Late Neonatal Sepsis

Despite advances in general neonatal care and the implementation of quality improvement measures, the occurrence of late neonatal sepsis (LNS) remains a persistent threat in NICUs. NTS disproportionately affects most preterm infants and is associated with considerable mortality and morbidity among survivors. (1)(2)(3)(4)(5)(6)(7)

Recognition and diagnosis of NTS is challenging; It often presents with varied and nonspecific clinical signs, (8) and common laboratory biomarkers function inconsistently to discriminate infected from uninfected infants. (9)(10)

This review focuses on current approaches to NTS risk assessment, diagnostic testing, antimicrobial management, and infection prevention. Finally, the authors summarized the survival outcomes and long-term morbidities associated with SNT and highlighted the need for neurodevelopmental follow-up of SNT survivors.

Sepsis is a life-threatening condition caused by infections that trigger a cascade of often fatal inflammatory immune responses.

Neonatal sepsis is defined as sepsis that occurs in the first 28 days after birth. (11) In view of the different pathogenesis and epidemiology of pathogens, neonatologists distinguish between early-onset sepsis (EOS) and NTS based on the time of infection onset. (2) (11) SIT is mainly defined as appearing in the first 48 to 72 hours after birth. (1) (11) (12)

In the premature NICU population, sepsis can occur much later; thus, in the context of research, SNT encompasses sepsis presenting 72 hours after birth or later and through NICU hospitalization.

Although there is a general research consensus defining the timing of neonatal sepsis subtypes, there is substantial heterogeneity in definitions of NTS across studies and major neonatal organizations, and there is no standard approach to diagnosing NTS in NICUs. (11) (12) (13) In combinations of variables, the definition is based on evaluation of microbiological cultures, clinical signs of infection and complementary laboratory data. (11) (12)

Most definitions include a positive blood culture as an essential criterion, although culture collection requirements and procedures can vary widely. Clinical signs of sepsis are the second main criterion. However, there is no consensus on the key indicator signs among a multitude of symptoms. (11) In summary, “culture-proven sepsis” can be defined by blood culture results, while the diagnosis of “culture-negative sepsis” or “clinical sepsis” is based on variable clinical signs consistent with infection. (eleven)

Septic shock is distinguished from sepsis when criteria for neonatal sepsis are met and blood pressure is below the 5th percentile for age requiring hemodynamic stabilization with fluids or inotropic agents. (eleven)

Heterogeneity in the definition of NTS hinders the interpretation and comparability of clinical trials and the development of evidence-based guidelines for the diagnosis and management of NTS. (13)

There are ongoing attempts to establish a consensus definition of SNT, with the goal of identifying specific neonatal physiologic targets and laboratory features that may allow for more rapid recognition and initiation of therapy. Furthermore, this may facilitate more standardized and comparable data collection worldwide that could contribute to diagnostic and therapeutic innovations in SNT. (11) (12)

Late neonatal sepsis (LNS) is mainly attributed to the acquisition of nosocomial or horizontal pathogens and exposure to the hospital or community environment.

Exposure to pathogens may occur due to contamination or colonization of indwelling invasive medical devices, contact with care providers, and/or other environmental sources and surfaces. Preterm birth and critical illness are major risk factors for TNS given their associated needs for central catheters, mechanical ventilation, prolonged parenteral nutrition, and surgical interventions. (3)(14)(15)

Predisposing factors also include maternal and perinatal risk factors, such as preeclampsia, chorioamnionitis, and intrauterine growth restriction, as well as length of hospital stay and comorbidities. (1)(3)(4)(15)(16)

The most immature babies experience the greatest infectious burden; TNS rates of 1.6% are reported in full-term infants, compared with 12% to 50% among very preterm and/or very low birth weight (VLBW) infants.(1)(2)(4) )(6) The mortality associated with NTS varies depending on the gestation and the organism and can be as high as 35% in the most vulnerable and shorter gestation babies.(6)(14)

Host response factors shape the inflammatory response to sepsis and contribute to the severity of the clinical presentation. Gestational age (GA)-specific patterns of immune function place preterm infants at increased risk for infection, adverse or sustained inflammation, and organ dysfunction. (17) (18) (19) Furthermore, microbial colonization and aberrations in microbiome development are implicated in increased susceptibility to NTS. (3) (20)

