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Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 108-112

Antimicrobial use in a neonatal intensive care unit during a 4-year period

1 Department of Pediatrics and Child Care, Pediatric Infectious Diseases Unit, Santa Casa de São Paulo School of Medicine, São Paulo, SP, Brazil
2 Caxias do Sul Federal University, Caxias do Sul, RS, Brazil

Date of Submission31-Aug-2020
Date of Decision05-Feb-2021
Date of Acceptance16-Feb-2021
Date of Web Publication15-May-2021

Correspondence Address:
Eitan Naaman Berezin
Department of Pediatrics and Child Care, Pediatric Infectious Diseases Unit, Santa Casa de São Paulo School of Medicine, Av Roberto Lorenz 482 CEP 05611-050 São Paulo, SP
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.jcn_143_20

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Background: Due to the difficulty in the diagnosis, high morbidity, and mortality, many empirical antimicrobial treatments have been used on suspicion of neonatal sepsis, leading to inappropriate use of broad-spectrum antibiotics and prolonged duration of therapies. Aim: The aim of this study was to characterize the antimicrobial use in the neonatal intensive care unit (NICU) in 4 years. Methods: This was a retrospective study from January 2013 to December 2016, in a 6-bed NICU from a private small hospital from the South of Brazil. To evaluate the antibiotic use, all results were quantified using days of therapy (DOT) measurement per 100 patients-day (DOT/100PD). Results: Three hundred and sixty-six patients were admitted into the unit. Total antimicrobial use decreased from 78.7 DOT/100PD in 2013 to 73.3 DOT/100PD in 2016. Individually, we observed a reduction from 22.2 to 15.9 DOT/100PD in ampicillin use and 22.7 to 14.2 DOT/100PD for gentamicin. Vancomycin utilization was stable 12.9 DOT/100PD, while oxacillin utilization is increased from 0.6 DOT/100PD to 7.8 DOT/100PD. Conclusions: The changes in antibiotic use during the years could be the result of the multiprofessional efforts in practicing antibiotic stewardship.

Keywords: Antimicrobial agents, neonatal sepsis, newborn

How to cite this article:
Manjabosco AC, Michelin L, Gallacci CB, Berezin EN. Antimicrobial use in a neonatal intensive care unit during a 4-year period. J Clin Neonatol 2021;10:108-12

How to cite this URL:
Manjabosco AC, Michelin L, Gallacci CB, Berezin EN. Antimicrobial use in a neonatal intensive care unit during a 4-year period. J Clin Neonatol [serial online] 2021 [cited 2022 Dec 2];10:108-12. Available from: https://www.jcnonweb.com/text.asp?2021/10/2/108/316172

  Introduction Top

Neonatal sepsis is defined as a clinical syndrome characterized by multiples nonspecific signs and symptoms associated with bacteremia in the 1st month of life.[1],[2] In a recent review, the incidence of neonatal sepsis is around 22 for each 1000 birth, and the mortality rate varied from 11% to 19%.[1] A multicenter study conducted in 2014 in eight Brazilian university hospitals, evaluating 1500 newborns, showed a high incidence and mortality rate from late sepsis in those with a birth weight below 1500 g, and about 76% of infections were caused by Gram-positive organisms, with most risk factors associated with routine practices in intensive care units.[2] Due to its high morbidity and mortality, empirical antimicrobial therapy is promptly initiated in infants with suspected sepsis, making antibiotics the most prescribed medications in the neonatal intensive care units (NICUs). As a result, many neonates who do not have infection often receive antimicrobial agents during a hospital stay and this inappropriate empirical treatment may lead to the emergence of antibiotic-resistant pathogens and serious side effects.[3],[4],[5] According to the study of the National Institute of Child Health and Human Development National Research Network with 6 956 very low birth weight infants, 56% of all infants have received at least one course of antibiotic treatment, even when proven sepsis was diagnosed in only 21% of all them.[6] Among the adverse effects of antibiotic utilization, we can describe changes in the intestinal flora, the appearance of resistant strains, and an increased risk of Candida colonization, and consequently invasive candidiasis.[7]

