1Professor and HOD, Department of Paediatrics, Srinivas Institute of Medical Sciences and Research Centre, Mangalore, Karnataka State, India.
2Final Year Pharm D, Srinivas College of Pharmacy, Valachil, Mangalore, Karnataka State, India
Sepsis is a leading cause of mortality in neonatal foals, and recent advancements have been achieved in comprehending the underlying pathophysiology. Early diagnosis and treatment aimed at supporting vital functions and neutralizing the effects of the causative organisms are crucial for achieving a successful outcome. Newborns infected with multi-drug-resistant (MDR) pathogens, which have restricted treatment alternatives, may get advantages from innovative antimicrobials. This review offers a comprehensive examination of the incidence, diagnosis, treatments, and management utilizing novel antibiotics. Current diagnostic techniques depend on traditional culture procedures, which are time-intensive and may postpone essential therapy decisions. The study analyses historical and contemporary microbiological methods, hematological parameters, and inflammatory biomarkers that could facilitate the diagnosis of sepsis. The prompt and precise diagnosis of infection will enhance clinical outcomes and reduce the excessive use of antibiotics. Novel antibiotics may be contemplated for neonates in the management of multidrug-resistant Gram-negative infections with restricted therapeutic alternatives and for Gram-positive infections with resistance issues..
Neonatal sepsis, also known as sepsis in newborns, is a dangerous illness that strikes infants under 28 days of age. When your body reacts severely to an infection, sepsis happens. When a newborn gets sepsis from an infection, their entire body may become inflamed. The baby's limbs and vital organs receive less blood flow as a result of this inflammation and blood clotting. It may result in death or organ failure.[1] Neonatal sepsis can be classified as either late onset (day of life 4 or later) or early onset (day of life 0–3). With a median age of onset of 6 hours, 85% of newborns with early-onset sepsis (EOS) present within 24 hours, 5% do so between 24 and 48 hours, and a smaller percentage do so between 48 and 72 hours. In premature neonates, onset is fastest. The acquisition of microorganisms from the mother is linked to early-onset sepsis. Hematogenous, transplacental transmission from an infected mother or, more frequently, ascending infection from the cervix are the two ways that infection can happen. As the newborn passes through the colonized birth canal at delivery, it may pick up organisms that colonize the mother's genitourinary (GU) tract. The following microbes are most frequently linked to early-onset infections: Haemophilus influenzae, Escherichia coli, Coagulase-negative Staphylococcus, Group B Streptococcus (GBS), and Listeria monocytogenes. Late-onset sepsis is acquired from the environment and manifests between days 4 and 90 of life. The following microorganisms have been linked to late-onset sepsis: Coagulase-negative,Numerous less common organisms, including Staphylococcus, Staphylococcus aureus, Ecoli, Klebsiella, Pseudomonas, Enterobacter, Candida, GBS, Serratia, Acinetobacter, Anaerobes, and many more[2]. The most common definition of EOS in preterm infants is that it happens during the first three days of life and is brought on by bacterial pathogens that are vertically transferred from mother to child either prior to or during delivery. Sepsis that develops after 72 hours in neonatal intensive care units (NICUs) and within 7 days of birth in term infants is known as late-onset sepsis (LOS). It can be caused by pathogens that are acquired vertically or horizontally, and it can occur up to 90 or 120 days of age. Neonates may also develop viral or fungal infections at 7 days of age, which need to be differentiated from bacterial sepsis.[3]All babies can get neonatal sepsis. However, due to their undeveloped immune systems, preterm babies are more likely than full-term babies to acquire sepsis. Premature babies lack the antibodies that shield them from several germs. This is because they are born before their birthing parent can give them the antibodies. Additionally, newborns with low birth weights, low Apgar scores, male birth assignments, and birthing parents with certain risk factors like an infection during pregnancy are more likely to develop neonatal sepsis.[1]Despite improvements in newborn medicine, neonatal sepsis continues to be a leading cause of morbidity and mortality. In high-income countries, the incidence ranges from 1 to 4 cases per 1000 live births; in low- and middle-income countries, it can range from 49 to 170 cases, with a case fatality rate of up to 24%. Even in individuals whose cultures were negative but who received antibiotic treatment, survivors of neonatal sepsis are more likely to experience unfavorable neurodevelopmental outcomes, such as cerebral palsy, hearing loss, visual impairment, and cognitive impairments.[4]
Epidemiology:
Neonatal sepsis epidemiology has been evolving over time.Since the 1990s, when intrapartum antibiotic prophylaxis and universal screening for GBS in pregnant women were implemented, the incidence of EOS has declined. LOS rates, however, have stayed largely unchanged. More EOS cases are now attributed to Escherichia coli.[5] Neonatal sepsis is one of the three main causes of the 2.7 million deaths that occur each year and a significant cause of morbidity globally.Infections alone are responsible for over 600,000 of these deaths in the United States, and 99% of them occur in poorer nations. South Asia is responsible for 3.5 million of the 6.9 million newborn sepsis cases that occur there annually. With 1.2 billion people, India bears a significant share of this illness load. The majority of these sepsis-related newborn deaths are thought to occur in rural India, where over 60% of the Indian population resides, despite the lack of population-based statistics.[6] In the US, incidence of EOS GBS infection have significantly decreased as a result of the broad adoption of intrapartum antibiotic prophylaxis (IAP) to lower vertical transmission of GBS infections in high-risk women.Although certain studies among VLBW preterm infants have revealed an increase in EOS caused by Escherichia coli, overall, it is not thought that IAP has changed the pathogens linked to EOS[7]. According to a recent study conducted by the Neonatal Research Network (NRN) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the overall incidence of EOS is 0.98 instances per 1000 live births, with rates rising in preterm newborns.Neonatal sepsis is far more common among black preterm neonates than in the general population, with 5.14 cases per 1000 births and a case fatality rate of 24.4%, according to studies that stratify the illness burden by race and gestational age. Preterm low birth weight infants have the highest rates of LOS.According to studies from the NICHD NRN, rates of blood culture-confirmed LOS were inversely correlated with gestational age, with about 21% of VLBW newborns weighing less than 1500g experiencing one or more episodes.Among VLBW newborns with LOS, coagulase-negative staphylococci (CoNS) have become the most frequently isolated pathogens.[8]
Etiology:
