Pediatr Drugs (2014) 16:67–81 DOI 10.1007/s40272-013-0057-x

REVIEW ARTICLE

Considerations in the Pharmacologic Treatment and Prevention of Neonatal Sepsis Chris Stockmann • Michael G. Spigarelli • Sarah C. Campbell • Jonathan E. Constance • Joshua D. Courter • Emily A. Thorell • Jared Olson • Catherine M. T. Sherwin

Published online: 12 November 2013 Ó Springer International Publishing Switzerland 2013

Abstract The management of neonatal sepsis is challenging owing to complex developmental and environmental factors that contribute to inter-individual variability in the pharmacokinetics and pharmacodynamics of many antimicrobial agents. In this review, we describe (i) the changing epidemiology of early- and late-onset neonatal sepsis; (ii) the pharmacologic considerations that influence the safety and efficacy of antibacterials, antifungals, and immunomodulatory adjuvants; and (iii) the recommended dosing regimens for pharmacologic agents commonly used in the treatment C. Stockmann
S. C. Campbell
J. E. Constance Division of Clinical Pharmacology, Department of Paediatrics, University of Utah School of Medicine, Salt Lake City, USA C. Stockmann
M. G. Spigarelli Department of Pharmacology and Toxicology, University of Utah College of Pharmacy, Salt Lake City, USA M. G. Spigarelli
C. M. T. Sherwin Clinical Trials Office, Department of Paediatrics, University of Utah School of Medicine, Salt Lake City, USA M. G. Spigarelli
C. M. T. Sherwin (&) Division of Clinical Pharmacology and Clinical Trials Office, Department of Paediatrics, University of Utah School of Medicine, Salt Lake City, USA e-mail: [email protected] J. D. Courter Pharmacy, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA E. A. Thorell
J. Olson Division of Paediatric Infectious Diseases, Department of Paediatrics, University of Utah School of Medicine, Salt Lake City, USA J. Olson Pharmacy, Intermountain Primary Children’s Medical Center, Salt Lake City, USA

and prevention of neonatal sepsis. Neonatal sepsis is marked by high morbidity and mortality, such that prompt initiation of antimicrobial therapy is essential following culture collection. Before culture results are available, combination therapy with ampicillin and an aminoglycoside is recommended. When meningitis is suspected, ampicillin and cefotaxime may be considered. Following identification of the causative organism and in vitro susceptibility testing, antimicrobial therapy may be narrowed to provide targeted coverage. Therapeutic drug monitoring should be considered for neonates receiving vancomycin or aminoglycoside therapies. For neonates with invasive fungal infections, the development of new antifungal agents has significantly improved therapeutic outcomes in recent years. Liposomal amphotericin B has been found to be safe and efficacious in patients with renal impairment or toxicity caused by conventional amphotericin B. Antifungal prophylaxis with fluconazole has also been reported to dramatically reduce rates of neonatal invasive fungal infections and to improve long-term neurodevelopmental outcomes among treated children. Additionally, several large multicenter studies are currently investigating the safety and efficacy of oral lactoferrin as an immunoprophylactic agent for the prevention of neonatal sepsis.

1 Neonatal sepsis 1.1 Burden of Neonatal Sepsis Over the last century, neonatal sepsis case-fatality rates decreased from 87 % in 1928 to 3 % in 2003 [1]. However, sepsis remains a leading cause of neonatal morbidity and mortality [2]. In developed countries, advancements in neonatal care continue to improve survival [3]. These achievements have largely occurred as a consequence of

68

C. Stockmann et al.

reducing early-onset neonatal sepsis (defined as a positive blood culture obtained\7 days after birth) [1]. Today, lateonset sepsis (defined as a positive blood culture obtained C7 days after birth) now constitutes the majority of neonatal cases [1]. 1.2 Pathogens The timing of neonatal infection is an important factor that can be used to guide diagnostic testing [4]. The primary pathogens known to cause early- and late-onset neonatal sepsis are featured in Table 1. The most common pathogens associated with early-onset neonatal sepsis are group B streptococci (GBS) and Escherichia coli, which together cause nearly 70 % of infections in this period [5]. Slightly less common causes of early-onset neonatal sepsis include viridans streptococci, Enterococcus species, enteric gramnegative bacilli, and Listeria monocytogenes. Maternal vaginal colonization with Staphylococcus aureus has also been demonstrated to occasionally result in vertical transmission during pregnancy [6]. Neonatal candidemia has also been infrequently reported within the first 7 days of life [7]. The etiological agents of early-onset neonatal sepsis are also capable of causing late-onset disease [8]. GBS and Table 1 Distribution of common early- and late-onset neonatal sepsis pathogens