For cases of proven sepsis, the full course of antibiotic therapy is indicated. On the other hand, the ideal duration of antimicrobial treatment in cases of clinical sepsis, without microbiological evidence, is the target of studies and concerns. Cotten et al. conducted a retrospective study involving 5693 extremely low birth weight newborns who survived more than 5 days and received initial empirical treatment, with negative blood culture after 72 h of life. They concluded that prolonged therapy duration was associated with an increased chance of necrotizing enterocolitis (NEC) and death, and death alone. For each additional day of antibiotic therapy, an increase of 4% for NEC and death, 7% for NEC alone, and 16% for death alone were associated.[5]

The antimicrobial overuse is common worldwide and decreasing antibiotic days of use, mortality, and sepsis-related mortality are critical goals for the patients in NICUs.[4],[7]

Antimicrobial Stewardship Programs (ASPs) aim to increase the judicious use of antimicrobial by optimizing the appropriate selection, dose, duration, and route of antimicrobial therapy,[8] and to assess the antimicrobial stewardship initiatives baseline measurement of antimicrobial use is required.[9],[10],[11] Detailed quantitative and qualitative knowledge of antibiotic use is essential to implement strategies for reducing overuse, underuse, and misuse of antibiotics to address the threat posed by resistant microorganisms. Implementation of ASP in neonatal wards and NICUs is important, owing to long hospital stays and the risk to develop hospital-acquired infections in this population, particularly in preterm and low birth weight infants. Antibiotic use in hospitals can be quantified using several methods. The defined daily dose (DDD) as assigned by the World Health Organization (WHO) has been the most commonly used unit of measurement to quantify (e.g., as the number of DDDs used per 100 hospital days) in various settings and is particularly recommended to compare drug use between (international) settings, and has it shown its value for this purpose.[8],[9],[12]

However, there is little information in describing antibiotic use in the neonatal population in Brazilian hospitals. Most data refer to the DDD as the standard measurement, although it is not an accurate reflection of antibacterial use in pediatric patients.

The WHO International Working Group for Drug Statistics Methodology does not recommend that the DDDs measurement be used in the assessment of antimicrobial use in pediatrics.[13] In children, the days of therapy (DOT) measurement is preferred for measuring antibiotic use because it is independent of age and weight-related differences in doses. The objective of this study was to characterize antimicrobial use over 4 years in the neonatal population using the DOT as the measurement.

  Methods Top

Settings: The Bruno Born Hospital is a tertiary general hospital located in Lajeado, Rio Grande do Sul-Brazil, and its Neonatal Unit is a 10-bed facility (6 NICU and 4 pediatric intensive care unit beds) within a 188-bed capacity private hospital. We performed a retrospective, single-center cohort study for 48 months and there were no changes in the structure or number of beds during this period. The study included all patients <28 days old at the time of admission, who were admitted in the NICU between January 1, 2013 and December 31, 2016.

Data collection: All data were collected from the electronic medical record of the patients, available in the Tasy® program used in the hospital.

Data elements included demographic patient characteristics, discharge diagnoses, antibiotics prescribed, and procedures performed. Clinical characteristics of the newborns were evaluated and registered

  1. Gestational age
  2. Birth weight: The weight was measured on a digital scale, with an accuracy of 5 g, in the care routine for the birth of all patients
  3. Gender: Male or female
  4. Adequacy of birth weight for gestational age: According to birth weight and gestational age through the intrauterine growth curve
  5. Method of delivery
  6. APGAR score in the 1st and 5th min of life
  7. Mother's age at the moment of birth.

