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Journal of Tropical Pediatrics, 2015, 61, 1–13

doi: 10.1093/tropej/fmu079
Clinical Review

Challenges in the diagnosis and management of
neonatal sepsis
by Alonso Zea-Vera1 and Theresa J. Ochoa1,2
1
Instituto de Medicina Tropical “Alexander von Humbolt” and Pediatrics, Universidad Peruana Cayetano Heredia, Lima, Lima 31, Peru
2
Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center, School of Public Health,
Houston, Texas, 77225, USA
Correspondence: Theresa J. Ochoa, Instituto de Medicina Tropical “Alexander von Humboldt”, Universidad Peruana Cayetano Heredia,
Av. Honorio Delgado 430, San Martin de Porras, Lima 31, Peru. Tel: 51-1-482-3910. Fax: 51-1-482-3404.
E-mail: <Theresa.J.Ochoa@uth.tmc.edu>

SU M MAR Y
Neonatal sepsis is the third leading cause of neonatal mortality and a major public health problem,
especially in developing countries. Although recent medical advances have improved neonatal care,
many challenges remain in the diagnosis and management of neonatal infections. The diagnosis of
neonatal sepsis is complicated by the frequent presence of noninfectious conditions that resemble
sepsis, especially in preterm infants, and by the absence of optimal diagnostic tests. Since neonatal
sepsis is a high-risk disease, especially in preterm infants, clinicians are compelled to empirically ad-
minister antibiotics to infants with risk factors and/or signs of suspected sepsis. Unfortunately, both
broad-spectrum antibiotics and prolonged treatment with empirical antibiotics are associated with
adverse outcomes and increase antimicrobial resistance rates. Given the high incidence and mortality
of sepsis in preterm infants and its long-term consequences on growth and development, efforts to
reduce the rates of infection in this vulnerable population are one of the most important interven-
tions in neonatal care. In this review, we discuss the most common questions and challenges in the
diagnosis and management of neonatal sepsis, with a focus on developing countries.

In recent years, a significant decrease in childhood countries die at home before they are registered.
mortality has been achieved worldwide [1]. However, Consequently, neonatal sepsis is likely underreported
neonatal mortality has decreased at much lower rates, in these countries, suggesting that its impact on mor-
and currently represents 40% of all childhood mortal- tality may be even higher [4].
ity [1, 2]. Every year 2.6 million neonates die; three- Newborns, especially preterms, are more suscep-
fourths of these deaths occur in the first week of life, tible to infections than children at any other age period
and almost all (99%) in low- and middle-income [5]. Innate immunity is affected by impaired cytokine
countries [1, 3]. Neonatal sepsis is the third leading production, decreased expression of adhesion mol-
cause of neonatal mortality, only behind prematurity ecules in neutrophils and a reduced response to
and intrapartum-related complications (or birth as- chemotactic factors [6]. Also, transplacental passage
phyxia) [2]. It is responsible for 13% of all neonatal of antibodies starts during the second trimester and
mortality, and 42% of deaths in the first week of life achieves its maximal speed during the third trimester.