Specifically, prolonged empiric antibiotic therapy for more than 4 days at birth is associated with 1.25 to 2.5 times higher adjusted odds of subsequent TNS and combined TNS/death. (twenty-one)

The role of genetics remains unclear, and NTS rates are not significantly different between babies born from singleton versus multiple gestation pregnancies. (14) Sex differences in immune function, development of infections, and potential increased susceptibility to sepsis in male infants are poorly understood. (22)

Ultimately, infection risk and clinical manifestation are driven by host factors (e.g., initial organ dysfunction or immaturity), type of pathogen, and potential antimicrobial resistance patterns. Causative pathogens vary widely across geographic regions and NICUs, and infectious epidemiology may change over time within the same unit.(4)(5)

Gram-positive bacteria constitute the majority of pathogens isolated in high-income countries,(1)(6) (14) (23) while gram-negative organisms predominate in some low- and middle-income countries.(5)

It should be noted that more than 50% of gram-positive bacteremias among premature newborns are caused by Staphylococcus coagulase negative (SCoN), (1)(6) (14) (23) an organism considered commensal of the skin in newborns to term. However, in premature neonates, SCoNs may represent true pathogens causing clinically significant infections. (17)(23) Ultimately, isolation of SCoN from blood cultures requires discrimination between possible culture contamination and true bacteremia in the individual patient and in the NICU.

Other important Gram-positive bacteria implicated in NTS include Staphylococcus aureus (isolated in 4%–18%), Enterococcus species (3%–16%), and group B Streptococcus (1.8%–8%), with wide variation between national data reported by the US National Institute of Child Health and Human Development (NICHD), the NeonIN surveillance network in England, and the German Neonatal Network (GNN). (1)(2)(4)(6) (24)

In the context of the increasing number of multidrug-resistant organisms, methicillin-resistant S. aureus (MRSA) represents a prevalent pathogen in Gram-positive NTS, responsible for 11% of S. aureus infections in the NeonIN surveillance cohort and 23% of S. aureus infections reported to the Centers for Disease Control and Prevention (CDC) National Nosocomial Infection Surveillance System. (24) (25)

The GNN and national Australian and New Zealand cohort data still report a MRSA prevalence of less than 1% of all pathogens isolated in VLBW infants with NTS (6% of S. aureus infections in GNN infants). . (6) (26) Other observational studies do not differentiate MRSA from methicillin-susceptible S. aureus . (1)(2)(4)

Late neonatal sepsis (LNS) caused by gram-negative pathogens is associated with increased disease severity, significantly increased mortality, and an increased likelihood of short- and long-term neonatal morbidities. (2)(3) (15) In nationwide cohorts in the United States, England, and Germany, Escherichia coli (proportions range from 3% to 13%), Klebsiella species (4% to 5%), Pseudomonas (2%–5%), Enterobacter species (2.5%–21%), Serratia (0.8%–2%), and Acinetobacter (0.1%–2%) account for the majority of cases of Gram-negative NTS. (1)(2)(4)(6) (24)

In recent decades, an increasing number of infections caused by multidrug-resistant Gram-negative bacteria (e.g., extended-spectrum b-lactamase [ESBL]-producing bacteria) have challenged the selection of antimicrobial therapy in NTS in high-risk NICU patients. risk. (5)

Fungal organisms are isolated in about 3% to 10% of NTS cases, with Candida species (mainly Candida albicans and Candida parapsilosis ) being detected most frequently. (2)(4)(6) Fungal infections have been associated with high mortality and should be particularly considered in the evaluation of SNT and in empiric therapy in sick preterm and term newborns who show clinical features possibly compatible with invasive fungal infections (e.g., rash, neutropenia/thrombocytopenia, hyperglycemia). (4)

Finally, viral pathogens (e.g., parainfluenza, echo, entero, coxsackie, adeno, rhino, and coronavirus) are increasingly recognized as causative agents of sepsis-like syndromes in preterm and term infants. (27) (28)

The clinical presentation of late neonatal sepsis (TLS) is nonspecific and varied, with respiratory signs, lethargy, tachycardia, feeding intolerance, and thermal instability (fever or hypothermia) commonly reported.

