Treatment Of Neonatal Sepsis Research Articles

Extended-interval dosing of gentamicin for treatment of neonatal sepsis in developed and developing countries.

Serious bacterial infections are the single most important cause of neonatal mortality in developing countries. Case-fatality rates for neonatal sepsis in developing countries are high, partly because of inadequate administration of necessary antibiotics. For the treatment of neonatal sepsis in resource-poor, high-mortality settings in developing countries where most neonatal deaths occur, simplified treatment regimens are needed. Recommended therapy for neonatal sepsis includes gentamicin, a parenteral aminoglycoside antibiotic, which has excellent activity against gram-negative bacteria, in combination with an antimicrobial with potent gram-positive activity. Traditionally, gentamicin has been administered 2-3 times daily. However, recent evidence suggests that extended-interval (i.e. >24 hours) dosing may be applicable to neonates. This review examines the available data from randomized and non-randomized studies of extended-interval dosing of gentamicin in neonates from both developed and developing countries. Available data on the use of gentamicin among neonates suggest that extended dosing intervals and higher doses (>4 mg/kg) confer a favourable pharmacokinetic profile, the potential for enhanced clinical efficacy and decreased toxicity at reduced cost. In conclusion, the following simplified weight-based dosing regimen for the treatment of serious neonatal infections in developing countries is recommended: 13.5 mg (absolute dose) every 24 hours for neonates of >2,500 g, 10 mg every 24 hours for neonates of 2,000-2,499 g, and 10 mg every 48 hours for neonates of <2,000 g.

New Diagnostic Tools for Neonatal Sepsis: The Role of a Real-Time Polymerase Chain Reaction for the Early Detection and Identification of Bacterial and Fungal Species in Blood Samples

SummaryEarly diagnosis and treatment of neonatal sepsis are essential to prevent severe and life threatening complications. Consequently, rapid diagnostic tests capable to differentiate infected from non-infected newborns have the potential to make a significant impact on neonatal care. A new real-time polymerase chain reaction (PCR; LightCycler® SeptiFast test MGRADE) has been proposed in the routine assessment of neonatal sepsis for the detection and identification of bacterial and fungal DNA from microorganisms which cause approximately 90% of all blood stream infections. The LightCycler® SeptiFast test can detect and identify simultaneously the 25 most important bacterial and fungal species causing bloodstream infections within few hours by using a small volume of a single whole blood sample. Real-time PCR can be easily incorporated into the hospital setting for term or near-term infants admitted to the neonatal intensive care unit for sepsis evaluation.

Determination of Extended-Interval Gentamicin Dosing for Neonatal Patients in Developing Countries

Infectious diseases account for an estimated 36% of neonatal deaths globally. The purpose of this study was to determine safe, effective, simplified dosing regimens of gentamicin for treatment of neonatal sepsis in developing countries. Neonates with suspected sepsis in the neonatal intensive care unit (NICU) at Christian Medical College and Hospital (CMC), Vellore, India (n = 49), and Dhaka Shishu Hospital (DSH), Bangladesh (n = 59), were administered gentamicin intravenously according to the following regimens: (1) 10 mg every 48 hours for neonates <2000 g; (2) 10 mg every 24 hours for neonates 2000-2249 g; and (3) 13.5 mg every 24 hours for neonates > or =2500 g. Serum gentamicin concentration (SGC) at steady state and pharmacokinetic indices were determined. Renal function was followed while under treatment and hearing was examined 6 weeks to 3 months after discharge. All neonates, except 1 weighing 2000-2249 g at DSH, had a peak SGC >4 microg/mL. Overall, 5 (10%) and 17 (29%) infants had a peak SGC level > or =12 microg/mL from CMC and DSH, respectively, and 10 (20%) and 4 (7%) cases from CMC and DSH, respectively, had a trough SGC level > or =2 microg/mL. However, no infant <2000 g had a trough SGC level > or =2 microg/mL. We found no evidence of gentamicin nephrotoxicity or ototoxicity. Safe, therapeutic gentamicin dosing regimens were identified for treatment of neonatal sepsis in developing country settings. Administration of these doses could be simplified through use of Uniject, a prefilled, single injection device designed to make injections safe and easy to deliver in developing country settings.