[2, 3]. Developing countries lack a surveillance sys- As a result, most preterm newborns have significantly
tem, and a high proportion of newborns in these reduced humoral responses [7]. Cytotoxic T-cell

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9–1. 16] (Table 1). In very-low-birth-weight economic burden of this condition in already poor newborns (<1500 g). coli. isolated in neonatal infections are more likely to have adverse one-fourth of episodes [15. most pathogens isolated in veloping countries. development index scores. Some low.1 per 1000 live births [4]. of disabilities in this population [8]. Despite the high burden of neonatal sepsis. Klebsiella sp and Candida sp. In addition. Together infected neonates face multiple challenges in diag. Various cutoff points classified neonatal sepsis in developing countries as have been used. countries. it is likely that highly un- WHAT ARE THE MOST COMMON CAUSES clean delivery practices lead to infections with noso- OF NEONATAL SEPSIS IN DEVELOPED comial agents very early in life [18]. includ. Late-onset sepsis presents mainly in high-quality evidence in diagnosis and treatment is very-low-birth-weight infants. [15].5 per 1000 live births 49–170 per 1000 live births. risk [13]. with a focus on de. culture-proven sepsis in [15.2  Challenges in the diagnosis and management of neonatal sepsis activity is also impaired during the newborn period sepsis is caused by maternally transmitted pathogens. In this review we address the OF NEONATAL SEPSIS IN DEVELOPING most frequent questions about the diagnosis and COUNTRIES? treatment of neonatal sepsis. responsible for gions hinder the development of clinical trials and half of episodes. The remaining cases neurodevelopmental outcomes at follow up. they cause one-third of episodes. In developing countries. . prolonged rupture of membranes and inad- crease even more the risk of infections in this equate intrapartum antibiotic prophylaxis increase its population. The main pathogen is CoNS. causes of late-onset sepsis include S. Physicians caring for are E. Coagulase-negative Staphylococcus (CoNS). newborns with prolonged hospitalizations. Less common nostic and treatment decisions. As a result. In developing The incidence of early-onset neonatal sepsis in countries. lack of developed countries is 3–3. aureus. pre- ures that preterm newborns commonly undergo in. 16]. 16]. get infected with community acquired pathogens toms start before 72 h of life) and late-onset (if even after 72 h [11]. Its incidence in lacking. The most common cause of early-onset 16 per 1000 live births and neonatal meningitis in sepsis is Group B Streptococcus (GBS).and hospital-acquired instead of early- epidemiological studies use 72 h [12]. [5]. maternal intrapartum fever.and middle-income to antibiotics than early-onset pathogens [17]. maturity.7 per 1000 live births consensus in definitions and variability between re. Other important etiologic agents global recommendations [10]. The situation in de. several authors have symptoms start afterward). are also experiencing the challenges of de. lower mental and psychomotor aureus. Infants with of episodes. followed by Escherichia coli. 9]. coli is more common than settings. Chorioamnionitis. central lines. but most community. use of but improvements in survival have not been accom. isolated in half 0. Early-onset and late-onset. Late-onset pathogens are more resistant home births [4].8–6. COUNTRIES? most neonates are born at the household and might Neonatal sepsis is divided into early-onset (if symp. parenteral feeding and mechanical ven- panied by proportional reductions in the incidence tilation [14]. GBS [16]. which are implementing tertiary care cen- ters. WHAT ARE THE MOST COMMON CAUSES veloped countries [11]. veloping countries is further complicated by a lack of Enterococcus sp and Pseudomonas aeruginosa [14. clinically diagnosed sepsis is present in developed countries is 0. This increases the social and teria [15. The susceptibility of the population. 15] reliable surveillance systems and high proportion of (Table 1). E. The multiple skin punctures and invasive proced. the hospital setting before 72 h of life are similar to those isolated afterward. from 48 h to 7 days. visual impairment and Listeria monocytogenes and other gram-negative bac- impaired growth [8. Late-onset sepsis is caused by nosocomial Advances in perinatal and neonatal intensive care infections and is more common in preterms and in have reduced the mortality rate of preterm infants. of early-onset sepsis are caused by Staphylococcus ing cerebral palsy.

