Future Directions in The Evaluation and Management of Neonatal Sepsis

Future Directions in the Evaluation and Management of Neonatal Sepsis Micah Bhatti, Alison Chu, Joseph R.
Hageman, Michael Schreiber and Kenneth Alexander Neoreviews 2012;13;e103 DOI: 10.1542/neo.13-2-e103
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Article
infectious diseases
Future Directions in the Evaluation and Management of Neonatal Sepsis

Micah Bhatti, MD, PhD,* Alison Chu, MD,* Joseph R. Hageman, MD,
Abstract
Although sepsis is one of the important etiologies of illness in hospitalized infants, it is often difcult to determine if an infant is truly infected and, moreover, how to treat these infections. To address the rst issue, researchers have begun to examine techniques to shorten the amount of time it takes to culture and identify organisms. On the clinical side, the development of biomarkers may help physicians to better identify infants who are likely ill from infection versus those infants who are unstable from other processes. The ability to distinguish between these cohorts will help to curtail excessive use of empirical antibiotics. Even if infants are determined to truly have infection on the basis of a positive culture, it is becoming more challenging to appropriately treat causative organisms, as multidrug resistance becomes more prevalent. Furthermore, it becomes more important to evaluate strategies to prevent these infections before they occur.
Michael Schreiber, MD,* Kenneth Alexander, MD, PhD*
Author Disclosure Drs Bhatti, Chu, Hageman, Schreiber, and Alexander have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
Objectives
After completing this article, readers should be able to:
1. Understand new developments in serum biomarker research. 2. Recognize the steps in identifying infectious organisms and how current research into new laboratory techniques may be able to expedite this process. 3. Understand the uses and limitations of less well-known antimicrobial agents in treating multidrug-resistant infections. 4. Understand the importance of hand hygiene and careful central catheter use in preventing neonatal infection. 5. Become familiar with recent research on the utility of nutrition, including early enteral feeding, human milk, and lactoferrin, in the prevention of infection.
Introduction
One of the most challenging aspects of neonatal sepsis is determining if an infant who is clinically unstable is truly infected. To improve our ability to accurately detect sepsis, research has been conducted assessing the use of various biomarkers. In addition, advancements in medical microbiology have led to faster detection of pathogens in blood samples. Another challenge to the management of critically ill infants is the emergence of Abbreviations multidrug-resistant (MDR) organisms that will require neoCLABSI: central lineassociated bloodstream infections natologists to use unfamiliar antibiotics with well-known toxCRP: C-reactive protein icities. In the wake of MDR organisms and limited antibiotics, EOS: early onset sepsis hospitals have implemented rigorous prevention programs. GBS: group B streptococcal We will review advances in the prevention and diagnosis of HRC: heart rate characteristics neonatal sepsis and the treatment of MDR infections.
LOS: MDR: PCR: PCT: WC-MS: late onset sepsis multidrug-resistant polymerase chain reaction procalcitonin whole-cell mass spectrophotometry
Advances in Sepsis Detection

Clinical sepsis is dened as a whole-body inammatory state (systemic inammatory response syndrome) and the presence of a known or suspected infection. (1) This seemingly
*Pritzker School of Medicine, University of Chicago, Chicago, IL. Department of Pediatrics, NorthShore University Health System, Evanston, IL, and Professor Emeritus of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL.
NeoReviews Vol.13 No.2 February 2012 e103
infectious diseases future of neonatal sepsis
straightforward denition poses two major challenges. First, although many clinicians almost automatically ascribe neonatal systemic inammatory response syndrome to infection, the causes of this syndrome are myriad and include many noninfectious processes. Second, the sensitivity of blood cultures for identifying pathogenic bacteria may be lower in neonates than in adults because of previous antibiotic treatment, small specimen volumes, and low-grade bacteremia. (2)(3) Complicating matters, it can take up to 48 hours to detect an organism on the basis of blood culture by using current methods (4) and then an additional 24 to 48 hours before the identity and antibiotic sensitivities are known. During this time, empirical antibiotics are administered. To improve the diagnosis of neonatal sepsis, new technologies are being introduced in clinical laboratories that will reduce the time required to identify a potential pathogen. In addition, various biomarkers and heart rate characteristics (HRC) monitoring are being assessed to determine whether it is possible to rapidly identify infected neonates.