Intravenous immunoglobulins and haematopoietic growth factors in the prevention and treatment of neonatal sepsis: ground reality or glorified myths?

Neonatal sepsis is a significant cause of morbidity and mortality in the neonatal intensive care unit. The epidemiology of neonatal infections is complex; however, they are in large part secondary to developmentally immature host defence mechanisms. These immunodeficiencies, which are exaggerated in premature and sick neonates, include quantitative and qualitative deficits in phagocytes, complement components, cytokines and immunoglobulins. Therapies that modulate or augment host defences may attenuate the virulence of neonatal infections. In this paper, we have reviewed immunotherapies that modulate the immune system of the neonate, including intravenous immunoglobulins and myeloid haematopoietic growth factors. Future studies should focus on investigating other abnormalities of neonatal host defence and/or combined immunotherapy approaches in an attempt to circumvent the immaturity of host defence and potentially reduce both the incidence and severity of neonatal sepsis.

Early Prediction of Sepsis-Induced Disseminated Intravascular Coagulation with Interleukin-10, Interleukin-6, and RANTES in Preterm Infants

The progression to disseminated intravascular coagulation (DIC) in infected very low birth weight (VLBW; <1500 g) infants is difficult to predict with precision at the onset of sepsis. We investigated the immunologic profiles of preterm infants with sepsis, using chemokine and cytokine measurements to predict the development of sepsis-induced DIC at the onset of infection. We measured a panel of chemokines and cytokines at 0 and 24 h after clinical presentation in VLBW infants with suspected infection requiring full sepsis screening. The chemokines measured were interleukin (IL)-8, interferon-gamma-inducible protein-10 (IP-10), monokine induced by interferon-gamma, monocyte chemoattractant protein-1, and regulated upon activation normal T-cell expressed and secreted (RANTES), and the cytokines were IL-6, IL-10, and tumor necrosis factor-alpha. Of 195 episodes of suspected clinical sepsis investigated, 62 were culture-confirmed septicemia or necrotizing enterocolitis (28 of these infants developed DIC), 22 were culture-negative clinical infections, and 111 involved noninfected episodes. All studied inflammatory mediators except RANTES showed significantly greater up-regulation in culture-positive infected infants than in noninfected infants at 0 and 24 h, whereas RANTES showed significant down-regulation. The model that used plasma IL-10 (>208 ng/L), IL-6 (>168 ng/L), and RANTES (<3110 ng/L) at 0 h had sensitivity, specificity, and positive and negative predictive values of 100%, 97%, 85%, and 100%, respectively, for identifying infected patients who subsequently developed DIC. IL-10, IL-6, and RANTES measured at clinical presentation sensitively and accurately predicted the development of DIC in severely infected infants. This information could be vital for early and effective treatment of neonatal sepsis.

Immunomodulation, Part III : Intravenous Immunoglobulin

Intravenous immunoglobulin therapy does not appear to be efficacious in the prevention of neonatal sepsis. The value of a 3-4 percent reduction in sepsis or any serious infection without a reduction in mortality must be weighed against the cost of the therapy. The efficacy of IVIG therapy in the treatment of neonatal sepsis remains uncertain. The results of the ongoing International Neonatal Immunotherapy Study should provide definitive answers regarding the effectiveness of this therapy. Long-term follow-up and cost (length of stay) are important components of this study. Ohlsson and Lacy recommend studies evaluating the effectiveness of IVIG preparations with high concentrations of antibodies to common unit- or geography-specific pathogens. The cost-effectiveness of the production and use of such products should be included in study designs. Part IV of this series will explore the use of the amino acid glutamine as an immunomodulating agent in neonates.