6–8 P. 4–12 Candida sp. coli 5–16 Group B Streptococcus 2–8 Coagulase-negative Staphylococcus 8–28 S. 1–5 Enterobacter sp. As a . 3–10 Salmonella sp. coli of increasing care to very-low-birth-weight newborns and S. GBS. Auxiliary tests have limited value and are sible for a lower proportion of hospital-acquired infec. difficult to interpret due to low sensitivity and chang- tions. aureus [19. without assessing the dangers of common outbreak gen in developed countries. E. overall. aureus 8–22 E. coli. caused by CoNS (Table 2).3–3 a Data from references [18–20]. aureus are the most commonly isolated older patients. 16–28 S. has risen to 28% [18]. Table 2. mainly Klebsiella sp and neonatal sepsis is getting an accurate diagnosis. CoNS is respon. 20] countries 50 years ago [18]. is responsible for only sources—similar to what happened in developed 2–8% of cases in developing countries [19. coli 8–18 E. and multiple conditions resemble neonatal sep- In contrast to high-income countries. In Latin American and Blood cultures also lack sensitivity due to specific Southeast Asian countries that are implementing characteristics of the neonatal population [5]. and infected newborns DIAGNOSIS might die before coming to medical attention [11]. One of the major difficulties in the management of Gram-negative bacteria. 0. aureginosa 3–5 Other Candida species 3–4 a Data from references [14–16]. Challenges in the diagnosis and management of neonatal sepsis  3 Table 1. except in some parts of Africa [19]. Unlike E. Common pathogens of neonatal sepsis in developing countriesa Community-acquired Hospital-acquired Pathogen Frequency (%) Pathogen Frequency (%) Klebsiella sp. This surge might be the result The most common pathogens are Klebsiella sp. Common pathogens of neonatal sepsis in developed countriesa Early-onset Late-onset Pathogen Frequency (%) Pathogen Frequency (%) Group B Streptococcus 43–58 Coagulase-negative Staphylococcus 39–54 E. aureus 6–18 Coagulase-negative Staphylococcus 1–5 Candida albicans 6–8 L. 20].5–6 Enterococcus sp. monocytogenes 0. tions. coli 18–29 E. sis [5]. 4–9 S. It is possible than infants with GBS infec- tion are underreported since this pathogen usually presents very early in life. 14–21 Klebsiella sp. (Table 2). aureus 13–26 S. CoNS prevalence acquired sepsis. only 12% of hospital-acquired sepsis is ing normal ranges during the neonatal period [5]. and S. newborns have very subtle presenta- pathogens in hospital-acquired infections [18]. coli 5–13 Other gram-negative bacteria 7–8 Klebsiella sp. sophisticated tertiary neonatal units. Gram-negative bacteria dominate in community. the most common patho. aureus 2–7 S. pneumonia 2–5 Pseudomonas sp.

Ribosomal RNA Sepsis share a similar clinical presentation to other unique to bacteria are detected by 16 s RNA.4  Challenges in the diagnosis and management of neonatal sepsis result. of white blood cells. One minations 24–48 h after the onset of symptoms classic study. pyrosequencing. but studies in the neonatal period have shown meconium aspiration. One recent study teremia. and it cannot determine bacterial antibiotic sen- boratory tests in developing countries is limited [12]. Low values these signs and referring them to the hospital signifi. as many as 60% of cultures will be falsely generated normal ranges based on gestational age negative with 0. maternal fever. 24]. negative sepsis is responsible for the majority of epi. the neonatal period because it varies significantly munity health workers to identify sick infants using with day of life and gestational age [5]. making it diagnosis for the identification of pathogens. culture. all of these capabilities [5]. but has a high frequency of contamin- tests are paramount for its diagnosis. CRP values are also affected by blood cultures could help increase the yield of this premature rupture of membranes. Its overall sensitivity polymerase chain reaction (PCR). ical signs—difficulty feeding. findings have low sensitivities [34. focusing on E. fetal distress and the etiology conflicting results [29. 35]. Auxiliary high sensitivity. Taking serial deter- most samples taken are of less than 0. In early-onset .5 ml [25]. including a very appealing biomarker [5]. Different cutoff points have been However. phil counts and high immature/total ratio are associ- ated with early-onset sepsis. Currently. found that achieves a sensitivity of 74–89% and specificity of neonates have high-colony-count bacteremia [26]. used. is 81% and specificity is 79% [41]. It has a common conditions in the neonatal period. a combination of findings is necessary to pro. severe chest in drawing and axillary temperature What laboratory tests are useful in the evaluation of >37. high absolute neutrophil of neonatal sepsis. 