The spectrum of disease severity ranges from moderate signs of infection to critical illness with severe organ dysfunction and potential multiorgan failure. (8)

Secondary sites of infection that are most frequently associated with late-onset bacteremia include pneumonia, urinary tract infections (UTIs), and soft tissue and skin infections, as well as necrotizing enterocolitis. Translocation of pathogens that colonize the neonatal intestine is a of the main causes of neonatal sepsis, especially in very immature premature newborns and infants with compromised intestinal integrity.

In infants with clinically apparent necrotizing enterocolitis, concurrent bloodstream infections (mostly of gram-negative origin) were detected in 40% to 60% of cases. (29) NTS is complicated by meningitis in approximately 5% of cases (in which a lumbar puncture was performed). (30)

Clinically, sepsis cannot be distinguished from meningitis, because the presentation is nonspecific and includes apnea, lethargy, and temperature instability, among other signs.

The ideal biomarker of late neonatal sepsis (NTS) would facilitate early diagnosis of culture-confirmed infections with high positive and/or negative predictive value, generalizability across gestational age and postnatal age stratum, and rapid response time. However, this biomarker has not yet been identified. Complete blood count with differential has limitations in both the diagnosis of NTS in premature and full-term infants.

Complete blood cell count indices may be normal in infected infants, and individual indices alone including white blood cell count, absolute neutrophil count, immature to total neutrophil ratio, and platelet count do not have sufficient sensitivity or specificity. for a reliable diagnosis of NTS. (31) C-reactive protein (CRP) is an acute phase reactant produced primarily in the liver, with maximum expression 36 to 48 h after stimulation.

The characteristics of the PCR test in identifying VLBW infants with culture-positive NTS are modest at best, with a median sensitivity of 62% and specificity of 74%. (32) Individual PCR measurements have limited diagnostic efficiency and cannot identify or exclude infection in a symptomatic infant at the time of sepsis evaluation. (32) However, 3 serial CRP measurements obtained over days improve the sensitivity to 98% and the negative predictive value to 99%. (33) Therefore, assessing CRP at presentation is unlikely to assist in clinical decision making, while repeated negative measurements may serve as a useful adjunct in the decision to discontinue antibiotics.

Procalcitonin, like CRP, is an acute phase reactant that is synthesized primarily in the liver in response to interleukin-6 (IL-6) and tumor necrosis factor (TNF), but appears to have more rapid kinetics. , with maximum levels detected 12 to 24 hours after stimulation. Test characteristics for procalcitonin are reported to be variable, with a mean sensitivity of 92% and a mean specificity of 80%. (3. 4)

In summary, CRP and/or procalcitonin values ​​alone obtained at the time of evaluation for late neonatal sepsis (NLS) have limited diagnostic utility , as they do not reliably rule out or confirm culture-confirmed infections. However, serial value trends over time can aid decision-making about antibiotic discontinuation in the context of clinical evaluations and culture data.

Many other biomarkers have been evaluated in the diagnosis of NTS. Proinflammatory cytokines (e.g., IL-6, IL-8, TNF-α) and cell surface markers (e.g., CD64, CD11b, soluble CD14, HLA-DR) have moderate diagnostic efficacy, (35 ) (36) (37) (38) (39) (40) which increases with serial measurements. (10) However, these markers may not have assays available in hospital laboratories, and are not routine in most centers. In the future, machine learning techniques may help in building biomarker panels that offer better diagnostic efficiency than individual biomarkers.

Positive blood cultures remain the gold standard for the diagnosis of NTS, as the sensitivity for the detection of bacteremia can be as high as more than 98%. (41)

Improvements in laboratory technology, including automated blood culture detection systems, have contributed to accelerating the time to detection and speciation of organisms. However, an adequate volume of blood cultures remains key for pathogen detection. (41)

Most SNT evaluations, especially in premature infants, yield negative blood culture results; (42) in a cohort of 99,796 VLBW infants with episodes of suspected NTS, only 8.9% of 164,744 blood cultures obtained were positive. (14) This count reflects the uncertainty that physicians face: on the other hand, SNT evaluations are initiated in the face of clinical instability (which, in the vast majority of cases, results from a non-infectious etiology), although Truly infected infants may also have false-negative blood cultures if there is a low level of circulating bacteremia, insufficient blood culture volume, or administration of antibiotics before culture collection.

