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ORIGINAL RESEARCH |
https://doi.org/10.5005/jp-journals-11002-0098 |
Concerns about Mis-/Overuse of Antibiotics in Neonates Born at ≤32 Weeks Gestational Age in Latin American Neonatal Units: Eight Years of Experience in the EpicLatino Database
1Department of Pediatrics, Universidad El Bosque, Bogota, Distrito Capital, Colombia
2Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
3Department of Pediatrics - Neonatology, University of British Columbia, Vancouver, Canada
4Department of Pediatrics and Neonatology, University of Calgary, Calgary, Alberta, Canada
5Department of Pediatrics and Neonatology, Clinica del Country, Bogotá, Colombia, Distrito Capital, Colombia
6Department of Pediatrics and Neonatology, Dalhousie University, Helifax, NB, Canada
7Department of Pediatrics and Neonatology, Central Hospital Dr. Ignacio Morones Prieto, SLP, San Luis Potosi, Mexico
8Department of Pediatrics and Neonatology, Hospital Metropolitano, Quito, Ecuador
9Department of Pediatrics and Neonatology, Nuestra Sra. de las Mercedes Maternity, Tucuman, San Miguel de Tucuman, Argentina
Corresponding Author: Angela B Hoyos, Department of Pediatrics, Universidad El Bosque, Bogota, Distrito Capital, Colombia, Phone: +57 3157926533, e-mail: angelahoyos@hotmail.com
How to cite this article: Hoyos AB, Salas A, Osiovich H, et al. Concerns about Mis-/Overuse of Antibiotics in Neonates Born at ≤32 Weeks Gestational Age in Latin American Neonatal Units: Eight Years of Experience in the EpicLatino Database. Newborn 2024; 3 (2):83–89.
Source of support: Nil
Conflict of interest: None
Received on: 25 April 2024; Accepted on: 23 May 2024; Published on: 21 June 2024
ABSTRACT
There is considerable variability in the duration of antibiotic in neonatal intensive care units (NICUs) all over the world and is highly dependent on gestational ages (GA). It is difficult to withhold antibiotics in critically ill preterm infants because the possibility of infection is difficult to exclude in these patients and the acuity of illness can progress rapidly with potentially disastrous consequences. Available data encouragingly suggest that the incidence of early onset sepsis (EOS) might be lower in EpicLatino units in Latin America compared with Canadian research network (CNN) in 2022 in <30 weeks, but late onset sepsis (LOS) is more frequent at different GA. However, there is an overall scarcity of detailed information from many countries. The annual reports from EpicLatino database do show a high degree of variability in outcomes and a need for cautious interpretation of these figures. However, we still need to establish clear standards for antibiotic use in premature infants; these drugs are essential for combating infections and saving lives but mis-/overuse can exacerbate the risk of late-onset infections, necrotizing enterocolitis (NEC), bacterial resistance, and increase the cost of care. In this study, we aimed to find information on the patterns of antibiotic use in infants born at ≤32 weeks’ gestation in the EpicLatino units during the period 2015–2022. A specifically designed questionnaire was sent to unit medical directors to determine whether the total antibiotic use per unit per 1,000 patient-days correlated with the incidence-rate ratios. This is a data-collecting/descriptive study that it will help us in designing further efforts and choosing the sites for intervention.
Keywords: Antibiotics per 1, 000 patient-days, Antibiotic use practices, Baby, EpicLatino database, Infant, Latin America and the Caribbean, Mortality, Neonatal intensive care units, Neonatal outcomes, Neonates, Newborn, Premature neonates.
KEY POINTS
The utilization of antibiotics in neonatal intensive care units (NICUs) in patients ≤32 weeks gestational age (GA) at birth worldwide shows considerable variability across countries and its study is constrained by ethical and practical limitations that impede comprehensive investigation.
Antibiotics might be essential for treatment of premature and critically ill infected infants, but over-/misuse of these drugs can exacerbate the risk of late-onset infections, necrotizing enterocolitis, infections with resistant bacterial strains, and increase the cost of care.
We need to establish clear parameters to guide antibiotic use in patients ≤32 weeks GA at birth, based on severity-of-illness and positive blood or cerebrospinal fluid cultures.
In this study, we examined the data in the EpicLatino database to compare antibiotic use in patients ≤32 weeks GA at birth at different NICUs. This database helped obtain a statistically relevant sample, more than the numbers we could find in individual units.