Exchange transfusion or intravenous immunoglobulin therapy as an adjunct to antibiotics for neonatal sepsis in developing countries: a pilot study

Both intravenous administration of immunoglobulin (IVIG) and exchange transfusion (ET) have been used for treatment of neonatal sepsis. No studies have compared ET with IVIG in neonates. The aim of the study was to investigate serial IgG and IgM serum levels in two groups of septic infants treated with either IVIG or ET as adjuvant therapy. A total of 88 infants with sepsis and gestational ages ranging from 32 to <37 weeks were enrolled consecutively. The effect of ET with fresh, whole blood and IVIG on immunoglobulin G and M levels was monitored over a 24-hour period. ET was performed on 33 infants, 33 infants received IVIG and 22 infants served as controls. There were nine deaths (27%) in the IVIG group, seven (21%) in the ET group and nine (41%) in the control group (p>0.05). IgG levels rose significantly 12 hours after administration of IVIG (p<0.01). There were no differences between the initial and 24-hour IgG levels in the IVIG group. IgG levels did not change significantly in the ET and control groups. IgM levels rose significantly 12 hours after ET and elevated IgM levels persisted for over 24 hours.

111 Extractive Protein C Use in Neonatale Sepsis

The protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotic, anti-inflammatory, and profibrinolytic properties. Most cases of disseminated intravascular coagulation (DIC) and thrombosis are observed in neonatal bacterial sepsis. Many therapies are used in treatment of DIC with different results. In the last few years, a new therapy with extractive protein C (PC) to regulate the activated coagulation is available. The aim of our study is to verify the efficacy of PC infusion in patients with neonatal bacterial sepsis. The rationale of the study is to stop the intravascular coagulation and thrombosis using a natural regulator (PC) of the coagulation cascade.We performed a pilot study in a cohort of 12 preterm and term newborn infants with DIC secondary to severe bacterial sepsis and documented PC activity deficit due to the sepsis. We used PC intravenously once a day. Evaluating the PC deficit of activity and body weight we computed the dosage of PC to administer to infuse to each patient. To verify the efficacy of therapy we evaluated every day the PC activity, D-Dimer assay, PCR, WBC and platelet count.Two infants died (one had a severe prenatal brain haemorrhage; one had severe early onset sepsis and deceased in few hours). Ten children showed a rapid response to the therapeutic efforts and survived without any sequelae. We observed improved clinical conditions and raising in PC activity and D-Dimers reduction. No adverse reactions were observed during and after Ceprotin administration in all patients.The successful employment of PC would break new grounds in the neonatal sepsis treatment with DIC and/or thrombosis complications. These preliminary data should be confirmed by further clinical trials and promote controlled randomized double blind trial.

Initial antibiotic therapy of neonatal sepsis

It is certain that in the past the types of bacterial agents responsible for neonatal sepsis and their sensitivity to antibiotics were not the same in all historical periods. However, the reports confirming the conclusion have been published only in the last three years. According to these facts, the bacterial causes of neonatal sepsis were analyzed in patients treated at the University children's hospital in Belgrade (S&M) as well as their sensitivity to antibiotics to determine the most effective initial therapy. Between January 2001 and June 2004, 35 neonates, aged from 1-30 days, with positive blood culture were treated. Gram-negative bacteria were the cause of sepsis in 57% of patients (Pseudomonas--20%, Klebsiella--20%, E. coli--8.5%, Acinetobacter--8.5%), gram-positive in 43% (coagulase-negative Staphylococci--14%, Staphylococcus epidermidis--14%, Staphylococcus aureus--9%, Streptococcus group B--3%, Listeria monocytogenes--3%). The bacteria were the most sensitive to carbapenems (85-89%), amikacin (68%), third-generation cephalosporins (47-50%), while the sensitivity to gentamicin was less than expected (48.5%). Sensitivity to ampicillin (8%) confirmed a high level of resistance to this antibiotic. All isolated Staphylococci were sensitive to vancomycin, and the overall methicillin resistance was 46%. Combined cefotaxime and amikacin therapy was the most effective of all suggested initial combinations of antibiotics (74%). The sensitivity to all other combinations of antibiotics was 51-71%. The most adequate initial combination of antibiotics for the treatment of neonatal sepsis is cefotaxime plus amikacin. The most adequate antibiotic for the treatment of nosocomial neonatal sepsis is carbapenem.

Vancomycin use in hospitalized pediatric patients.

