In recent years, the improvement of technologies for advanced life support applied to prematurity complications resulted in increased survival of preterm infants with earlier gestational age and low birth weight.1,2 Due to immaturity of the immune system and the need for several invasive procedures, hospitalized neonates, especially premature infants, are susceptible to healthcare-associated infections (HAI). This is one of the most significant adverse events associated with morbidity and mortality in this age group.1–5

The diagnosis of HAI in newborns is difficult due to the lack of specific symptoms. At this age, HAI commonly shares symptoms with other diseases, such as respiratory distress syndrome, prematurity hypotension, metabolic disorders, and others.1,6–10 Beginning early treatment is fundamental for improving the prognosis of these patients. Therefore, treatment is initiated before receiving laboratory results, which contributes to the exposure of this population to antimicrobial agents (ATM), often unnecessary.6–11 Furthermore, the difficulty in obtaining sufficient samples for cultures and the low sensitivity of this test leads many physicians to decide to continue ATM for treating presumed neonatal sepsis,6,8 which is up to eight-fold over-treated than confirmed HAI cases, according to some studies.6

The increase of HAI caused by resistant bacteria is a multifactorial issue. Currently, it is a worldwide concern due to the associated high morbidity and mortality and increased hospitals costs.1,3,8,12 The inability of the pharmaceutical industry to create new drugs at the same rate as the development of resistance is also an important issue to consider.3,9–11 The excessive use of ATM, especially broad-spectrum agents, is already recognized as a key factor for the development of resistance.1,6,7,9,11–16 In recent years, the emergence of increasingly resistant strains has been observed,2,6,8 as demonstrated by clinical trials in adult and pediatric populations. However, in the neonatal population, there is a lack of studies assessing this association.8,13,17

The aim of this work was to perform a systematic review of the relationship between inadequate use of ATM and increase in neonatal sepsis related to healthcare assistance, due to bacterial resistance. For this review, the attributes considered when selecting the articles were: population, exposition, comparison, outcome, and study type, according to the acronym PECOS.18,19 The definition was as follows: P, neonates with sepsis diagnosis in Neonatal Units; E: inappropriate use of ATM; C, adequate use of ATM or no indication of infection; O, resistant bacterial infection; S, original studies.

The search of PubMed, Scopus, Embase and the Virtual Health Library resulted in 616 articles. Additionally, the reference analysis resulted in four articles, with a total of 620 articles. Among these, 16 (2.6%) were excluded as duplicates, 587 (94.7%) did not satisfy the inclusion criteria, and two (0.3%) were unclear regarding type and duration of ATM therapy. Of the 15 (2.4%) articles selected, one (0.15%) was excluded because it was only available in Mandarin. The others were evaluated and qualified (Fig. 1).

Fig. 1.

Diagram of the selection of articles on antimicrobial use and increase of neonatal sepsis related to assistance by resistant bacteria.

(0.2MB).

Among the 14 analyzed articles, all of them were observational studies: 10 prospective cohort and four case-control studies. In this review, there were no randomized trials or interventional studies. Ten studies described the appearance of Gram-negative bacteria (GNB) and four studies attributed the use of ATM to resistant bacterial infection and colonization. Further details about the studies are available in Table 1.

The review considered evidences of very low quality, as determined by the GRADE scale.20 Table 2 shows the GRADE evaluation of all assessed studies.

In 2002, the Centers for Disease Control (CDC) started a campaign to prevent antimicrobial resistance with 12 steps, including reinforcing the need for caution when choosing an ATM, using ATM for the shortest duration, and restricting ATM use by culture results.2,6,7,9,13,26,27 Despite the fact that the recommendations do not focus specifically on neonatal care, Cantey7 and Patel27 presented the applicability of these guidelines in a neonatal unit.