37]. only when stimulated. Deciding as in the TaqMan Array Card. low values of absolute neutro- cantly reduces neonatal mortality [23. convulsions.5  C—that should prompt neonatal a newborn with signs of infection? referral to a hospital [21]. ation. of the infection [37. What is the value of blood cultures in the diagnosis high values of white blood cells and absolute neutro- of neonatal sepsis? phil counts are not informative [34]. respiratory rate >60 per min. a more recent study including other com. 74–95% [36. with 96% sensi- What are the main clinical signs of neonatal sepsis? tivity and 96% specificity [32]. but access to la. high immature/total ratio and low platelet and is affected by blood volume inoculated. newborns might be suboptimal. Other authors have also Complete blood cell count is difficult to interpret in included cyanosis and grunting [22]. the most commonly mon neonatal-sepsis pathogens found that 68% of used cutoff is 10 mg/l [38]. prenatal counts are associated with late-onset sepsis [35]. but early stages of infection [36. molecular biology laboratories and special equipment. Multiple and day of life [39]. High or low Blood culture is the gold standard for the diagnosis white blood cells counts. A meta-analysis of 23 studies on controversy. sitivities [33]. coli infection. However. level of bacteremia and laboratory Despite their association with infection. In this type of sepsis.5 ml sample volumes [28]. These new assays require advanced The World Health Organization identified seven clin. ranging from 0. the recommended minimal unacceptable low sensitivities.5  C or <35. In low-colony-count bac. and other ‘lab on a how to incorporate these tests is under great chip’ devices [31]. 40]. movement which are not available in many hospital settings. In developing countries. use of microfluidic technology such vide a correct diagnosis of neonatal sepsis. 30]. 37]. real-time PCR. test. Training com. especially during the blood volume for cultures in newborns is 1 ml. molecular diagnosis of neonatal sepsis found that real- time PCR assays performed the best. A single value of C-reactive protein (CRP) has sodes [4]. antibiotic use. its positivity rate is low counts. Important advances have been made in molecular Procalcitonin increases faster than CRP.2–95 mg/l. Since CRP undergoes a septic infants have low-level bacteremia (10 physiological 3 day rise after birth and is lower in Colony-forming units (CFU)/ml) and 42% have premature infants. using a single value for all counts 1 CFU/ml [27].

like CRP. PCR: polymerase chain reaction. WBC: white blood cell. achieving a sensitivity of 82–90% approaches that are being implemented to im- [41]. In late-onset sepsis. and these factors should be accounted to inter- shortly after birth have a sensitivity of only 49% pret its values [39]. Most studies have used a cutoff between 0. CRITERIA FOR THE DIAGNOSIS OF NEONATAL SEPSIS (MODIFIED FROM REFERENCE [43])a Clinical variables • Temperature instability • Heart rate 180 beats/min or 100 beats/min • Respiratory rate >60 breaths/min plus grunting or desaturations • Lethargy/altered mental status • Glucose intolerance (plasma glucose >10 mmol/l) • Feed intolerance Hemodynamic variables • Blood pressure 2 SD below normal for age • Systolic pressure <50 mm Hg (newborn day 1) • Systolic pressure <65 mm Hg (infants  1 month) Tissue perfusion variables • Capillary refill >3 s • Plasma lactate >3 mmol/l Inflammatory variables • Leukocytosis (WBC count >34 000  109/l) • Leukopenia (WBC count <5000  109/l) • Immature neutrophils >10% • Immature:Total neutrophil ratio >0.1 mg/dl or 2 SD above normal value • IL-6 or IL-8 >70 pg/ml • 16S PCR positive Interpretation • Proven Sepsis: A positive blood culture or PCR in the presence of clinical signs and symptoms of infection.2 • Thrombocytopenia <100 000  109/l • CRP >10 mg/l or 2 SD above normal value • Procalcitonin >8. CD64 neutrophil marker and 2 ng/ml [38]. a SD: standard deviation. • Probable Sepsis: Presence of signs and symptoms of infection and at least two abnormal laboratory results when blood culture is negative. there are new non-culture-based tive than CRP. It has the is significantly affected by day of life and gestational additional advantage of requiring small amounts of . CRP: C-reactive protein.3 prove the diagnosis [5]. [41]. its sensitivity is 70–77%. However. procalcitonin is more sensi. • Possible Sepsis: Presence of clinical signs and symptoms of infection plus raised CRP or IL-6/IL-8 level when blood culture is negative. CoNS: Coagulase- negative Staphylococcus or Staphylococcus non-aureus. For CoNS two positive blood cultures or one positive blood culture plus a positive CRP. Challenges in the diagnosis and management of neonatal sepsis  5 BOX 1. sepsis. Currently. procalcitonin has a high sensitivity and specificity. IL: interleukin. but values taken age.