Etiological agents

E. coli remain common pathogens beyond 7 days of life. Other common causes of late-onset neonatal sepsis include coagulase-negative staphylococci (CoNS), gram-negative enteric bacilli, nosocomially acquired gram-negative pathogens, and Candida albicans and Candida parapsilosis [7]. Streptococcus pneumoniae and Haemophilus influenzae are less frequent causes of late-onset neonatal sepsis [8]. The immaturity of the neonatal immune system, the environment of the neonatal intensive care unit, and care-related factors, including the placement of central venous catheters, arterial lines, mechanical ventilation, and chest tubes make neonates uniquely susceptible to infection. Although the most common etiological agents of neonatal sepsis are described above, a wide range of other infectious organisms are known to less frequently cause neonatal sepsis [9]. Consequently, any bacterial isolate from a sterile site in a clinically ill neonate should be considered to represent a true pathogen, unless sufficient evidence exists to establish it as a contaminant. 1.3 Neonatal Pharmacology The pharmacokinetic processes of absorption, distribution, metabolic biotransformation, and excretion dictate drug activity and are crucial processes to understand in the Early-onset (\7 days of life)

Late-onset (C7 days of life)

Gram-positive bacteria Coagulase-negative staphylococci

-

???

Enterococcus species

?

??

Group B streptococcus

???

?

Listeria monocytogenes

?

?

Staphylococcus aureus

?

???

Streptococcus pneumoniae

?

?

Viridans streptococci Gram-negative bacteria

?

?

Citrobacter species

-

?

Enterobacter species

?

??

Escherichia coli

???

??

Haemophilus influenzae

?

-

Klebsiella species

?

??

Neisseria meningitidis

-

?

Pseudomonas species

-

?

Salmonella species

-

?

Serratia marcescens

-

?

Bacteroides species

?

?

Clostridium species

-

?

? -

? ?

Anaerobic bacteria

Most commonly isolated (???), frequently isolated (??), occasionally isolated (?), rarely isolated (-). Adapted from Edwards et al. [131]

Fungi Candida albicans Candida parapsilosis

Pharmacologic Treatment of Neonatal Sepsis

context of neonatal development [10, 11]. During this period, human growth is non-linear and characterized by profound changes in body composition and organ function [12]. Moreover, prematurity, low birthweight, and critical illness further complicate dosing in this population. During the first few days of life, drug disposition can change rapidly with changes in total body water, which can result in a doubling of total body weight [13]. These developmental and clinical factors are rarely seen in adult medicine and may demand individualized dosing of certain medications [12, 14]. In this review, we systematically examine the selection and dosing of antibacterials, antifungals, and immunomodulatory adjuvants that are commonly used in the treatment of neonatal sepsis. Additionally, we review the pharmacologic consequences of neonatal maturation as it applies to the disposition and action of antimicrobial agents. However, it must also be noted that, pathogen identification and local epidemiology are critical factors that form the foundation for the selection of appropriate antimicrobial agents.

2 Treatment 2.1 Neonatal Antimicrobial Pharmacology The safety and effectiveness of antimicrobial pharmacotherapies depend upon physiological parameters that govern the fundamental pharmacokinetic processes of Fig. 1 Physiological changes that influence the pharmacokinetic characteristics of antimicrobials prescribed for the treatment of neonatal sepsis

69

absorption, distribution, metabolism, and elimination [15]. Growth and development exert a substantial influence upon drug disposition [16, 17]. Among neonates, drug pharmacokinetics can change rapidly with the maturation of hepatic and renal function [12]. Furthermore, pharmacokinetic variability is high in this population, owing to differences in gestational and postnatal age, the presence of hypoxia, cardiovascular and gastrointestinal pathologies, end-organ perfusion, and many other factors [18]. Absorption is the pharmacokinetic process that governs how much of an administered drug enters the body [19]. Intravenous administration is common among neonates to ensure rapid, complete absorption. However, with respect to orally administered agents, two parameters are frequently used to quantify absorption, which include the time-independent factor known as the extent of absorption (bioavailability) and the time-dependent factor known as the absorption rate. Bioavailability is a function of the fraction of the drug that is absorbed and the fraction that undergoes first-pass hepatic inactivation. The absorption rate is a function of the route, formulation, and physicochemical characteristics of the drug as well as physiological processes such as gastric emptying and blood flow. In neonates, developmental differences in the physiological composition and function of the stomach, intestine, and biliary tract can alter drug absorption (Fig. 1) [20]. Throughout infancy, prolonged gastric emptying time may decrease drug entry into the intestine, the principal site of drug absorption [21]. Although few studies have investigated the effects of developmental changes in gastric

