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ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 116-120

Does prolonged initial empirical antibiotics treatment increase morbidity and mortality in preterm infants <34 weeks?


NICU Department, East Jeddah Hospital, Al Sulimanyyah District, Jeddah, Kingdom of Saudi Arabia

Date of Web Publication2-Aug-2018

Correspondence Address:
Dr. Tariq Rushdi Alsafadi
Neonatologist Consultant, East Jeddah Hospital, Jeddah
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_86_17

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  Abstract 


Background: Antibiotics are commonly used in the early postnatal period in preterm infants; its overuse can affect gut colonization and increased the risk of invasive infection. Aims: This study aims to determine whether the prolonged initial empirical antibiotic treatment (PIEAT) increased the risk of necrotizing enterocolitis (NEC), late-onset sepsis (LOS), and death in preterm infants <34 weeks. The secondary study objective was to reveal if severity of illness and sepsis laboratory tests were potential causes for PIEAT. Design: The study was a retrospective study. Setting: This study was conducted at three Neonatal Intensive Care Units (NICUs). Materials and Methods: NICUs medical records from January 2013 to March 2017. Inclusion criteria: (1) preterm infants < 34 weeks, (2) antibiotics started in the 1st postnatal day, (3) negative initial blood culture, (4) patients survived ≥5 days, (5) patients free of NEC in the first 4 postnatal days, and (6) patients without major congenital anomalies. Statistical Analysis: Logistic regression analysis. Results: Five hundred and eighty-seven neonates were eligible. Mean gestational age ± standard deviation (SD): 31.1 ± 2.8 weeks. Mean birth weight ± SD: 1440 ± 380 g. Mean of the duration of initial empirical antibiotic treatment ± SD: 7 ± 3.6 days. PIEAT increased the risk of NEC (odds ratio [OR]: 1.11, confidence interval [CI]: 1.011—1.219), and LOS (OR: 1.133 CI: 1.027—1.251). PIEAT did not significantly increase mortality (OR: 1.083 CI: 0.82—1.42). Sepsis laboratory tests that predicted PIEAT were abnormal leukocytes counts (OR: 1.078 CI: 1.012—1.167) and positive C-reactive protein (CRP) (OR: 1.15 CI: 1.036—1.277). The indicators of severity of illness, high-frequency oscillation ventilation (OR: 0.956 CI.826—1.106), and inotrope use (OR: 1.108 CI: 0.95—1.22) did not predict PIEAT. Conclusion: PIEAT ≥4 days for suspected early-onset sepsis with negative initial blood culture increased the risk of NEC and LOS in preterm infants < 34 weeks. Abnormal white blood cell count, thrombocytopenia, and positive CRP in the first 4 days with negative initial blood culture were potential causes of PIEAT.

Keywords: Late-onset sepsis, mortality, necrotizing enterocolitis, preterm <34 weeks, prolonged antibiotic


How to cite this article:
Alsafadi TR, Alotaibi B, Banabilah H, Bukhary E, Garrada S, Alghamdi A, Almohammal M, Alshumrani N, Alqasim M, Abdulkhahar SA. Does prolonged initial empirical antibiotics treatment increase morbidity and mortality in preterm infants <34 weeks?. J Clin Neonatol 2018;7:116-20

How to cite this URL:
Alsafadi TR, Alotaibi B, Banabilah H, Bukhary E, Garrada S, Alghamdi A, Almohammal M, Alshumrani N, Alqasim M, Abdulkhahar SA. Does prolonged initial empirical antibiotics treatment increase morbidity and mortality in preterm infants <34 weeks?. J Clin Neonatol [serial online] 2018 [cited 2018 Oct 17];7:116-20. Available from: http://www.jcnonweb.com/text.asp?2018/7/3/116/238407




