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INTRODUCTION
Neonatal septicemia, a global clinical issue, is a major cause of morbidity and mortality in infants. It is characterized by a blood stream infection in neonates caused by pathogenic microbes like bacteria, viruses, and fungi, resulting in systemic inflammatory responses (Lawn et al., 2014). Neonatal sepsis is commonly categorized as early onset or late onset based on the age of onset (Shane et al., 2017). The diagnosis of sepsis is not ruled out if a microbiological pathogen cannot be isolated (Singer et al., 2016). According to the 2016 Sepsis-3 consensus definition in adults, sepsis is characterized as a critical condition resulting from an uncontrolled immune response to infection leading to organ dysfunction (Schlapbach and Kissoon, 2018). A redefined concept of pediatric sepsis, encompassing a broader age range beyond the neonatal period similar to the Sepsis-3 definition, is under consideration (Schlapbach, 2017). There is a lack of consensus on a universal definition of neonatal sepsis in the scientific literature (Wynn et al., 2014). Therefore, numerous newborns receive a diagnosis of probable or possible sepsis or presumed symptomatic infection but no bacterial etiology identified, commonly termed as suspected sepsis (National Institute for Health and Care Excellence (NICE), 2012). Low- and Middle-Income Countries (LMICs) exhibit a higher prevalence of neonatal sepsis, imposing a considerable burden on global healthcare systems. Annually, there are in excess of 3 million instances of neonatal sepsis, resulting in over 500,000 deaths (Fleischmann-Struzek et al., 2018). India significantly contributes to the global neonatal mortality rate, with neonatal sepsis accounting for nearly one-third of these deaths annually (Tzialla et al., 2018). Most high-income countries neonatal sepsis publications typically focus on culture-confirmed cases, neglecting neonates treated with antibiotics for culture-negative sepsis. Consequently, data on culture-negative sepsis are limited, despite it contributing to the elevated antibiotic utilization in neonatal healthcare settings (Cantey et al., 2016). Moreover, although there are no variations in infection-associated morbidity and mortality, there exists notable diversity in antibiotic utilization among NICUs and countries (Schulman et al., 2015). These findings indicate potential antibiotic overutilization in specific NICUs, posing significant short- and long-term health risks for individual infants (Esaiassen et al., 2017). Nevertheless, delaying antibiotic administration in neonates with confirmed infections can increase mortality and morbidity rates (Cordery et al., 2008). Efficient sepsis management and antimicrobial stewardship efforts are challenged by culture-negative neonatal sepsis. Neonatal septicemia rates vary by region. Globally, incidence is around 15-20 per 1,000 live births, while in certain underserved areas of India, rates may escalate to 30-60 per 1,000 live births (Klingenberg et al., 2018). Factors such as low birth weight, preterm deliveries, inadequate hygiene, and restricted healthcare access have been identified as contributory elements (Downie et al., 2013). Neonatal sepsis is treated through supportive care, prompt initiation of empirical antibiotic therapy, and early detection. Early detection methods, such as Polymerase Chain Reaction (PCR) and biomarker analysis (e.g., procalcitonin and C-reactive protein), have enhanced diagnostic capabilities (Flannery and Puopolo, 2018). Despite this, professional judgment remains crucial for initiating treatment in resource-constrained settings (Zaidi et al., 2009). The primary approach to treating neonatal sepsis involves the administration of antibiotics targeting common pathogens, including Staphylococcus aureus, Klebsiella pneumoniae for LOS, and Escherichia coli and Group B Streptococcus for EOS (Fouda et al., 2021). The emergence of Multidrug-Resistant (MDR) infections, particularly bacteria producing Extended-Spectrum Beta-Lactamases (ESBLs), poses considerable therapeutic challenges (Mukhopadhyay and Puopolo, 2012). In NICUs, the implementation of antibiotic stewardship programs is necessary to mitigate the excessive and inappropriate use of antibiotics (Heath et al., 2017). This study aims to evaluate the therapeutic efficacy of commonly prescribed antibiotic regimens and monitor resistance patterns in