Immature immune system of preterm neonates puts them at higher risk of sepsis. Routine antibiotic treatment was compared with no antibiotics unless clinically indicated.
Immature immune system of preterm neonates puts them at higher risk of sepsis. Routine antibiotic treatment was compared with no antibiotics unless clinically indicated.
Immature immune system of preterm neonates puts them at higher risk of sepsis. Routine antibiotic treatment was compared with no antibiotics unless clinically indicated.
A. Tagare*, S. Kadam, U. Vaidya, A. Pandit Division of Neonatology, Department of Pediatrics, KEM Hospital, Rasta Peth, Pune, India Received 22 May 2009; accepted 8 September 2009 Available online 18 November 2009 KEYWORDS Antibiotics; Preterm; Routine; Sepsis Summary The immature immune system of preterm neonates puts them at higher risk of neonatal sepsis. We conducted a part-blinded randomised controlled trial to compare the effect of routine antibiotic treatment on the incidence of clinical sepsis in pretermneonates. Pretermneonates with- out other risk factors for infection admitted in the rst 12 h of life were ran- domised to receive routine antibiotics or to a control group (no antibiotics unless clinically indicated). The primary outcome variable was the inci- dence of clinical sepsis. Secondary outcomes were the incidence of positive blood cultures, necrotising enterocolitis (NEC) stage II or III, or death, and the duration of hospital stay. The incidence of clinical sepsis was compara- ble in both groups (intervention 31.9%, control 25.4%; P 0.392). Mortality was equivalent in both groups. The control group had signicantly more pos- itive blood cultures (P 0.002). The incidence of NEC and the duration of hospital stay were comparable in both groups. In low risk preterm neonates we found no evidence that routine antibiotic use has a protective effect. 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. Introduction Infection is an important cause of morbidity and mortality in neonatal intensive care units (NICUs). Preterm infants are at higher risk of infection for various reasons including their immature immune response and frequent need for invasive manage- ment. This has led to trials of routine or pro- phylactic use of antibiotics in preterm neonates receiving interventions such as ventilation, central venous catheterisation and parenteral nutrition, with variable results. 1e5 Prophylaxis using non- absorbable enteral antibiotics has been reported to reduce the incidence of necrotising enterocoli- tis (NEC). 6 However, information on the role of * Corresponding author. Address: Division of Neonatology, Department of Pediatrics, KEM Hospital, Rasta Peth, Pune 411011, India. Tel.: 91 20 66037342; fax: 91 20 26125603. E-mail address: docamikast@gmail.com 0195-6701/$ - see front matter 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2009.09.010 Journal of Hospital Infection (2010) 74, 332e336 Available online at www.sciencedirect.com www.elsevierhealth.com/journals/jhin routine systemic antibiotic use in the care of low risk preterm neonates is limited. Hence we designed a randomised controlled trial to compare the incidence of clinical sepsis in preterm neo- nates receiving antibiotics routinely with the inci- dence in a control group. Methods Design and setting A part-blinded, randomised controlled trial was conducted between February and December 2008 in the neonatal intensive care unit at KEM Hospital, Pune, in urban western India. This is a 40-bedded tertiary care unit with >1200 annual admissions. The unit caters for both inborn and outborn babies with no segregation according to place of birth. The unit follows strict hand-washing protocols and has a written infection control policy. There are 11 high dependency beds. The unit has guidelines for ventilation, parenteral nutrition and follow-up of high risk babies. Eligibility criteria Preterm neonates (gestation <37 weeks) admitted to our unit within the rst 12 h of life were eligible for enrolment after obtaining informed parental consent. Exclusion criteria (1) Maternal risk factors including leaking per vagina for more than 24 h, fever >38