EOS is frequently caused by in-utero transmission, which involves the retrograde transfer of pathogens from the vagina/cervix to the uterus and into the amniotic fluid, or vertical transmission, which involves the infection spreading to the newborn as they pass through the vaginal canal after delivery.Because of this, GBS a widespread commensal colonizer of female gastrointestinal and genitourinary tracts is frequently mentioned as the most frequent causal organism of EOS in developed nations.Another important cause is E. Coli, which has been linked to 10% to 35% of EOS cases and has been shown in some studies to have a higher incidence in EOS-affected neonates than GBS.[9]The rates of E. Coli isolation in very low birth weight (VLBW) infants are also alarmingly on the rise.Other significant, albeit less frequent, causes of EOS include Staphylococcus aureus, Listeria monocytogenes, Coagulase-negative staphylococci (CoNS), and Haemophilus influenzae.Since EOS is typically treated with a combination of an aminoglycoside (gentamicin, for example) and ampicillin or penicillin, it is crucial to track data on antibiotic sensitivity in the most commonly identified bacteria. Nearly of GBS isolates are ampicillin and penicillin sensitive, according to recent data from EOS cases in industrialized nations.Although the majority of E. Coli isolates are probably responsive to gentamicin, these isolates have a greater degree of resistance (10%) to conventional cover.[10] On the other hand, postnatal environmental exposure to infection causes LOS. This may be transmitted by medical personnel, medical facilities, and other caretakers. In this instance, the most frequent sources of infection are CoNS, such as Staphylococcus epidermidis.Other pertinent causes include Staphylococcus aureus, Candida species, and Enterobacteriaceae.However, there is disagreement on the percentage of cases in which CoNs are contaminants rather than the cause of sepsis, as well as how these cases can be identified and evaluated.Compared to other isolated LOS pathogens, CoNs are frequently more resistant to conventional antibiotic regimens and may need further protection.[11] Sepsis is comparatively uncommonly caused by viral infections. However, they should be taken into consideration in cases of antibiotic-resistant sepsis because they can frequently mimic the symptoms of bacterial sepsis, particularly with Herpes Simplex Virus (HSV) infections.Apart from vertically transmitted HSV, other viral agents linked to sepsis or sepsis-like syndromes in neonates include enteroviruses, Cytomegalovirus (CMV), and other TORCH infections.For instance, CMV is associated with and present in bacterial neonatal sepsis, despite being a major cause of congenital hearing loss and other neonatal morbidities.Immune dysregulation brought on by both bacterial sepsis and CMV infection may create favorable circumstances for the recurrence of either infection or cause it to occur concurrently[12].Gram-negative bacteria like Klebsiella and E. Coli account for a large proportion of neonatal sepsis cases in developing countries, where nosocomial infections are more common and seen earlier, while GBS is less common. It is important to note that there are significant regional differences in the aetiological makeup of neonatal sepsis, with one analysis of patients in sub-Saharan Africa finding that Salmonella enterica and Acinetobacter species are the most frequent cause of EOS, with no cases attributable to GBS[13]. Table 1 summarizes and compares the major causative agents of both EOS and LOS in developed countries.
Table 1. Major causative pathogens of early-onset versus late-onset neonatal sepsis
|
Early-onset sepis major pathogens |
Frequency (%) |
Late-onset sepsis major pathogens |
Frequency (%) |
|
Group B Streptococcus |
30-60 |
CoNS |
39-85 |
|
E. Coli |
10-35 |
Staphylococcus aureus |
5-18 |
|
Gram -Ve Bacteria excluding E. Coli |
7-30 |
E. Coli |
5-13 |
|
Staphylococcus aureus |
1-7 |
Klebsiella Species |
4-9 |
|
CoNS |
1-5 |
Candida Species |
3-8 |
|
Listeria Monocytogenes |
0-1 |
Enterococcus Species |
6-15 |
Pathophysiology:
The primary cause of the heightened vulnerability of neonates to sepsis is their undeveloped immune systems. T lymphocytes, macrophages, and polymorphonuclear neutrophils are unable to execute a full inflammatory response in newborns due to their immature function. Neonatals are also unable to produce a sufficient mounting response against infectious pathogens, either quantitatively or qualitatively, due to their low levels of immunoglobulins at birth. The transmission of immunological globulins to the fetus is reduced by the premature's short time in the uterus. Compared to term infants, preterm babies are far more likely to develop sepsis due to this immunoglobulin deficit.[14] Sepsis's pathophysiology and clinical manifestations are mostly the result of the immune system's reaction to the infection rather than the direct effects of the pathogen on the body. The systemic inflammatory response syndrome is one example of this (SIRS). When a foal experiences infection or inflammation, variations in its heart rate, respiration rate, temperature, and/or white cell count are referred to as SIRS. These changes are thought to be signs of cytokine activation. Since leucocytes are the primary source of these cytokines, leucocyte activation has been the subject of much research into the pathophysiology of sepsis and SIRS.[15] Depending on the degree of early delivery, the stratum corneum—the outermost layer of the epidermis that serves as the first line of defense against innate immunity—does not fully develop until roughly 10 days after birth, and this can be prolonged by several weeks. Vernix, a biofilm created in the third trimester that serves as an extra mechanical barrier for a few hours after birth, is also insufficient in neonates born before 28 weeks of gestation. Additionally, Vernix offers antimicrobial peptides (AMPs) such as lysozyme and lactoferrin.In extremely preterm infants, the relative lack of vernix further raises the risk of EOS[16]. Premature delivery affects the amount of preformed antibodies that neonates can access at birth because the third trimester is when the greatest amount of maternal igG antibody transference takes place. Additionally, premature neonates have a comparatively higher number of goblet cells, which makes respiratory secretions more viscous and impairs mucociliary clearance. Additionally, these babies have lower levels of surfactant proteins, which are crucial for respiratory mucosal defense.Other important risk factors to think about include ruptured membranes for more than eighteen hours, chorioamnionitis or intra-amniotic infection, and maternal infection (usually UTIs followed by vulvovaginitis) during pregnancy. [17]
Comman Pathogens:
Early-Onset Sepsis :Together, Escherichia coli (E coli) and Group B streptococcus (GBS) are responsible for around 70% of EOS cases.E. Coli (10%–15% of cases) is the second most prevalent infection in term neonates, after GBS (40%–45% of cases). In the preterm population, these figures are inverted, with GBS accounting for only 20% to 25% of infections and E. Coli for 50% of cases.While GBS is more common overall, E. Coli is the primary cause of EOS-related morbidity and mortality.Other uncommon pathogens include Listeria monocyto genes, gram-negative bacilli (Enterobacter spp. and Haemophilus influenzae), Streptococcus pneumoniae, Staphylococcus aureus, and Enterococcus species. Infections with several bacteria are uncommon[18].