Neonates with clinical suspicion of infection had their blood samples collected in the volume of 1 ml and immediately inoculated in bottles for blood culture. Samples were initially submitted to a continuous automated system for bacterial detection (Bactec fluorescent series system® Becton Dickinson Microbiology System). Then, an automated bacterial identification panel (MicroScan Walk-Away® Dade Behring Inc.) was used to identify the bacterial species and perform the antibiotic susceptibility

Units of measure: To evaluate trends of antibiotic use, the rate was expressed as DOT per 100 patient-days (DOT/100PD) as the metric. DOT is calculated as the aggregate sum of antibiotics used per patient per day. If a single patient received two different antimicrobial agents within 2 days, it counted as four DOT.[9] The general antibiotic use included any antibiotic with intravenous, oral, or intramuscular routes of administration and excluded systemic antifungal agents and antiviral agents. We calculated the general antibiotic use DOT/100PD by year and evaluated the trends of each antibiotic use during the study period.

Statistical Analyses: Statistical differences in annual drug utilization rates were analyzed using an SPSS version 13.0 program. A value of P < 0.05 was considered statistically significant.

Ethical considerations: The project was approved by the Ethics Committee by the number 69127017.2.0000.5479. Once no procedure was performed during the study and the retrospective analysis of the medical records gave no risks to patients, the informed consent was deemed to be unnecessary.

  Results Top

During the study period, 366 patients were admitted to the NICU. The total patient-day evaluated each year of the study was 1 710 in 2013, 1 896 in 2014, 2 202 in 2015 and 1 860 in 2016.

Of the total number of newborns, 92.6% (339) were born at the institution itself, 64.2% (235) of which were attended by the Unified Health System. Regarding the profile of the newborns, 59% (216) were female, with an average weight of 2091.7 g (±851.7), gestational age of 34 weeks (21–41), and weight adequacy with gestational age distributed as follows: 28.4% SGA, 67.2% SGA, and 4.4% SIG. The prevalence of natural birth was 25.1% (92). The median length of stay of newborns in the NICU was 13 days (1–166), with the time of use of mechanical ventilation of 4 days (1–70), and the use of parenteral nutrition for 9 days (1–79). Umbilical catheterization (arterial or venous) was performed in 29.5% of hospitalized newborns.

The overall mortality in the NICU during the study period was 9.6%, being: 7.3% in 2013, 11.8% in 2014, 13.3% in 2015, and 6.5% in 2016.

Considering early sepsis, there was a drop in its prevalence from 43.9% to 38% of cases over 4 years, with an average prevalence of 42.3%. Factors associated with late sepsis are indicated in [Table 1], and the clinical features of the newborns considered with early-onset sepsis are indicated in [Table 2].
Table 1: Neonatal factors associated with late-onset sepsis

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Table 2: Neonatal characteristics associated with early-onset sepsis

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Regarding the occurrence of late sepsis, whether clinical or confirmed, the average prevalence in the ICU was 27.6% during the study period.

The overall rate of positivity of blood cultures in cases of late sepsis was 37.7% over the 4 years, varying from 55.5% in 2013 to 19% in 2016. In 32 cases of late sepsis (31.7%), the blood culture test was not requested.

Evaluating the results of blood cultures, Staphylococcus coagulase negative was the most prevalent microorganism (41%), followed by Klebsiella sp. (22%). Other bacteria such as Escherichia coli and Pseudomonas aeruginosa appeared in a smaller proportion (7%).

Total antimicrobial use decreased from 78.7 DOT/100PD to 73.3 DOT/100PD over 2013–2016 fiscal years (6.9% decrease over the four years). In 2015, we observed a higher decrease when comparing to 2013 (7.9%) This decrease was reciprocally associated with an increase of 28.8% in PD this year. The individual antimicrobial use over the 4 years was determined and reported for each year [Table 3]. The percent change in use from 2013 to 2016 was also reported.
Table 3: Antimicrobial use rates in DOT/100PD (Bruno Born Hospital 2013-2016)

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Ampicillin and gentamicin were the most prescribed antimicrobial drugs during the study. Gentamicin had a statistically significant decreasing trend after linear regression was processed, 22.7 DOT/100PD in 2013 to 14.2 DOT/100PD in 2016.

