Author Affiliations
Abstract
Early neonatal sepsis (EOS) is a major cause of neonatal morbidity and mortality. This randomized controlled trial (RCT) compared the efficacy of ampicillin plus gentamicin versus ampicillin plus cefotaxime in EOS treatment. Conducted at the department of pediatrics, Hayatabad Medical Complex, Peshawar, from January 2024 to July 2024, the study included 212 neonates randomized into Group A (ampicillin + gentamicin, n=106) and Group B (ampicillin + cefotaxime, n=106). Results showed treatment efficacy of 79.24% in Group A and 91.50% in Group B, with ampicillin plus cefotaxime demonstrating superior efficacy. Findings suggest that ampicillin plus cefotaxime may be a more effective alternative for EOS treatment, emphasizing the need to reevaluate standard neonatal sepsis treatment protocols considering evolving antibiotic resistance.
Keywords
Neonatal sepsis, Ampicillin, Gentamicin, Cefotaxime, Antibiotic resistance.
Introduction
Sepsis remains a leading cause of mortality and morbidity, especially during the first five days of life and in low and middle-income countries (LMIC).[1] Hospital infection also remains a major cause of mortality in children despite progress encountered in the last decades. World Health Organization (WHO) recommends ampicillin (or penicillin; cloxacillin if staphylococcal infection is suspected) plus gentamicin for empiric treatment of neonates with suspected clinical Sepsis.[2] When referral is not possible, once daily gentamicin plus oral amoxicillin may be used. It is known, however, that in many countries, agents with a broader spectrum, such as third-generation cephalosporin, are commonly used to treat neonatal and infant Sepsis.[3] Against this background, concerns are increasing regarding bacterial pathogens with reduced susceptibility to empiric medication with variations both between and within LMIC.[3]
The majority of cases of EOS result from vertical transmission of bacteria from the mother to the neonate during the intrapartum period. Late-onset sepsis (LOS) is due to the horizontal transmission of pathogens from the environment or the hands of the caregiver. The pattern of bacterial pathogens responsible for neonatal sepsis has changed over time and varies from place to place. There is a difference in the causative organisms for neonatal sepsis between developed and developing countries. Within developing countries, there are regional variations in the spectrum of organisms causing neonatal sepsis.[5-7]
The incidence of proven EOS was 4.9%. Among neonates receiving ampicillin (n = 142) orpenicillin (n = 141) change of antibiotic regimen within 72 h (10 ⁄ 142 vs. 10 ⁄ 141; odds ratio (OR) 1.02; 95% confidence interval (CI) 0.40–2.59), 7-day mortality (11 ⁄ 142 vs. 14 ⁄ 141; OR 0.76; 95% CI 0.33–1.75) and overall treatment success (85.91%) (122 ⁄ 142 vs. 120 ⁄ 141) occurred at similar rates. Kaplan-Meier analysis revealed almost identical treatment success rates for both treatment Regimens (p = 0.92). There were no differences in treatment failure rates between centers (12.0% in unit A vs. 15.6% in unit B) and treatment periods (13.5% in first vs. 14.1% in secondperiod). The use of gentamicin plus ampicillin has at least four fundamental advantages over the use of other antimicrobials in the pediatric population; These include excellent evidence-based clinical use in pediatrics for a longer period, their synergistic effects, their broad spectrum activity, and also the excellent activity of ampicillin to eradicate Listeria monocytogenes.[8-10] Ascertaining an appropriate combination of ampicillin with gentamicin or cefotaxime for empirical therapy of neonatal EOS in our local population, trends in the epidemiology of EOS show a decreasing incidence of group B streptococcus (GBS) disease following the widespread adoption of prenatal screening and treatment protocols.[2-4]
Methodology
Study design: RCT
Setting: Department of Pediatrics, Hayatabad Medical Complex, Peshawar.
Duration of study: January 2024 to July 2024.
Sample size: It was 212 (106 in each group), keeping 85.91% efficacy in group A and 92.0% in group B, with 95% CI, 80% power of test, 5% level of significance, and 5% margin of error on the WHO sample size calculator.
Sampling technique: Non-probability, consecutive sampling.