LATE-ONSET SEPSIS:Gram positive bacteria are the most common cause of late-onset sepsis, although viruses, fungi, and gram negative bacteria can also be responsible. The most prevalent gram-positive LOS agents are GBS (1% of cases), S aureus (7% of cases), and coagulase-negative staphylococci (50% of cases). Gram-negative bacteria, such as E. Coli, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumonia, and Enterobacter spp., account for 20% to 42% of LOS cases.[19] The most prevalent gram-negative organism is E. Coli, whereas P. aeruginosa is the most lethal. Usually affecting VLBW infants, fungal LOS rates range from 5% to 28%, depending on the hospital.Candida albicans and Candida parapsilosis are the most frequent fungi, and they are increasingly seen in individuals who have central venous catheters.Although they are the least frequent agents linked to LOS, viruses have a big influence on the long-term results of those who are impacted. The most prevalent viral infections are herpes simplex viruses, which can cause symptoms anywhere from five to twenty-eight days of life.[20]
Diagnosis:
A complete blood cell (CBC) count and differential, C-reactive protein (CRP) measurements, and other infection markers are among the laboratory tests used to assess for early-onset and late-onset sepsis. The gold standard is still the culture of blood, urine, and cerebrospinal fluid (CSF) samples. For initial identification, a Gram stain can help determine whether an organism is gram-positive or gram-negative. Emerging DNA-based identification methods have the potential to enhance culture outcomes and offer quick diagnostic data.Multiplex polymerase chain reaction (PCR) for rapid pathogen detection may limit exposure to broad-spectrum antibiotics while enabling more prompt selection of targeted antibiotic therapy.[21]
Clinicians may decide to only culture the cerebrospinal fluid (CSF) of infants with confirmed or suspected sepsis due to the low incidence of meningitis in newborns with negative blood culture results. However, neonates with negative blood culture results and suspected sepsis have a 38% chance of developing culture-positive meningitis, according to data from large studies. Accordingly, when assessing the infant who may have sepsis, a lumbar puncture should be taken into consideration. [22]
The imaging tests used in the workup of neonatal sepsis should focus on the symptoms of the newborn and may include computed tomography (CT) scanning, magnetic resonance imaging (MRI), and head ultrasonography in cases of meningitis, as well as chest radiography to assess pulmonary involvement.
Cultures
Aerobic and anaerobic cultures are appropriate for most of the bacterial pathogens associated with neonatal sepsis. In neonates with massive hemolysis, bowel-related processes, abscesses, or refractory pneumonia, anaerobic cultures are particularly crucial. In one study, 16% of early-onset sepsis in infants with very low birthweights was caused by anaerobic infections.The organism of infection should typically be visible in 36–48 hours according to the results of bacterial cultures; the organism is then initially identified 12–24 hours after growth. While obtaining two cultures from different sites has been demonstrated to be helpful in determining whether commensal species represent a genuine infection or a contaminated sample, single-site blood cultures are effective for isolating bacteria in neonates with sepsis.An umbilical cord blood culture could be taken into consideration[23].
Complete Blood Cell (Cbc) Count And Differential
While the sensitivity and specificity of these markers are low, serial monitoring of the CBC may help distinguish sepsis from nonspecific abnormalities caused by the stress of delivery. A CBC and differential may be ordered serially to identify changes related to the infection (e.g., thrombocytopenia or neutropenia) or to track the emergence of a left shift or changes in the ratio of immature to total neutrophils[24].
Platelet Count
In the first 10 days of life, a healthy newborn's platelet count is rarely less than 100,000/µL (normal, ?150,000/?L). 10% to 60% of infants with sepsis have thrombocytopenia, which is defined as a platelet count of less than 100,000/µL. It can persist for up to three weeks and may be a presenting sign of neonatal sepsis.However, the usefulness of thrombocytopenia in the initial workup of neonatal sepsis is questionable because it is a late indicator of serious bacterial infection and an insensitive and nonspecific finding.The mean platelet volume (MPV) and platelet distribution width are considerably higher in neonatal sepsis after two to three days of life due to the appearance of newly formed platelets. These tests could help identify the cause of thrombocytopenia. Nevertheless, the diagnosis of neonatal sepsis is not aided by the presence of thrombocytopenia because of the wide range of causes of the condition and its delayed onset[25].
White Blood Cell Counts And Ratios:
White blood cell (WBC) counts and ratios have a low positive predictive value and are still very nonspecific, despite being more sensitive than platelet counts in identifying sepsis. Up to 50% of culture-proven sepsis cases may initially show normal WBC counts. Unusual WBC counts in non-infected infants can also be caused by the stress of delivery or by a number of other factors. Compared to an elevated WBC count (>20,000/µL), a low WBC count (< 5>[26].
C-Reactive Protein (CRP), Procalcitonin, And Other Markers:
Of infants with systemic bacterial infections, 50% to 90% have elevated levels of CRP, an acute-phase protein linked to tissue injury, at some point. CRP levels increase as a result of interleukin (IL)-6 production by macrophages, T cells, and adipocytes. This is particularly true for infections involving deep tissue cellulitis or abscesses.CRP levels typically start to rise four to six hours after an infection starts, turn abnormal 24 hours later, peak in two to three days, and stay high until the inflammation goes away. Although it is not advised to use the CRP level as the only indicator of neonatal sepsis, it can be used as a serial study during infection or as part of a sepsis workup to evaluate the response to antibiotics, ascertain the length of therapy, or detect an infection relapse[27].Serum levels of immunoglobulin M (IgM) can be useful in identifying intrauterine infections, particularly if they have been present for a while. Intrauterine infection is suggested by elevated IgM levels in umbilical cord sera. The usefulness of this assay is restricted by the clinical availability of such testing and the availability of prompt results[28]. Infection markers like CD11b, soluble CD14 subtype, CD64, IL-6, IL-8, IL-10, and granulocyte-colony stimulating factor (G-CSF) have been shown to be useful as supplementary tests for assessing sepsis in neonates.Using combinations of tests and serial measurements can further increase their value. Although these tests may be helpful in determining when to stop antibiotic therapy, it is currently generally agreed that they should not be used alone to determine whether antibiotic therapy is necessary[29].