C in the three days before delivery, foul-smelling liquor or history of urinary tract infection; (2) fetal distress; (3) need for resuscitation beyond positive pressure ventilation; (4) presence of respiratory distress for more than 6 h; (5) need for respiratory support. By applying these exclusions our trial population con- sisted of preterm neonates at lower risk of infection. Ethics approval The study protocol was approved by the institu- tional ethics committee. Randomisation, allocation concealment and blinding Neonates eligible for enrolment were randomly allocated either to the intervention or to the control group using computer-generated random numbers contained in sealed envelopes. The con- sultant neonatologists who made clinical decisions to initiate septic screens or antibiotics, the out- come assessors and the statistician were masked to the allocation status of neonates. The junior doctors (fellows) and nursing staff were unblinded. Intervention Neonates in the intervention group received rst- line intravenous antibiotics (amoxicillin clavu- lanic acid and amikacin) for ve days from the day of birth. The control group did not receive routine prophylactic antibiotic treatment. Primary outcome: incidence of sepsis Neonates were screened for sepsis in the presence of any four of the following clinical signs as assessed by a neonatologist blinded to the trial allocation: (1) sick-looking neonate; (2) tempera- ture instability; (3) heart rate instability; (4) poor perfusion; (5) unexplained alteration of glucose control; (6) feed intolerance; (7) abdominal dis- tension; (8) respiratory distress; (9) altered level of consciousness; or (10) seizures. The sepsis screen consisted of blood count with peripheral smear, C-reactive protein (CRP) estimation and blood culture. The sepsis screen was considered positive when two or more of the following were present: (i) total leucocyte count (TLC) <5000/mm 3 ; (ii) absolute neutrophil count <1800/mm 3 ; (iii) band to total polymorph ratio >0.2; and (iv) CRP >1.0 mg/dL. Clinical sepsis was dened as the presence of four or more predened clinical features together with a positive sepsis screen. In response to a rst episode of sepsis, in the in- tervention group second-line antibiotics were ini- tiated (piperacillin tazobactam and amikacin) whereas in the control group rst-line antibiotics were initiated (amoxicillin clavulanate and amikacin). Antibiotics were changed according to blood culture results. Therapeutic antibiotics were stopped if blood cultures were negative af- ter three days of incubation: in the intervention group it was intended not to stop antibiotics be- fore ve days, even if blood cultures taken in re- sponse to clinical sepsis were negative after three days, but in fact this situation did not arise. Secondary outcomes These included: (1) incidence of positive blood cultures; (2) clinical outcomes including death, Antibiotic use in preterm neonates 333 discharge without sepsis and treated sepsis; (3) incidence of necrotising enterocolitis (stages II and III by modied Bells grading); 7 and (4) duration of hospital stay. Sample size calculation The incidence of clinical sepsis in our unit was 33% overall and 25% in low risk preterm neonates. The necessary sample size for 80% power to detect an effect size of 20% was 63 in each limb. Statistical methods For statistical analysis SPSS version 11.8 was used. ManneWhitney U-test and c 2 -test were used as appropriate. P <0.05 were considered signicant. Results During the study period 515 preterm neonates were admitted to the unit (Figure 1), of whom 140 were enrolled and randomised either to the intervention (N 69) or to the control group (N 71). Baseline characteristics (Table I) were comparable. The incidence of clinical sepsis was 18/71 (25.4%) in the control group and 22/69 (31.9%) in the intervention group (P 0.392). Sepsis occurred mainly during the rst ve days of life. Clinical outcomes such as death, discharge without sepsis and treated sepsis were comparable in both groups (Table II). Two babies in each group died: three due to NEC and one (in the control group) due to Klebsiella pneumoniae sepsis. We performed limited subgroup analysis accord- ing to birth weight. Among neonates with birth weight <1500 g the incidence of clinical sepsis was comparable (intervention group 16/27, 59.3% vs control group 11/26, 42.3%; P 0.217), as was the incidence of death (intervention group 2/27, 7.4% vs control group 1/26, 3.8%; P 0.45). Among neonates with birth weight >1500 g the incidence of clinical sepsis was also comparable (interven- tion group 6/42, 14.3% vs control group 7/45, 15.6%; P 0.868). Only one baby of birth weight >1500 g died (control group). Eleven of the 40 episodes of clinical sepsis were associated with positive blood cultures, all of which were deemed clinically signicant (nine Klebsiella sp., one E. coli, one Acinetobacter bau- mannii). However, these were not evenly distrib- uted between the groups. Of the 18 episodes of clinical sepsis in the control group, 10 (55.5%) were associated with positive blood cultures, whereas of the 22 episodes of clinical sepsis in the intervention group only one (4.5%) was associ- ated with positive blood cultures (P 0.002). The duration of hospital stay was comparable in both groups (Table II). The overall incidence of NEC during the trial was 8.6%. In the intervention group the incidence of NEC was 13% (9/69) while in the control group it