Emerging molecular diagnostic complements (e.g., bacterial ribosomal 16s RNA reverse transcriptase polymerase chain reaction [RT-PCR]) amplify small amounts of pathogen genetic material, with reported sensitivity and specificity as high as 90% and 96%. (9) However, these techniques are expensive, do not differentiate between live and dead bacteria, and can lead to the amplification of pathogenic material unrelated to the clinical phenotype.

Although urine cultures should be routinely obtained during SNT evaluations, inclusion is variable, occurring in as few as 7% and as many as 50% of SNT evaluations. (43) (44) UTIs were reported in 8% to 11% of SNT evaluations in which a urine culture was submitted, and tend to occur more often in premature infants with lower birth weight and older postnatal age (diagnosis of Average UTI reported at 42 days postnatal). (44) (45)

Variation in urine culture practices may arise from lack of clinical suspicion of UTI, technical challenges in obtaining sterile cultures (particularly in very immature infants or those with anatomical differences), and/or perceived lack of patient stability in obtaining a urine sample. Furthermore, there is no consistent definition of UTI applicable to NICU patients, cut-off points for urinalysis indices vary considerably, and UTI can frequently occur in the absence of positive blood cultures. Ideally, urine samples should be collected sterile (via urethral catheterization or suprapubic puncture), as opposed to external bag collection, which carries greater risks of growth of contaminating pathogens.

Antibiotic therapy before collection of urine cultures reduces the diagnostic efficiency of UTIs, emphasizing the importance of collection of urine samples at the time of evaluation for sepsis and before exposure to antibiotics. (43) (44)

Inclusion of cerebrospinal fluid (CSF) diagnosis in the evaluation of NTS should be considered, particularly among preterm and febrile neonates less than 28 days of age, because clinical signs of meningitis are nonspecific and may overlap with other infectious processes. (46) (47) Obtaining CSF culture samples prior to antibiotic administration is the gold standard. However, it is challenging to accurately estimate rates of meningitis complicating NTS.

Lumbar punctures are often not performed as part of SNT evaluations, and those performed after initiation of antibiotics may reveal growth of false-negative cultures in CSF samples. Variations in lumbar puncture yield rates could be attributable to several factors, including clinician awareness of the low estimated prevalence of SNT-associated meningitis (2%–5%) and reluctance to perform lumbar punctures (particularly in very young or clinically unstable infants). (15) (45) (48)

In a cohort of 2989 VLBW infants, only 24% of SNT evaluations included CSF cultures, with significant practice variation (7%–49% across 8 centers). Of those patients in whom CSF cultures were performed, only 2% were considered to have meningitis. (45) Importantly, consistent evidence suggests that a significant proportion of meningitis cases (30%–70%) occur in the absence of bacteremia. (45) (46) (47) Diagnostic adjuncts, particularly in infants with pretreatment cultures or uninterpretable CSF indices, may include pathogenic RT-PCR or cytokine profiling. (49)

Improvements in NTS risk assessment strategies are necessary for better discrimination between heterogeneous NICU populations and early identification of NTS progression. Due to lack of sensitivity and specificity, definitions of sepsis based on systemic inflammatory response syndrome criteria have largely been abandoned in adult patients, with a shift to metrics focused on organ dysfunction associated with infections also being useful. to predict morbidity and mortality attributable to sepsis. (50) (51)

Revisions to pediatric sepsis definitions are in progress and also appear to be shifting toward metrics focusing on organ dysfunction. (52) The Neonatal Sequential Organ Failure Assessment (nSOFA) is a proposed tool to quantify neonatal multiple organ dysfunction and the associated mortality risk. (53) Quantifies respiratory, cardiovascular, and hematologic dysfunction using clinical data readily available in electronic medical record format.

Observational studies have shown that changes in nSOFA findings over time correlate with SNT-attributable and all-cause mortality in preterm infants. (53) (54)

Computer-based algorithms have attracted considerable interest as early warning systems for the diagnosis of NTS. Vital signs-based approaches include heart rate signature algorithms to identify inflammation-induced periods of minimal heart rate variability, decelerations, and/or tachycardia.