Coagulation Studies:
Infected infants may develop disseminated intravascular coagulation (DIC). It is challenging to predict which infants will be impacted when sepsis first appears. Infants with DIC may require blood products, such as fresh frozen plasma (FFP) and cryoprecipitate, to replace coagulation factors consumed in conjunction with DIC. They also exhibit abnormalities in their prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer levels. Coagulation should be assessed by looking at these values if infants exhibit symptoms that are consistent with impaired coagulation (such as gastric blood, bleeding from intravenous or laboratory puncture sites, or other bleeding)[30].
Urine Testing:
Urine is not required for chemical and microscopic analysis in neonates with suspected sepsis during the first 72 hours of life because the majority of urinary tract infections in this population are secondary to hematogenous seeding of the kidney by bacteremia. However, especially in neonates with symptoms, a urinalysis and urine culture should be carefully considered as part of subsequent workups for sepsis. Because of the possibility of bacterial contamination, urine cultures should only be performed on specimens obtained by urethral catheterization or suprapubic aspiration. When approximately 1,000 CFU/ml of bacteria from a single colony are identified, catheter-obtained urine cultures have a 99% specificity and a 95% sensitivity when compared to suprapubic tap specimens. Bag urine specimens, on the other hand, have a 100% sensitivity but a low specificity[31].
Cerebrospinal Fluid Testing:
Although lumbar puncture (LP) is a crucial procedure for obtaining cerebrospinal fluid (CSF) in infants with suspected sepsis in order to rule out meningitis, its routine application in neonates is debatable. High-risk neonates who seem healthy or whose clinical symptoms seem to be caused by noninfectious conditions like RDS have a very low risk of concurrent meningitis. Meningitis can occur concurrently in up to 23% of newborns with bacteremia. Therefore, in neonates with a strong clinical picture suggestive of neonatal sepsis or who have a positive blood culture and have never had an LP, there should be a very low threshold for obtaining CSF through LP[32].Moreover, lumbar puncture should be part of every neonatal sepsis evaluation, not only if cultures come back positive, because up to 38% of patients with meningitis will have a negative blood culture. It should be mentioned that an LP performed when the neonate has previously received antibiotics may result in CSF cultures that are falsely negative. Additionally, lumbar puncture would help rule out enteroviral or parechovirus meningitis, meningoencephalitis, or neonatal herpesvirus infection.[33]
Treatment And Management:
Numerous factors, such as age, the site of infection, the suspected causative organism, patterns of microbiological resistance, and the resources available, influence management. Although there is agreement among researchers that antibiotic therapy should begin as soon as neonatal sepsis is suspected, opinions differ on how long the course of treatment should last. Historically, the treatment for suspected neonatal sepsis has often involved aggressive antibiotic initiation due to the neonate's immunosuppression. Diagnostic studies are often ordered and treatment initiated before sepsis is proven[34]. The American Academy of Pediatrics, American College of Obstetricians and Gynecologists, and the Centers for Disease Control and Prevention recommend sepsis screening or treatment for risk factors related to group B Streptococcus infections. However, this approach has been questioned due to the negative impact of unnecessary antibiotic exposure, including interference with breastfeeding establishment, gut microbiome alternations, increased childhood obesity, and development of antimicrobial resistance[35].
A newer approach, the Kaiser Sepsis Calculator, uses a multivariate predictive model to reduce the use of empiric antibiotics and blood cultures without increasing morbidity or mortality rates. The model should be limited to term and late preterm infants of 34 weeks' gestation or later and implemented at an institutional level, considering local resources and the incidence of early-onset sepsis. A standardized approach will lead to improved risk identification and buy-in from stakeholders, such as obstetricians, nursing staff, and other care team members[36].
Current Treatment Options
There are currently far too few treatment options available for MDR organisms in NICUs, especially for Gram-negative strains. With 75–100% clinical success rates, colistin has been the most widely used antibiotic in the past two decades to treat MDR P. aeruginosa, A. baumannii, and CRE in neonates.[37] The use of tigecycline, fluoroquinolones, and polymyxin B is less commonly documented than the use of meropenem at high doses, as an extended infusion, or in combination with other antimicrobials, which is the second most commonly reported agent. The safety profile of polymyxins is not ideal, though, as nephrotoxicity and severe electrolyte imbalances have been documented in newborns in 10–19% of cases.Linezolid and daptomycin are the mainstays for treating Gram-positive bacteria with poor clinical response to oxacillin or vancomycin or with unfavorable susceptibility profiles, such as methicillin-resistant S. aureus (MRSA), VRE, and CONS. However, daptomycin use may be dubious in the case of pneumonia, while linezolid demonstrated variable clinical responses with clinical cure rates ranging from 63 to 100%[38]. Adults with infections brought on by organisms with undesirable susceptibility profiles can be treated with a variety of approved antimicrobials. Currently, the mainstays of treatment for bloodstream infections (BSIs) and infections of various sites caused by Gram-negative strains with few available treatment options are beta-lactams/beta lactamase inhibitors and cefiderocol. Along with lipoglycopeptides like televancin (which is not authorized for use in the EU) and oritavancin, the novel oxazolidinone tedizolid, and the fourth-generation cephalosporin ceftobiprole, ceftaroline and dalbavancin are among the primary treatment options for Gram-positive strains with resistance concerns. Finally, for the treatment of intra-abdominal infections brought on by susceptible strains, eravacycline, a novel tetracycline with activity against Gram-positive cocci and Gram-negative bacilli, is being considered[39]. Newly developed antimicrobials, such as beta-lactams/beta-lactamase inhibitors, such as ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, imipenem/relebactam, or cefiderocol, may be promising tools for treating MDR Gram negatives in the NICU, while ceftaroline and dalbavancin may be treatment options for Gram-positive strains with resistances of concern. This is due to the lack of available treatment options for newborns. Although there have been more reports of these antimicrobials being used in newborns and infants in recent years, the potential for expanding their use to these populations has not yet been evaluated. Reviewing what is currently known about the use of these antibiotics in newborns was the goal of this study.[40]
Empirical Therapy
