organisms found in the group of neonates with MDRO were Staphylococcus haemolyticus (16.7%), Acinetobacter baumannii (13.3%), and Staphylococcus hominis (13.3%), and the rest being other types of organisms with a percentage of less than 10%. In the group of non-MDRO neonates, many fungi were found, namely Candida parapsilosis (30.0%), followed by Klebsiella pneumoniae organisms (10.0%) and the rest were other types of organisms with a percentage of less than 10%. The species of organisms found are shown in Table 2.

Table 2.  Organisms isolated from blood culture

The bivariate analysis showed a significant correlation between the incidence of MDRO in neonates on LBW group (OR= 3.755, 95%CI=1.239–11.385, p=0.017), preterm birth group (OR=6.417, 95%CI=2.084-19.755, p=0.001), and duration of antibiotic administration >7 days group (OR=5.231, 95%CI=1.657-16.515, p=0.003) were shown in Table 3. To discover the dominant variable at risk for incidence of MDRO, a multivariate logistic regression analysis was performed.

Table 3. Bivariate analysis of factors associated with the incidence of MDRO

        *p-value <0.05

            The multivariate analysis showed a significant correlation between preterm birth (OR=7.632, 95%CI=1.158-50.293, p=0.035) and duration of antibiotics administration >7 days (OR=3.939, 95%CI=1.106-14.032, p=0.034) with the incidence of MDRO in neonates were shown in Table 4.

Table 4. Logistic regression multivariate analysis of factors associated with the incidence of MDRO*

*Only variables with p-value <0.05

The description of the APGAR score based on the incidence of MDRO in this study used the Mann Whitney test. Mann Whitney test was conducted to see whether there was a difference in APGAR scores in the MDRO group and the non-MDRO group. Our study found that the 1^st minute APGAR score had p value=0.662 (p>0.05), the 5^th minute got p value=0.514 (p>0.05) and the 10^th minute had p value=0.306 (p>0.05) were not significantly related to the incidence of MDRO in neonates at Dr. Moewardi hospital Surakarta is shown in Table 5.

Table 5. APGAR scores based on incidence of MDRO

Discussion

Our study found that the most common types of organisms in the group of neonatal sepsis patients with MDRO were Klebsiella pneumoniae (33.3%), Staphylococcus haemolyticus (16.7%), Acinetobacter baumannii (13.3%), and Staphylococcus hominis (13.3%), and the rest were other types of organisms with a percentage of less than 10%. This is different from the research by Estiningsih et al in 2016, it was observed that the bacterias that infected NICU patients at dr. Soeradji Tirtonegoro hospital were Pseudomonas sp (30.4%), Klebsiella sp (23.9%), Serratia sp (15.2%), and Enterobacter sp (15.2%). This differences because each hospital has a different pattern of organisms.^15,16 In our study, it was observed that the Klebsiella pneumonia was most commonly organism found in MDRO patients where the organisms were gram-negative bacterium which is in line with study by Litzow et al (2009) in the Philippines, Tsai et al (2014) in Taiwan, Thatrimontrical et al (2019) in Thailand and research by Giuffre et al (2016) in Italy which stated that there was a tendency for a rapid increase in gram-negative bacterial infections that cause MDRO conditions in neonatal patients treated in the NICU.^3,7,13,17 Our study also was in line with the research by Ballot et al in 2019 in Johannesburg, South Africa and Yuse et al (2016) in Jordan, that the most commonly found organism was Klebsiella pneumoniae.^18,19

Based on the gestational age in the bivariate analysis between preterm birth and the incidence of MDRO in neonates in our study, the results obtained OR = 6.417 (95%CI=2.084 –19.755) with p=0.001 (p <0.05) then followed by multivariate analysis with the results obtained OR=7.632 (95%CI=1.158-50.293) with value of p = 0.035 (p <0.05) which mean that preterm birth had risk of 7.632 times the incidence of MDRO, thus preterm birth was one of the dominant factors at risk of MDRO incidence. Our research result is in line with Begum et al's study in 2016 where premature infants had a correlation with the incidence of sepsis, both early onset and late onset sepsis due to an immature immune system which was at risk for MDRO.^10,13,19 In the 2016 study by Giuffre et al, it was stated diverse that preterm birth was not the independent risk factor for MDRO incidence in neonates. The absence of a significant association might indicate cross-transmission phenomenon during treatment in the NICU.¹³

In the bivariate analysis between the duration of antibiotics administration >7 days and the incidence of MDRO in neonates in our study, the results obtained OR=5.231 (95%CI=1.657–16.515) with p=0.003 (p <0.05). Then proceed by multivariate analysis and then obtained OR=3.939 (95%CI=1,106-14,032) with p=0.034 (p<0.05) which mean that duration of antibiotics administration >7 days had risk of 3.939 times the incidence of MDRO, thus the duration of antibiotics administration >7 days was one of the dominant risk factors for the occurrence of MDRO. Our research results are in accordance with the study of Giuffre et al in 2016 which stated that the average duration of administration of Ampicillin-Gentamicin antibiotics was 7.4 days as the independent risk factor for MDRO in neonates.¹³ The bacterial selective pressure comes from the use of antibiotic doses. When the doses of antibiotics used reach or are close to sublethal doses, the selective pressure of antibiotics can force changes in the body's behavior, physiology and biochemistry. Genes and proteins in the expression of resistant bacteria will change, the body's protective and immune defenses will gradually weaken, and the risk of MDRO increases.²