was 4.2% (3/71): this differ- ence was not signicant at the 5% level (P 0.062) but the data are compatible with the possibility that routine antibiotics increase the incidence of NEC. Discussion Before starting the study the incidence of clinical sepsis among low risk neonates in the unit was 25%. More than 60% of neonates admitted to this unit are outborn and there is no segregation of inborn and outborn neonates, which might explain the relatively high incidence. We were keen to know whether routine antibiotic treatment would re- duce the incidence of sepsis. However, in this Total no. of preterm admissions = 515 Excluded from study Eligible for randomisation = 140 Control = 71 Intervention = 69 Age >12 h at admission = 160 Respiratory distress >6 h need for respiratory support = 163 Resuscitation at birth = 24 Consent not requested/not given = 28 Figure 1 Distribution of study infants. Total no. of preterm admissions 515 334 A. Tagare et al. study, which had 80% power to detect a 20% difference in the incidence of sepsis, neither the incidence of clinical sepsis (31.9% vs 25.4%) nor mortality (2.8% vs 2.9%) were signicantly differ- ent between the intervention and control groups. Patel et al. investigated giving postnatal peni- cillin prophylaxis (PP) to all live-born infants. 8 This did seem to reduce the incidence of clinical sepsis and sepsis-related deaths, mainly in neo- nates >37 weeks of gestation and mainly due to a reduction in group B streptococcal infection. Most of the babies enrolled however were full term and mothers with risk factors received ante- natal penicillin prophylaxis, so comparison with our trial is not appropriate. In a randomised controlled trial involving 130 high risk neonates performed in a centre where such babies received routine antibiotic prophy- laxis, Auriti et al. showed that single dose ampicil- lin and netilmicin was equivalent to a three-day course. 9 Again this is not directly comparable with our study, which compares routine prophy- laxis with no routine prophylaxis in lower risk infants, but it may be that neither of their anti- biotic strategies was better than no antibiotics. A notable nding in our study was that the control group had signicantly more positive blood cultures (10/18) than the intervention group (1/22). A similar nding was reported when routine penicillin prophylaxis was studied. 8 This is difcult to explain given similar rates of clinical sepsis but it does suggest that routine prophylaxis would alter the positive and negative predictive values of blood cultures, which in turn might adversely affect decision-making in neonatal care. Recently Cotton et al. have shown that prolonged initial empiric antibiotic therapy in neonates is associated with NEC. 10 In our study, NEC occurred more frequently in the intervention group than in the control group but this was not statistically signicant; moreover, the study was not powered to examine this outcome. Table I Baseline characteristics Parameter Control Intervention P-value (N 71) (N 69) Gestational age (weeks) 34.0 (29.0e36.0) a 34.0 (27.0e36.0) a 0.073 b Birth weight (g) 1600 (810e2415) a 1545 (760e2500) a 0.812 b Day of sepsis 4 (2e10) a 4 (2e10) a 0.649 b Inborn (birth place) 45 (63.4%) 37 (53.6%) 0.241 c Vaginal delivery 17 (23.9%) 23 (33.3%) Elective LSCS 44 (62.0%) 36 (52.2%) 0.433 c Emergency LSCS 10 (14.1%) 10 (14.5%) Pregnancy-induced hypertension 36 (50.7%) 28 (40.6%) Other maternal risk factors 20 (28.2%) 19 (27.5%) 0.118 c No maternal risk factor 15 (21.1%) 22 (31.9%) LSCS, lower segment caesarean section. a Median (range). b ManneWhitney U-test. c c 2 -Test. Table II Secondary outcomes Parameter Control Intervention P-value (N 71) (N 69) Death 2 (2.8%) 2 (2.9%) Discharge without sepsis 53 (74.6%) 47 (68.1%) 0.678 a Treated sepsis 16 (22.5%) 20 (29.0%) Culture-positive sepsis 10 (14.1%) 1 (1.4%) 0.002 a Necrotising enterocolitis 3 (4.2%) 9 (13.0%) 0.062 a NICU stay (days) 9 (2e45) b 9 (2e51) b 0.932 c NICU, neonatal intensive care unit. a c 2 -Test. b Median (range). c ManneWhitney U-test. Antibiotic use in preterm neonates 335 Prophylactic antibiotics have been associated with a lower incidence of catheter-related infec- tions, but generally it is felt that the risk of acquiring resistant organisms outweighs any bene- t. 1,3,5,11 Furthermore prophylactic antibiotics did not reduce morbidity and mortality in neonates with central venous catheters or who were receiving mechanical ventilation. 2,4 Antibiotic use in NICUs is associated with the emergence of resis- tant Gram-negative organisms such as Klebsiella and Pseudomonas spp., whereas antenatal prophy- laxis against group B streptococcal infection has been shown to increase infections associated with resistant E. coli. 12e14 Colonisation with Gram-negative bacilli among babies in NICUs in- creases greatly when antibiotics are continued for more than three days, whereas antibiotics such as ampicillin and third generation cephalo- sporins have been shown to select for extended spectrum b-lactamase (ESBL)-producing Gram- negative organisms. 