HRC Monitoring
Research into cardiac electrical patterns has revealed that reduced variability and transient decelerations in heart rate may be early indicators of clinical instability and are hypothesized to be mediated by the cholinergic antiinammatory pathway. (5) The HRC index is a statistically derived interpretation of the beat-to-beat variation in a patient. (6) A low index indicates normal variation, but as normal variation is lost, the index rises, as does the risk of clinical deterioration. A recent randomized controlled trial of >3,000 very low birth weight infants revealed that the use of HRC monitoring signicantly decreased the 30-day mortality rate after a septic-like event without a signicant increase in antibiotic days. (5) The mechanism by which mortality is decreased in the monitored cohort remains unclear. In a separate study, neonates with culture-proven sepsis had a statistically higher HRC during the 24 hours leading up to the septic episode compared with healthy controls. (6) However, neonates with culture-negative, septic-like events had a statistically similar rise in HRC. Therefore, HRC is able to serve as an early warning of impending clinical instability, and additional research is needed to determine if it can differentiate between true sepsis versus a culturenegative, septic-like event.
Serum Biomarkers
Although a positive blood culture remains the standard for diagnosing neonatal sepsis, many investigators have assessed measuring the host response as an adjunct to
e104 NeoReviews Vol.13 No.2 February 2012
culture-based diagnosis. The goal of serum biomarker research is to identify a means by which an infected child can be identied rapidly, before the onset of lifethreatening symptoms. A good diagnostic host marker for sepsis with a high negative predictive value would reduce the inappropriate use of antibiotics, health care costs, and lengths of hospital stays. (7) An ideal biomarker should be elevated early in the course of infection and stay elevated for a sufcient period to provide opportunity for sampling. The biomarker should have well-dened values to differentiate infected from noninfected infants, with a very high sensitivity and negative predictive value. (8) It also is helpful if its values reect the progression of disease and response to therapy. (8) Several serum biomarkers have been evaluated as potential indicators of neonatal sepsis. C-reactive protein (CRP), the most commonly used biomarker, is synthesized within 6 hours of exposure to an infectious process and usually becomes abnormal within 24 hours. (7) Because CRP takes up to 24 hours after the onset of an infection to become abnormal, it has little utility in assisting in the early detection of sepsis. CRP is also limited in that other processes in addition to infection can result in elevation, including trauma and ischemia. (7) It does have a high specicity, between 93% and 100%; thus, a normal CRP in a septic-appearing neonate is unlikely to be ill because of an infectious process. Levels generally remain elevated until the infection is controlled; therefore, CRP can serve as a marker of successful treatment. Procalcitonin (PCT) is a 116amino acid peptide precursor to calcitonin that rises in response to most infections and some inammatory processes. (9) The increase of PCT in sepsis seems to correlate with the severity and mortality of disease, and increases in PCT occur more rapidly than increases in CRP. (10) A metaanalysis of 22 studies found that PCT was more accurate in the diagnosis of late onset sepsis (LOS) than CRP. (9) A separate meta-analysis included 29 studies and found a pooled sensitivity and specicity of 81% and 79%, respectively. (11) In the neonate, PCT is increased during the rst 2 days of life and is theorized to be secondary to peripartum proinammatory changes, making it less diagnostic during this time period. (12) Levels can also be elevated in infants with noninfectious processes, such as respiratory distress syndrome, hemodynamic failure, and perinatal asphyxia, as well as postresuscitation. (10) Other immunologic markers are being studied for their utility in the detection of neonatal sepsis. Proinammatory cytokines such as interleukin-6 and interleukin-8 were initially thought to be excellent markers for detecting infection, but the very short half-life of circulating
cytokines signicantly increased the rate of false-negative results. (8)(12) Increased levels of circulating calprotectin, a major product of innate immune cells, were shown to have higher sensitivity and specicity (89% and 96%, respectively) for LOS sepsis than CRP, and, in one cohort of very low birth weight infants, levels were not inuenced by postnatal age. (13) Advances in ow cytometery have allowed the investigation of cell surface antigens as potential markers. A study found CD64 expression to be signicantly increased in infants with culture-proven sepsis compared with those with culture-negative sepsis or healthy controls, with a sensitivity of 88.6% and a negative predictive value of 94%. (14) Despite thorough investigation into many other proteins and small molecules, no single biomarker has been perfect for detecting neonatal sepsis. Therefore, investigators have tried combining markers in an effort to boost their sensitivity and specicity. (8)(15) A study combining four different markerssoluble intercellular adhesion molecule 1, CRP, soluble E-selectin, and serum amyloid Awas able to generate a sensitivity of 90% and a negative predictive value of 91.3%. (16) Another study using a proteomic approach found that combining proapolipoprotein C-II and a des-arginine variant of serum amyloid A was effective in identifying sepsis, with a negative predictive value of 100% in their cohort. (17) Thus, the next phase in the early detection of neonatal sepsis will be the development of a panel of readily measurable markers that will assist in determining which infants are at increased risk for impending sepsis. Although the study of biomarkers may assist in the early detection of sepsis, virtually all of the biomarkers studied to date are nonspecic indicators of infection and inammation. They are incapable of providing information about the etiology of the infection, and therefore the microbiology laboratory remains necessary to identify the pathogen.
