Ampicillin versus penicillin in the empiric therapy of extremely low-birthweight neonates at risk of early onset sepsis
Corresponding Author
Tuuli Metsvaht
Pediatric and Neonatal Intensive Care, Tartu University Clinics
Tuuli Metsvaht, MD PhD, Pediatric and Neonatal Intensive Care Unit, Lunini 6, 51014 Tartu, Estonia. Email: [email protected]Search for more papers by this authorMari-Liis Ilmoja
Pediatric Intensive Care, Tallinn Children's Hospital, Tallinn
Search for more papers by this authorMirjam Merila
Department of Pediatrics, Tartu University Clinics, Tartu, Estonia
Search for more papers by this authorLea Maipuu
Pediatric and Neonatal Intensive Care, Tartu University Clinics
Search for more papers by this authorPiia Müürsepp
Department of Pediatrics, Tartu University Clinics, Tartu, Estonia
Search for more papers by this authorKadri Julge
Pediatric Intensive Care, Tallinn Children's Hospital, Tallinn
Search for more papers by this authorCorresponding Author
Tuuli Metsvaht
Pediatric and Neonatal Intensive Care, Tartu University Clinics
Tuuli Metsvaht, MD PhD, Pediatric and Neonatal Intensive Care Unit, Lunini 6, 51014 Tartu, Estonia. Email: [email protected]Search for more papers by this authorMari-Liis Ilmoja
Pediatric Intensive Care, Tallinn Children's Hospital, Tallinn
Search for more papers by this authorMirjam Merila
Department of Pediatrics, Tartu University Clinics, Tartu, Estonia
Search for more papers by this authorLea Maipuu
Pediatric and Neonatal Intensive Care, Tartu University Clinics
Search for more papers by this authorPiia Müürsepp
Department of Pediatrics, Tartu University Clinics, Tartu, Estonia
Search for more papers by this authorKadri Julge
Pediatric Intensive Care, Tallinn Children's Hospital, Tallinn
Search for more papers by this authorAbstract
Background: There are no comparative data on the impact of different empiric antibiotic regimens on early bowel colonization as well as on clinical efficacy in extremely low-birthweight (ELBW) neonates at risk of early onset sepsis (EOS).
Methods: A subgroup analysis was carried out of ELBW neonates recruited into a two-center, prospective, cluster randomized study comparing ampicillin and penicillin both combined with gentamicin, within the first 72 h of life. A composite primary end-point (need for change of antibiotics within 72 h and/or 7 day all-cause mortality) and the rate and duration of colonization by opportunistic aerobic microorganisms were assessed using hierarchical models corrected for study center and period.
Results: In the ampicillin (n= 36) and penicillin (n= 39) groups change of antibiotics, 7 day mortality and the composite end-point occurred at similar rates. Neonatal intensive care unit mortality for infants with gestational age <26 weeks was lower in the ampicillin group. Ampicillin treatment was associated with a higher colonization rate by Klebsiella pneumoniae, including ampicillin-resistant strains.
Conclusion: Preliminary data indicate an urgent need for adequately powered studies of early antibiotic therapy in the subpopulation of ELBW neonates at risk of EOS.
References
- 1 Mtitimila EI, Cooke RW. Antibiotic regimens for suspected early neonatal sepsis. Cochrane Database Syst. Rev. 2004; (4): CD004495.
- 2 Ronnestad A, Abrahamsen TG, Medbo S et al. Septicemia in the first week of life in a Norwegian national cohort of extremely premature infants. Pediatrics 2005; 115: e262–8.
- 3 Stoll BJ, Gordon T, Korones SB et al. Early-onset sepsis in very low birth weight neonates: A report from the National Institute of Child Health and Human Development Neonatal Research Network. J. Pediatr. 1996; 129: 72–80.
- 4 Klinger G, Levy I, Sirota L, Boyko V, Reichman B, Lerner-Geva L. Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants. Am. J. Obstet. Gynecol. 2009; 201: 38. e1–6.