Based on birth weight in bivariate analysis between LBW/VLBW and MDRO incidences in neonates in our study, the results obtained OR=3.755 (95%CI=1.239–11.385) with p=0.017 (p<0.05). Furthermore, multivariate analysis was performed to obtain OR=0.540 (95%CI=0.077-3.797) with p value=0.535 (p>0.05) which mean that LBW was not the dominant factor at risk for MDRO. Our results were not the similiar as the study by Ballot et al in 2019 which stated that there was a correlation between the incidence of LBW, prematurity, maternal HIV infection and oxygenation in the initial 28 days with the incidence of multidrug resistant Enterobacteriace.²¹ Intrauterine growth disorders could affect birth weight and development of the respiratory, cardiovascular, neurological, hematological and immunological systems. Neonates with VLBW have the highest risk of infection due to low immunity.²² This difference might be due to the large discrepancy in the number of subjects in that study were 2437 neonates, while the total subjects of our study were 60 neonates.

LOS in the MDRO group obtained a value of OR=2.667 (95%CI=0.924–7.699) p=0.067 (p>0.05) which mean that there was no significant correlation between LOS and the incidence of MDRO. This is not in line with the study of Abdel-Hady et al which stated that the total number of days in the hospital was an independent risk factor for Klebsiella pneumoniae caused infection of Extended Spectrum Beta-Lactamase (ESBL). The study said that the hospital environment played an important role in the transmission of these pathogens, especially the spread from medical personnels.^22,23 This difference may be due to the group of MDRO neonates in our study who obtained LOS <15 days because there was mortality of 21 neonates in MDRO group, while in the non-MDRO group there were 16 neonates died.

In the using of invasive mechanical ventilation in the MDRO group, the value was OR=0.857 (95%CI=0.288–2.547) p=0.781 (p > 0.05) which mean that there was no significant relationship between the using of invasive mechanical ventilation with MDRO incidence. Our study is different from the research by Wang et al in 2020 and Tsai et al in 2014 which stated that there was an effect of using invasive mechanical ventilation on the incidence of MDRO, with the longer the duration of ventilator use, then the higher the incidence of MDRO. This might happen because both the group of patients with MDRO and not MDRO used only small number of ventilators in our study. This may be due to differences in the number of research subjects which are very different where in the 2014 Tsai’s study with total sample size 1106 neonates and differences in research methods where the study was a prospective cohort study conducted for eight years.^2,3

APGAR score in the 1^st minute had p=0.662 (p>0.05), in the 5^th minute got p=0.514 (p>0.05) and in the 10^th minute had p=0.306 (p>0.05). All three there were no significant difference between the MDRO group and the non-MDRO group, thus the 1^st minute, 5^th minute, and 10^th minute APGAR scores were not associated with the MDRO incidence, although the APGAR scores of MDRO group tended to be lower (mean score 1-5-10 minutes = 5.37–6.6–7.8) compared to the non-MDRO group (mean score 1-5-10 minutes = 5.60–6.97–8.3) in our study. This is not in line with the study of Geyesus et al (2017) in Egypt which stated that the APGAR score in the 5^th minute with a score <7 was an independent risk factor for sepsis which then led to an MDRO condition in neonates.¹⁹ This difference occurred perhaps because in our study the average APGAR score obtained in both the MDRO and non-MDRO groups at 5^th minutes both obtained a score of <7.

The incidence of MDRO caused by nosocomial hospital infections commonly referred to as hospital-acquired infections (HAI's) which one of the preventions of this condition is isolation precautions that is evaluation of hand hygiene adherence, which can be a risk factor for MDRO incidence in neonates.^16,25,26 The longer the patient was hospitalized, the exposure to HAI's will increase as well as the MDRO incidence in neonates.^.26 In our study, we had not been able to analyze medical personnel’s hand hygiene adherence because the data used is retrospective data which there was no data on hand hygiene compliance.

Conclusions

Preterm birth (OR=7.632, 95%CI=1.158-50.293, p value=0.035) and duration of antibiotics administration >7 days (OR=3.939, 95%CI=1.106-14.032, p value=0.034) had significant correlation with the incidence of MDRO in neonatal patients at Dr. Moewardi hospital Surakarta. Klebsiella pneumoniae was the most common organism found to cause MDRO incidence in neonatal patients at Dr. Moewardi hospital Surakarta.

Acknowledgment

The authors are grateful and thanks to Pediatric Department of Dr. Moewardi Hospital, Surakarta which provide facilities for the authors.

Conflict of interest

None declared.

Role of the funding source

The authors received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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