To assess vancomycin utilization at children's hospitals, to determine risk factors for vancomycin use and length of therapy, and to facilitate adapting recommendations to optimize vancomycin prescribing practices in pediatric patients. Two surveys were conducted at Pediatric Prevention Network hospitals. The first (Survey I) evaluated vancomycin control programs. The second (Survey II) prospectively reviewed individual patient records. Each hospital was asked to complete questionnaires on 25 consecutive patients or all patients for whom vancomycin was prescribed during a 1-month period. In Survey I, 55 of 65 (85%) hospitals reported their vancomycin control policies. Three quarters had specific policies in place to restrict vancomycin use. One half had at least 3 vancomycin restriction measures. In Survey II, personnel at 22 hospitals reviewed 416 vancomycin courses, with 2 to 25 (median = 12) patients tracked per hospital. Eighty-two percent of the vancomycin prescribed was for treatment of neonatal sepsis, fever/neutropenia, fever of unknown origin, positive blood culture, pneumonia, or meningitis. In an additional 6% (26/416), vancomycin was prescribed for patients with beta-lactam allergies and in 13% (56/416) for prophylaxis. Median duration of prophylaxis was 2 days (range: 1-15 days). Almost half (196, 47%) of the patients who received vancomycin were in intensive care units; 27% of the vancomycin courses were initiated by neonatologists and 19% by hematologists/oncologists. The predominant risk factor at the time of vancomycin initiation was the presence of vascular catheters (322, 77%); other host factors included cancer chemotherapy (55, 13%), transplant (30, 7%), shock (24, 6%), other immunosuppressant therapy (17, 4%), or hyposplenic state (2, <1%). Other clinical considerations were severity of illness (96, 23%), uncertainty about diagnosis (51, 12%), patient not responding to current antibiotic therapy (40, 10%), or implant infection (13, 3%). When vancomycin was initiated, blood cultures were positive in 85 patients (20%); cultures from other sites were positive in 45 (11%), and Gram stains of body fluids were positive in 37 (9%). In 29 (7%) patients, organisms sensitive only to vancomycin were isolated before vancomycin initiation. Reasons for discontinuing vancomycin included: therapeutic course completed (125, 30%), negative cultures (106, 25%), alternative antibiotics initiated (75, 18%), illness resolved (14, 3%), or patient expired (13, 3%). Final results of blood culture isolates resistant to beta-lactam antibiotics included 48 coagulase-negative staphylococcus, 5 Staphylococcus aureus, and 10 other species. At children's hospitals, vancomycin is initiated for therapy in patients who have vascular catheters and compromised host factors. Only 7% had laboratory-confirmed beta-lactam-resistant organisms isolated at the time vancomycin was prescribed. Efforts to modify empiric vancomycin use in children's hospitals should be targeted at intensivists, neonatologists, and hematologists. Initiatives to decrease length of therapy by decreasing the number of surgical prophylaxis doses and days of therapy before laboratory results may decrease vancomycin exposure.

Immunotherapy in the prophylaxis and treatment of neonatal sepsis.

Neonatal sepsis is a significant cause of morbidity and mortality in the neonatal intensive care unit. The epidemiology of neonatal infections is complex; however, they are in large part secondary to developmentally immature host defense mechanisms. These immunodeficiencies, which are exaggerated in premature and sick neonates, include quantitative and qualitative deficits in phagocytes, complement components, cytokines, and immunoglobulins. Therapies that modulate or augment host defenses may attenuate the virulence of neonatal infections. In this paper, we have reviewed immunotherapies that modulate the immune system of the neonate, including: intravenous immunoglobulins, myeloid hematopoietic growth factors, and granulocyte transfusions. Future studies should focus on investigating other abnormalities of neonatal host defense and/or combined immunotherapy approaches in an attempt to circumvent the immaturity of host defense and potentially reduce both the incidence and severity of neonatal sepsis.

The current role of colony-stimulating factors in prevention and treatment of neonatal sepsis

To review the role of colony-stimulating factors as adjuncts in the therapy of neonatal sepsis. Data provided by animal experiments and in vitro experiments in human neonates demonstrate the inability of newborn infants to significantly upregulate colony-stimulating factor expression during infectious challenge. In a few clinical trials, exogenous administration of colony-stimulating factors has been associated with reduced neonatal morbidity and mortality. However, reviewing the existing data on colony-stimulating factor administration in neonates, evidence for efficacy and benefit of these adjuncts in treating neonatal sepsis still appears to be poor. Further randomized, placebo-controlled clinical trials, particularly for the subgroups of premature infants or infants with neutropenia, are urgently warranted before routine application of these cytokines can be recommended.