We aggregated antibiotic days per 1,000 patient-days for each unit in patients ≤32 weeks GA at birth over an extended period of 8 years. A logistic regression analysis was performed to identify the most critical factors. Data from the unit with the best results were used as the baseline.
INTRODUCTION
Antimicrobial agents are one of the most frequently prescribed class of medications in NICUs.1 A point prevalence study across 29 NICUs, Clark et al. revealed that 47% of infants were receiving at least one antibiotic at the time of data extraction.2 In 2021, a global assessment of antimicrobial agents prescribed to NICU infants found that 26% of infants across 84 NICUs from 29 countries received at least one antimicrobial agent. The most common reasons for antibiotic use were “rule-out” sepsis (32%) and “culture-negative” sepsis (16%). Antibiotic use remained frequent and prolonged regardless of culture results, with units employing step/down programs showing reduced antibiotic usage.3 Critically ill preterm infants pose a challenge for withholding antibiotics due to the difficulty in excluding infection, potentially leading to rapid progression of illness if untreated.4
In high-income countries, blood cultures confirmed early/late-onset infection (early were defined as early those seen within the first 72 hours after birth and late thereafter), in 0.4–0.8/1000 term infants.5–8 While antibiotics may be life-saving for infants with culture-negative sepsis, culture-negative presumed sepsis significantly contributes to high antibiotic consumption in NICUs.8,9 Antibiotics may be life-saving for a few infants who actually have culture-negative sepsis.10 Nevertheless, the statistics in culture/negative sepsis is problematic since there is no way to confirm that those patients did have bacterial sepsis, and most units will complete full curse assuming it was a bacterial sepsis. There are concerns that overuse of broad-spectrum antibiotics can promote colonization with antibiotic-resistant bacteria.11,12
The management of neonates born at >36 weeks’ gestation with suspected or proven early onset bacterial sepsis has changed dramatically in the last decades.13 New tools like the Kaiser Permanente neonatal early onset sepsis (EOS) risk calculator and NICE guideline for full term based on incidence in each unit, has been useful to decrease the antibiotic use identifying asymptomatic cases.14,15 However, the diagnosis of EOS in babies <36 weeks are more challenging, and delivery characteristics of extremely preterm infants present an opportunity to identify those with a lower risk of EOS and may inform decisions to initiate or extend antibiotic therapies.16
The EpicLatino database originates data from Latin American units from middle-income countries with culture laboratory facilities. The conventional categorization of medical literature into high-income (HIC) and low-to-middle income (L/MIC) is inconvenient for middle-income countries due to statistical disparities.17 The EpicLatino database comprises units sharing common Spanish ancestry, language, Catholic religion, history, customs, and values, making it an ideal source for statisticalanalysis.
Although EpicLatino shows lower relatively lower rates of EOS than in other peri-equatorial/tropical regions in the world, caution is warranted due to limited site representation and the need for careful interpretation.18,19 The belief that blood cultures may confirm infections in only half or less of all infants with suspected sepsis, creates important ethical and practical constraints in withholding antibiotics.20,21 However, confirming infection solely through positive cultures remains the gold standard, since many culture-negative infections may not be caused by bacteria. It is for this reason that many studies require infections demonstrated by cultures. For example, the data of the Canadian neonatal network (CNN) from which EpicLatino was born, only count bacterial sepsis as those with a positive blood or CSF culture.22
We looked for information in the records in the EpicLatino database. A high degree of variability in clinical practice is readily noticeable with a need for clear standards for antibiotic use. There was a high degree of variability and a clear need for standards for antibiotic use.23 These are essential for combating infections and saving lives, but the mis-/overuse of these drugs can also exacerbate the risk of late onset sepsis (LOS), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia, prevalence of multi-drug resistant bacterial strains, and higher costs-of-care.24
In the clinical setting, we often initiate antibiotics due to multiple reasons; one important factor that alters the risk-to-benefit ratio is inadequate maternal/fetal clinical information such as a suspicion of chorioamnionitis. We need consensus-based guidelines that might include acute phase reactants, positive blood or cerebrospinal fluid cultures, and others to guide the choice and duration of specific treatment. Over time, as the group gains confidence, it might be possible to tighten these protocols. A better understanding of various predisposing factors will facilitate clear and timely decisions.