Monitoring has been associated with reduced all-cause and sepsis-related mortality in randomized controlled trials. (55) Furthermore, predictive bioinformatics approaches, such as machine learning modeling and artificial intelligence methods, have evolved. These aim to assess patient-level risk based on clinical data, including vital signs, laboratory results, and clinical parameters (e.g., mechanical ventilation or vasopressor support). (56)

Although these approaches are promising, further evaluation of performance in sepsis recognition and outcome assessment is needed before clinical implementation. Omics-based strategies for sepsis diagnosis (metabolomic, proteomic, and genomic approaches) are also being evaluated but are not yet ready for clinical application. (57)

Prompt initiation of antibiotic therapy is crucial.

Additionally, hemodynamic stabilization through volume replacement and/or vasopressor support may be necessary to counteract vasodilation and capillary leak and subsequent hypoperfusion and hypovolemia. Supportive care may also include supplemental oxygen and/or mechanical ventilation, management of acid/base and electrolyte disturbances, and transfusion of blood products. Aggressive supportive interventions are particularly required in infants with fulminant sepsis and development of septic shock.

> Antibiotic treatment

Antibiotic therapy should be administered as soon as possible once concern for late neonatal sepsis (LNS) is identified and ideally after culture specimens have been obtained. Delaying antibiotics for suspected NTS in a level IV NICU was independently associated with increased 14-day mortality (47% increased risk of death for each additional 30 minutes of delay). (58)

While immediate empiric antibiotic therapy is essential, antibiotic use for suspected TNS should be weighed against potential risks (including toxicity, negative interference with healthy skin and gut microbiota, and antibiotic selection pressures). .

There is no consensus on the ideal empiric antibiotic regimen for late neonatal sepsis (NLS), and practices vary considerably with respect to antibiotic selection and duration of treatment. (26) (59) (60) (61) Empirical broad-spectrum antibiotics for TNS generally include 2 agents with complementary spectra of activity. β-lactam agents (e.g., ampicillin, oxacillin, nafcillin) are commonly used to provide gram-positive bacterial coverage. (60) However, given the high rates of NTS due to SCoN (often resistant to β-lactam antibiotics), vancomycin may be preferred for initial gram-positive coverage.

Additional patient factors that may influence decision-making in the empiric use of vancomycin include the presence of central catheters and known colonization with MRSA, as well as local resistance patterns. Vancomycin use in the NICU is widespread: it was the sixth most frequently prescribed medication among NICU patients in a large US cohort, and after ampicillin and gentamicin, it was the third most common antibiotic . (62) However, due to the associated risks of acute kidney injury, the use of vancomycin requires monitoring of renal function and drug level for toxicity.

Agents that target Gram-negative bacteria include aminoglycosides (e.g., gentamicin), third- to fourth-generation cephalosporins (e.g., cefotaxime, cefepime), and carbapenems (e.g., meropenem). (63) (64) Given its broad aerobic activity and anaerobic coverage, piperacillin-tazobactam, a b-lactam antibiotic with b-lactamase inhibitor, is frequently used in the context of presumed intra-abdominal sources of infection. Due to its poor central nervous system (CNS) penetration, piperacillin-tazobactam is not recommended in cases of clinical concern for meningitis. Instead, a third- to fourth-generation cephalosporin, or carbapenem, is preferred for coverage of the gram-negative CNS.

C arbapenems are potent b-lactam antibiotics with the widest range of in vitro activity against gram-positive and gram-negative bacteria (including ESBL-producing Enterobacteriaceae) and are essential reserve antibiotics. (64) Linezolid, fosfomycin, and daptomycin are additional reserve antibiotics that can be used in multidrug-resistant Gram-positive infections. Ciprofloxacin and colistin have been used, despite concerns about adverse effects, in neonatal infections with multidrug-resistant Gram-negative bacteria. (56)

The use of these antibiotics should be limited to definitive, antibiogram-guided therapy of infections with a multidrug-resistant pathogen.

They are not recommended as routine empiric therapy. The authors suggest that physicians consider consultation with an infectious disease specialist in cases where use of a reserve antibiotic may be indicated.