Molecular Microbiology
Isolation of a bacterial pathogen from blood requires growth of the organism in liquid media, subculture of the organism on solid media, and identication of the organism according to its characteristic appearance, growth properties, metabolism of various substrates, and expression of certain surface proteins. (5)(18) The entire process can take up to 4 days before the identity and sensitivities of a bacterium can be reported to the clinical care team. To reduce the time required to identify a pathogen, there is a shift toward identifying bacteria on the basis of genotypic analysis. The two most promising methods are whole-cell mass spectrophotometry
(WC-MS) and amplication and sequencing of 16S ribosomal nucleic acid. (19)(20) In WC-MS, bacterial cells undergo ionization that generates a unique protein spectral ngerprint. The protein spectral ngerprint allows bacterial identication by using a spectral database of known bacteria. (21) WC-MS can determine the identity of an organism in <10 minutes, reducing the time from sample collection to pathogen identication to 3 days. Current devices can resolve the species and genus of >90% of bacterial isolates, a rate that is superior to traditional biochemical approaches. (22) The recent development of automated whole-cell mass spectrophotometers will make this technology accessible to most clinical laboratories in the near future. (18) Ongoing research is being conducted to determine if WC-MS may be used to identify bacteria in samples taken directly from positive blood culture bottles, which would bypass the need for subculturing and reduce bacterial identication time to 2 days. (23) Nucleic acid amplication and sequencing of 16S ribosomal nucleic acid is now considered the gold standard for identifying bacteria, although routine use has been limited by expense and time. (20) Several approaches are being used to bring 16S ribosomal nucleic acid detection into the clinical laboratory. The most advantageous is broad-range polymerase chain reaction (PCR), which utilizes amplication by using nonspecic 16S ribosomal DNA primers on DNA extracted directly from blood or spinal uid without previous culturing. (2) Detection of a pathogen by using broad-range PCR takes <8 hours and requires <500 mL of sample. (19) The PCR product can be sequenced or probed to determine the identity of the pathogen. Therefore, in <24 hours, a physician would know whether a patient is bacteremic, and if so, with what pathogen. Implementation of 16S PCR in the detection of neonatal sepsis has been shown to decrease inappropriate use of antibiotics. (24) In recent studies, the sensitivity of broad-range PCR varied widely, from 41% to 100%. (19) More reliable methods for DNA extraction and the development of automated systems are necessary before this technique is ready for the clinical laboratory. (2)
Treating MDR Infections

Many clinicians are now nding that their infant patients are infected with antibiotic-resistant nosocomial pathogens such as vancomycin-resistant Enterococcus, carbapenemaseproducing Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. (25) Described here are several antibiotic agents, not routinely used in the NICU, that are capable of treating infections caused by resistant organisms. As with older antibiotics, the emergence of
microbial resistance to these newer antibiotics is inevitable and has, in many cases, already occurred. Thus, continued judicious use of antibiotics is necessary to maintain the usefulness of these new antimicrobials.