Inclusion criteria:
- During the study period, all neonates were admitted within 72 hours of life, needing early empiric antibiotic treatment for EOS.
- Patients of either gender.
Exclusion criteria:
- Patients having prior administration of a different antibiotic regimen for more than 24 hours.
- Patients with the presence of suspected or proven meningitis, necrotizing enterocolitis (NEC), or peritonitis.
- Patients with severe sepsis (defined as clinical and laboratory symptoms of sepsis and signs of at least one organ dysfunction).
- Patients with septic shock with isolation of micro-organisms are resistant to the study regimen in the maternal urinary tract, birth canal, or other situations that require different antibacterial regimens.
After getting approval from the research committee. Patients referred from the Obstetrics &Gynecology unit to the department of pediatrics and meeting inclusion criteria were inducted in the study. Written informed consent was also obtained from parents/guardians of patients. All clinical and laboratory findings were recorded according to the clinical routine. Patients were randomly allocated into two groups using the lottery method. In Group A, infants were subjected togentamicin (4–5 mg/kg 24–48 hourly, based on gestational (GA) and postnatal age (PNA)) was combined with ampicillin (25 mg/kg 8-12 hourly, based on GA and PNA) and With cefotaxime G (25 000 IU/kg 8–12 hourly, based on GA and PNA) in Group B. Microbiological samples from blood was collected on admission and thereafter from Sterile body sites as clinicallyindicated. All microbiological samples were analyzed using Routine methods and evaluated according to the CSLI criteria. Efficacy in both groups was determined when there was no growth of gram-negative micro-organisms on MacConkey agar within 72 hours in either group. All information pertaining to age, gender, birth weight, pre-term status, and efficacy in both groups was recorded in a Proforma attached to this synopsis.
Data analysis: Data was entered and analyzed in SPSS version 23.0. Mean±standard deviations (SDs) were calculated for Numerical variables like age, gestational age, and birth weight. Frequencies and Percentages were calculated for categorical variables like gender, preterm, and efficacy in both groups. Both groups were compared for efficacy using a chi-square test. Efficacy in both groups was stratified with age, gestational age, gender, birth weight, and pretermstatus to see effect modifiers. Post-stratification chi-square test was applied. Keeping P value < 0.05 as significant. All results were expressed in the form of tables and graphs.
Results
This study was conducted on 212 (106 neonates in each group) in the department of pediatrics, Hayatabad Medical Complex, Peshawar.
In Group A, the mean and SDs for age were 40±13.16. Mean and standard deviations (SDs) for gestational age were 35±1.63. Mean and SDs for weight were 2500±114.50. In Group B, the mean and SDs for age were 40±8.74. Mean and SDs for gestational age were 35±2.06. Mean and SDs for weight were 2500±159.78(Table 1). In Group A, 50 (47.16%) neonates were recorded in the 01 to 36 hrs age group, and 56 (52.83%) patients were recorded in the 37 to 72 hrs age group. In Group 50 (47.16%), Neonates were recorded in the 01 to 36 hrs age group, and 56 (52.83%) patients were recorded in the 37 to 72 hrs age group (Table 2). In Group A, 73 (68.86%) neonates were male, and 33 (31.13%) neonates were female. In Group B, 86 (81.13%) neonates were male, and 20 (18.86%) neonates were female (Table 3). In Group A, 38 (35.84%) neonates were preterm, and in Group B, 25 (23.58%) neonates were neonates (Table 4). As per efficacy in both groups, 84 (79.24%) neonates showed effective results, and 97 (91.50%) neonates showed effective results (Table 5). Age, gender, gestational age, and birth weight were controlled through stratification and are hence presented in tables 7 to 9, respectively.