There are significant concerns about the increasing number of multidrug-resistant bacteria among NICU cohorts worldwide, (60) (65) driven by the widespread use of vancomycin, third- to fourth-generation cephalosporins, and carbapenems. (63) (64)

Empirical antibiotics are often used inappropriately, in terms of unnecessarily broad spectrums and prolonged treatment durations in the setting of negative cultures. In an evaluation of antibiotic utilization in the NICU as defined by the CDC’s 12-Step Campaign to Prevent Antimicrobial Resistance, up to 25% of all antibiotic courses were considered inappropriate (39% were antibiotic regimens that were inappropriately continued for >72 hours duration, others related to inappropriate targeting of pathogens). (65)

Ultimately, local organism epidemiology, resistance patterns, and antibiotic stewardship should guide individual regimens. Judicious and rational use is mandatory, and antibiotic regimens should be reduced as soon as data on organism speciation and antibiotic susceptibility are available. Of note, quality improvement initiatives in settings with low MRSA prevalence have demonstrated a reduction in vancomycin utilization (in favor of antistaphylococcal penicillins) and reduction in vancomycin-associated acute renal failure, without any impact in mortality. (66) (67)

The duration of antibiotics for culture-proven infections varies by organism and site. Although bacteremia is usually treated with antibiotics for 10 to 14 days (depending on the organism), meningitis requires longer courses of 14 to 21 days, especially in gram-negative meningitis. (68)

The duration of empiric antibiotics to rule out TNS commonly ranges from 48 to 72 hours, with interruption upon receipt of negative cultures. Since most blood culture growth occurs within 36 hours (with subsequent culture growth driven largely by SCoN), shorter empiric antibiotic durations may be appropriate. (69)

> Complementary therapeutic interventions

There is an ongoing search for effective adjuvant therapies for neonatal sepsis, primarily aiming for beneficial modulation of both sepsis-induced hyperinflammation and that related to sepsis-related functional immunosuppression. (17) (18) (19) (70)

Sepsis is characterized by excessive induction of pro-inflammatory reactions and anti-inflammatory pathways, activation of the coagulation cascade and complement system, sepsis-induced neutropenia and thrombocytopenia, and biochemical imbalances resulting in an oxidative state associated with a reduction in plasma and tissue levels of antioxidants (such as glutathione).(70)

Clinical and experimental data indicate exaggerated and sustained proinflammatory responses but impaired counterregulatory responses in preterm infant sepsis and impaired resolution of inflammation. Numerous therapeutic interventions have been studied for their potential usefulness in counteracting these mechanisms. However, many of these approaches have failed to affect the prognosis of SNT or are not yet ready for clinical application. (60) (70) 
(71) (72) (73) (74) (75) (76) (77) (78) (79) (80) (81) (82) (83) (84) (85 ) (86) (87) (88) (89)

Strategies focused on infection prevention are key to reducing the burden of NTS. (90) (91) (92)

Preventive measures include hand hygiene, adherence to infection control protocols, implementation of antimicrobial stewardship programs (ASP), and care practices, including early initiation of enteral feeding and use of breast milk. . (91) (93)

Preventive immunomodulatory strategies target beneficial modulation of the skin and gut microbiome, inflammatory immune responses, and oxidative stress. (70)

> Hand hygiene, antiseptic measures and colonization screening

Hand hygiene remains one of the most effective measures to reduce infections associated with care providers. (94)

The use of non-sterile gloves by staff for patient contact may provide additional protection as an additive to hand hygiene. A randomized controlled trial demonstrated reductions in TNS cases among extremely preterm infants whose caregivers used nonsterile gloves after hand hygiene, compared with hand hygiene alone. (95)

Strict adherence to aseptic protocols before insertion of lines and catheters, in particular, is a key preventive measure. (96) Antiseptics such as chlorhexidine gluconate provided in aqueous and alcoholic forms (0.05%–2%) and octenidine dihydrochloride effectively reduce skin colonization with pathogens in preterm and term neonates. (97) However, national surveys reveal substantial variation in disinfection practices. In fact, there is no strong evidence in favor of any specific skin disinfectant, and there is no consensus on whether alcoholic or aqueous formulations should be preferred.