Gram-Positive Infections
Gram-positive organisms are the most commonly isolated organism in the laboratory evaluation of LOS. Unfortunately, antimicrobial resistance among Gram-positive organisms is now common. Recent studies have reported the use of linezolid and daptomycin in children and neonates for treatment of infections caused by Gram-positive organisms resistant to b-lactams and vancomycin. Linezolid is an oxazolidinone antimicrobial that was licensed by the US Food and Drug Administration for use in pediatrics in 2002. The drugs antimicrobial effect is mediated through disruption of bacterial protein synthesis induced by linezolid binding to ribosomal RNA. (26) Although linezolid is bacteriostatic against all Staphylococcal and Enterococcal species, it has been successfully used to treat neonatal methicillin-resistant Staphylococcal and vancomycin-resistant Enterococcus infections. (26) A subset analysis of 63 neonatal patients included in a pediatric Phase III study compared the use of linezolid with vancomycin in the treatment of resistant Gram-positive infections and revealed equal cure rates and lower adverse events in the linezolid group. (27) Linezolid has good penetration into the skin and lungs and is approved for the treatment of pediatric skin and soft-tissue infections and nosocomial pneumonias. Linezolid is not recommended as a rst-line drug in the treatment of endocarditis or catheter-related infections because it is bacteriostatic and has been associated with high adverse events in adult patients with catheter-related infections. However, linezolid has been used successfully to treat pediatric bloodstream infections and endocarditis caused by vancomycin-resistant organisms. (28) Adverse effects of linezolid treatment are seen more commonly in therapy courses lasting >2 weeks and include reversible myelosuppression and lactic acidosis. During treatment with linezolid, patients should have their serum lactate and blood cell counts checked periodically. Currently, resistance to linezolid is rare; however, outbreaks of linezolid-resistant organisms have been reported. (29) Daptomycin is a cyclic lipopeptide antimicrobial derived from Streptomyces roseosporus and is bactericidal against resistant Gram-positive organisms. The mechanism of action is poorly understood, but daptomycin is theorized to form pores in the cell membranes of Grampositive organisms. (30) Although daptomycin has had great success in treating adult bloodstream infections
and endocarditis, it is not currently approved by the US Food and Drug Administration for use in pediatric patients. (31) A small number of reports describe the successful off-label use of daptomycin for the treatment of resistant infections that occurred in neonates while receiving vancomycin therapy. (31)(32) Daptomycin is inactivated by pulmonary surfactant, rendering it ineffective in treating pulmonary infections. Until appropriate pharmacokinetic studies are performed in the pediatric population, daptomycin should be used only as a second-line drug for treatment of neonatal vancomycin-resistant infections, including bloodstream infections and endocarditis.
Gram-Negative Infections
In neonates with LOS in the United States and other developed countries, Gram-negative organisms are isolated less frequently than Gram-positive organisms. However, in some developing nations, Gram-negative organisms are more common in both early onset sepsis (EOS) and LOS. (33) Unfortunately, the global epidemic of antibiotic resistance has created a major problem in treating Gramnegative sepsis everywhere. (34) Therefore, the evaluation of antimicrobial agents effective against Gram-negative organisms not previously used in the pediatric population has become critically important. Here we review the use of ciprooxacin and colistin in neonates. Ciprooxacin is a uoroquinolone that inhibits bacterial DNA topoisomerases. (35) Ciprooxacin is bactericidal against most Gram-negative organisms, including P aeruginosa. The use of uoroquinolones in pediatrics has been limited by reports of increased musculoskeletal adverse events in young animals. (36) A recently published systematic review suggests that there is increased risk of arthropathy in ciprooxacin-treated pediatric patients, but that this risk is relatively low and that the arthropathy is reversible. (36) Despite concerns over possible adverse effects, ciprooxacin has been approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections in children. It has been used off-label in many countries with good outcomes in the treatment of various Gram-negative infections. (35) A systematic review of ve cohort studies evaluated the use of ciprooxacin for the treatment of neonatal sepsis caused by antibiotic-resistant Gram-negative organisms. (37) Two of the ve cohorts assessed clinical response, with one showing a signicantly higher survival rate in the ciprooxacin-treated group versus treatment with ampicillin, gentamicin, and/or cefotaxime. The other cohort reported equal survival rates between the ciprooxacintreated group and the control group. None of the ve cohorts reported any major adverse events associated with