70

emptying and intestinal motility on antimicrobial drugs, it is generally appreciated that many drugs are absorbed more slowly among neonates, resulting in a longer period of time before peak blood concentrations are achieved [20]. However, gastric pH is poorly maintained in neonates. At birth, gastric pH has been reported to range from 6–8 due to the presence of alkaline amniotic fluids [22]. Within 24 h, the pH decreases to a range of 1–3. For acid labile drugs, such as the oral penicillins, this translates to an increase in neonatal concentrations when compared with older children or adults [23]. After a drug has been absorbed, it can then be delivered to other sites in the body, including the site of action [19]. This process is known as drug distribution. Clinically, the concentration of drug in the blood is most closely correlated with the concentration of the drug at its site of action after the distribution phase. For drugs with relatively long half-lives (e.g., gentamicin in neonates\1 week post-gestational age), care must be taken to not obtain blood samples too quickly after administering the dose, as this has the potential to reflect the concentration of the drug in the central compartment rather than the concentration of drug at the site of action [24]. The timing of serum concentration monitoring varies widely among neonatal intensive care units. In a study conducted in the UK, 43 neonatal intensive care units were surveyed, and 23 % recommended obtaining blood samples for routine therapeutic drug monitoring before the second dose of gentamicin, 40 % recommended collection before the third dose, 9 % recommended collection before the second or third dose, and 28 % had no written monitoring recommendations [25]. Guidance regarding the timing of vancomycin routine therapeutic drug monitoring was also highly variable [25]. Drug distribution is also related to the volume of distribution, which represents the hypothetical volume required to account for the total amount of drug in the body, assuming that it was equally distributed at the same concentration throughout the blood. In practice, a small volume of distribution indicates that the drug is minimally distributed throughout the body and is primarily retained in the blood. A large volume of distribution indicates that the drug readily distributes into peripheral tissues, organs, or body fluids. The volume of distribution is heavily influenced by total body water, extracellular fluid volume, and the physicochemical properties of the drug. As neonates feature substantially higher total body water and extracellular fluid volumes, they generally have a larger volume of distribution for water-soluble drugs [26]. For agents like gentamicin, which readily distributes into extracellular water, the volume of distribution is higher for neonates than for older children or adults [26]. Clinically, this results in a requirement for larger doses to achieve comparable peak concentrations. Additionally, neonates have lower concentrations of human serum albumin and alpha1-acid glycoprotein and decreased

C. Stockmann et al.

affinity for protein–drug binding [27]. Decreased protein binding can result in an increase in the amount of unbound drug in the blood, which results in an increase in the apparent volume of distribution [28]. An increased volume of distribution may lead to enhanced elimination from the body if elimination occurs from the pool of unbound drug. For clinical decision-making, it is recommended that unbound drug concentrations be evaluated when alterations in protein binding are suspected. Drug metabolism can occur in a variety of tissues; however, the primary sites of metabolism are the liver, kidneys, and biliary tract [19]. Most antimicrobials are relatively lipid soluble and must be converted into more water-soluble compounds to be excreted from the body [29]. The metabolic biotransformation reactions that accomplish this are significantly decreased in neonates [30]. Additionally, the degree of enzyme maturation is not consistent across all drug-metabolizing enzymes [31, 32]. In fact, ‘grey baby syndrome’, which is characterized by shock and rapid cardiovascular collapse, was caused by the accumulation of chloramphenicol in neonates due to the immaturity of their hepatic glucuronide-conjugating enzymes (UDP-glucuronyl transferase) [33]. It is now well established that chloramphenicol may be safely prescribed at lower doses with appropriate drug monitoring [22]. For many drugs, the kidney is the primary organ responsible for the elimination of drugs and their metabolites from the body [19]. Neonatal renal elimination is governed by glomerular filtration, tubular secretion, and tubular reabsorption [19]. The rate at which each of these physiological processes matures varies. Glomerular filtration involves active nephrogenesis, which begins at 9 weeks’ and is finished by approximately 36 weeks’ gestation [34]. Following birth, glomerular filtration increases rapidly during the first 2 weeks of life and then rises steadily to reach adult levels by approximately 1 year of age [35]. Aminoglycoside and glycopeptide antibiotics are primarily eliminated via glomerular filtration and therefore clearance is highly correlated with maturational changes that occur early in life [36]. In contrast, penicillins are primarily eliminated by proximal tubular secretion [37]. Tubular secretory pathways also mature during the first year of life and can exert a profound effect upon renal elimination [38]. Additionally, neonates also feature decreased tubular reabsorption and do not exhibit the typical diurnal variation in urinary pH until 2 years of age [39]. This indicates that the kidney’s capacity for eliminating some drugs is decreased in neonates and may not fully develop until several years after birth. Moreover, renal dysfunction secondary to underlying pathologies may further impair renal elimination and necessitate dosage adjustments for drugs such as vancomycin that are normally eliminated by the kidney [40].