In very immature premature neonates, potential safety and toxicity issues, such as the risk of thyroid dysfunction associated with the use of povidone-iodine, must be taken into account. (97)

In particular, 1% chlorhexidine gluconate was found to be even more effective than 1% povidone-iodine in reducing blood culture contamination rates in moderately preterm and full-term neonates. (98) However, adverse skin reactions to chlorhexidine have been reported in very immature premature infants. (97) Aside from topical and systemic side effects, antiseptic regimens have the potential to promote bacterial resistance. An observational study in 2 NICUs in the United Kingdom and Germany, using chlorhexidine gluconate versus octenidine, demonstrated that long-term use of chlorhexidine for skin antisepsis may select for tolerance to chlorhexidine and octenidine among SCoN isolates. (99)

Finally, there is no convincing evidence of any beneficial effect of full body washing with antiseptics, such as chlorhexidine bath, in premature infants. (100) Instead, there are concerns about altering skin pH and the skin microbiome, as well as altering the innate antimicrobial and immunological properties of the skin. (100)

In addition to antiseptic placement techniques, quality improvement efforts related to the prevention of bloodstream infection (CLABSI) stipulate a package of care measures, including dressing change practices, reduction of daily catheter accesses central catheter and timely removal of the central catheter, with the aim of preventing colonization of central vascular catheters and the systemic dissemination of pathogens.

In a US-based initiative, a 19% reduction in CLABSI rates was documented among a collaboration of tertiary and quaternary NICUs after implementation of standardized CLABSI prevention packages. (101)

Implementation of weekly colonization screening of VLBW infants for high-risk or multidrug-resistant bacteria and subsequent individual assessment of the extent of hygiene measures has been associated with reduced rates of sepsis. (102) Routine use of systemic antibiotic prophylaxis for CLABSI prevention and routine vancomycin catheter locks, in contrast, are not recommended because of the substantial risk of selection of resistant organisms and rather high numbers needed to treat. (103)

> Antimicrobial stewardship

PAAs are collaborations between prescribing physicians, infectious disease specialists, and pharmacists with the goal of critical evaluation and reduction of antibiotic exposure. Examples of PAA-guided interventions include empiric antibiotic selection guidance and restrictions on broad-spectrum antibiotic use, as well as standardization of antibiotic treatment durations.

Single-center reports on the implementation of AAPs in NICUs have demonstrated reductions in antibiotic initiation, improved selection of narrow-spectrum antibiotics, and improved rates of timely antibiotic discontinuation. However, the programs have had a variable impact on overall antibiotic utilization. (93) (104)

SNT contributes significantly to neonatal mortality and morbidity. (1)(3)(5)(7) Outcomes are affected by etiology and causative pathogen, GD, underlying comorbidities, presence of organ dysfunction, and cumulative number of infections. Lower GA, greater disease severity, and intra-abdominal, pulmonary, and CNS sites of primary infection are associated with higher mortality in neonatal NTS. (15) (53)

> Mortality

Estimates of mortality associated with SNT vary depending on the neonatal subpopulation of interest. In a large NICHD Neonatal Research Network cohort study that included more than 10,000 VLBW infants, those with NTS experienced significantly higher all-cause mortality compared to uninfected infants (24% vs. 18% ). (4)

Among VLBW infants, all-cause mortality estimates range from 4.2% of NTS infants in GNN, (6) to 15% of infants in a large US cohort. from the Pediatrix database. (14)

Mortality related to late neonatal sepsis (NLS) varies most by organism class; Specifically, fungal and gram-negative sepsis is associated with increased mortality compared to gram-positive sepsis. Among a large US cohort of VLBW infants, mortality attributable to sepsis occurred in 15% of gram-positive NTS, 20% of gram-negative NTS, and 31% of fungal NTS. (4)

In another large cohort study of more than 108,000 VLBW infants, organism-specific mortality was highest in NTS caused by Pseudomonas (occurring in 35% of all Pseudomonas infections ), followed by H influenzae (33%). ), Candida (29%) and S. aureus (21%). (14)