OBJECTIVE
In this study, we recorded the duration of antibiotic therapy and standardized these data using statistical methods. We also sought to identify the determinants of the duration of antibiotic therapy. This is an exploratory study, but these figures are extremely important for us in designing further studies/choosing sites for intervention.
Materials and Methods
We examined the EpicLatino database, which includes data from 32 units in Latin America and the Caribbean, from the period 2015–2022 (Table 1) for infants born with a GA ≤32 weeks.25 We designed a questionnaire (Table 2) and sent it to directors of EpicLatino units to find whether the total antibiotic use per unit per 1,000 patient-days correlated with incidence rate ratios (IRRs). We included all patients in the database to avoid bias related to the severity of illness.
| Units | City/Country |
|---|---|
| Centenario H. de Esp. Miguel Hidalgo | Aguascalientes, Mexico |
| Clínica Dávila | Santiago, Chile |
| Clínica de Santa María de Santiago | Santiago, Chile |
| Clínica del Country | Bogotá, Colombia |
| Clínica la Colina | Bogotá, Colombia |
| Clínica Materno Infantil San Luis | Bucaramanga, Colombia |
| Clínica San Felipe | Lima, Perú |
| Clínica Santa Bárbara | Quito, Ecuador |
| Clínica Somer | Rio Negro, Colombia |
| Clínica Universitaria Colombia | Bogotá, Colombia |
| Clínica Vespucio | Santiago, Chile |
| Colsanitas – Clínica Pediátrica UCI Neonatal | Bogotá, Colombia |
| Curaçao Medical Center | Willemstad, Curaçao |
| H Regional DR Rafael Pascacio Gamboa | Tuxtla Gutiérrez, México |
| Hospital Central Dr. Ignacio Morones Prieto | San Luis Potosí, México |
| Hospital Civil de Ipiales E.S.E | Ipiales, Colombia |
| Hospital de los Valles | Quito, Ecuador |
| Hospital Departamental San Vicente de Paul | Garzón, Huila, Colombia |
| Hospital Dr. Florencio Escardó | Tigre, Argentina |
| Hospital Español de Mendoza | Mendoza, Argentina |
| Hospital General EISS de Manta | Manta, Ecuador |
| Hospital Italiano de La Plata | La Plata, Argentina |
| Hospital Luis Lagomaggiore | Mendoza, Argentina |
| Hospital Metropolitano | Quito, Ecuador |
| Hospital Militar Central | Bogotá, Colombia |
| Hospital Regional Universitario de Colima | Colima, México |
| Hospital San Francisco de Quito | Quito, Ecuador |
| Hospital San José | Bogotá, Colombia |
| Hospital Santísima Trinidad | Asunción, Paraguay |
| Los Cobos Medical Center | Bogotá, Colombia |
| Maternidad Nuestra Sra. de las Mercedes | Tucumán, Argentina |
| S.E.S. Hospital de Caldas | Manizales, Colombia |
| 1. Do you initiate antibiotics in premature infants ≤32 weeks gestation as follows: A) Initiate antibiotics in all or almost all premature infants ≤32 weeks GA after birth due to the risk of infection?46 B) Select premature infants ≤32 weeks gestation for antibiotic administration based on risk factors or laboratory tests. |
| 2. If premature infants ≤32 weeks gestation are born outside your institution, do you manage them the same way as those born in your institution?47 A) Yes B) No |
| 3. If the mother has received prenatal antibiotics, do you use the same criteria to initiate antibiotics in premature infants ≤32 weeks gestation? A) Yes B) No |
| 4. Do you take blood cultures, if possible, for all premature infants who are going to receive antibiotics? A) Yes B)No |
| 5. If you select the premature infants to whom antibiotics will be administered at birth (skip this question if you administer them to almost all infants): A) Select premature infants based on risk factors B) Select premature infants based on laboratory results obtained within the first 24 hours C) Do not perform tests and rely on clinical follow-up D) Both A and B |
| 6. For premature infants who undergo blood cultures: A) If the premature infant is stable and the blood cultures are negative, antibiotics are discontinued within 24–72 hours B) Despite negative results, antibiotics are often continued for 5–10 days due to a lack of confidence in the results |
| 7. In addition to blood cultures, what laboratory tests do you use to decide whether to initiate/continue antibiotics? A) Complete blood count B) C-reactive protein C) Procalcitonin D) No tests are used to make this decision E) Other tests not listed F) A and B, or A and D |