- 5 Lopez Sastre JB, Coto Cotallo GD, Fernandez Colomer B. Neonatal sepsis of vertical transmission: An epidemiological study from the “Grupo de Hospitales Castrillo”. J. Perinat. Med. 2000; 28: 309–15.
- 6 Schultz C, Temming P, Bucsky P, Gopel W, Strunk T, Hartel C. Immature anti-inflammatory response in neonates. Clin. Exp. Immunol. 2004; 135: 130–36.
- 7 Strunk T, Temming P, Gembruch U, Reiss I, Bucsky P, Schultz C. Differential maturation of the innate immune response in human fetuses. Pediatr. Res. 2004; 56: 219–26.
- 8 Tessin I, Trollfors B, Thiringer K, Larsson P. Ampicillin-aminoglycoside combinations as initial treatment for neonatal septicaemia or meningitis. A retrospective evaluation of 12 years' experience. Acta Paediatr. Scand. 1991; 80: 911–16.
- 9 Stoll BJ, Hansen NI, Higgins RD et al. Very low birth weight preterm infants with early onset neonatal sepsis: The predominance of gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002–2003. Pediatr. Infect. Dis. J. 2005; 24: 635–9.
- 10 Bizzarro MJ, Dembry LM, Baltimore RS, Gallagher PG. Changing patterns in neonatal Escherichia coli sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis. Pediatrics 2008; 121: 689–96.
- 11 Laugel V, Kuhn P, Beladdale J et al. Effects of antenatal antibiotics on the incidence and bacteriological profile of early-onset neonatal sepsis. A retrospective study over five years. Biol. Neonate 2003; 84: 24–30.
- 12 Schrag SJ, Stoll BJ. Early-onset neonatal sepsis in the era of widespread intrapartum chemoprophylaxis. Pediatr. Infect. Dis. J. 2006; 25: 939–40.
- 13 Kuo KC, Shen YH, Hwang KP. Clinical implications and risk factors of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae infection in children: A case-control retrospective study in a medical center in southern Taiwan. J. Microbiol. Immunol. Infect. 2007; 40: 248–54.
- 14 Crivaro V, Bagattini M, Salza MF et al. Risk factors for extended-spectrum beta-lactamase-producing Serratia marcescens and Klebsiella pneumoniae acquisition in a neonatal intensive care unit. J. Hosp. Infect. 2007; 67: 135–41.
- 15 Graham PL 3rd, Della-Latta P, Wu F, Zhou J, Saiman L. The gastrointestinal tract serves as the reservoir for Gram-negative pathogens in very low birth weight infants. Pediatr. Infect. Dis. J. 2007; 26: 1153–6.
- 16 Burman LG, Berglund B, Huovinen P, Tullus K. Effect of ampicillin versus cefuroxime on the emergence of beta-lactam resistance in faecal Enterobacter cloacae isolates from neonates. J. Antimicrob. Chemother. 1993; 31: 111–16.
- 17 Bennet R, Eriksson M, Nord CE. The fecal microflora of 1–3-month-old infants during treatment with eight oral antibiotics. Infection 2002; 30: 158–60.
- 18 de Man P, Verhoeven BA, Verbrugh HA, Vos MC, van den Anker JN. An antibiotic policy to prevent emergence of resistant bacilli. Lancet 2000; 355: 973–8.
- 19 Metsvaht T, Ilmoja M-L, Parm Ü, Maipuu L, Merila M, Lutsar I. Comparison of ampicillin plus gentamicin vs penicillin plus gentamicin in empiric treatment of neonates at risk of early onset sepsis. Acta Paediatr. 2010; 99: 665–72.
- 20 Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm. Rep. 2002; 51: 1–22.
- 21 Young TE, Mangum B. Neofax: A Manual of Drugs Used in Neonatal Care, 17th edn. Acorn Publishing, Raleigh, NC, 2004.
- 22 Lutsar I, Tamm E, Metsvaht T, Roos R. Antimicrobial Drug Administration for Children. AS Medicina, Tallinn, 2005.