In 4094 VLBW infants with culture-proven sepsis in the German Neo-KISS surveillance system, infection with Klebsiella species (hazard ratio [HR] 3.17; 95% confidence interval [CI] 1.69– 5.95), Enterobacter species (HR 3.42; 95% CI 1.86–6.27), E coli (HR 3.32; 95% CI 1.84–6.00), and Serratia species ( HR 3.30, 95% CI 1.44–7.57) were associated with significantly higher mortality risk compared to S. aureus . (105)

Of note, available epidemiological data show that SCoN-related mortality rates in VLBW infants range from 1.6% to as high as 11.5%. (23) (106)

Morbidity

Neurodevelopmental impairment ( NDD) is an important sequelae of NTS. (107) (108) (109) CNS injury results from direct bacterial cytotoxicity, adverse systemic inflammation (even without pathogen invasion into the CNS), and altered cerebral perfusion in the setting of hemodynamic instability. (108) (110)

Bacterial meningitis has potentially devastating outcomes and affected infants are at the highest risk of poor neurocognitive development: up to 10 times the risk of developing moderate or severe neurological disability by the age of 5 years (in up to 15% of meningitis survivors). ). (111) Furthermore, white matter is particularly vulnerable to oligodendrocyte injury and aberrant maturation in the face of inflammatory cascades, especially in premature neonates. (109) (110)

In a US cohort of more than 6000 VLBW infants, adverse neurodevelopmental outcomes at 18 to 22 months corrected age were identified in nearly 50% of infants with a history of culture-confirmed sepsis. (112) Compared with uninfected newborns, those with culture-proven sepsis had significantly higher odds of having DND. (112)

Emerging literature is investigating the relationship between DND and culture-negative NTS syndromes. A Swiss cohort study of 541 infants born between 24 and 28 weeks GA identified that culture-proven sepsis, but not suspected culture-negative sepsis, was associated with an increased risk of DND and cerebral palsy, compared with uninfected infants. (113)

A recent US study of more than 3900 VLBW infants born at 22 to 26 weeks GA found infants with culture-negative sepsis at increased risk for DND. (7) Higher risks of DND associated with SNT in childhood appear to persist.

A French cohort study identified SNT as a significant risk factor for cerebral palsy at the age of 5 years (adjusted odds ratio 1.7, 95% CI 1.1-2.6). (114) Among infants born at less than 28 weeks GA, those with a history of NTS were at increased risk for DND at the age of 10 years compared to uninfected infants. DND appeared to manifest largely as intellectual impairment, assessed as low IQ. (107)

Ultimately, adverse and/or sustained inflammatory immune responses in NTS are an important contributor to the multifactorial pathogenesis of diseases of prematurity, and drive organ injury and lifelong morbidity, such as bronchopulmonary dysplasia. (18) (108) (110) (115)

Finally, SNT has been associated with postnatal growth retardation, potentially attributable to inflammation and/or nutritional deficiencies in the context of critical illness. (112) (116)

In a matched cohort study of 700 VLBW infants born before 32 weeks’ gestation with sepsis (most of whom were SNT), growth failure manifested at least 3 weeks after SNT and persisted until discharge from the NICU. . (116)

The management and prevention of NTS pose ongoing challenges in current neonatal care, particularly in the context of growing populations of very immature premature infants and increasing rates of multidrug-resistant organisms. Early recognition of infants with suspected sepsis is critical to improve the timeliness of therapy and optimize outcomes.

Future advances in NTS care may focus on improving diagnostic accuracy through the discovery of biomarkers, the incorporation of technology and/or computer algorithms for use in the recognition of NTS, and the quality of implementation of preventive measures based in improvement. Sustained or adverse SNT-driven inflammation has been associated with increased neonatal morbidity, including poor neurodevelopmental outcomes, particularly in preterm neonates.

Ongoing efforts to better elucidate the unique characteristics of early and adverse immunity from inflammation may facilitate the development of immunomodulatory therapy targets. Ultimately, antimicrobial stewardship is vital and clinicians should critically evaluate prescribing practices to target the most limited effective antimicrobial regimens based on local antibiograms and susceptibility patterns. Additionally, more research is needed to better define ideal empiric antibiotic regimens, recognize center-specific variation in patient populations, care practices, and infection epidemiology.