Calil et al.2 and Landre-Paige et al.26 evaluated the efficacy of the ATM control measures. In a cohort study, Landre-Paige et al.26 demonstrated that simple measures, such as organization of the nursing staff, hand washing, and development of criteria to guide initiation of empiric treatment for early sepsis, were effective in reducing the incidence of nosocomial infections. The empiric treatment used included ampicillin and gentamicin, but was questionable, because in severe cases, the treatment included ceftazidime, which counters the recommendations to reduce the use of cephalosporins.2,10,12,16 The same treatment was maintained during the two phases of the study. Landre-Paige et al. have also shown a significant reduction in the prescription of empiric ATM (from 100% to 51%) as well as a meaningful reduction of HAI (from 10.9 to 2.9/1000 patients per day) and resistant bacteria, mostly GNB (from 79% to 12%).

The prospective cohort study conducted by Calil et al.2 evaluated the impact of periodic training of professionals in a tertiary neonatal unit, including training on the rational use of ATM, hand washing, and the withdraw of ceftriaxone from empiric treatment of early and late sepsis in newborns weighting less than 1500 g. This study demonstrated an important reduction in multidrug-resistant bacteria. Evaluating only colonization by this type of pathogen, they observed an odds ratio (OR) of 2.5 associating the use of ceftriaxone and colonization by multidrug-resistant bacteria, and observing a greater occurrence during ceftriaxone utilization. While assessing the occurrence of infection by a multidrug-resistant microorganism, a decrease from 18 to two infections per year was observed after the implementation of the stewardship program, although the number of nosocomial multidrug-resistant bacterial infections was low.

In a cohort study, Zingg et al.13 also described a reduction of 2.9% per year in the use of ATM, with no increase in mortality. This study observed a low incidence of multidrug-resistant bacterial infections during the study, thus it was not possible to compare data before and after implementation.

In prospective cohort study by Flidel-Rimon et al.28 two periods were evaluated. In the first period, the incidence of infection by resistant Klebsiella pneumoniae was assessed after implementation of hand washing training, improvement of sterile technique, and isolation of patients colonized/infected with resistant bacteria. The first period displayed a notable reduction in the incidence of HAI from 12.5 to 5.3 per 1000 patients, but the incidence of infection by resistant K. pneumoniae remained stable at approximately 2.5 per 1000. However, after modification of the empirical treatment, replacing ceftazidime with piperacillin/tazobactam, the incidence was reduced from 2.5 to 0.45 per 1000 patients.

In a prospective cohort study, Tsai et al.29 compared patients infected by GNB that were sensitive or multidrug-resistant to the first choice ATM. Multivariate analyses revealed that previous use of 3rd generation cephalosporin and meropenem and use of vancomycin and meropenem were risk factors associated with infection by multidrug-resistant bacteria. The empiric treatment guidelines in the neonatal unit permitted the use of vancomycin and cefotaxime, both of which are considered broad-spectrum and 2nd line antibiotics by the CDC.7,27

During the review, eight articles evaluated risk factors of infection by GNB producers of extended-spectrum β-lactamases (ESBL). The incidence of these bacteria is increasing worldwide, which is particularly alarming because this resistance mechanism can be transmitted by plasmids, which facilitate the acquisition of resistance by other bacteria.5,14,15,17,30–33

In searching for risk factors of infection by resistant GNB, the cohort studies conducted by Abdel-Hady et al.,5 Le et al.,31 and Murki et al.14 and the case-control study conducted by Huang et al.17 identified the previous use of 3rd and 4th generation cephalosporins as risk factors for infections by ESBL-producing GNB. Abdel-Hady et al.5 observed an OR of 4.9 in the association with previous use of 3rd generation cephalosporins. In a study by Le et al.,31 previous use of cephalosporins presented an OR of 33.7, and an OR of 3.09 for each additional day of ampicillin and gentamicin use and an OR of 1.55 associated with prolonged exposure to cefotaxime and tobramycin. Huang et al.17 demonstrated an OR of 12.8 for the association with the previous use of 3rd generation cephalosporins, and Murki et al.14 reported a significant statistical association between previous use of cephalosporins and infection by ESBL-producing GNB.

In a cohort study, Singh et al.33 evaluated patients colonized by ESBL-producing GNB who developed infection by this bacteria. A multivariate analysis identified birth weight greater than 1000 g and prolonged exposition to ATM, independent of the ATM class, as risk factors. In case-control studies, Crivaro et al.30 and Linkin et al.32 also identified prolonged ATM exposure as a risk factor associated with colonization and infection by ESBL-producing GNB. These two studies evaluated infection associated with previous colonization and had a small sample of multidrug-resistant infections, increasing the risk of study bias. The study by Crivaro et al.23 presented an adequate sample and better methodological quality for evaluating colonization. However, the study by Linkin et al.29 was based on a small sample size and a literature review of risk factors for colonization and infection by ESBL-producing bacteria.