the use of ciprooxacin. Two signicant limitations to the use of ciprooxacin in neonates are the paucity of pharmacokinetic data in the neonatal population and the very high doses of ciprooxacin needed to successfully treat infections caused by Acinetobacter and Pseudomonas organisms. (37) Resistance to uoroquinolones has been well documented and may be increasing in certain parts of the world. (34) In an effort to minimize resistance, the use of ciprooxacin should be restricted to infections caused by resistant organisms. Colistin is a polymyxin initially discovered in 1947, and it functions as a detergent, dissolving the cellular membranes of Gram-negative organisms. (38) Systemic polymyxins fell into disuse in the early 1980s in favor of less toxic aminoglycosides and broad-spectrum b-lactams. However, with the continued emergence of MDR organisms, polymyxins have again found use as the only antibiotic left to treat some Gram-negative infections. In a retrospective study of neonates with MDR Gram-negative infections susceptible to only colistin, 12 neonates were bacteremic; two had concomitant meningitis. (39) Of the colistin-treated cohort, two-thirds of the patients survived, including one with meningitis. Two infants developed renal impairment, the main toxicity associated with colistin use, but both infants had multiorgan dysfunction before starting colistin therapy. In view of the situations requiring its use, which are often desperate, the rate of colistin-related nephrotoxicity is tolerable; however, regular monitoring of patients renal function during colistin therapy is recommended. (38) Colistin dosing guidelines have not been well established in the neonatal population. Finally, although rare, resistance to colistin has emerged, leaving patients mortally infected by organisms resistant to all commercially available antibiotics. (40) It should be emphasized that none of the antibiotics discussed here are superior for treatment of infections sensitive to older, more commonly used antibiotics. The use of these newer antibiotics should remain restricted to the denitive therapy of infections caused by resistant organisms. None of these drugs should be used for empirical therapy. The recommended doses of antibiotics mentioned here and in the two previous articles are listed in Table 1.
the safe use and early removal of intravascular catheters. Other potentially promising interventions for prevention of LOS are being studied, including the concept of bundles, early enteral feeding, nutritional supplements, and maternal vaccination.
Reducing Central-LineAssociated Bloodstream Infections

Although there is an abundance of research evaluating complex and expensive methods for prevention of neonatal sepsis, there are several simple, low-cost strategies that are highly effective. First and foremost is good hand hygiene. (41) Despite being a well-studied and established means for preventing and controlling transmission of infectious organisms, hand hygiene is poorly instituted, and the rates of hand hygiene protocol adherence by care providers are often well below 50%. Nonetheless, improved compliance with hand hygiene protocols can be achieved through a multimodal approach. A bundle is a group of specic, evidence-based practices that, when performed together, result in improved patient outcomes. (42) The bundle concept has been applied successfully to reduce central lineassociated bloodstream infections (CLABSI). A study in the NICU setting revealed that the use of an insertion and maintenance bundle, including improved hand hygiene, use of good sterile technique during placement (sterile gown, sterile gloves, surgical mask and hat, and thorough skin disinfection), aseptic technique when accessing the catheter, and daily inspection of central catheters reduced CLABSI by 67%. The use of antimicrobial prophylaxis remains a highly controversial method for preventing CLABSI. A Cochrane review assessing the use of a prophylactic systemic antibiotic found that almost 10 infants need to be given preventative antibiotics to avoid one case of infection. (43) Given the toxicities associated with broad-spectrum antibiotics and the potential for resistant organisms, antimicrobial prophylaxis is not recommended. Similarly, although there are some data supporting the use of vancomycin catheter locks for prevention of CLABSI, (44) the risk of selection of vancomycin-resistant organisms is substantial. Further studies need to be conducted before vancomycin line locks can be used outside of a controlled clinical trial. (45)
Prevention of LOS
Although research involving the prevention of EOS has largely been limited to the use of intrapartum prophylaxis, there is a myriad of proposed interventions for the prevention of LOS. Of these many proposed preventive interventions, the only established effective means for decreasing the rate of LOS are hand hygiene and
Nutrition and Nutritional Supplements

Altered bacterial colonization of the gut in premature infants as a consequence of delayed enteral feeding, antibiotic exposure, and immature gut barrier function may impair the development of innate and adaptive immunity.
Table 1.