27–0. but it is also part of the skin flora and a common con- ize before 24 h. nil. probable and possible sepsis [43] (Box 1). should have a lumbar puncture done. Simplicity is also important for these case definitions in order to minimize the work-load to already busy MANAGEMENT and understaffed units. interleukin 6 from contamination? and 8 are the most widely studied [38]. In asymptomatic new- Epidemiological surveillance systems are necessary borns evaluated for early-onset sepsis only due to to develop interventions for the management of neo. timal antibiotic regimen [10]. none of these classifications have two-thirds of candida meningitis—have negative been widely adopted. One-third of cases—and Unfortunately. is also being studied Institute of Child Health and Human Development as a possible biomarker [5]. New alternatives (NICHD) Neonatal Research Network published under development include the use of genomics specific criteria to define CoNS sepsis. early-onset sepsis [48]. The lack of an . while meningitis surveillance tool in developing countries [44]. Currently. Differentiating true infection from contam- Manose-binding lecitin. natal meningitis is 0. common patholo. cal therapy. of neonatal sepsis are scarce and failed to find an op- tutions [44]. In every symptomatic newborn eval- institutions can be analyzed to identify those with uated for sepsis. neonatal sepsis definitions must be neonates with bacteremia. 43]. we proposed an algorithm adapted fects. found that lumbar puncture was not from Haque’s definitions to be used as a diagnostic associated with increased mortality. Meningitis is more common to the certainty of the diagnosis into culture. These criteria classify episodes according weight newborns [48]. They rise CoNS is the most common cause of late-onset sepsis. Other criteria have also been published. The incidence of neo- [43]. positive CRP are required to diagnose culture- proven sepsis. in these infants a lumbar puncture can be post- ventions. taminant. maternal risk factors. significantly increased it [49]. Stoll et al. Also. Clinical trials evaluating the treatment neonatal sepsis diagnosis varies widely between insti. blood cultures [49. Two positive and proteomics for identification of host response blood cultures or one positive blood culture plus a biomarkers. using clin. limiting their clinical use [5]. 43].44 per 1000 live births and ical and laboratory information. regardless of the time of presentation. especially with gram- consistent and reproducible between institutions. auxiliary tests do not have enough neonatal sepsis is controversial and varies signifi- sensitivity and specificity to be used on their own cantly between centers [47]. diagnose a CoNS infection [46]. the incidence of meningitis is natal sepsis and to evaluate the results of such inter. Despite reported adverse ef- Recently. a lumbar puncture must be greater deficiencies and prioritize resources. evaluating a newborn for sepsis? gies that resemble sepsis and the low positivity rate The use of lumbar puncture for the evaluation of of cultures.6  Challenges in the diagnosis and management of neonatal sepsis blood [42]. performed. The National pathway of the complement. very rapidly after a bacterial infection but normal. Multiple cytokines have been studied How to differentiate CoNS infection for the diagnosis of neonatal sepsis. temic inflammatory response plus an infectious focus. them agree that two positive cultures are necessary to In adults. As a result. If these conditions are not met. negative rods. This definition cannot be applied to newborns Are lumbar punctures necessary when due to nonspecific clinical signs. but the How to interpret the results of multiple tests? patient received more than 5 days of anti-staphylococ- One of the major setbacks for the management. All To achieve this. in infants evaluated for late-onset sepsis than for proven. the episode is considered probable sepsis surveillance and research in neonatal sepsis is the [14]. Long-term data from different regions or poned [51]. sepsis is defined by the presence of a sys. geneous [52]. Specific criteria for neonatal sepsis. most developing The management of neonatal sepsis is highly hetero- countries do not have such definitions.5–14 per 1000 in very-low-birth- [10. important for the lectin ination is very challenging [45]. most of lack of globally accepted case definitions [10. 50]. have been published increases to 6.