  Introduction Top


Antibiotics are the most commonly prescribed medications in newborn intensive care nurseries.[1] Concerns about occult intrauterine infection precipitating premature labor, premature rupture of membranes, and chorioamnionitis often prompt initiation of empirical antibiotic treatment.[2] Although antibiotic treatment of premature infants may be prudent given these considerations, the duration of treatment is often arbitrary, based not on positive culture results but on the clinician's perceived risk of infection.[3] Intensive broad-spectrum antibiotic use can have serious, unintended consequences in premature infants, including rapidly increasing drug resistance in sepsis cases[4] and increased risk of invasive fungal infection.[5] Antibiotic therapy may have significant adverse consequences in early postnatal weeks[6],[7] coinciding with the time of initial gastrointestinal colonization which may predispose to necrotizing enterocolitis (NEC).[8],[9] The primary study objective was to determine whether prolonged initial empirical antibiotic treatment (PIEAT) increased the risk of NEC, late-onset sepsis (LOS), and death in preterm infants <34 weeks. The secondary study objective was to reveal if severity of illness and sepsis laboratory tests were potential causes for PIEAT.


  Materials and Methods Top


A retrospective study of medical records for all preterm infants <34 weeks who were admitted to the three Neonatal Intensive Care Units (NICUs) from January 2013 to March 2017.

Inclusion criteria: (1) preterm infants <34 weeks, (2) antibiotics started in the 1st postnatal day, (3) negative initial blood culture, (4) patients survived ≥5 days, (5) patients free of NEC in the first 4 postnatal days, and (6) patients without major congenital anomalies.

Initial empirical antibiotic treatment (IEAT) was defined as antibiotics initiated within the 1st postnatal day. PIEAT was defined as ≥4 days of IEAT with sterile initial blood culture result. Duration of IEAT (DIEAT) was defined as number of days until the administration of all initially administered antibiotics was discontinued. For infants with positive blood culture results after the 1st postnatal day, DIEAT was calculated using the date of the first positive culture result as the end date. NEC defined as stage ≥2 according to the modified Bell criteria.[10] LOS defined as positive blood, urine, or cerebrospinal fluid culture after the 3rd postnatal day.

Data were coded and entered using Excel 2013 and SPSS version 18. Data were summarized using mean, standard deviation (SD), and range for quantitative variables and number and percent for qualitative variables. Comparison between groups was done using the Chi-square test for qualitative variables, independent sample t-test for normally distributed quantitative variables, while the Mann—Whitney test was used for qualitative variables which are not normally distributed. Logistic regression analysis was done for predictors of neonatal outcome NEC, death, and LOS. The logistic regression model included maternal, perinatal, and neonatal variables, shown previously to be associated with NEC and death.[11],[12] These variables included: birth weight (BW), gestational age (GA), gender, mode of delivery, premature rupture of membrane (PROM), defined as rupture of membrane >18 h, pregnancy-induced hypertension, multiple births and asphyxia, defined as Apgar score <5 at 5 min. Blood cultures were processed by BACTEC (Becton Dickinson, Sparks, Maryland, United States) system. The usual practice was to take 1 ml blood for culture from the peripheral veins or umbilical venous or arterial catheter. The Logistic regression model included two factors that assess severity of illness in the first 4 postnatal days: 1-high-frequency oscillation [HFO] ventilation. 2-Inotrope use. It included also three sepsis laboratory tests in the first 4 postnatal days: 1-abnormal white blood cell (WBC) counts, defined as WBC >19 or <6 × 109/L. 2-thrombocytopenia, defined as platelets count <150 × 109/L. 3-positive C-reactive protein (CRP), defined as CRP >1 mg/dl. CRP was done using latex agglutination technique, WBC, and platelet counts were measured on an automated counter. We used the same logistic regression model to assess if severity of illness or sepsis laboratory tests could be a potential cause for prolongation of antibiotics. All variables were entered as categorical variables except for BW, GA, DIEAT, and length of hospital stay.