Dosing of Antimicrobial Agents

Dosing 1 mg/kg per dose q24h 50 mg/kg per dose <7 d 2 kg: ql2h 2 kg: q8h GBS meningitis: 300 mg/kg per d divided q8h >7 d <1.2 kg: q12h 1.2L2 kg: q8h >2 kg: q6h GBS meningitis: 300 mg/kg per d divided q6h 25 mg/m2 per dose q24h 50 mg/kg per dose <7 d, <2 kg: q12h <7 d, 2 kg: q8h >7 d <1.2 kg: q12h 1.2L2 kg: q8h >2 kg: q6h 10 mg/kg per dose q12ha 2.55 mg/kg per d (expressed as colistin base) divided q6hq12h Limited data regarding neonatal dosingb 12 mg/kg per dose q24h 2.5L3.5 mg/kg per dose q8hq24h based on postnatal age, weight, and serum concentrations (varies according to institution) 10 mg/kg per dose GA 34 wk PNA <7 d: q12h PNA 7 d: q8h GA 35 wk: q8h GA 30 wk: 20 mg/kg per dose q12h GA >30 wk PNA 07 d: 20 mg/kg per dose q12h PNA >7 d: 20L40 mg/kg per dose q8h 1015 mg/kg per dose q6hq24h based on postnatal age, weight, and serum concentrations (varies by institution)
Agent Amphotericin B (conventional) Ampicillin
Caspofungin Cefotaxime
Ciprooxacin Colistimethate Daptomycin Fluconazole Gentamicin Linezolid
Meropenem
Vancomycin
Dosing regimens from Lexicomp online (http://online.lexi.com/). Only agents mentioned in the articles of this series are included. GA, gestational age; PNA, postnatal age. a Higher doses may be necessary to treat organisms such as Pseudomonas and Acinetobacter. (37) b Use of 10 to 15 mg/kg q24h has been reported. (31)
Based on this hypothesis, research has been conducted to determine if early enteral feedings with human milk may be protective against sepsis in the neonate. Although early enteral feeding may have benet, there is concern that early enteral feeding also increases the risk of necrotizing enterocolitis. In a few retrospective studies, there was an inverse relationship between risk of nosocomial infection and the initiation of feeding, without increased risk for necrotizing enterocolitis. (46)(47) Human milk, which contains lactose, nucleotides, oligosaccharides, and lactoferrin, has been shown to be protective against a variety of infections in the newborn. (48) Lactoferrin, a glycoprotein found in
human milk, has antimicrobial, anti-inammatory, and immunomodulatory properties. A statistically signicant decrease in the rates of sepsis was seen in infants randomized to receive lactoferrin supplementation (4.6%) versus those receiving placebo (17.3%, p<0.001). (49) Because poor bacterial gut colonization secondary to prematurity and antibiotic exposure may increase the risk of infection, therapeutic colonization of the neonatal gut with probiotic organisms may help to prevent LOS. However, studies using different combinations of Lactobacillus species, Bidobacterium species, and Streptococcus thermophilius have been inconclusive. (50)
Maternal Group B Streptococcal Vaccination

Another potential mechanism for prevention of EOS and LOS is the use of vaccines. Initial investigations into the development of group B streptococcal (GBS) vaccines have been promising. The vaccines target conserved surface antigenic proteins, such as the Sip protein located on the cell surface or immunogenic proteins from GBS pili. If a protective immune response is achieved, it would inhibit GBS adhesion to host tissue and prevent transepithelial migration. Although not yet commercially available, several vaccines are close to being released and will hopefully prove to be efcacious in decreasing the rates of EOS and LOS caused by GBS. (51)
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Conclusions
The diagnosis of neonatal sepsis continues to be a major clinical challenge. In an effort to improve outcomes of infected infants, research is being conducted to improve our ability to detect sepsis sooner and identify organisms more quickly. The use of biomarkers and the HRC index will hopefully provide additional tools for neonatologists to recognize and treat potentially infected infants. New technology being introduced into the microbiology laboratory will be able to conrm the presence of a pathogen by using faster and more reliable methods. Another important challenge in neonatal sepsis is the increasing rates of antimicrobial resistance, requiring the use of unfamiliar antimicrobial agents to treat MDR organisms. Initial studies of newer antibiotics are promising, but larger studies are needed to better evaluate these agents and provide better neonatal pharmacokinetic data. Lastly, because novel treatment agents will only take us so far, more research is needed to determine how to prevent these infections. ACKNOWLEDGMENTS The authors thank Elisabeth Mouw, PharmD, for her assistance with dosing recommendations for antimicrobial agents presented in Table 1.