Including only culture-proven sepsis would result Neonates with risk factors for early-onset sepsis or in the exclusion of culture-negative sepsis that still compatible clinical condition should receive prompt require antibiotic therapy. is a safe option. grow by 48 h. This regimen during their hospitalization. courses are given empirically before 72 h of life. Also. Continuing sociation between neonatal antibiotics and wheezing antibiotics for more than 7 days vs. coli ac- als. penicillin plus tobramycin for sus. negative blood cultures? comes [57]. Most of the antibiotic tivity against GBS and Listeria monocytogenes [53].157] and death stable [53]. A study of hospital-acquired infections. Poupolo et al. GBS and E. Prolonged antibiotic therapy in. However. and 97% by 72 h. this should be the initial therapy for Almost all neonates in an NICU receive antibiotics suspected early-onset sepsis [16.5) [60. Vancomycin should be reserved for pected early-onset sepsis. Antibiotics can be safely stopped at 48–72 h in neo- sporins is associated with increased risk of candida. neonatal sepsis? als. Finding an adequate end.10) and death (OR Stopping antibiotics after the blood culture is re- 1. sis—central vascular access. some studies found an as. comparing thrombocytopenia. Considering the high resist- What are the consequences of excessive ance to methicillin. de- point also obstructs the implementation and inter. does not increase treatment failure [68].12) [62. has the additional advantage of having synergistic ac- tive blood culture [55]. Since the reported antibiotic management of neonatal sepsis [53]. ported negative at 48 h in clinically stable patients scend the neonatal period. but only 5% have a posi. apy for late-onset sepsis [53]. 17]. and Every neonate with signs of late-onset sepsis 60% of these courses are prolonged for more than should receive empiric antibiotic therapy [53]. ation cephalosporins but only 10% are resistant to aminoglycosides [15. necrotizing enterocolitis (OR: 1. CoNS infec- velopment and spread of resistant pathogens in the tions are rarely fulminant and starting therapy with an NICUs [57]. tobramycin. 65]. found that 35% of lated are resistant to methicillin.45). Most cultures that creases the risk of late-onset sepsis (OR: 2. stopping them during childhood [64]. When to stop antibiotics in newborns with Antibiotics are also associated with adverse out. In de- 48–72 h despite negative blood culture and a stable veloped countries. Around 90% of positive blood cultures (OR: 1. knowledge of the most common pathogens and count for most episodes of early-onset sepsis in de- their antibiotic resistance patterns should guide the veloped countries [16]. some experts recommend using antibiotic use? vancomycin plus an aminoglycoside as empiric ther- Inappropriate antibiotic use is associated to the de. resistance to the combination of ampicillin plus ami- Antibiotics are among the most used medications noglycosides in the past 10 years has remained at in the neonatal intensive care units (NICU) [54]. Newborn with risk factors for candida sep- risk of colonization with resistant pathogens [58]. In the absence of clinical tri. less than 10%. 61]. veloped a risk stratification tool to select neonates pretation of trials [10]. found that newborns who alosporins or carbapenems and extreme prematur- received cefotaxime in the previous 30 days were 33 ity—should receive fungal empiric therapy [66]. one-fourth of neonates receive at least one inappropriate course of gram-negative pathogens are resistant to third-gener- antibiotics during their NICU stay [56]. turn positive after 72 h are contaminants [67]. that need empiric therapy [13]. 63]. endotracheal intubation. Patel et al. exposure to broad-spectrum ceph- cefotaxime vs. times more likely to develop an extended-spectrum beta-lactamase infection [59]. nates with negative blood cultures who are clinically invasive disease [odds ratio (OR): 2. The use of third-generation cephalo. The authors found that confirmed cases of methicillin-resistant pathogens amoxicillin plus cefotaxime increased by 18-fold the [14. One study compared amoxicillin plus anti-staphylococcal penicillin plus an aminoglycoside cefotaxime vs. 17]. after 3 days in extremely-low-birth-weight neonates . almost three-fourths of CoNS iso- clinical condition [55]. empiric antibiotic therapy [53]. Adverse effects of antibiotics tran. Challenges in the diagnosis and management of neonatal sepsis  7 accepted definition of sepsis in neonates is one of What is the best empiric therapy for the main obstacles for the performance of these tri.