  Results Top


A total of 854 records were screened, 587 patients were eligible. Distribution of patients and type of antibiotics across NICUs were listed in [Table 1]. Mean GA ± SD: 31.1 ± 2.8 weeks, ranged from 24 to 33 weeks, numbers of study neonates according to gestational age was shown in [Figure 1]. Mean BW ± SD: 1440 ± 380 g, ranged from 500 to 2400 g. Mean DIEAT ± SD: 7 ± 3.6 days ranged from 3 to 33 days, numbers of study neonates according to the DIEAT was shown in [Figure 2]. Mean length of hospital stay ± SD: 29 ± 21 days ranged from 5 to 212 days, other patients' characteristics were listed in [Table 2].
Table 1: distribution of patients and type of antibiotics across NICUs

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Figure 1: Numbers of study neonates according to gestational age

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Figure 2: Numbers of study neonates according to the duration of initial empirical antibiotic treatment

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Table 2: characteristics of 587 preterm infants

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Neonates who received PIEAT were more likely to had lower GA (P < 0.001), lower BW (P = 0.001), ventilated by HFO (P = 0.032), received inotrope (P = 0.008), had abnormal WBC count (P = 0.004), positive CRP (0.005), and more NEC (P = 0.018).

By multivariate binary logistic regression, DIEAT (P = 0.028), length of hospital stay (P = 0.004), and abnormal WBC count (P = 0.042), significantly predict NEC. With each additional day of IEAT, the odds of NEC increased (odds ratio [OR]: 1.11, confidence interval [CI]: 1.011—1.219).

Only DIEAT significantly predicts LOS (P = 0.013), with each additional day of IEAT the odds of LOS increased (OR: 1.133 CI: 1.027—1.251).

GA (P = 0.028), length of hospital stay (P = 0.002), multiple gestations (P = 0.039), significantly predict mortality, but not DIEAT (P = 0.566) [Table 3].
Table 3: Logistic regression analysis testing for significant predictors of NEC, LOS, and death

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Sepsis laboratory tests that predicted PIEAT were abnormal WBC counts (OR: 1.078 CI: 1.012—1.167 P = 0.022) and positive CRP (OR: 1.15 CI: 1.036—1.277 P = 0.009) but not thrombocytopenia (OR: 1.03 CI: 0.95—1.11 P = 0.39). The indicators of illness severity, HFO ventilation (OR: 0.956 CI: 826—1.106 P = 0.546), and inotrope use (OR: 1.108 CI: 0.95—1.22 P = 0.214) did not predict PIEAT.


  Discussion Top


This study showed an association between PIEAT and both NEC and LOS in preterm infants <34 weeks, which may be explained by disruption of colonization of developing gastrointestinal tract. Although it is not known to what extent antibiotic exposure disrupts colonization of the developing infant gastrointestinal tract, preterm infants have intestinal microflora distinct from that of healthy, full-term infants.[13],[14] Moreover, several observations suggest the importance of gastrointestinal colonization to the health of premature infants.

Our results showed that abnormal WBC count, thrombocytopenia, and positive CRP in the first 4 days with negative initial blood culture were potential causes of PIEAT; this could be explained by that the sensitivity of one blood culture to detect neonatal bacteremia is approximately 90%, but still not 100% which might have given physicians an excuse to extend antibiotics duration till the sepsis laboratory tests normalized.[15],[16]

Many adjuvant tests are helpful in predicting sepsis (acute phase reactant, cytokines, and procalcitonin). A number of acute phase reactants have been used to identify the septic newborn. Many of these tests are highly sensitive; however, they lack specificity, resulting in a poor predictive value.[17] Cytokines are not routinely measured because of their high cost of testing and because no single biomarker or panel of tests is sufficiently sensitive to reliably detect neonatal sepsis.[18] Although procalcitonin is a promising marker, it appears not to be sufficiently reliable as the sole or main diagnostic indicator for neonatal sepsis, and at this time, it is not routinely available in hospital laboratories. Automated systems for continuous monitoring of blood cultures have shortened the time to identify positive blood cultures. In most cases of neonatal sepsis, a blood culture will become positive within 24—36 h.[19]