the treatment of neonatal septicemia. The research seeks to provide evidence-based guidelines for optimizing treatment protocols through the analysis of outcomes like antibiotic susceptibility, microbiological resistance trends, and alterations in pertinent biomarkers. The importance of this research lies in the association between early antibiotic exposure and the emergence of multidrug-resistant bacteria, difficult-to-treat infections, disturbance of microbiota development, and heightened susceptibility to chronic diseases later in life. Inappropriate antibiotic use in neonates and young children is linked to elevated mortality rates, increased acute and chronic morbidity, and a substantial escalation in healthcare costs. Excessive antibiotic usage in neonates and infants in NICUs primarily stems from the need to rule out sepsis. To enhance treatment outcomes, it is crucial to comprehend antibiotic utilization and resistance patterns in neonatal sepsis. These findings can bolster efforts at regional and global levels to combat Antimicrobial Resistance (AMR), which undermines the effectiveness of existing therapeutic strategies. Need for the Study: Neonates may present with nonspecific clinical signs of infection, potentially delaying the detection of late-onset infections. Empirical treatment often leads to unnecessary antibiotic administration due to the time required for microbiological culture to confirm pathogenic organisms in blood samples. The extensive use of broad-spectrum antibiotics increases selective pressure, fostering the development of drug resistance like extended-spectrum β-lactamases. Early antibiotic exposure in infancy can adversely affect the developing microbiome, a concern for vulnerable neonates, especially those who are sick or premature. Various biomarkers have been proposed to aid in diagnosing late-onset infections in neonatal infants, reducing stress on compromised organs like the gastrointestinal tract of preterm infants and addressing antimicrobial resistance. Combining biomarkers with blood culture can assist in assessing infection likelihood in suspected newborns. CRP levels in serum, an acute-phase reactant synthesized by hepatocytes in response to inflammatory cytokines from white blood cells reacting to microbial pyrogens, are commonly used. Evaluating the accuracy of serum CRP could make it a valuable late-onset infection indicator in neonates. However, the utilization of serum CRP in diagnostic algorithms for late-onset infections currently lacks solid supporting evidence for guideline formulation or protocol development. Research on CRP precision and other late-onset infection biomarkers has mostly been conducted at single centers due to small sample sizes. Neonatal sepsis remains a significant contributor to mortality and disability-adjusted life years (DALYs) in neonates, particularly in LMICs, despite advancements in neonatal care. This study aims to address the lack of reliable data on the efficacy of empirical antibiotic treatments in India. By focusing on practical clinical scenarios, this research can bridge the gap between theory and practice, enhancing neonatal outcomes and prompting policy enhancements.
MATERIALS AND METHODS
In a prospective observational study conducted in NICU of Dhiraj General Hospital, Vadodara, the efficacy of various antibiotic groups in treating neonatal septicemia was investigated in neonates aged 0-28 days. Ethical approval was obtained from the Sumandeep Vidyapeeth Institutional Ethics Committee (SVIEC/ON/PHAR/BNPG22/DEC/23/13). A sample size of 58 was determined using Cochran’s formula based on prevalence in the setting. Participants' parents or guardians were informed about the study, and informed consent was obtained. Excluded were patients with clinical sepsis or lacking laboratory evidence, with only those with suspected or proven sepsis included. Data collection included CRP levels, culture reports, identification of causative organisms, time to normalize CRP levels, and associated risk factors in early-onset and late-onset sepsis. Sepsis diagnosis relied on laboratory parameters and cultures. Data was entered using Epiinfo and analyzed in Microsoft Excel, presenting quantitative data as percentages and graphically. Assessment of antibiotic therapy efficacy was based on CRP level decline and time to normalization, providing insight into antibiotic impact on neonatal septicemia in NICU patients (Figure 1).