The current role of colony-stimulating factors in prevention and treatment of neonatal sepsis

Objectives: To review the role of colony-stimulating factors as adjuncts in the therapy of neonatal sepsis. Data summary: Data provided by animal experiments and in vitro experiments in human neonates demonstrate the inability of newborn infants to significantly upregulate colony-stimulating factor expression during infectious challenge. In a few clinical trials, exogenous administration of colony-stimulating factors has been associated with reduced neonatal morbidity and mortality. However, reviewing the existing data on colony-stimulating factor administration in neonates, evidence for efficacy and benefit of these adjuncts in treating neonatal sepsis still appears to be poor. Conclusion: Further randomized, placebo-controlled clinical trials, particularly for the subgroups of premature infants or infants with neutropenia, are urgently warranted before routine application of these cytokines can be recommended.

Myeloid hematopoietic growth factors and their role in prevention and/or treatment of neonatal sepsis

Sepsis continues to be an important cause of morbidity and mortality among both full-term and preterm infants, secondary to an immaturity in neonatal host defense. The incidence of neonatal sepsis ranges from 30% in very low birth weight infants to 0.4% in preterm neonates and 0.1% in term neonates. The dysregulation of the expression and production of hematopoietic cytokines in the neonate contributes to quantitative and qualitative deficiencies in neonatal myeloid progenitor activity and decreased availability and function of mature effector neutrophils. These abnormalities contribute in large part to the increased incidence and mortality associated with neonatal sepsis. In this review, we have summarized and analyzed the studies investigating the dysregulation, expression and production of myelopoietic growth factors in neonates, the preclinical in vivo effects of myelopoietic growth factors in neonatal animals, the preclinical in vivo effects of myelopoietic growth factors during experimental sepsis in neonatal animals, the in vitro effects of growth factors on human neonatal phagocytic immunity, and clinical results of myelopoietic growth factors in human neonates. Future studies should be focused on investigating other abnormalities of neonatal host defense and multiple and simultaneous approaches to circumvent identified defects to attempt to reduce both the incidence and severity of neonatal host defense.

Myeloid colony-stimulating factors: use in the newborn.

Bacterial and fungal sepsis are major causes of morbidity and mortality in the newborn. Multiple factors contribute to this increased susceptibility to infection, including quantitative and qualitative neutrophil defects, with a reduction in neutrophil number and function. Neutropenia in the newborn may occur in association with sepsis and has a poor prognosis. In addition to antibiotic therapy and supportive care, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce morbidity and mortality. Granulocyte CSF is the physiological regulator of neutrophil production and function. Administration of G-CSF results in increased neutrophil production and counts and improved neutrophil function. Several studies of animal and human newborns having neutropenia or suspected sepsis investigated the use of G-CSF and GM-CSF to elevate neutrophil counts and reduce morbidity and mortality in this population. Results of small clinical trials using G-CSF and GM-CSF in very low-birth-weight infants having neutropenia show increased neutrophil counts and a reduced incidence of sepsis during the neonatal period. Despite these promising early results, further studies of the safety and efficacy of G-CSF and GM-CSF administration in neonates are required before their routine use can be recommended as either prophylaxis or treatment for neonatal sepsis.

Neonatal sepsis: diagnosis and treatment

OBJECTIVE: Review the literature on diagnosis and treatment of neonatal sepsis. METHODS: The most important articles on neonatal sepsis were selected through MEDLINE. RESULTS: The present review analyzes the different methods of diagnosis, laboratory and clinical, as well as the different therapeutic managements of neonatal sepsis. CONCLUSION: Neonatal sepsis is a severe disease that must be diagnosed early and properly treated in order to avoid lethal outcome.