There are two types of treatment for neonatal infections: antimicrobial therapy for known (definitive) or suspected (empirical) pathogens. Antimicrobial selection is influenced by exposures (community versus hospitalized at the time of symptom onset) and early or late onset presentation. A comprehensive history, physical examination, and cultures of clinical specimens are the most crucial elements. Antimicrobial therapy administration should not be unduly delayed for specimen collection in critically ill neonates in septic shock, even though it is preferable to obtain cultures prior to the initiation of antimicrobial therapy in order to maximize recovery of organisms. The antimicrobial resistance patterns of bacterial isolates frequently found in the neonatal intensive care unit or in community settings should generally serve as the basis for empirical therapy. Third-generation or fourth-generation cephalosporin medications should be saved for suspected Gram-negative meningitis, while ampicillin and an aminoglycoside (typically gentamicin) should be the first empirical treatment for early-onset bacterial infections.Carbapenems, like meropenem, are necessary to treat infections caused by Gram-negative bacteria that produce extended-spectrum ?-lactamases. Babies admitted to the neonatal intensive care unit are increasingly receiving treatment with piperacillin-tazobactam and ampicillin-sulbactam; however, tazobactam's CNS penetration is unreliable, so it shouldn't be used to treat meningitis. Sulbactam, a ?-lactamase inhibitor, appears to reach high concentrations in the CSF when combined with ampicillin [41]. Coagulase-negative staphylococci are more likely to cause healthcare-associated infections in a neonatal intensive care unit than S aureus and Gram-negative bacteria. Coagulase-negative staphylococci-induced bloodstream infections in preterm infants are linked to significant short-term morbidity and long-term neurodevelopmental impairment, but they are not linked to higher mortality. With advancements in blood culture methods that yield real-time culture results, infants not colonized with MRSA could begin narrow empirical therapy using an aminoglycoside and a ?-lactam antistaphylococcal antibiotic, like nafcillin, and adjust it if pathogen recovery indicates a different antimicrobial coverage. It has been demonstrated that this approach lowers the use of vancomycin in the neonatal intensive care unit[42]. When fungal infections, such as candidiasis, aspergillosis, and zygomycoses, are suspected and diagnosed, they should be aggressively managed. In high-risk infants with risk factors for invasive candidiasis, empirical antifungal therapy with amphotericin deoxycholate can be considered. Using a guide that includes neonatal dosing by weight and gestational age, as well as involving a pediatric infectious disease physician, can optimize the use of antimicrobials. Peak and trough measurements of antimicrobials may be helpful to minimize toxicity if the antimicrobial will be administered for longer than two to three days, and in the treatment of specific infections, such as meningitis, where CSF penetration is required. Trough measurements may be indicated in infants with compromised kidney or liver function.[43]
Directed Therapy
The most suitable antibiotic or antibiotics should be used after the pathogens have been identified, their susceptibilities have been determined, and the site or sites of infection have been located. Gentamicin works in concert with penicillin or ampicillin to treat GBS until the blood and CSF cultures are sterile, at which point it can be stopped. For L monocytogenes, ampicillin by itself is sufficient, but the aminoglycoside also works in concert at the beginning of treatment.If synergy is shown to provide bactericidal and postantibiotic effects, an aminoglycoside should be added to an antibiotic that contains penicillin to treat enterococci. When cultures are sterile or the clinical condition improves, the aminoglycoside can be stopped. Vancomycin is used to treat infections caused by enterococci that are resistant to ampicillin without the need for an aminoglycoside.Vancomycin continues to be the preferred medication for confirmed infections since most, if not all, of the coagulase-negative staphylococci isolates are resistant to ?-lactam medications, including the penicillinase-resistant penicillins. Rifampin could be helpful in cases of persistent, source-unknown coagulase-negative staphylococcal bacteremia. Alternative treatments like daptomycin and linezolid ought to be saved for cases where first-line medications are ineffective or ineffective[42]. Ampicillin (if susceptible) or an aminoglycoside is adequate treatment for Gram-negative enteric bacteria. However, a third-generation or fourth-generation cephalosporin (such as cefotaxime, ceftazidime, or cefepime if coverage of Pseudomonas spp. is required) or carbapenem agent (such as meropenem) should be used if meningitis is suspected or confirmed. The most effective treatment for invasive infections caused by Enterobacteriaceae species that produce extended-spectrum ?-lactamase (ESBL) is carbapenem, though cefepime may also be used. Consultation with an infectious disease specialist is necessary for the treatment of infections brought on by Enterobacteriacaea species that produce carbapenemase; an aminoglycoside, colistin, or high-dose tigecycline may be required in addition to a carbapenem-containing regimen[44]. Anaerobic infections can be treated with clindamycin, ampicillin-sulbactam, or metronidazole; metronidazole is recommended for infections affecting the central nervous system. There isn't enough evidence to support the precise length of antimicrobial therapy, but at the very least, antibiotics should be taken until cultures are sterile and there is a clinical recovery. This typically corresponds to a minimum of seven days for bloodstream infections, fourteen days for meningitis that is Gram-positive, and twenty-one days for meningitis that is Gram-negative. The extensive use of vancomycin has led to the emergence of pathogens such as vancomycin-resistant enterococci and vancomycin-insensitive S aureus. Even though neonatal units where MRSA is endemic often use vancomycin, its use can be minimized by restricting empirical therapy to neonates who have a severe infection, potentially caused by MRSA or coagulase-negative staphylococci, and by stopping treatment after 48 hours if blood culture results are sterile. Clindamycin may be an appropriate substitute for treatment of uncomplicated bacteremia and skin and soft tissue infections in neonates caused by MRSA when susceptibility results are available and there is no indication of CNS or endovascular involvement. Due to intestinal dysbiosis brought on by antibiotic exposure, it has been demonstrated that infants exposed to antibiotics have greater rates of necrotizing enterocolitis, sepsis, and morbidity than infants not exposed to antibiotics[45] When meningitis is taken into account, amphotericin deoxycholate is still the recommended treatment for invasive candidiasis; for hepatic or splenic candidiasis, liposomal amphotericin or an echinocandin (caspofungin or micafungin) are alternatives. For organisms that are susceptible, fluconazole may be a useful treatment. The host infant's underlying condition, the length of time that cultures are positive, the severity of the illness, and the ability to eliminate the source—if the infection is linked to central venous catheter access—all affect how well a treatment works.[42]
Table 2. Directed Therapy for Confirmed Neonatal Bacteremia [16]
|
Medication |
Indication |
Dose and Duration |
Side Effects |
|
Ampicillin |
Gram-positive and negative agents; important in empiric therapy related to action against L monocytogenes |
50-100 mg/kg/dose Every 6-12 h 10-14 d |
Fever Hives or rash Vomiting, diarrhea |
|
Cefotaxime |
Synergistic with gentamicin for severe gram-negative sepsis; gram-negative meningitis |
50 mg/kg/dose Every 6-12 h 10-14 d |
Fever Phlebitis, Rash Vomiting, diarrhea Eosinophilia |
|
Gentamicin |
Empiric therapy for gram-negative agents; synergistic with ampicillin or cephalosporin in confirmed gram-negative sepsis |
4-5 mg/kg/dose Every 24-48 h 10-14 d |
Ototoxicity Vomiting, diarrhea Nephrotoxicity Anemia Thrombocytopenia |
|
Meropenem |
Gram-positive and negative cephalosporin resistant strains |
20-30 mg/kg/dose Every 8-12 h 10-14 d |
Rash Convulsions Vomiting, diarrhea |
|
Nafcillin |
Empiric antistaphylococcal; confirmed S aureus |