RESULTS
The research involved 58 neonates with neonatal septicemia admitted to the NICU at Dhiraj Hospital. Among them, 27 (47%) were female and 31 (53%) were male. 28 (48%) cases were classified as EOS, while 30 (52%) were classified as LOS according to Table 1. The population studied consisted of individuals with confirmed or suspected diagnoses excluding clinical sepsis. The research identified Low Birth Weight (<2.5 kg) and Severe Birth Asphyxia as the predominant risk factors associated with EOS, with 43 and 37 incidences, respectively. Conversely, factors like per vaginal leaking and history of multiple vaginal examinations, although significant risks in other contexts, were not associated with EOS in this study setting. For LOS, the most prevalent risk factors were previous invasive procedures (e.g., ventilation, catheterization, surgery), occurring in 29 cases, followed by preexisting intravenous fluid use (26 cases), history of prior hospitalization (24 cases), and ongoing Total Parenteral Nutrition (TPN) use (21 cases). Cord care practices did not contribute to LOS diagnosis in this study setting (Table 2). A total of 35 culture reports were conducted among 58 individuals during their hospitalization, with 28 showing growth of causative organisms. Among these, the primary causative agent for neonatal sepsis in our environment was identified as Acinetobacter Baumanii complex (14 cases), followed by Klebsiella Pneumonia (6 cases) (Figure 2). This study comprises 6 groups of antibiotic treatments administered to 58 neonates, as shown in Table 3. Following the administration of different antibiotic therapies, the patient's CRP level reduction was measured and compared to the initial CRP level at the time of diagnosis to calculate the difference. The average differences in CRP levels for each antibiotic group were then calculated. Group 3 demonstrated the highest CRP difference (53.48083), indicating its efficacy, while Group 1 showed the lowest difference (28.67364), suggesting relatively lower effectiveness (Table 4). Table 4 displays the mean number of days required to calculate the average difference mean of CRP for each antibiotic group. Group 3 had the longest duration to determine its CRP average difference mean, whereas Group 6 was the quickest. Ultimately, Group 4 exhibited the highest ratio of average difference mean of CRP to average days taken (5.2456), suggesting a more efficient decrease in total average CRP levels. This was followed by Group 6 (4.4208), Group 2 (3.9342), Group 3 (3.7886), Group 5 (3.3404), and Group 1, which showed the lowest ratio (3.2578).
| Variables | Count | Percentage |
|---|---|---|
| Sex | ||
| Male | 31 | 53% |
| Female | 27 | 47% |
| Diagnosis | ||
| EOS | 28 | 48% |
| LOS | 30 | 52% |
| Risk factor for EOS | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Low birth weight (<2.5 kg) | Maternal Febrile Illness | Meconium stained liquor foul smelling liquor | Leaking PV (>24 hr) | Multiple per vaginal examinations (>3) or single unclean examination | Prolonged and difficult delivery | Severe birth asphyxia | |||
| Sl. No. | 43 | 11 | 21 | 0 | 0 | 15 | 37 | ||
| Risk factor for LOS | |||||||||
| Top Feeding | Bottle feeding /Unhygienic feeding practices | Use of animal milk /babulin /gripe water | Previous hospitalization | Cord care taken | Superficial Infections * | Invasive procedures** | On intravenous fluid at the time of diagnosis of sepsis | On TPN | |
| Sl. No. | 2 | 3 | 1 | 24 | 0 | 5 | 29 | 26 | 21 |
| Group No. | Antibiotics | |||||
|---|---|---|---|---|---|---|
| 1 | Cefoperazone Salbactum | Amikacin | Meropenem | |||
| 2 | Meropenem | Colistin | Tigecycline | Vancomycin | ||
| 3 | Cefoperazone Salbactum | Meropenem | Amikacin | Colistin | Vancomycin | Tigecycline |
| 4 | Meropenem | Vancomycin | Colistin | |||
| 5 | Meropenem | Amikacin | Linezolid | Vancomycin | Colistin | |
| 6 | Cefoperazone Salbactum | Meropenem | Colistin |
| Antibiotics | Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 |
|---|---|---|---|---|---|---|
| Average Difference Mean of CRP | 28.67364 | 43.42 | 53.48083 | 47.60143 | 33.55222 | 31.56091 |
| Average Days taken by each Antibiotic therapy group to exhibit given CRP difference | ||||||
| Antibiotics | Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 |
| Average Days Taken | 8.272727 | 11.75 | 14.66667 | 9.142857 | 10.33333 | 7.090909 |
DISCUSSION
The study had a balanced demographic distribution (53% male, 47% female), reducing sex-related bias. Low birth weight and severe birth asphyxia were identified as key risk factors for EOS, aligning with Liu et al.'s emphasis on perinatal stressors as significant contributors to EOS (Liu et al., 2021). In a study by Shruti Murthy et al., invasive procedures and extended intravenous therapy were identified as primary risk factors for nosocomial infections, with invasive ventilation and central line utilization playing key roles (Murthy et al., 2020). Acinetobacter baumannii complex was identified as the predominant pathogen, with Klebsiella pneumoniae following as the second most common causative agent. Wen et al., confirmed Klebsiella's prevalence in neonatal sepsis, especially in low- and middle-income nations (Wen et al., 2021). The prevalence of Acinetobacter baumannii highlights regional diversity in pathogen profiles, possibly impacted by specific antibiotic usage and infection control strategies. The research results indicated that the combined use of meropenem, vancomycin, and colistin (Group 