15e18 This phenomenon in NICUs has been termed unnatural selection. 19 Indian NICUs are already facing antibiotic crisis, as reected in reports of the increasing incidence of neonatal sepsis with resistant organ- isms. 16,17,20,21 Routine antibiotic use in the care of preterm neonates is likely to contribute to such problems so it is important that this strategy is criti- cally examined. Our study suggests that in low risk neonates routine prophylaxis is not benecial. In conclusion, routine antibiotic use in low risk preterm neonates does not appear to have any protective effect. Routine antibiotic use reduces the yield of blood cultures among babies with clinical sepsis. Conict of interest statement None declared. Funding sources None. References 1. Craft AP, Finer NN, Barrington KJ. Vancomycin for prophy- laxis against sepsis in preterm neonates. Cochrane Database Syst Rev 2004;(2):CD001971. 2. Inglis GD, Jardine LA, Davies MW. Prophylactic antibiotics to reduce morbidity and mortality in ventilated newborn in- fants. Cochrane Database Syst Rev 2007;(3):CD004338. 3. Harms K, Herting E, Kron M, Schiffman H, Schulz-Ehlbeck H. Randomized, controlled trial of amoxicillin prophylaxis for prevention of catheter-related infections in newborn in- fants with central venous silicone elastomer catheters. J Pediatr 1995;127:615e619. 4. Jardine LA, Inglis GDT, Davies MW. Prophylactic systemic antibiotics to reduce morbidity and mortality in neonates with central venous catheters. Cochrane Database Syst Rev 2008;(1):CD006179. 5. Moller JC, Nelskamp I, Jensen R, et al. Comparison of van- comycin and teicoplanin for prophylaxis of sepsis with coag- ulase negative staphylococci (CONS) in very low birth weight (VLBW) infants. J Perinat Med 1997;25:361e367. 6. Bury RG, Tudehope D. Enteral antibiotics for preventing necrotizing enterocolitis in low birthweight or preterm in- fants. Cochrane Database Syst Rev 2001;(1):CD000405. 7. Walsh MC, Kliegman RM. Necrotising enterocolitis: treat- ment based on staging criteria. Pediatr Clin North Am 1986;33:179. 8. Patel DM, Rhodes PG, Le Blanc MH, Graves GR, Glick C, Morrison J. Role of postnatal penicillin prophylaxis in pre- vention of neonatal group B streptococcus infection. Acta Pediatr 1999;88:874e879. 9. Auriti C, Rava` L, Di Ciommo V, Ronchetti MP, Orzalesi M. Short antibiotic prophylaxis for bacterial infections in a neo- natal intensive care unit: a randomized controlled trial. J Hosp Infect 2005;59:292e298. 10. Cotten CM, Taylor S, Stoll B, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009;123: 58e66. 11. Cooke RW, Nycyk JA, Okuonghuae H, Shah V, Damjanovic V, Hart CA. Low-dose vancomycin prophylaxis reduces coagu- lase-negative staphylococcal bacteraemia in very low birth- weight infants. J Hosp Infect 1997;37:297e303. 12. Arifn H, Navaratnam P, Kee TK, Balan G. Antibiotic resis- tance patterns in nosocomial Gram-negative bacterial in- fections in units with heavy antibiotic usage. J Trop Pediatr 2004;50:26e31. 13. Levine EM, Ghai V, Barton JJ, Strom CM. Intrapartum anti- biotic prophylaxis increases the incidence of gram-negative neonatal sepsis. Infect Dis Obstet Gynecol 1999;7:210e213. 14. Hyde TB, Hilger TM, Reingold A, Farley MM, OBrien KL, Schuchat A. Trends in incidence and antimicrobial resis- tance of early-onset sepsis: population-based surveillance in San Francisco and Atlanta. Pediatrics 2002;110:690e695. 15. Isaacs D. Rationing antibiotic use in the neonatal unit. Arch Dis Child Fetal Neonatal Ed 2000;82:F1e2. 16. Jain A, Roy I, Gupta MK, Kumar M, Agarwal SK. Prevalence of extended-spectrum beta-lactamase-producing Gram- negative bacteria in septicaemic neonates in a tertiary care hospital. J Med Microbiol 2003;52:421e425. 17. Krishna BVS, Patil AB, Chandrasekhar MR. Extended spec- trum b lactamase producing Klebsiella pneumoniae in neonatal intensive care unit. Indian J Pediatr 2007;74: 627e630. 18. Pessoa-Silva CL, Meurer Moreira B, Almeida VC, et al. Ex- tended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a neonatal unit: risk factors for infection and colonisation. J Hosp Infect 2003;53:198e206. 19. Isaacs D. Unnatural selection: reducing antibiotic resistance in neonatal units. Arch Dis Child Fetal Neonatal Ed 2006;91: F72eF74. 20. Isaacs D. Neonatal sepsis: the antibiotic crisis. Indian Pe- diatr 2005;42:1e5. 21. Sehgal R, Gaind R, Chellani H, Agarwal P. Extended-spec- trum beta lactamase-producing gram-negative bacteria: clinical prole and outcome in a neonatal intensive care unit. Ann Trop Paediatr 2007;27:45e54. 336 A. Tagare et al.