Pharmacologic Treatment of Neonatal Sepsis

71

Table 2 Comparative pharmacokinetics, bioavailability, protein binding, central nervous system penetration, metabolism, and excretion of antibiotics used in the empiric treatment of neonatal sepsis Antibiotic class

Oral bioavailability

Protein binding

CNS penetration

Metabolism

Excretion

t‘

Poorly absorbed

\25 %

Extracellular fluids and vascularized tissues; poor CSF penetration

None

Renal

\1 week PGA: 5–14 h;

10 %

Penetrates most tissues; poor CSF penetration

Hepatic (10 %)

Renal (25–40 %)

2–7 days PNA: 4 h; 8–14 days PNA: 2.8 h; 15–30 days PNA: 1–1.8 h

Not administered orally

30–50 %

Penetrates most tissues; adequate CSF penetration when meninges are inflamed

Hepatic

Renal (60 %)

BW B1.5 kg: 4.6 h

Poorly absorbed

30 %

Penetrates most tissues; erratic CSF penetration

None

Aminoglycosides Gentamicin

C1 week PGA: 3–5 ha

Aminopenicillins Ampicillin

50 %

Cephalosporins Cefotaxime

BW [1.5 kg: 3.4 h

Glycopeptides Vancomycin

Renal; minimal biliary

4–11 h (dependent upon renal maturation)

Comparative pharmacokinetic data are derived from DiCenzo et al., Yoshioka et al., Rodvold et al. [132–134] a

For neonates \1 week PGA, the t‘ of aminoglycoside agents is inversely associated with BW

BW birthweight, CNS central nervous system, CSF cerebrospinal fluid, PGA post-gestational age, PNA postnatal age, t‘ elimination half-life

2.2 Antibacterials Antibiotic therapy should be initiated promptly when the diagnosis of neonatal sepsis is suspected or proven and appropriate cultures have been obtained. It is often prudent to administer empiric parenteral antibiotics; usually as the combination of a penicillin and an aminoglycoside (Table 2) [3]. Ampicillin is favored due to its activity against gram-positive infections, including GBS, L. monocytogenes, and some gram-negative coverage. Gentamicin is often added for its activity against many gram-negative pathogens that are common causes of early-onset neonatal sepsis (e.g., E. coli and other Enterobacteriaceae species). If staphylococcal infection is suspected, the initial treatment should include a penicillinase-resistant penicillin or vancomycin. The macrolide antibiotic erythromycin features activity against most gram-positive bacteria, including strains of penicillin-resistant staphylococci [41]. However, macrolide agents cannot be recommended as first-line therapies for the treatment of neonatal sepsis due to the high rate of resistance detected among many community-associated methicillin-resistant S. aureus (MRSA) strains [42]. The oxazolidinone agent linezolid also features activity against gram-positive bacteria, including MRSA, vancomycin-resistant enterococci, and penicillinase-resistant S. pneumoniae [43]. Although few neonatal studies exist, a single randomized controlled trial

demonstrated that linezolid was equally as efficacious as vancomycin in the treatment of gram-positive infections and was associated with fewer drug-related adverse effects [44]. For the treatment of multidrug-resistant organisms, such as Klebsiella pneumoniae and extended-spectrum blactamase-producing Enterobacteriaceae, the carbapenem agents imipenem and meropenem may be considered [45]. Meropenem is typically preferred for the treatment of resistant bacterial infections in neonates owing to its lower potential for inducing epileptogenic activity and nephrotoxicity when compared with imipenem [46]. In cases of suspected or proven meningitis, cefotaxime may be preferable due to its superior cerebrospinal fluid (CSF) penetration. However, the empiric use of cefotaxime should be limited to cases with neurologic involvement, as it has been reported to increase the risk of death and the development of invasive candidiasis [47, 48]. Additionally, antibiotics that displace bilirubin from albumin-binding sites (e.g., ceftriaxone and sulphonamides) should be avoided during the neonatal period [49]. Local, institutional epidemiology also plays a vital role in determining the selection of appropriate antibiotic agents for empiric use. Blood cultures remain the ‘gold standard’ for the detection of bacteremia [50]. However, blood cultures are not 100 % sensitive, which may be attributed to antenatal antibiotic therapy, the small volume of blood obtained from preterm neonates, and transient or intermittent bacteremia,

72

C. Stockmann et al.

Table 3 Antibiotic dosing and monitoring recommendations for the treatment of neonatal sepsis Antibiotic