- 23 Metsvaht T, Oselin K, Ilmoja ML, Anier K, Lutsar I. Pharmacokinetics of penicillin g in very-low-birth-weight neonates. Antimicrob. Agents Chemother. 2007; 51: 1995–2000.
- 24 Wilson ML, Mitchell M, Morris AJ. Principles and procedures for blood cultures; approved guideline. CLSI 2007; 27: 1–67.
- 25 Stoll BJ, Hansen N, Fanaroff AA et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N. Engl. J. Med. 2002; 347: 240–47.
- 26 Bell MJ, Ternberg JL, Feigin RD et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg. 1978; 187: 1–7.
- 27 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 gm. J. Pediatr. 1978; 92: 529–34.
- 28 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 2001; 163: 1723–9.
- 29 ARPAC. PFGE typing protocol recommended by ARPAC for Acinetobacter baumannii. Available from URL: http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1194947313339 (accessed June 2009).
- 30 Holmsgaard KW, Petersen S. Infants with gestational age 28 weeks or less. Dan. Med. Bull. 1996; 43: 86–91.
- 31 Hoekstra RE, Ferrara TB, Couser RJ, Payne NR, Connett JE. Survival and long-term neurodevelopmental outcome of extremely premature infants born at 23–26 weeks' gestational age at a tertiary center. Pediatrics 2004; 113: e1–6.
- 32 Schelonka RL. Detente in the war against bugs. Pediatr. Infect. Dis. J. 2007; 26: 600–601.
- 33 Parm U, Metsvaht T, Sepp E et al. Impact of empiric antibiotic regimen on bowel colonization in neonates with suspected early onset sepsis. Eur. J. Clin. Microbiol. Infect. Dis. 2010; 29: 807–16.
- 34 Parm U, Metsvaht T, Sepp E et al. Risk factors associated with gut and nasopharyngeal colonization by common Gram-negative species and yeasts in neonatal intensive unit patients. Early Hum. Dev. 2011; 87: 391–9.
- 35 Donskey CJ. The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens. Clin. Infect. Dis. 2004; 39: 219–26.
- 36 Tagare A, Kadam S, Vaidya U, Pandit A. Routine antibiotic use in preterm neonates: A randomised controlled trial. J. Hosp. Infect. 2010; 74: 332–6.
- 37 Mitt P, Adamson V, Loivukene K et al. Epidemiology of nosocomial bloodstream infections in Estonia. J. Hosp. Infect. 2009; 71: 365–70.
- 38 Jones B, Peake K, Morris AJ, McCowan LM, Battin MR. Escherichia coli: A growing problem in early onset neonatal sepsis. Aust. N. Z. J. Obstet. Gynaecol. 2004; 44: 558–61.
- 39 Larson EL, Cimiotti JP, Haas J et al. Gram-negative bacilli associated with catheter-associated and non-catheter-associated bloodstream infections and hand carriage by healthcare workers in neonatal intensive care units. Pediatr. Crit. Care Med. 2005; 6: 457–61.
- 40 Hutchin T, Haworth I, Higashi K et al. A molecular basis for human hypersensitivity to aminoglycoside antibiotics. Nucleic Acids Res. 1993; 21: 4174–9.
- 41 Bitner-Glindzicz M, Pembrey M, Duncan A et al. Prevalence of mitochondrial 1555A–>G mutation in European children. N. Engl. J. Med. 2009; 360: 640–42.
- 42 Vandebona H, Mitchell P, Manwaring N et al. Prevalence of mitochondrial 1555A–>G mutation in adults of European descent. N. Engl. J. Med. 2009; 360: 642–4.
- 43 Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for spontaneous preterm labour: The ORACLE II randomised trial. ORACLE Collaborative Group. Lancet 2001; 357: 989–94.
- 44 Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: The ORACLE I randomised trial. ORACLE Collaborative Group. Lancet 2001; 357: 979–88.
- 45 Al-Sabbagh A, Moss S, Subhedar N. Neonatal necrotising enterocolitis and perinatal exposure to co-amoxyclav. Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F187.