Oxacillin had an increasing trend over the 4 years, from 0.6 DOT/100PD to 7.8 DOT/100PD. Reduction trends were observed for most of the antimicrobial agents, but after linear regression did not have P < 0.05. Percentual changes in use over the years demonstrated reduction for most individual agents, and exceptions included oxacillin (1242% increase), cefepime (766% increase), meropenem (84% increase), and trimethoprim-sulfamethoxazole (56%). Despite the high percentual increase rate, the use of these antimicrobial agents did not exceed 7.8 DOT/100PD.

  Discussion Top

Due to the vulnerability of neonates, and particularly of preterm infants, empirical antimicrobial therapy is frequently initiated in this population.[10] The balance between adequate and unnecessary antibiotic use in neonates remains a challenge, although there is considerable variation in the overall use of antibiotics, as well as the selection of antibiotic agents.[11] This study shows that the reduction of antibiotic use is possible and still safe for neonates DDD as defined by the WHO has been the most frequently used unit of measurement to measure antibiotic use. However, measuring antibiotic use in pediatrics is a problem as the WHO DDD methodology is not always applicable in children.[14] Based on the narrow range of body weights in the neonatal population we suggest, illustrated by the example of antibiotics, that the neonatal DDD is a good alternative unit of measurement, both in research and for benchmarking purposes. We, therefore, aimed to evaluate neonatal DDDs for antibiotics in a Brazilian neonatal Unit. It is difficult to compare antimicrobial use at one institution with another, not only because of differences in patient populations but also because most data concerning antimicrobial use have been reported in the DDD, and limited national studies have been published considering the neonatal population. However, report the trend in antimicrobial use at a Brazilian NICU by quantifying it in DOT per 100 patient-days makes this study useful for comparisons, once this is the preferred metric for children.

We observed a 6.9% decrease in the rate DOT/100PD over 4 years, although the decline was not statistically relevant. Comparing to the study performed by Dalton et al.,[15] which reported an 11.2% change in antimicrobial use in the neonatal population, from de 69.93 DOT/100PD to 62.1 DOT/100PD in 2014, we concluded that we still have been using more antimicrobial agents in this specific population, although both centers have reported the same reduction trend. Prolonged duration of therapy for possible early-onset sepsis is probably the main cause of the higher antimicrobial use at our unit, although our sample represents the pattern of a small community hospital, different from a large academic health-care center. Antimicrobial use rates for individual agents have been described, and most agents had a reduction in the percentual change over the years of 2013 and 2016. Aminoglycosides were the most frequently prescribed class of antimicrobial agents. Gentamicin had a significant (P < 0.05) decreasing trend, and we believe this is due to the effort to shorten the length of therapies, especially when no microorganism was isolated in blood culture. In contrast, we observed an increasing trend in the oxacillin use, and this increase could be justified by the politics to discourage the vancomycin use when treating infections not caused by methicillin-resistant Staphylococcus aureus. According to Levy et al.,[8] ampicillin, gentamicin metronidazole, and rifampin use decreased significantly from 2007 to 2010, but probably because of the replacement of the combination therapy by monotherapy with broad-spectrum drugs. When considering the broad-spectrum drugs, we observed an increasing rate of use of meropenem and cefepime, probably due to the failure to de-escalate or suspend the therapy when the patient was clinically well and no organism was identified in blood culture. This study also showed a decreased rate of use of vancomycin due to the increasing in oxacillin utilization as the first choice for late-onset sepsis.