Route

Age

Gentamicin

IV, IM

PNA B 7 days PNA [ 7 days

Ampicillina

IV, IM

PNA B 7 days PNA [ 7 days

Cefotaximea

IV, IM

PNA B 7 days PNA [ 7 days

Linezolid

IV

PNA B 7 days PNA [ 7 days

Vancomycin

IV

GA B 28 weeks

GA [ 28 weeks

Dosing recommendations Weight \ 2 kg

5 mg/kg/dose every 48 h

Weight C 2 kg

4 mg/kg/dose every 24 h

Weight \ 2 kg

4–5 mg/kg/dose every 24–48 h

Weight C 2 kg

4 mg/kg/dose every 12–24 h

Weight \ 2 kg

50 mg/kg/dose every 12 h

Weight C 2 kg

50 mg/kg/dose every 8 h

Weight \ 2 kg

50 mg/kg/dose every 8 h

Weight C 2 kg

50 mg/kg/dose every 6 h

Weight \ 2 kg

50 mg/kg/dose every 12 h

Weight C 2 kg

50 mg/kg/dose every 12 h

Weight \ 2 kg Weight C 2 kg

50 mg/kg/dose every 8–12 h 50 mg/kg/dose every 8 h

Weight \ 2 kg

10 mg/kg/dose every 12 h

Weight C 2 kg

10 mg/kg/dose every 8 h

Weight \ 2 kg

10 mg/kg/dose every 8 h

Weight C 2 kg

10 mg/kg/dose every 8 h

SCr \ 0.9 mg/dL

15 mg/kg/dose every 12 h

SCr 0.9–1.1 mg/dL

20 mg/kg/dose every 24 h

SCr 1.2–1.4 mg/dL

15 mg/kg/dose every 24 h

SCr 1.5–1.8 mg/dL

10 mg/kg/dose every 24 h

SCr [ 1.8 mg/dL

15 mg/kg/dose every 48 h

SCr \ 0.7 mg/dL

15 mg/kg/dose every 12 h

SCr 0.7–0.9 mg/dL

20 mg/kg/dose every 24 h

SCr 1.0–1.2 mg/dL

15 mg/kg/dose every 24 h

SCr 1.3–1.6 mg/dL

10 mg/kg/dose every 24 h

SCr [ 1.6 mg/dL

15 mg/kg/dose every 48 h

Dosing recommendations were obtained from the American Academy of Pediatrics’ Red Book [56] GA gestational age, IM intramuscular, IV intravenous, PNA postnatal age, SCr serum creatinine a

Higher dosages are recommended for the treatment of meningitis [56]

among other factors [51–53]. Nevertheless, blood cultures that remain sterile beyond 72 h of incubation reliably indicate that antibiotic therapy may be stopped if a focus of infection has not been delineated and the neonate is clinically stable [54]. Among bacteremic neonates, 96 % of blood cultures become positive within 48 h of incubation [55]. The bacteriologic results of sterile site cultures should be used to guide appropriate antimicrobial therapy, which often involves selecting antibiotics with a narrower spectrum of activity. Recommended antibiotic dosing regimens are featured in Table 3. The suggested duration of antibiotic therapy is 7–10 days for bacteremic neonates with no evidence of a focal infection. For neonates with meningitis due to GBS or gram-negative enteric bacilli, the duration of antibiotic therapy should not be\21 days, or 14 days past a sterile CSF culture [56]. Therapeutic drug monitoring is challenging in the neonatal intensive care unit, largely due to ethical

restrictions concerning the safety and effectiveness of repeatedly obtaining blood samples from preterm neonates with limited total blood volumes [22]. Serial blood sampling has been reported to result in neonatal anemia, which has led many clinical laboratories to pursue testing strategies that can establish drug concentrations from \75 lL of serum [22]. There are relatively few antimicrobial agents for which neonatal therapeutic drug monitoring is recommended. For the aminoglycosides, including gentamicin, individualized dosing regimens may be established using data derived from routine monitoring of drug concentrations [24]. For neonates up to 7 days of life with normal renal function, Touw et al. [24] recommend monitoring gentamicin concentrations immediately following administration of the first dose and 12–18 h post-dose. These recommendations stem from a report by El Desoky et al. [57], which showed a strong correlation between the number of gentamicin concentrations measured and decreased neonatal mortality due to sepsis.