25 mg/kg/dose Every 6-12 h 10-14 d |
Fever Phlebitis Cholestasis Nephritis Neutropenia |
|
Penicillin G |
Confirmed GBS |
25,000-50,000 units/kg/dose Every 8-12 h 10 d |
Allergic reaction Phlebitis, rash Colitis Neutropenia |
|
Piperacillin/ tazobactam |
Gram-positive and negative ?-lactamase– producing bacteria; synergistic with gentamicin for P aeruginosa |
100 mg/kg/dose Every 8-12 h 14 d Dosing based on piperacillin |
Fever, flushing Rash Vomiting, diarrhea Elevated liver enzymes Anemia |
|
Vancomycin |
Empiric antistaphylococcal; confirmed CoNS and MRSA |
0-15 mg/kg/dose Every 6-24 h CoNS: 7 d MRSA: 10-14 d |
Ototoxicity Red man syndrome Phlebitis Nephrotoxicity Neutropenia |
Ampicillin:
Ampicillin is a semi-synthetic formulation of penicillin that has been expanded in its antimicrobial activity by the additional amino groups that increase its penetration in gram-negative cell membranes. When susceptibility has been established, it is recommended for the treatment of EOS with gram-negative organisms, susceptible H. influenzae, Streptococci, Enterococcus, and L.monocytogenes.Time-dependent bacterial killing is mediated by ampicillin, and frequent dosing keeps the drug concentration above the MIC for extended periods of time, which is believed to increase efficacy. Neonatal (premature and term) with the relatively immature renal function will maintain necessary levels with less frequent dosing because ampicillin is cleared by the kidneys.[46] Due to a lack of neonatal PK data and comparatively low drug toxicity, ampicillin dosages are rarely modified for renal insufficiency, even though this is also true for infants with acute renal dysfunction. A significant increase in clearance with increasing gestation and postnatal age was shown in an open label PK study involving 28 infants born before 34 weeks and 45 infants born after 34 weeks. Neonates rarely experience the side effects of ampicillin that older children do, such as rash, diarrhea, and an increased propensity to bleed. Compared to penicillin use, empirical early use has been associated with increased colonization with Klebsiella pneumonia. High doses have been linked to an increased risk of seizures in simulated models, underscoring the necessity of PK and toxicity studies in neonates.[47]
Cefotaxime:
The most often prescribed systemic cephalosporin for newborns is cefotaxime. Cefotaxime, a broad-spectrum, low-toxicity antibiotic with superior CSF penetration, targets particular penicillin-binding proteins, giving it a longer spectrum than ampicillin. Cefotaxime is most commonly added to empirical regimens to provide coverage in suspected meningitis or to increase coverage against gram-negative bacilli, especially when ampicillin-resistant E. coli is a concern. Although cefepime and ceftazidime have very broad-spectrum coverage (e.g., for Pseudomonas and other ESBL organisms), they are not currently recommended for the empirical treatment of neonatal EOS. However, they may be used in situations where cefotaxime is not available. Because ceftriaxone has a high affinity for serum albumin, increases the risk of hyperbilirubinemia, and is incompatible with fluids that contain calcium, it is rarely used in newborns.[48] The duration that cefotaxime levels stay above the minimum inhibitory concentration (MIC) is maximized by low-dose, frequent-interval regimens, which is similar to ampicillin and other renally-cleared medications with time-dependent killing. Failure to reduce the dosing interval after the first week in neonates born after 32 weeks gestation was linked to sub-therapeutic cefotaxime levels, according to a study that used scavenged blood specimens from 100 neonates born between 23 and 42 weeks gestation. Interval adjustments by postnatal age and gestational age at birth were suggested by this study. Cephalosporin-related adverse drug reactions, such as allergy, diarrhea, bleeding, seizures, and bone marrow suppression, have mostly been documented in adults. Neonatal cephalosporin use is linked to higher rates of fungal colonization, infection, and mortality, as was previously mentioned.[49]
Gentamicin:
Protein synthesis is inhibited and the organism is eventually killed when aminoglycosides bind irreversibly to the bacterial ribosome's 30s subunit. In neonates, the most commonly used aminoglycosides are amikacin, gentamicin, and tobramycin. For the majority of Pseudomonas strains, tobramycin offers better coverage, while amikacin may be used to treat organisms that are resistant to gentamicin. However, gentamicin continues to be the best option for empirical treatment of EOS when there is no drug shortage. Although aminoglycosides can be used to treat a wide range of gram-negative organisms, gentamicin is mostly used in combination therapy due to concerns about cumulative toxicity with prolonged therapy and poor outcomes in adult patients with gram-negative sepsis treated with aminoglycoside monotherapy[50]. In neonatal EOS, extended interval, high-dose regimens are intended to reach trough concentrations of less than 2 mg/L while reaching peak concentrations over MIC of 8–10. Peak concentrations of aminoglycosides above MIC are associated with the death of bacteria. Because preterm neonates have a larger volume of distribution, higher doses are required to reach a comparable peak concentration. Gentamicin is excreted by the kidneys, so neonates who have renal damage or immaturity have a lower clearance rate. Therefore, in neonates who are premature, have kidney damage, or are in the first few days of life when renal clearance is lower, longer dosing intervals are advised. For neonates with hypoxic injury receiving therapeutic hypothermia, longer interval dosing at 36-hour intervals has also been suggested in order to achieve the necessary trough levels. Due to several conflicting factors, it is challenging to determine the prevalence of renal and ototoxicity in neonates. In order to maintain appropriate trough levels, serum drug levels should be monitored during prolonged therapy and therapy in neonates with significant renal compromise.[51]
Meropenem:
Meropenem is a carbapenem beta-lactam antibiotic that has a wide range of activity against bacteria that produce ESBLs and pseudomonas. In contrast to imipenem, the FDA has approved its use in premature neonates. The majority of enterococci and methicillin-resistant staphylococci are resistant to meropenem. When an ESBL bacteria is isolated or maternal ESBL colonization is known, meropenem is the recommended medication[52]. Meropenem also mediates renal clearance-mediated time-dependent killing, necessitating interval adjustments as gestational and postnatal ages increase. A prospective PK study involving 188 neonates with suspected intraabdominal infection born at 23–40 weeks gestation revealed a significant influence of postmenstrual age and serum creatinine levels. Nine neonates had varying CSF levels, but they were always higher than the therapeutic target. Because meropenem binds to GABA receptors in the brain, it is thought to be a safer option than imipenem for lowering the seizure threshold. Just two of the 200 neonatal adverse events linked to meropenem administration were deemed to be drug-related, including one case of fungal infection.[53]
Oxacillin/Nafcillin:
Staphylococci's penicillinases have no effect on these semi-synthetic penicillin derivatives. When compared to vancomycin, beta-lactam antibiotics are linked to better survival rates in adults infected with methicillin-sensitive S. aureus (MSSA). The preferred medication for MSSA, which is isolated in less than 5% of cases of neonatal EOS, is oxacillin/nafcillin. The kidney eliminates oxacillin, while the liver eliminates nafcillin. Neonatal PK dosing has not been well-informed by recent studies. Both medications exhibit time-dependent killing and a safety profile comparable to other penicillins[54].