Our results were consistent with other studies, Cotten et al. found that the odds of NEC or death and odds of death were increased with PIEAT of ≥5 days, and a trend toward increased odds was demonstrated for NEC. A significant association was found between initial antibiotic course of ≥4 days and the combined outcome of LOS or death in 4039 extremely low birth weight (ELBW) infants.[6] Kuppula et al. reported increase in the odds of having LOS, and composite outcome of LOS, NEC, or death with each additional day of IEAT as well as of PIEAT ≥5 days in 365 very low birth weight (VLBW) infants.[20] Alexander et al. found that antibiotic exposure for >10 days increased the risk of developing NEC by nearly threefold in case—control study.[21] Shah et al. reported that PIEAT of ≥4 days in preterm <28 weeks increase the odd of LOS.[22] Abdel Ghany et al. found that each empirical treatment day was associated with increased odds of death, NEC, and the composite measure of NEC or death in 207 VLBW infants.[23]

Our results did not show association between PIEAT and severity of illness which is consistent with Cordero and Ayres that studied a cohort of 742 ELBW infants with initial sterile blood cultures, 60% received empirical antibiotics for >3 days. They concluded that the decision to extend the duration of empirical antibiotic therapy appeared to be an institutional decision, not based on severity of illness.[3]

Our study is a pioneer in including older preterm infants (<34 weeks) in the cohort, different regimens of prophylactic antibiotics were used across NICUs, which suggest that the potential risk of PIEAT was not related to a specific regimen. The study weaknesses were being retrospective and not including all risk factors for NEC and LOS such as type of milk feeding, central line, use of antacid, and antenatal steroid.


  Conclusion Top


PIEAT ≥4 days for suspected early-onset sepsis with negative initial blood culture increased the risk of NEC and LOS in preterm infants <34 weeks. Abnormal WBC count, thrombocytopenia, and positive CRP in the first 4 days with negative initial blood culture were potential causes of PIEAT. Further research, which better understands the neonatal inflammatory response to sepsis, may result in the identification of sensitive and specific markers of inflammation or the development of pathogen-specific rapid diagnostic tests for the early detection of neonatal sepsis. With a sensitive and specific marker for systemic bacterial infection, the management of neonatal sepsis would be significantly altered so that antimicrobial therapy could be safely withheld in infants for whom sepsis is unlikely.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Cotten CM, McDonald S, Stoll B, Goldberg RN, Poole K, Benjamin DK Jr., et al. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006;118:717-22.  Back to cited text no. 5
    
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Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sánchez PJ, 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;123:58-66.  Back to cited text no. 6
    
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Benjamin DK Jr., Stoll BJ, Fanaroff AA, McDonald SA, Oh W, Higgins RD, et al. Neonatal candidiasis among extremely low birth weight infants: Risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006;117:84-92.  Back to cited text no. 7
    
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Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics 1983;72:317-21.  Back to cited text no. 8
    
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Fanaro S, Chierici R, Guerrini P, Vigi V. Intestinal microflora in early infancy: Composition and development. Acta Paediatr Suppl 2003;91:48-55.  Back to cited text no. 9
    
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Walsh MC, Kliegman RM. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatr Clin North Am 1986;33:179-201.  Back to cited text no. 10
    
11.
Uauy RD, Fanaroff AA, Korones SB, Phillips EA, Phillips JB, Wright LL, et al. Necrotizing enterocolitis in very low birth weight infants: Biodemographic and clinical correlates. National institute of child health and human development neonatal research network. J Pediatr 1991;119:630-8.  Back to cited text no. 11
    
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Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF, et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 2005;115:696-703.  Back to cited text no. 12
    
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Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J 2009;3:944-54.  Back to cited text no. 14
    
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Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Remington JS, editors. Infectious Diseases of the Fetus and Newborn Infant. 7th ed. Philadelphia: Elsevier Saunders; 2010. p. 222.  Back to cited text no. 15
    
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20.
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21.
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22.
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23.
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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