  Conclusions Top

Although it has been only a 4-year study, knowing the population profile of germs and the antimicrobial trends of use leads the medical team to choose the best strategies and duration of treatments in the NICU. The implementation of ASP involving all multidisciplinary teams will lead to a certain reduction in the consumption of this class of medication bringing not only economic benefits but also improvements in patients' survival.[16]

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Conflicts of interest

There are no conflicts of interest.

  References Top

Fleischmann-Struzek C, Goldfarb DM, Schlattmann P, Schlapbach LJ, Reinhart K, Kissoon N. The global burden of paediatric and neonatal sepsis: A systematic review. Lancet Respir Med 2018;6:223-30.  Back to cited text no. 1
de Souza Rugolo LM, Bentlin MR, Mussi-Pinhata M, de Almeida MF, Lopes JM, Marba ST, et al. Late-onset sepsis in very low birth weight infants: A Brazilian Neonatal Research Network Study. J Trop Pediatr 2014;60:415-21.  Back to cited text no. 2
Tzialla C, Borghesi A, Serra G, Stronati M, Corsello G. Antimicrobial therapy in neonatal intensive care unit. Ital J Pediatr 2015;41:27.  Back to cited text no. 3
Tripathi N, Cotten CM, Smith PB. Antibiotic use and misuse in the neonatal intensive care unit. Clin Perinatol 2012;39:61-8.  Back to cited text no. 4
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. 5
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;110:285-91.  Back to cited text no. 6
Kaufman DA. “Less is more”: Decreasing antibiotic days in the NICU. J Pediatr (Rio J) 2013;89:424-5.  Back to cited text no. 7
Levy ER, Swami S, Dubois SG, Wendt R, Banerjee R. Rates and appropriateness of antimicrobial prescribing at an academic children's hospital, 2007-2010. Infect Control Hosp Epidemiol 2012;33:346-53.  Back to cited text no. 8
Natsch S, Hekster YA, de Jong R, Heerdink ER, Herings RM, van der Meer JW. Application of the ATC/DDD methodology to monitor antibiotic drug use. Eur J Clin Microbiol Infect Dis 1998;17:20-4.4  Back to cited text no. 9
Araujo da Silva AR, Marques A, Di Biase C, Faitanin M, Murni I, Dramowski A, et al. Effectiveness of antimicrobial stewardship programmes in neonatology: A systematic review. Arch Dis Child 2020;105:563-8.  Back to cited text no. 10
Versporten A, Sharland M, Bielicki J, Drapier N, Vankerckhoven V, Goossens H, et al. The antibiotic resistance and prescribing in European Children project: A neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J 2013;32:e242-53.  Back to cited text no. 11
Gerber JS, Kronman MP, Ross RK, Hersh AL, Newland JG, Metjian TA, et al. Identifying targets for antimicrobial stewardship in children's hospitals. Infect Control Hosp Epidemiol 2013;34:1252-8.  Back to cited text no. 12
World Health Organization. Guidelines for ATC Classification and DDD Assignment. Oslo: WHO Collaborating Centre for Drug Statistics Methodology, Norwegian Institute of Public Health; 2002.  Back to cited text no. 13
Pakyz AL, Gurgle HE, Ibrahim OM, Oinonen MJ, Polk RE. Trends in antibacterial use in hospitalized pediatric patients in United States academic health centers. Infect Control Hosp Epidemiol 2009;30:600-3.  Back to cited text no. 14
Dalton BR, MacTavish SJ, Bresee LC, Rajapakse N, Vanderkooi O, Vayalumkal J, et al. Antimicrobial use over a four-year period using days of therapy measurement at a Canadian pediatric acute care hospital. Can J Infect Dis Med Microbiol 2015;26:253-8.  Back to cited text no. 15
Liem TB, Heerdink ER, Egberts AC, Rademaker CM. Quantifying antibiotic use in paediatrics: A proposal for neonatal DDDs. Eur J Clin Microbiol Infect Dis 2010;29:1301-3.  Back to cited text no. 16


  [Table 1], [Table 2], [Table 3]


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