| Antibiotics initiated after the second day of life: |
| 8. If a premature infant deteriorates (increased apnea, dusky color, lethargy, persistent vomiting, abdominal distension, among others): A) Blood cultures are taken, and antibiotics are initiated regardless of the results of other tests, if performed. B) Blood cultures and other tests are taken, and antibiotics are initiated based on the results of the other tests. C)Antibiotics are initiated before taking blood cultures or other tests, if performed. |
| 9. For premature infants who received antibiotics:8 A) If the premature infant is stable, there have been no changes in the laboratory findings, and blood cultures are negative, antibiotics are discontinued within 24–72 hours. B) Despite negative blood cultures, antibiotics are often continued for more than 72 hours due to a lack of confidence in the results. |
| 10. Duration of antibiotic treatment in premature infants ≤32 weeks gestation with positive blood cultures:15 A)Antibiotics are discontinued when symptoms resolve or 2–3 days later, regardless of the treatment duration. B) Antibiotics are only discontinued if a new blood culture is negative and/or the previously positive laboratory tests completely normalize, regardless of symptoms. C) The duration depends on the type of organism. D) The established treatment duration in the unit is always completed (7, 10, 14, 21 days). E) Options C and D include our management in the unit. |
| 11. Use of antibiotics in premature infants ≤32 weeks gestation with negative blood cultures:15 A) It is common to complete the antibiotic course, even if blood cultures are negative due to a lack of confidence in them. B) It is uncommon to continue antibiotics with negative blood cultures, only in highly symptomatic patients or in conditions such as enterocolitis. C) All premature infants at a predetermined GA (<30, <28, or <26 weeks gestation) receive antibiotic regimens of 7, 10, 14, or 21 days regardless of symptoms or laboratory tests. |
| Use of antibiotics in your unit: |
| 12. In your unit, do you think that: A) Antibiotics are used excessively. B) Antibiotics are used sparingly. |
We used negative binomial regression with standard errors and confidence intervals (CIs) computed for IRRs to analyze comparative statistics on antibiotic days per 1,000 patient-days between units using the unit with the best results as a baseline.26–28 Stata 18 software was used for statistical analysis. The variables used to adjust the regression analysis were NEC, GA at birth, infected patients (positive blood or cerebrospinal fluid cultures), length of stay, time-period (before/after 2020), and mortality. We reviewed other variables such as inborn/outborn, suspected chorioamnionitis, SNAPEII score, but as we found no significant difference with the use of antibiotics, we did not include them in the logistic regression so as not to lose power.
RESULTS
Figure 1 illustrates the antibiotic usage in units compared with Unit 2, which we used as our baseline as it had the lowest number of antibiotic days per 1,000 patient-days, and sufficient case numbers. The light blue color on the graph represents the number of cases in each unit. The two numbers next to each dot represent the number of antibiotic days per 1,000 patient-days alongside the adjusted IRR and its 95% CI adjusted for the mentioned variables.
Fig. 1: EpicLatino Database 2015–2022. Premature infants ≤32 weeks GA, actual value [days of antibiotics per 1,000 patient-days (DA/P)] and adjusted incidence rate ratio (IRR) (95% CI) on logarithmic scale adjusted for GA, positive blood/CSF cultures, length of stay, NEC, time period and death
Table 3 shows the criteria used by Unit 2 to reduce antibiotic use. All units that responded to the questionnaire (representing 99.5% of records) exhibited 1–6 differences compared with the baseline unit. There was no apparent correlation between responses and IRRs for each unit. Notably, among units that perceived themselves as using few antibiotics (as indicated in the final question), the average IRR for these units was 2.4, and three of them had an IRR above 3.