Pessoa-Silva et al.15 conducted a cohort study to identify risk factors for infection by ESBL-producing bacteria. The authors did not identify previous use of ATM as a risk factor, although the colonization by ESBL-producing bacteria was a risk factor, with an OR of 5.9. In the same study, the authors found that previous use of 3rd generation cephalosporins and aminoglycosides were associated with infection by ESBL-producing GNB, with an OR of 4.6 during the first nine days of hospitalization and an OR of 2.43 after nine days. The authors concluded that previous use of 3rd generation cephalosporins and aminoglycosides are also risk factors for infection by ESBL-producing bacteria.

The oldest publication identified in the present review was a cohort study from the early 1980s conducted by Bryan et al.34 The study included the replacement of gentamicin by cefotaxime following an outbreak of gentamicin-resistant K. pneumoniae in a neonatal unit. For 11 years, before the appearance of these resistant bacteria, the first choice of empirical treatment was gentamicin. After eight months of cefotaxime use, no resistant K. pneumoniae was identified. However, cefotaxime-resistant Enterobacter cloacae emerged as an important pathogen and continued to be prevalent even after the restored use of gentamicin as empiric treatment. Despite the fact that cefotaxime was associated with faster development of resistance, the mortality rate did not increase during the study. This study has several methodological limitations, including a small sample size and lack of statistical tests in their analyses. The study conclusion can be explained by the fact that cefotaxime was a new drug at that time, with the same spectrum to GNB, but with fewer nephrotoxic and ototoxic effects than gentamicin. Spritzer et al.35 presented a similar conclusion in a cohort study evaluating care in a neonatal unit after introduction of cefotaxime for five years. Given the short time it was used in large scale, the capacity of cephalosporins to induce resistance quickly was not known and was proved later.2,10,12,16

The most recent study was conducted by Yusef et al.4 This epidemiological study of the most prevalent microorganisms in a neonatal unit in Jordan compared patients infected by multidrug-resistant and sensitive bacteria. Despite the statistical significance of the association between previous use of meropenem and vancomycin with infection by multidrug-resistant microorganisms, in a multivariate analysis this association was not confirmed. However, when assessing infections with carbapenemase-producing Acinetobacter baumannii and K. pneumoniae (KPC), the exposure and time of exposure to vancomycin and meropenem presented a strong association (OR = 0.07). One of the most significant biases of this study was the use of empiric treatment of vancomycin and meropenem for late neonatal sepsis, considering their categorization as wide spectrum and second-line therapies.7,27

The CDC-recommended restriction on vancomycin use is aimed at preventing the development of vancomycin-resistant Enterococcus (VRE), which is considered a global issue because of the high mortality associated with this difficult to treat agent.12,16,36,37 Studies evaluating risk factors related to VRE infection in neonatal unit care were not found. However, there are studies associating colonization by these agents, which can be considered a risk factor for infection.2,12,15,16,30,32,33,36 During an outbreak of VRE in neonatal care units, Iosifidis et al.36 and Malik et al.37 assessed risk factors associated with colonization by this microorganism, and identified previous use of ATM, mainly 2nd line agents, such as vancomycin, meropenem and cefepime, as potential risk factors.

Despite the low quality of evidence, the described studies demonstrated an association between inadequate use of ATM and increase of resistant HAI in neonatal units. There is significant difficulty in performing high-quality studies because of ethical issues when conducting randomized trials in this population. In addition, there are other factors associated with the occurrence of multidrug-resistant bacterial infections, such as lack of personnel training, inadequate hand washing by the staff, and inadequate sterilization of the materials and aseptic technique procedures at the units, which may be biases in these studies. Thus, new studies are warranted in order to understand bacterial ATM resistance and propose adequate treatments to improve quality of care for newborns.

The authors declare no conflicts of interest.