

to remind the physicochemical incompatibilities Figure 3: duration of parenteral antibac terial of Ceftriaxone, particularly wit h the solutions therapy containing calcium salts. On this matter it is

recommended that Ceftriaxone is not mixed in Observance of therapy solutions containing calcium, and when Among the 214 neonates, 165 presented solutions of calcium are administered, regularity in the administration of the therapy, Ceftriaxone is dripped on a separate way for a which is 77.1 %. The 49 cases of irregularities period during which cal cium is not dripped even (22.9 %) consisted of defects of administration if ways at first are different (AFSSAPS, 2006). of half or the whole daily antibacterial dose. The neonatology department of the University

Hospital of Cocody adapts to these III- DISCUSSION recommendations, but is -it sufficient to avoid Data analysis of the 214 neonates recruited any fatal interaction? Only the regular practice during this study period allowed us describing of Phar macovigilance could bring elements of antibacterial strategy, and finding the daily answer to this concern of the therapeutic follow - difficulties inherent to the therapeutic coverage up. of neonatal infections at the University Hospital If the French agency admits an association of of Cocody. two antibacterial molecules in all the situations Antibac terial therapy consisted almost of neonatal infections, the fact remains that it exclusively in double-antibacterial therapy recommends that the neonates whose clinical associating a beta-lactam (Amoxicillin, state is worrisome receive an intravenous triple - Ceftriaxone, or Cefotaxim) with an antibacterial therapy associating Cefotaxim + aminoglycoside (Netilmicin or Gentamycin), Ampicillin or Amoxicillin + aminoglycoside. according to the recommendations of the French We noted only 3 cases of triple -antibacterial agency Agence N ationale d’Accréditation et therapy while number of neonates concerned d’Évaluation en Santé (ANAES, 2002). In case wit h our study presented rather worrisome of jaundice at the entry of the neonate, disorders like hemodynamic, respiratory, and/or Ceftriaxone was not prescribed; in case of neurological ones. It is advisable to note appearance of jaundice during the therapy,

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, N° 5, Vol. 1: 20-27 N’guessan-Irié et al., 2016 however that about the antibacterial therapy the international accepted superior limits. This regimens, Mtitimila and Cooke (2007), by practice would be justified by the interest to comparing the efficiency and the unwanted take into account the maximum of germs, effects of various strategies in the care of the because that the isolation of specific germs is presumed premature neonatal infection, not common at the University Hospital of concluded that no proof stemming from Cocody. randomized essays suggests superiority of a Furthermore, use of antibacterial molecules strategy to another one. should be in accordance with the sensibility of About dosage of the antibacterial medicine, the bacterial ecosystem of the sanitary structure. international recommendations are: For that purpose, the bacterial ecosystem of the Amoxicillin: 50 Mg/Kg twice a day in direct neonatal block in the University Hospital of intravenous injection (Lönnerholm et al, 1982), Cocody showed sensitivity to beta-lactams and this unitarian dose which can be doubled in case to some aminoglycosides, i.e. Kanamycin, of meningitis without exceeding 200 Mg/Kg per Gentamycin and Amikacin. So use of ß-lactams day (de Chillaz et al, 1999). (amoxicillin, ceftriaxone, cefotaxim) and Cefotaxim: for premature neonates 25 Mg/Kg in gentamycin at the newborn children in this direct intravenous injection, twice a day before study would thus respect the specter of 7 days of life, and three times a day after 7 days sensibility of the bacterial ecosystem of the of life; for forward neonates 25 Mg/Kg in direct University Hospital of Cocody. However, the intravenous injection, three times a day before 7 use of netilmicin includes easily in days of life, and four times a day after 7 days of consideration of the pharmacokinetic life; in case of meningitis 100 Mg/Kg two to homogeneity of the family of aminoglycosides. three times a day (Aujard et al, 1997); Besides, the bacterial epidemiology varies Ceftriaxone: 50 Mg/Kg once a day in direct according to periods, countries, and even intravenous injection, with possibly a first dose regions, preventing from extrapolation of the of 100 Mg/Kg (van Reempts et al, 1995); therapeutic proposals made from the experience Netilmicin or Gentamycin: 2 to 6 Mg/Kg of a center, both for curative and preventive according to the gestational and postnatal age protocols (Aujard, 2011). once a day in slow intravenous drip of thirty On another hand, the intramuscular injection of minutes (Roze et al, 1989). aminoglycosides is not recommended by the With regard to the intervals this above, the fact not only of the local necrosis risk, but also antibacterial dosages of used at the University of the irregular medicinal absorption by this Hospital of Cocody correspond to the values of way at the neonate: the ideal would be the use

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, N° 5, Vol. 1: 20-27 N’guessan-Irié et al., 2016 of the electric syringes, or in defect the slow antibacterial therapy in neonatology at the intravenous way. University Hospital of Cocody is corresponding Regarding duration of antibacterial therapy, the in several points, while adapting itself to the French agency (ANAES, 2002) specifies that it socioeconomic realities. There is however a will be variable, but recommends whether it is problem with aminoglycosides administration in the shortest possible: more specifically, within intramuscular way, source of local necrosis but the framework of our study, the therapy by also irregular medicinal absorption, as well as aminoglycosides was made on a maximum of 5 the absence of practice of pharmacovigilance in days in conformity with the French agency’s the therapeutic follow-up of these neonates recommendation of 2 days and more for the receiving antibiotics. severe infections or in particular germs. So we recommend that the nursing staff in As regards the accessibility to antibacterial neonatology is formed in the strict respect for medicine, it is advisable to note that, even therapy application, in aminoglycosides though the room of hospitalization of the administration in slow intravenous injection, neonate has no cost, the spending susceptible to and in the practice of pharmacovigilance. We be caused by the lack of availability of also call on the University Hospital’s authorities antibacterial medicine within the hospitable to make available quality medicine, and ask the stock as well as the biological analyses both scientific community of infectiology to adopt a during the initial assessment and during the national consensus for the therapeutic protocol controls, could explain, partially, irregularities of the neonatal infections. sometimes in antibacterial administration. Besides, application of the therapy by the nursing staff was sometimes failing, making pharmacotherapeutic not optimal to some neonates.

CONCLUSION Antibacterial therapy of neonatal infections consisted essentially in double-antibacterial therapy associating Ceftriaxone with Netilmicin. Compared with the international recommendations, the practice of the

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