| Numerical variables | Mean and SDs | ||
| Group A (n=106) | Group B (n=106) | Overall (n=212) | |
| Age | 40±13.16 | 40±8.74 | 40±12.46 |
| Gestational Age | 35±1.63 | 35±2.06 | 35±2.45 |
| Weight | 2500±114.50 | 2500±159.78 | 2500±125.50 |
Table 1: Descriptive statistics (n=212)
| Age range | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | |
| 01 to 36 hrs | 50 | 47.16% | 50 | 47.16% |
| 37 to 72 hrs | 56 | 52.83% | 56 | 52.83% |
Table 2: Frequencies and percentages for age (n=212)
| Gender | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | |
| Male | 73 | 68.86% | 86 | 81.13% |
| Female | 33 | 31.13% | 20 | 18.86% |
Table 3: Frequencies and percentages for gender (n=212)
| Pretermstatus | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | |
| Yes | 38 | 35.84% | 25 | 23.58% |
| No | 68 | 64.15% | 81 | 76.41% |
Table 4: Frequencies and percentages for preterm status (n=212)
| Efficacy | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | |
| Yes | 84 | 79.24% | 97 | 91.50% |
| No | 22 | 20.75% | 09 | 8.49% |
Table 5: Efficacy in both groups (n=212)
| Age | Efficacy | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | ||
| 01-36 hrs | Yes | 37 | 34.90% | 46 | 43.39% |
| No | 13 | 12.26% | 4 | 3.77% | |
| 37-72 hrs | Yes | 47 | 44.33% | 51 | 48.11% |
| No | 09 | 8.49% | 05 | 4.71% | |
Table 6: Stratification of efficacy with respect to age (n=212)
| Gender | Efficacy | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | ||
| Male | Yes | 59 | 55.66% | 81 | 76.41% |
| No | 14 | 13.20% | 5 | 4.71% | |
| Female | Yes | 25 | 23.58% | 16 | 15.09% |
| No | 08 | 7.54% | 4 | 3.77% | |
Table 7: Stratification of efficacy with respect to gender (n=212)
| Gestational age | Efficacy | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | ||
| < 34 weeks | Yes | 27 | 24.47% | 24 | 22.64% |
| No | 11 | 10.37% | 1 | 09.94% | |
| >34 weeks | Yes | 57 | 53.77% | 73 | 68.86% |
| No | 11 | 10.37% | 8 | 7.54% | |
Table 8: Stratification of efficacy with respect to gestational age (n=212)
| Birth weight | Efficacy | Group A (n=106) | Group B (n=106) | ||
| Frequencies | Percentages | Frequencies | Percentages | ||
| <2500 gm | Yes | 58 | 54.71% | 56 | 52.83% |
| No | 18 | 16.98% | 5 | 4.71% | |
| >2500 gm | Yes | 26 | 24.52% | 41 | 38.67% |
| No | 4 | 3.77% | 4 | 3.77% | |
Table 9: Stratification of efficacy with respect to birth weight (n=212)
Discussion
Sepsis remains a leading cause of mortality and morbidity, especially during the first five days of life and in low and middle-income countries (LMIC).[11] Hospital infection also remains a major cause of mortality in children despite progress encountered in the last decades. WHO recommends ampicillin (or penicillin; cloxacillin if staphylococcal infections are suspected) plus gentamicin for empiric treatment of neonates with suspected clinical Sepsis; when referral is not possible, once daily gentamicin plus oral amoxicillin may be used. It is known, however, that in many countries, agents with a broader spectrum, such as third-generation cephalosporins, are commonly used to treat neonatal and infant sepsis.[12]Against this background, concerns are increasing regarding bacterial pathogens with reduced susceptibility to empiric medication with variations both between and within LMIC.[13] The majority of cases of EOS result from vertical transmission of bacteria from the mother to the neonate during the intrapartum period.
LOS is due to the horizontal transmission of Pathogens from the environment or the hands of the caregiver. The pattern of bacterial pathogens responsible for neonatal sepsis has changed over time and varies from place to place. There is a difference in the causative organisms for neonatal sepsis between developed and developing countries. Within developing countries, there are regional Variations in the spectrum of organisms causing neonatal sepsis.[14]
The incidence of proven EOS was 4.9%. Among neonates receiving ampicillin (n = 142) or penicillin (n = 141) change of antibiotic regimen within 72 hrs (10/142 vs. 10/141; OR 1.02; 95% CI 0.40–2.59), 7-day mortality (11/142 vs. 14/141; OR 0.76; 95% CI 0.33–1.75) and overall treatment success (85.91%) (122/142 vs. 120/141) occurred at similar rates.