4) showed the best balance in reducing CRP levels and achieving a prompt clinical response. These findings align with previous research by David Carr et al., emphasizing the significance of combination therapy in combating multi-drug resistant pathogens (Carr et al., 2019). The dependence on empirical broad-spectrum treatments raises concerns regarding antimicrobial resistance, highlighting the necessity for therapy guided by culture results. This study employed a prospective observational approach to gather data on demographics, characteristics, risk factors, pathogen profiles, and the effectiveness of antibiotics based on CRP levels. In comparison to the retrospective study by Karacanoglu et al., which had a larger cohort of 1735 neonates, the current study offers a more concentrated analysis but lacks the broad generalizability of the former (Karacanoğlu et al., 2020). Karacanoglu et al. utilized a Tollner Scoring System for sepsis diagnosis, while this study used CRP levels, indicating a simpler diagnostic method. In contrast, Chaparro et al., investigated antibiotic pharmacokinetics in neonates with advanced analytical techniques and a broader array of biomarkers (Chaparro et al., 2020). The study was limited to using CRP as the only biomarker due to resource constraints. Although CRP is a widely recognized inflammatory marker, its specificity is limited compared to more advanced tools such as procalcitonin or molecular diagnostics, as demonstrated in studies by Rub et al., and Klungenberg et al., potentially affecting the strength of the results (Klungenberg et al., 2020; Rub et al., 2021). Fouzia Naeem and colleagues showed that an Antibiotic Stewardship Program (ASP) effectively decreased total antibiotic consumption and enhanced neonatal results (Naeem et al., 2019). Although an Antimicrobial Stewardship Program (ASP) was not utilized in this study, the results implicitly endorse the necessity of stewardship initiatives. They emphasize the varying effectiveness of antibiotic treatments and the dangers linked to extended use of broad-spectrum antibiotics. The limited implementation of stewardship interventions in low-resource settings in this study mirrors the difficulties highlighted by Dhanya Dharmapalan et al., who also pointed out the high levels of antibiotic resistance in these areas (Dharmapalan et al., 2021). Acinetobacter baumannii was predominant in this study, differing from Jinchun Li et al.'s report where Staphylococcus epidermidis was noted as the most prevalent pathogen in a tertiary care environment (Li et al., 2020). The variation could be attributed to differences in study cohorts, with Li et al.'s group comprising mainly preterm neonates with extended hospitalization. Moreover, this research noted elevated resistance levels to standard antibiotics, in line with global patterns highlighted by Russell et al., underscoring the critical necessity for innovative empirical treatments due to escalating resistance (Russell et al., 2017). This research emphasizes the importance of individualized antibiotic treatment and enhanced infection control measures in NICUs. The study supports the use of pathogen-specific strategies and advocates for the adoption of antimicrobial stewardship programs to address resistance issues. Future studies should explore the integration of advanced diagnostic tools and assess the effectiveness of targeted interventions in reducing neonatal sepsis rates. Limitations of this study, such as its single-center design and small sample size, constrain the generalizability of the results. Reliance solely on CRP as a biomarker and restricted access to culture data due to financial constraints may have underestimated pathogen diversity. Comparison with multicenter research and advanced diagnostic techniques underscores the necessity for larger, well-equipped studies to validate these results. This study adds to the existing literature on neonatal sepsis by identifying important risk factors, pathogen profiles, and antibiotic effectiveness. While the findings align with overall trends in neonatal sepsis management, they also underscore unique regional challenges, emphasizing the importance of globally standardized yet locally adaptable treatment protocols.
CONCLUSION
The study highlights the complex nature of neonatal septicemia in a resource-limited NICU. The findings emphasize the significant burden of sepsis, with an equal distribution of EOS and LOS among neonates. Risk factors such as severe birth asphyxia, low birth weight, and invasive procedures were identified as key contributors. Pathogen profiling revealed Acinetobacter baumannii and Klebsiella pneumoniae, indicating regional variability and a growing concern for multidrug-resistant infections. The study showed that a combination of meropenem, vancomycin, and colistin (Group 4) was the most effective in balancing reduction in CRP levels with time to clinical response. However, the study underscores the importance of culture-guided antibiotic therapy to prevent the overuse of broad-spectrum antibiotics and reduce the risk of antimicrobial resistance. It supports the urgent implementation of antibiotic stewardship programs in NICUs to optimize treatment regimens, address the increasing challenge of drug resistance, and minimize antibiotic misuse. While offering valuable insights into the management of neonatal sepsis in this clinical setting, the study is limited by sample size and reliance on CRP as the sole parameter for assessing the findings.