14 days) is significantly associated Escherichia coli resistance to gentamicin is 13–48%. Both of these trials had small sample sizes In developing countries. associated with brain abscess (i. micin. aureus infection.8  Challenges in the diagnosis and management of neonatal sepsis (<1000 g) with negative blood cultures increased [53]. lected population [53]. Immature/total neutrophil Citrobacter. current recommendations state that days. central nervous system imaging (ultrasound or risk infants like those with central lines.. Despite these levels sepsis must receive a full antibiotic course for 10–14 of resistance. aureus infection) a hospitalized and treated with ampicillin plus genta- course of 7–10 days might be sufficient [53]. that there was no difference in treatment failure if Considering the lack of high-quality evidence and the neonate was asymptomatic and with normal the poor understanding of the effect of steroids on CRP at the seventh day. 73]. Previous studies have excluded high. Enterobacter). to amikacin is 43% and to pathogen. 77]. Newborns with compli- ratio and procalcitonin have also been tested to cated meningitis required prolonged antibiotic guide therapy with encouraging results. but larger tri. Around uated the choice and duration of antibiotic therapy 30–90% of Klebsiella sp isolates in hospital settings . third-generation cephalosporin must be used [53]. adjunctive dexamethasone is significantly shorter hospitalizations [74]. trial testing 7 vs. Another not recommended in neonatal meningitis [77]. 14 days of therapy found pairment. a newborn with suspicion of sepsis should be >1500 g birth-weight and not S. Single and serial values taken after 24 h of onset of The recommended duration of therapy is 14 days for symptoms have a high negative predictive value gram-positive meningitis. antibiotic resistance of com- and were performed in neonates with a gestational munity-acquired infections has increased significantly age >32 weeks and birth weight >1500 g. 14 days of therapy. als need to be performed before they can be used for A trial testing the adjunctive use of dexametha- this indication [72. 4% are CoNS sepsis [76]. monocitogenes menin- that CRP has a negative predictive value of only 86% gitis [77]. ampicillin plus cefotaxime or ampicillin survival [69]. The management of neonatal meningitis is based on Resistance of hospital-acquired infections is also expert recommendations. a short course of third-generation cephalosporins is 57–66%. found a nonsignificant trend to. in asymptomatic newborns at day 7. However. All neonates with meningitis should have at 48 h [71]. Conversely. The value of CRP to some pathogens have a higher likelihood of being guide antimicrobial therapy might be limited to a se. Newborns with culture-proven resistant to methicillin [20. mechanical computed tomography) to rule out complications.e. 80]. plus an aminoglycoside is recommended [77]. therapy [53. Are there special considerations of neonatal sepsis ward greater treatment failure in the short course treatment in developing countries? arm [75]. resistance to length of optimal duration might also depend on the gentamicin is 60–72%. no clinical trials have eval. In S. Serratia. but this trial has several limitations [79]. Klebsiella sp. vancomycin plus a and reduce the duration of antibiotic therapy [53]. very high in developing countries [18]. to amikacin is 15% and to third-generation cephalo- treatments of only 3 days have been effective in sporins is 19–64%. but the 10-day group had the developing brain. 21 days for gram-negative (98–100%) [70]. with higher treatment failures [75]. antibiotic (7 vs. However. physicians must keep in mind the local resistance patterns when deciding empiric How to treat neonatal meningitis? therapy [80]. aureus. In a neonate with early-onset meningitis the hospitalization length but had no effect on (<72 h). ventilation or birth asphyxia. A more recent trial found that sepsis? dexamethasone decreased mortality and hearing im- One trial comparing 10 vs. In selected cases (>32 weeks gestational age. In the CRP has emerged as a valuable tool to guide case of late-onset meningitis. neurological deficits or hearing impairment at 2 How long to treat a newborn with culture-proven years of age [78]. In the case of S. The in the past 20 years [80]. sone in 52 neonates showed no difference in mortal- ity. a recent study found meningitis and >21 days for L.