Pharmacologic Treatment of Neonatal Sepsis

73

Table 4 Comparative pharmacokinetics, bioavailability, protein binding, central nervous system penetration, metabolism, and excretion of antifungals used in the treatment of neonatal sepsis Antifungal class

Oral bioavailability

Protein binding

CNS penetration

Metabolism

Excretion

t‘

Amphotericin B

Poorly absorbeda

90 %a

Poor CSF penetration (\5 % of plasma concentration)a

Minimal hepatica

Renala

50 h

Liposomal amphotericin B

Poorly absorbeda

Unknown

Poor CSF penetration (\1 % of plasma concentration)a

Unknown

Unknown

100–153 ha

80 %a

3–4 %a

Good CSF penetration (74 % of plasma concentration)a

Minimal hepatica

Renal (90 %); feces (10 %)

3–6 h

[90 %a

11–12 %a

Good CSF penetration (75 % of plasma concentration)a

Minimala

Renala

Pre-term: 74 h; 1 week PNA: 53 h; 2 weeks PNA: 47 h

Caspofungin

Poorly absorbed

97 %a

Poor CSF penetration (0 % of plasma concentration)a

Hepatica

Renal (42 %); feces (35 %)

40 h

Micafungin

Poorly absorbed

[99 %

Poor CSF penetration (0 % of plasma concentration)a

Hepatic

Feces (71 %)

7h

Polyenes

Cytosine analogs 5-Fluorocytosine

Azoles Fluconazole

Echinocandins

Comparative pharmacokinetic data are derived from Baley et al., Walsh et al., Smith et al., Wurthwein et al., Piper et al., Wade et al., and Doby et al. [69, 72, 74, 135–138] CNS central nervous system, CSF cerebrospinal fluid, PNA postnatal age, t‘ elimination half-life a

Data obtained from adults (applicability to neonates is unclear)

Multiple gentamicin serum concentration measurements were also associated with a decrease in the number of subtherapeutic peak concentrations and toxic trough concentrations [57]. Although neonatal data are sparse, many neonatal intensive care units have also adopted routine therapeutic drug monitoring for the glycopeptide antibiotic vancomycin [58]. In a consensus guideline published by the Infectious Diseases Society of America, the American Association of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists, Rybak et al. [59] recommend that adults have a vancomycin trough concentration measured before administering the fourth dose. It is unclear whether this is the optimal timing of sample collection for neonates. In 2011, Kadambari et al. [25] surveyed 43 neonatal intensive care units throughout the UK and reported that 72 % of them routinely measured vancomycin trough concentrations and that 62 % obtained their samples before the third dose. In light of this variation in clinical practice, further study is needed to establish an optimal sampling time for neonatal vancomycin dosing.

2.3 Antifungals C. albicans and C. parapsilosis are the most commonly identified fungal pathogens in the neonatal intensive care unit [60]. Candidiasis is rare among infants born at full term, although the cumulative incidence of candidemia is 7 % in pre-term neonates with a birthweight\1,000 g [61]. A definitive diagnosis of fungemia requires isolation of the organism from blood or another normally sterile site. However, Aspergillus and Zygomycetes are notable exceptions as they are rarely isolated from blood, but are known to cause life-threatening disseminated multi-organ infections [62, 63]. When weighing the decision to initiate empiric therapy for Candida, several risk factors should be considered, including prematurity and low birthweight, thrombocytopenia, and recent exposure to broad-spectrum antibiotics [64, 65]. The empiric use of amphotericin B has been retrospectively studied among a cohort of septic neonates with a birthweight \1,500 g and one or more risk factors for candidemia [66]. The authors

74

C. Stockmann et al.

Table 5 Antifungal dosing and monitoring recommendations for the treatment of neonatal sepsis Antifungal

Route

Age

Dosing recommendations

Amphotericin B

IV

–

–

0.5 mg/kg/dose every 24 h

Liposomal amphotericin B

IV

–

–

3–5 mg/kg/dose every 24 h

5-Fluorocytosine

PO

PNA B 7 days

Weight B 2 kg

75 mg/kg/day every 8 h

Weight [ 2 kg

75 mg/kg/day every 6 h

PNA [ 7 days

Weight B 2 kg

75 mg/kg/day every 6 h

Weight [ 2 kg

75 mg/kg/day every 6 h

Fluconazole

IV, PO

–

Loading dose

25 mg/kg

–

Maintenance dose

12 mg/kg/dose every 24 h

Caspofungin

IV

–

–

25 mg/m2/dose every 24 h

Micafungin

IV

–

–

2 mg/kg/dose every 24 ha

Weight \ 1 kg Weight C 1 kg

10 mg/kg/dose every 24 hb 7–10 mg/kg/dose every 24 hb

Dosing recommendations were obtained from the American Academy of Pediatrics’ Red Book [56] IV intravenous, PNA postnatal age, PO oral a