| 1. Premature infants ≤32 weeks gestation who will receive antibiotics are selected based on risk factors and/or laboratory tests. |
| 2. Antibiotics are not used solely based on being born outside the institution or maternal antibiotic use. |
| 3. Antibiotics are only administered if clinical symptoms are present and confirmed by laboratory data (complete blood count and C-reactive protein). |
| 4. If the premature infant is stable and blood cultures are negative, antibiotics are discontinued within 24–72 hours, provided that the clinical picture and laboratory results allow it. |
| 5. If the premature infant deteriorates during their stay, tests are conducted, and a collective decision is made whether to initiate antibiotics or not. |
| 6. Antibiotics are discontinued when symptoms disappear or 2–3 days later, regardless of the treatment duration. Continuation of antibiotics with negative cultures is very rare. |
| 7. In reality, this unit genuinely uses a minimal amount of antibiotics. |
DISCUSSION
In this study, we found that there is a fair degree of variability in antibiotic administration practices in the EpicLatino units even after adjusting with a regression analysis for GA, NEC, infections (positive blood or cerebrospinal fluid cultures), length of stay, time-period (before/after 2020), and mortality. These findings suggest a potential for improvement in our clinical practice with continuing education and development of clinical care protocols to reduce regional variability. As in most retrospective studies, the gaps in data points, are an important limitation. Extending the study in a retrospective-prospective format or a completely new study might have benefits. Many new variables may need to be included such as an index for severity-of-infection. Some of the maternal factors may have to be included in more detail; we only had chorioamnionitis as a single variable in this analysis. Presumed or histopathologically proven chorioamnionitis could be differentiated even if antibiotic use in the newborn may not change the results.29,30 Measurement of acute phase reactants in cord blood or early neonatal period could be considered.
In this study, we utilized GA rather than birth weight because this parameter is more accurately recorded in EpicLatino database. In most existing studies, gestational age at birth has been viewed as a more precise indicator of fetal maturation than birth weight.31 In this context, newer machine learning methods could offer low-cost alternatives.32 IUGR is a frequently seen variable and could be an independent negative confounder in many neonatal outcomes.30,33
To understand the practices leading to this marked disparity in the duration of antibiotic administration, our questionnaire on antibiotic use practices has identified the knowledge, attitudes, and practices as important determinants of success of such an approach in different regions.34 We did not find a clear association with IRRs and this needs further study.35 Units that believed they used few antibiotics may not be fully aware of their higher antibiotic usage.36,37 On the other hand, even though antibiotic overuse and resistance are being identified ever more frequently but under-recognition of sepsis remains an issue resulting in campaigns from the World Health Organization (WHO).38
The phenomenon of variation in clinical practices needs study. In many cases, the variation in the utilization of health services cannot be explained by variation in patient illness.34 Such variations can be substantial, persistent, and might be even difficult to understand in some locations. There could well be hitherto unknown, associated cultural and/or professional factors. The variations in clinical practice have been described by many investigators across many healthcare settings and these are not always easy to explain.34,39–43 On possible reason could be the “professional uncertainty” perceived by the medical care-providers in certain situations.40,41 These choices might get influenced by environmental circumstances and local standards.44 Hence, application and acceptance of protocols in a consortium as large as the EpicLatino will take persistence and time.45
One model of medical care views three major domains to explain residual unwarranted variation: capacity (allocative decisions, organizational design, and lack of acumen), evidence (lack of adherence to guidelines, unjustified deviation of evidence base) and agency (providers’ needs and preferences, lack of engagement).48 Overall, some variation is a norm and we need to monitor its impact on outcomes. It is noteworthy that a significant number of units claim to adhere to internationally recognized concepts of good antibiotic usage practices.49 However, some units may report their desired practices rather than actual practices.37,50 It might be beneficial for each EpicLatino unit to explore possibilities for reducing antibiotic usage as a quality plan.51
ACKNOWLEDGMENT
The authors would like to thank the EpicLatino units for their efforts in maintaining this database, allowing us to improve quality and to Pablo Vasquez-Hoyos for his assistance with statistical analysis.
ORCID
Angela B Hoyos https://orcid.org/0000-0002-5403-3268
Ariel Salas https://orcid.org/0000-0002-4676-7747
Horacio Osiovich https://orcid.org/0000-0001-5290-2565
Carlos A Fajardo https://orcid.org/0000-0001-7353-0385
Martha Baez https://orcid.org/0009-0002-7530-0713
Luis Monterrosa https://orcid.org/0000-0001-7576-7036
Carolina Villegas-Alvarez https://orcid.org/0000-0002-3930-8745
Fernando Aguinaga https://orcid.org/0000-0001-7685-7279
Maria I Martinini https://orcid.org/0000-0001-6905-1955
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