American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Know the clinical manifestations, laboratory features, and differential diagnosis of neonatal sepsis. Know the effective techniques for control of nosocomial infection in the nursery, neonatal intensive care unit, and obstetrical unit. Know the pathogenesis and prevention of transmission of infections with multidrug-resistant bacteria.
19. Esparcia O, Montemayor M, Ginovart G, et al. Diagnostic accuracy of a 16S ribosomal DNA gene-based molecular technique (RT-PCR, microarray, and sequencing) for bacterial meningitis, early-onset neonatal sepsis, and spontaneous bacterial peritonitis. Diagn Microbiol Infect Dis. 2011;69(2):153160 20. Bizzini A, Jaton K, Romo D, Bille J, Prodhom G, Greub G. Matrix-assisted laser desorption ionization-time of ight mass spectrometry as an alternative to 16S rRNA gene sequencing for identication of difcult-to-identify bacterial strains. J Clin Microbiol. 2011;49(2):693696 21. Welker M, Moore ER. Applications of whole-cell matrixassisted laser-desorption/ionization time-of-ight mass spectrometry in systematic microbiology. Syst Appl Microbiol. 2011;34(1):211 22. van Veen SQ, Claas EC, Kuijper EJ. High-throughput identication of bacteria and yeast by matrix-assisted laser desorption ionization-time of ight mass spectrometry in conventional medical microbiology laboratories. J Clin Microbiol. 2010;48(3):900907 23. Moussaoui W, Jaulhac B, Hoffmann AM, et al. Matrix-assisted laser desorption ionization time-of-ight mass spectrometry identies 90% of bacteria directly from blood culture vials. Clin Microbiol Infect. 2010;16(11):16311638 24. Brozanski BS, Jones JG, Krohn MJ, Jordan JA. Use of polymerase chain reaction as a diagnostic tool for neonatal sepsis can result in a decrease in use of antibiotics and total neonatal intensive care unit length of stay. J Perinatol. 2006;26(11):688692 25. Bizzarro MJ, Gallagher PG. Antibiotic-resistant organisms in the neonatal intensive care unit. Semin Perinatol. 2007;31(1):2632 26. Kocher S, Mller W, Resch B. Linezolid treatment of nosocomial bacterial infection with multiresistant Gram-positive pathogens in preterm infants: a systematic review. Int J Antimicrob Agents. 2010;36(2):106110 27. Deville JG, Adler S, Azimi PH, et al. Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates. Pediatr Infect Dis J. 2003;22(suppl 9):S158S163 28. Garazzino S, Tovo PA. Clinical experience with linezolid in infants and children. J Antimicrob Chemother. 2011;66(suppl 4):iv23iv41 29. Mazzariol A, Lo Cascio G, Kocsis E, Maccacaro L, Fontana R, Cornaglia G. Outbreak of linezolid-resistant Staphylococcus haemolyticus in an Italian intensive care unit [published online ahead of print July 27, 2011]. Eur J Clin Microbiol Infect Dis. doi: 10.1007/s10096-0111343-6 30. Steenbergen JN, Alder J, Thorne GM, Tally FP. Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother. 2005;55(3):283288 31. Hussain A, Kairamkonda V, Jenkins DR. Successful treatment of methicillin-resistant Staphylococcus aureus bacteraemia in a neonate using daptomycin. J Med Microbiol. 2011;60(pt 3):381383 32. Cohen-Wolkowiez M, Smith PB, Benjamin DK Jr, Fowler VG Jr, Wade KC. Daptomycin use in infants: report of two cases with peak and trough drug concentrations. J Perinatol. 2008;28(3):233234 33. Vergnano S, Sharland M, Kazembe P, Mwansambo C, Heath PT. Neonatal sepsis: an international perspective. Arch Dis Child Fetal Neonatal Ed. 2005;90(3):F220F224 34. Ho J, Tambyah PA, Paterson DL. Multiresistant Gram-negative infections: a global perspective. Curr Opin Infect Dis. 2010;23(6): 546553 35. Leibovitz E. The use of uoroquinolones in children. Curr Opin Pediatr. 2006;18(1):6470
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Future Directions in the Evaluation and Management of Neonatal Sepsis Micah Bhatti, Alison Chu, Joseph R. Hageman, Michael Schreiber and Kenneth Alexander Neoreviews 2012;13;e103 DOI: 10.1542/neo.13-2-e103
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