Kaplan-Meier analysis revealed almost identical treatment success rates for both treatment Regimens (p = 0.92). There were no differences in treatment failure rates between centers (12.0% in unit A vs. 15.6% in unit B) and treatment periods (13.5% in first vs. 14.1% in second period) 5 which as compared to this study, where in efficacy in both groups, 84 (79.24%) neonates showed effective results and 97 (91.50%) neonates showed effective resultswhich as compared to this study, where in efficacy in both groups, 84 (79.24%) neonates showed effective results and 97 (91.50%) neonates showed effective results. (Table 5) The use of gentamicin plus ampicillin has at least four fundamental advantages over the Use of other antimicrobials in the pediatric population; These include excellent evidence-based clinical use in pediatrics for a longer period, their synergistic effects, their broad spectrum activity, and also the excellent activity of ampicillin to eradicate Listeria Monocytogenes.[15-19]One hundred and eighty-seven children affected by bacterial meningitis were treated intravenously at daily doses of 150 to 300 mg/kg cefotaxime. The causative microorganisms were Neisseria meningitis, Streptococcus pneumoniae, Haemophilus Influenza, enteric gram-negative bacilli, and Staphylococcus species. The sterilization of the cerebrospinal fluid was achieved in the first 72 hours of treatment in 90.1% of patients.[20] One hundred and seventy-two patients (92.0%) were cured. Cefotaxime is an effective, safe and well tolerated antibiotic for the treatment of childhood bacterial meningitis and sepsis, as compared to this study, where in efficacy in both groups, 84 (79.24%) Neonates showed effective results, and 97 (91.50%) neonates showed effective results.[17]
Limitations: This study is limited by its single-center design, potential selection bias from non-probability sampling, and short-term follow-up. Future multi-center studies with larger sample sizes and extended follow-up are needed to enhance generalizability.
Recommendation: We recommend considering ampicillin plus cefotaxime as a viable alternative for empiric treatment of early neonatal sepsis, given its superior efficacy. Future studies should be multicenter with larger sample sizes and extended follow-up to validate these findings, assess long-term outcomes, and refine dosing strategies. Clinicians must also factor in local pathogen profiles and resistance patterns when selecting appropriate therapies.
Conclusion
In conclusion, patients admitted to the NICU, ampicillin combined with gentamicin and Cefotaxime could be equally used in the empiric treatment of suspected EOS, but in my study, penicillin plus cefotaxime gave better results as compared to penicillin plus gentamycin.
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Acknowledgments
Not reported
Funding
No external funding was received; all research efforts and financial support were provided by the authors.
Author Information
Corresponding Author:
Bilal Noor
Department of Paediatric Medicine
Doggar Hospital, Pakistan
Email: Bilalzk261@gmail.com
Co-Authors:
Hamid Iqbal
Department of Pediatric Medicine
Naseerullah Babar Hospital Peshawar, Pakistan
Muhammad Suliman
Department of Clinical Technology
Doggar Hospital, Pakistan
Naveed Iqbal
Department of Dentistry
MTI Abbottabad University, Khyber Medical University, Pakistan
Sadia Nasir
Department of Obstetrics & Gynaecology
MTI Khyber Teaching Hospital Peshawar, Pakistan
Authors Contributions
Bilal Noor was responsible for selecting the main topic. Hamid Iqbal contributed to the literature review and study design. Muhammad Sulaman handled data collection, while Naveed Iqbal performed data analysis. Sadia Nasir was responsible for grammar correction.
Ethical Approval
Ethical approval for the study was granted by the ethical board of Hayatabad Medical Complex Peshawar, with reference number HMC/IRB/7/24. Data was collected after taking written consent from the parents of enrolled children in our study.
Conflict of Interest Statement
The authors declare no conflicts of interest.
Guarantor
None
DOI
Cite this Article
Bilal N, Hamid I, Sulaman M, Naveed I, Sadia N. Comparison of the Efficacy of Ampicillin Plus Gentamicin versus Ampicillin Plus Cefotaxime for the Treatment of Early Neonatal Sepsis. medtigo J Pharmacol. 2025;2(1):e3061211. doi:10.63096/medtigo3061211 Crossref