Rationale and Potential Use of Cytokines in the Prevention and Treatment of Neonatal Sepsis

Despite advances in the use of newer antimicrobials and aggressive supportive care, sepsis and its sequalae remain a major source of morbidity and mortality in the neonate. The VLBW neonate is especially at high risk. We and others have demonstrated that neonatal MNC are deficient in their production of G-CSF and GM-CSF, which, in part, may explain the neonates propensity to develop neutropenia during times of sepsis. G-CSF and GM-CSF have been shown to both enhance neonatal neutrophil superoxide production in vitro and to increase circulating neutrophil numbers through expansion of the NSP in the BM in neonatal rats and humans. G-CSF is protective (if given with or before antibiotics) during experimental GBS in the neonatal rat and appears to be well tolerated (both short term and 2 years after its use) in the human neonate. In a phase II randomized pilot multicenter study, GM-CSF prophylaxis in the VLBW neonate was well tolerated during 4 weeks of administration and was noted to have significantly reduced the incidence of nosocomial infections. Future efficacy and safety studies in more neonates need to be completed and assessed before the routine pharmacologic use of G-CSF or GM-CSF is recommended to prevent and treat neonatal sepsis.

The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis

The use of intravenous immunoglobulin (IVIG) for the prevention and treatment of sepsis in neonates is appealing because of the relative immunodeficiency of the neonate and the desire to improve the relatively poor outcome even with optimal antimicrobial treatment. The effectiveness of IVIG for these uses has been studied in numerous prospective as well as retrospective small and large trials that have had discordant conclusions. Meta-analysis demonstrates the marginal but significant benefit of prophylactic IVIG administered shortly after birth in preventing early onset sepsis in premature low birth weight newborns (P = .0193, two-sided). The expense of prophylactic use of IVIG administration for the relatively large premature newborn population given the minimal benefit as demonstrated by original studies and by meta-analysis is not justified. In contrast, meta-analysis of studies of IVIG for the treatment of neonates with sepsis shows a significant and unequivocal sixfold decrease in the mortality rate (P = .007, two-sided) when IVIG is administered in addition to standard therapies. The additional benefit of decreasing the risk for acute mortality indicates that the inclusion of IVIG should be considered a part of the routine therapy of neonatal sepsis.

Early diagnosis and treatment of neonatal sepsis.

Perinatally acquired bacterial neonatal sepsis is a low incidence, high risk disease with a relatively benign treatment. Accurate diagnosis is difficult because there is no definitive diagnostic test; even blood cultures have an unacceptably low sensitivity. Therefore, the clinician must accept that a number of neonates who do not have the disease will have treatment initiated for sepsis. In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection, historical, clinical, and laboratory data can be used together in a management approach to achieve optimal results. A systemized approach using history, examination, sepsis screen laboratory tests, and cultures is presented to guide clinical management.

Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis.

To determine the effectiveness of intravenous immune globulin (IVIG) in the prevention and treatment of neonatal sepsis. All published studies of IVIG for the prevention or treatment of neonatal sepsis were reviewed. Peer-reviewed, prospective, randomized trials with high merit were analyzed by two meta-analyses. The effect of prophylactic IVIG was evaluated by comparison of the numbers of cases of sepsis (bacteremia in the presence of systemic manifestations of sepsis), and of therapeutic IVIG by comparison of the numbers of deaths resulting from early-onset sepsis. Meta-analysis of 4933 evaluable newborns in 12 studies of IVIG prophylaxis showed a statistically significant negative association with the incidence of sepsis in premature low birth weight newborns given IVIG shortly after birth (P = .0193, two-sided). The heterogeneity across these studies precluded estimation of a common odds ratio. Meta-analysis of 110 evaluable cases of neonatal sepsis in three studies of IVIG treatment of neonatal sepsis showed a significant decrease in the mortality rate for neonates with sepsis given IVIG (P = .007, two-sided). The common odds ratio was .173 (95% confidence interval = .031 to .735). Using conservative and objective outcome rating criteria, the addition of IVIG to standard therapies is of minimal but demonstrable benefit in preventing sepsis when administered prophylactically to premature low birth weight newborns, and of unequivocal benefit in preventing death when administered therapeutically for early-onset neonatal sepsis. The likelihood of newborns with sepsis living past the neonatal period was improved nearly sixfold when IVIG was administered in addition to standard therapies.