Penicillin:
Penicillin G has a long history of therapeutic use in neonates and is a water-soluble intravenous formulation with a narrow spectrum. Penicillin formulations that permit gradual release from deep intramuscular injections and are recommended for the treatment of congenital syphilis include benzathine and procaine. Although it is uncommon in the United States, penicillin and an aminoglycoside are used together as empirical therapy for certain newborns. For GBS, Treponema pallidum, groups C and G streptococci, and susceptible strains of viridans streptococci and enterococci, penicillin is still the recommended final treatment. Penicillin kills pathogens based on how long the unbound drug in the serum stays above the minimum inhibitory concentration (MIC). Levels should remain above the MIC for approximately half of the dosing interval. In the initial days following birth, preterm and term neonates should have their intervals adjusted because penicillin, like other beta-lactam antibiotics, is eliminated by the kidney. A common penicillin dose recommendation of 50,000 units/kg/dose every 12 hours was found to produce peak and trough concentrations in 18 infants born less than 28 weeks gestation that were 1000 and 100 times higher than the MIC90 value for GBS (MIC value that inhibits 90% of isolates), respectively. For the treatment of GBS meningitis, current recommendations call for significantly higher dosages.[55]
Piperacillin-Tazobactum:
The broad-spectrum antibiotic piperacillin, a semi-synthetic beta-lactam, is effective against S. aureus, the majority of Streptococci sp., H. influenzae, Neisseria meningitidis, L. monocytogenes, several gram-negative rods, and numerous anaerobes. The piperacillin component is shielded from beta lactamase degradation by the tazobactum component. This antibiotic is more frequently used for necrotizing enterocolitis and late-onset sepsis, and it is rarely indicated in the immediate neonatal period. Among the antimicrobials used in 305 NICUs in the US, piperacillin-tazobactam use increased the most from 2005 to 2010. Its broad spectrum, which includes anaerobes, and its safety record make it a good option for intra-abdominal pathology and polymicrobial infections. Even though some enterobacteriaceae that produce extended-spectrum beta lactamases (ESBLs) are sensitive to piperacillin-tazobactam in vitro, carbepenems are still the recommended medication of choice because of the better outcomes seen in adults[56]. Piperacillin-tazobactam, like the majority of penicillins, mediates time-dependent killing with renal clearance that rises with postnatal and gestational age. Birth weight and postmenstrual age had a significant impact on the dosing regimen, according to a PK study conducted on 71 neonates born between 26 and 41 weeks of gestation. Another study of 32 neonates born between 23 and 40 weeks gestation discovered that long infusions were not required to reach therapeutic goals and that postmenstrual age alone was sufficient to determine the dosing regimen. Neonates rarely experience negative side effects.[57]
Vancomycin:
This glycopeptide is rarely indicated soon after birth and works by preventing the formation of peptidoglycan cell walls. Vancomycin is mainly used to treat beta-lactam-resistant bacteria like Streptococcus pneumonia, Staphylococcus pneumonia, and Enterococci. The 24-hour area under the curve for serum concentration divided by MIC (AUC) best illustrates the time-dependent killing of vancomycin, which is eliminated by the kidneys unaltered. Dosing schedules for neonatal vancomycin are still up for debate. Vancomycin use in adults has been linked to nephrotoxicity and ototoxicity, as well as rash, red-man syndrome, and altered colonization; however, it is unknown how common these side effects are in newborns. Overall, the use of trough drug levels to customize long-term care is supported by the unexplained variability of drug exposure in PK studies.[58]
Chloramphenicol
Therapeutic concentrations of chloramphenicol will be achieved in serum and cerebrospinal fluid with daily doses of 25 mg/kg in preterm and term infants during the first week of life and 37 . 5-50 mg/kg for older term babies[59].
Trimethoprim/Sulfamethoxazole
Trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis. Trimethoprim-sulfamethoxazole inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. Trimethoprim-sulfamethoxazole should not be used if hyperbilirubinemia and kernicterus are of concern in the newborn[60].
Netilmicin
Ampicillin and netilmicin is a safe antibiotic combination for neonates suspected of late sepsis. This, in turn, may be important in reducing vancomycin overuse and the potential for bacterial resistance to this antimicrobial agent.[61]
Treatment of Multi-Drug Resistant Gram-Negative Bacteria
Ceftazidime/Avibactam
Ceftazidime/avibactam is a cephalosporin/beta-lactamase inhibitor, with excellent activity against KPC and OXA-48-like producing CRE and non-carbapenemase-producing CRE, and it is currently approved for use in patients ?3 months for the treatment of complicated intra-abdominal infections, complicated UTIs, hospital-acquired pneumonia, and BSI associated with those conditions; it is also approved for treatment of infections caused by Gram negatives with limited treatment options . Case reports on preterm infants included newborns of 27–29 weeks, in whom treatment was started at 11–46 days of life and continued for 10 to 14 days in the case of UTI or BSI and for 21 to 47 days in the case of meningitidis [62].