Dosing recommendations for the treatment of candidemia and invasive candidiasis

b

Dosing recommendations for the treatment of disseminated candidiasis

found no evidence of Candida-related mortality among six subjects who received empiric amphotericin B, whereas 11 (61 %) of 18 historical controls died of Candida infection [66]. However, prospective studies are needed to evaluate the safety and efficacy of empiric antifungal use. Antifungal therapy is often initiated in neonates when fungal elements are observed on gram stain or when yeasts are isolated from body fluids [67]. To our knowledge, no antifungal agents have been approved for use among neonates by the US Food and Drug Administration (FDA). Moreover, pharmacokinetic data are limited for many antifungal agents in this population (Table 4). To attain the maximum effect from these antifungal agents, further studies are needed to define their pharmacokinetic and pharmacodynamic properties, which are unique for each class and can vary even among members of the same class. Amphotericin B deoxycholate is the most widely studied antifungal agent and has been reported to feature similar kinetics among neonates and adults [67]. Several case reports have suggested that liposomal amphotericin B may be safely used for the treatment of invasive fungal infections in neonates; however, pharmacokinetic data are scarce [68]. Clearance of 5-fluorocytosine (flucytosine) is proportional to the glomerular filtration rate, which has the potential to increase blood concentrations among preterm neonates with immature renal function [69]. The half-life of fluconazole among neonates has been reported to range from 47 to 74 h, which is more than twice as long as the half-life reported among adult patients (30 h) [70]. Yet, despite this prolonged half-life, once-daily dosing of fluconazole has been safely used for the

treatment of disseminated neonatal candidiasis [71]. More recently, a limited number of studies have evaluated the safety, effectiveness, and pharmacokinetics of caspofungin and micafungin for the treatment of invasive fungal infections in children and adolescents [72–75]. The cumulative evidence from these studies suggests that caspofungin and micafungin are safe and efficacious in older children; however, their appropriateness for neonates is unknown. Recommendations for the dosing of antifungal agents are featured in Table 5. The optimal duration of therapy for the treatment of invasive fungal infections in neonates is unknown; however, guidelines for the treatment of neonatal candidiasis suggest treating for 14–21 days after the resolution of signs and symptoms and negative repeat blood cultures [76].

2.4 Immunomodulatory Adjuvants Many organs and tissues in the body are still maturing at the time of delivery [12], including the immune system [77]. Serum immunoglobulin concentrations vary with gestational age, placental transfer of maternal immunoglobulin, postnatal age, and the ability of the neonate to produce functional immunoglobulin [78]. Pre-term neonates are at increased risk of developing infectious diseases as a consequence of their immature immune system [79]. These deficiencies have been the subject of extensive study, which has demonstrated that neonates have decreased antibody concentrations; complement activity; polymorphonuclear leukocyte production, mobilization,

Pharmacologic Treatment of Neonatal Sepsis

and function; T-lymphocyte cytokine production; and plasma and cell surface fibronectin [80]. The combination of these factors has spurred efforts to develop therapeutic interventions targeted at each of these components of the immature immune system. Pre-term infants have low serum concentrations of polyvalent immunoglobulin G (IgG), which has the potential to help prevent or treat infections [81, 82]. Several immunomodulatory mechanisms have been attributed to IgG, including an increase in opsonic activity, activation of the complement system, antibody-dependent cytotoxicity, and decreased production of pro-inflammatory cytokines [83–85]. A meta-analysis of seven trials involving 338 neonates with proven or suspected neonatal sepsis found no evidence for improved survival among those infants who received intravenous IgG [86]. More recently, a large prospective trial was conducted in which 3,493 infants were recruited and randomized to receive 48 h of intravenous IgG or placebo [87]. The authors reported no difference in mortality or major disability at 2 years of age. In 28 additional pre-planned subgroup analyses, there was no evidence of benefit or harm. In aggregate, these findings suggest that intravenous IgG does not result in improved outcomes when used as an adjunctive therapy for neonates with proven or presumed sepsis. Neonatal neutrophils are functionally immature and rarely present in sufficient quantities to effectively prevent the development of invasive bacterial and fungal infections [88]. In animal models of sepsis, neonatal animals inoculated with a lethal dose of bacteria frequently develop a rapid neutropenia that occurs before death, which is characterized by the exhaustion of bone marrow neutrophil reserves and the absence of an increase in neutrophil production [88]. Clinical studies have shown that among neonates with proven or presumed sepsis, neutropenic neonates have higher mortality than non-neutropenic neonates [89]. Neonatal neutrophils also exhibit functional impairment, perhaps as a consequence of their low cell mass and reduced reproductive capacity. Additionally, it has been suggested that neonatal neutrophils feature signal transduction defects, cell surface receptor dysregulation, impaired mobility, compromised cytoskeletal integrity, and altered metabolic pathways [90]. Technological advances in recent years have renewed interest in evaluating the use of granulocyte transfusions in the treatment of neutropenic neonates [91]. Pammi and Brocklehurst [92] conducted a meta-analysis to evaluate the evidence for improved clinical outcomes among neutropenic neonates who were randomized to receive granulocyte transfusions or placebo. There was no difference in all-cause mortality among neutropenic neonates who did and did not receive granulocyte transfusions. However, the authors caution that only four trials met their inclusion criteria (n = 79 infants), limiting their ability to draw any firm