a recent trial did not find a reduction Currently. neonatal sepsis. or in developing countries but rises to 56% in South as neonatal skin antisepsis has also reduced Asia [18]. This information will help to ment feasible [81. and decreases rates of infection health-care workers might try to prolong their use by [87. 24]. including antibiotic therapy at home. many families can not afford and preterm infants that improves cognitive and be- the cost of these medications. due primarily to the multiple anti-infective. but one has the additional advantage of being very cheap. Chemoprophylaxis has also been used to prevent age and can easily be administered once a day [83]. procaine penicillin and ceftriaxone offer wide cover. however. the sample size was reduces mortality significantly [23. If they are obtained. fun- zole plus intramuscular gentamicin significantly gal prophylaxis with fluconazole has demonstrated reduced neonatal mortality in rural communities. itions and pathogen variability between different . study estimated that home antibiotics alone reduce Multiple trials are ongoing to test the value of lacto- case fatalities by 35% [82]. to cleanse the umbilical cord stump. leading to con. aureus to methicillin is 38% during labor. Challenges in the diagnosis and management of neonatal sepsis  9 are resistant to commonly used antibiotics against Interventions to increase hand washing rates have gram-negative bacteria. like carbapenems countries [86]. efficacy in reducing invasive Candida infections in However. 91]. The susceptibility of washing and clean practices during delivery and this naı¨ve population. define lactoferrin’s role in clinical settings [89]. Escherichia coli developing areas lack the basic facilities to imple- resistance rates are slightly lower but still very high. 83]. clear protocols for generalized testing and lar procaine penicillin plus intramuscular gentamicin. Also. ongoing trials are testing new simplified in the composite outcome of invasive candidiasis and regimens for home-based treatment. In the nity setting [81]. doses and populations. Oral supplementation with bovine hospitalized? lactoferrin significantly reduced the incidence of Some mothers refuse to hospitalize their children. death. USA. havior skills. have been established for many years-[92]. trial in Turkey [90. cotrimoxazole plus gentamicin seems to extremely-low-birth-weight neonates (<1000 g) be less effective than the other two regimens [84]. the lactoferrin group. Home treatment with intramuscu. ment them. pecially in developing countries. community management of group found a nonsignificant reduction of sepsis in neonatal sepsis. as first-line regimens. and resistance rates are been successful. 88]. What are the most effective strategies to prevent neonatal sepsis? CONCLUSION Multiple preventive interventions have been de. Neonatal sepsis is a major public health problem es- signed to decrease sepsis rates in neonates. In a pilot study in Peru. Intramuscular gentamicin. several hospitals in alarmingly high in Southeast Asia. Breast feeding is another effective strategy in term resource communities. Simplified antibiotic regi. our tries [81]. treatment of GBS colonization in pregnant women intramuscular ceftriaxone alone and oral cotrimoxa. raising questions on the universal use of prophylactic fluconazole [94]. inflammatory and immunoregulatory factors trans- mitted through milk. The protective effects of human milk are using the leftovers on other patients. In these low. ferrin in prevention of neonatal sepsis using different mens are being developed to make home-manage. GBS screening and intrapartum anti- Oral antibiotics like cotrimoxazole. Using chlorhexidine in vaginal washes Overall resistance of S. However. or late-onset sepsis in an Italian trial and in a second hospitals might be unavailable in developing coun. lack of consensus in the defin- afterward reduce neonatal sepsis significantly [85]. and vancomycin. [93]. (Accepted for publication) Bovine lactoferrin management includes several interventions. Hand. anti- tamination and outbreaks of resistant bacteria [18]. however. cefuroxime and biotic prophylaxis have significantly reduced early- amoxicillin are also potential options in the commu. onset neonatal sepsis in developed countries. Community small. Lactoferrin is one of these How to treat infected newborns who cannot be factors [89]. In these cases. High resistance levels force physicians to the incidence of neonatal sepsis in developing use broad-spectrum antibiotics.

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