Ceftolozane/Tazobactam
Ceftolozane/tazobactam is a cephalosporin/beta-lactamase inhibitor with enhanced activity against P. aeruginosa, approved for the treatment of complicated intra-abdominal infection, and complicated UTIs including pyelonephritis with no restrictions of age, provided the patients are ? 7 days and ? 32 weeks of gestation, and for the treatment of hospital-acquired pneumonia in adults.In patients >2 years with complicated intra-abdominal infections ceftolozane/tazobactam in combination with metronidazole was effective as meropenem and well-tolerated[63].
Cefiderocol
Cefiderocol is a siderophore cephalosporin with excellent activity against carbapenemases and it is currently approved for the treatment of Gram negatives with limited treatment options in adults.Treatment with cefiderocol was started at 9 [88] and 20 days of life [89] and continued for 14 and 9 days, respectively.Cefiderocol also showed superiority to the best available therapy and high-dose meropenem for the outcomes of clinical cure, microbiological eradication, and mortality at 28 days in the case of infections caused by metallo-beta-lactamase-producing Gram negatives[64].
Amikacin And Tobramycin
Amikacin and tobramycin are aminoglycosides with in vitro activity against gentamicin-resistant bacteria.Both aminoglycosides have potential utility in neonatal sepsis given their spectra of activity against Gram-negative bacteria that are gentamicin resistant and staphylococci. Given its stability to a wider range of AMEs, amikacin is the more promising choice in an AME-prevalent environment. Both agents would rely on another antibiotic in a potential combination regimen to provide activity against streptococci[65].
Fosfomycin
Fosfomycin is a broad-spectrum antibiotic belongs to the class of phosphonic antibiotics. Fosfomycin has potential for affordable treatment of neonatal sepsis in combination with other antimicrobials while sparing carbapenems in the context of increasing antimicrobial resistance.With the dosing of 50mg/kg IV, comparing infants 1-3d old and 3-4 weeks old. Amikacin and fosfomycin have several attributes that make them potential candidates for use in neonatal sepsis[66].
Flomoxef
Flomoxef is an oxacephem class ?-lactam antibiotic. A combination of flomoxef and amikacin may be a clinically effective regimen for treating neonatal sepsis in LMIC settings. As for dosing Preterm and Term infants: 40 mg/kg Q8 if PNA ?7 days, and 50 mg/kg Q8 if PNA ?8 days.As monotherapy, both flomoxef and amikacin are safe and well tolerated.19 Whilst it is likely that combination therapy will be safe it is possible there may be unanticipated drug–drug interactions and potentiated toxicities when the drugs are used in combination[67].
Cefepime
Cefepime is a ?-lactam and fourth-generation cephalosporin.Cefepime has a broad spectrum of activity and, although not specifcally licensed for neonatal use, experience with it in neonatal settings is extensive. Its reduced afnity for ESBLs render it potentially useful in AMR-prevalent settings, and it has a safe toxicity profle in neonates[68].
Aztreonam
Aztreonam is a monobactam, a type of beta-lactam antibiotic.Aztreonam is effective against most gram-negative aerobic bacteria, including Pseudomonas aeruginosa, Escherichia coli, and Klebsiella spp. It's inactive against gram-positive bacteria. Aztreonam (90-125 mg/jkg-d] administered in two or three doses; mean dosage, 110 mg/jkg-dj) was given iv in combination with penicillin (100,000 U/[kg·d], three times daily) [69]
Imipenem
Neonates with septicemia due to Gram negative bacteria resistant to beta-lactam to received imipenem-cilastatin therapy.Dosing IV 60 mg/kg doses of imipenem with amikacin (15 mg kg/d) were administered every day. Imipenem-cilastatin combination was not responsible for any complication.[70]
Treatment of Gram-Positive Bacteria with Resistance of Concerns
Ceftaroline
Ceftaroline is a 5th generation cephalosporin with activity against Gram positives including MRSA and MDR S. pneumoniae, and it is currently approved for the treatment of patients of any age, including newborns, with SSSIs or community-acquired pneumonia . In 11 infants of 7–60 days with LOS treated with ceftaroline plus ampicillin and optional aminoglycoside, no treatment failure was observed.. In patients ?2 months with complicated community-acquired pneumonia, ceftaroline showed similar efficacy in comparison to vancomycin plus ceftriaxone, with clinical cure observed in 83% vs. 78% of cases, respectively . Ceftaroline also showed similar efficacy in comparison to ceftriaxone for the treatment of community-acquired pneumonia, with clinical cure observed in 92% vs. 89% of cases, respectively.[71]
Dalbavancin
Dalbavancin is a long-acting semisynthetic lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens, including S. aureus including MRSA, S. pneumoniae, S. agalactiae, S. pyogenes, and Enterococcus spp., and it is currently approved for the treatment of SSSIs in patients >3 months. Dalbavancin was administered for the treatment of BSIs in patients from birth to 3 months and SSSIs from birth to 18 years known or suspected to be caused by susceptible Gram positives , mainly MSSA.[72]
Prevention
Preventing sepsis is largely limited to established practices, including the early identification of risk factors during pregnancy (such as placentitis and premature placental separation), maintaining meticulous birth hygiene, and ensuring complete passive transfer of immunity through the measurement of IgG concentrations. Prophylactic antimicrobial treatment in healthy neonatal foals has not demonstrated benefits in preventing infectious diseases and is no longer advised [73]. Early recognition of compromised neonates and prompt initiation of treatment are crucial for achieving positive outcomes, making patient education in this area essential.
CONCLUSION:
Sepsis is still linked to a high risk of morbidity and mortality in the neonatal population, even with the advent of IAP, improvements in diagnostic techniques, and more focused therapies. The diagnosis and management of sepsis are complex and necessitate the amalgamation of our understanding of the neonatal immune system with the most reliable evidence for identifying high-risk infants.The alterations in antimicrobial susceptibilities of prevalent pathogens and the rising survival rates of extremely preterm neonates underscore the deficiencies in the existing drug information for this population. The objectives of antibiotic therapy should be to achieve the intended effect with minimal toxicity for the patient while mitigating selection pressures for both the unit and the community. Research on placental antibiotic kinetics and neonatal-specific pharmacokinetics is essential to establish optimal prophylactic and therapeutic dosing regimens for the prevention and treatment of perinatal infections.
REFERENCES
Edwin Dias*, Sandhra Nair, A Comprehensive Review of Diagnosis and Management of Neonatal Sepsis: Focus on Newer Antibiotic Drugs, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 1, 859-880. https://doi.org/10.5281/zenodo.14632344
10.5281/zenodo.14632344