75

conclusions. Further research is warranted to conduct adequately powered trials to determine whether granulocyte transfusions or other pharmacologic interventions intended to enhance the function of the immune system are safe and effective in treating neonatal sepsis. 2.5 Considerations in the Treatment of Neonatal Meningitis Neonatal meningitis typically arises from invasion of the bloodstream by organisms that have colonized mucosal surfaces [93]. Pathogens are often introduced to neonatal mucosal surfaces as a consequence of contact and aspiration of intestinal and genital tract secretions during birth [93]. Additionally, neonates with long stays in the intensive care unit and/or neonatal nursery may also acquire multiple forms of nosocomial pathogens [94]. Following seeding of the organism from the bloodstream into the CSF, the inflammatory response of the host is activated, which results in cerebral vasculitis, interstitial edema, increased permeability of the blood–brain barrier, and increased intracranial pressure [95]. The combination of these factors ultimately leads to neuronal injury and apoptosis, which may be associated with diffuse or focal brain damage [96]. Antimicrobial therapy for the treatment of neonatal meningitis is indicated if the results of the CSF evaluation are suggestive of an on-going infection. The initial empirical selection of antimicrobials for bacterial meningitis should be based on the neonate’s age, distribution of likely pathogens, and the susceptibility patterns of gram-negative organisms. Once the causative pathogen has been identified and its in vitro susceptibility pattern has been established, therapy should be narrowed appropriately [97]. The recommended duration of antimicrobial therapy depends upon the organism identified and the clinical course of the neonate. For patients with uncomplicated GBS meningitis and for meningitis caused by other gram-negative organisms such as L. monocytogenes or Enterococcus a 14-day course is recommended [98]. Neonates with complicated GBS meningitis require a longer course of therapy [99]. For neonates with meningitis caused by E. coli or other gram-negative pathogens, a 21-day course of therapy is the minimum recommended duration [56]. Neonates with ventriculitis, abscesses, or multiple infarcted areas may require prolonged treatment (up to 8 weeks of therapy) [100, 101].

3 Prevention 3.1 Intrapartum Chemoprophylaxis The incidence of early-onset neonatal sepsis has declined dramatically in recent decades due to prevention strategies

76

aimed at reducing vertical transmission of GBS [102]. As of 2002, the US Centers for Disease Control and Prevention (CDC) has recommended universal antenatal screening for women at 35–37 weeks of gestation and intrapartum chemoprophylaxis for women who are colonized with GBS [103]. Following the publication of these guidelines, further decreases in the incidence of invasive GBS disease have been reported [104, 105]. Despite the successful reduction in invasive GBS disease achieved through intrapartum chemoprophylaxis, GBS remains the most common cause of early-onset neonatal sepsis [5]. Additionally, intrapartum chemoprophylaxis has proven to be ineffective in preventing late-onset GBS disease [106]. The most promising strategy for preventing late-onset GBS disease is now thought to be the development of serotype-specific capsular polysaccharideconjugate vaccines [107]. A trivalent conjugate GBS vaccine is currently the subject of several phase II clinical trials in pregnant women (ClinicalTrials.gov identifiers: NCT01446289, NCT01412801, and NCT01193920). If future trials demonstrate the safety and effectiveness of conjugate GBS vaccines, maternal immunization may complement universal screening for GBS carriage and has the potential to further reduce the incidence of neonatal sepsis.

3.2 Antifungal Prophylaxis Systemic neonatal fungal infections are associated with substantial morbidity, mortality, and high rates of neurodevelopmental impairment [108]. Preterm neonates, particularly those with a birthweight\1,500 g, are at high risk for developing a systemic fungal infection [109]. For this high-risk population, antifungal prophylaxis has been proposed in an effort to reduce the incidence of neurodevelopmental sequelae and death due to fungal sepsis [7]. Nystatin and fluconazole are widely used in the prophylaxis of neonates in many nurseries and intensive care units [110]. The most recent meta-analysis evaluated more than 1,000 neonates weighing \1,500 g and found that fluconazole prophylaxis was associated with an 85 % reduction in the rate of systemic fungal disease and a 24 % reduction in all-cause mortality [109]. Moreover, the authors reported no adverse effects or signs of adaptive fungal resistance after an 8-year follow-up period in several neonatal intensive care units that engaged in routine fluconazole prophylaxis [109]. However, additional long-term studies are needed to establish the optimal duration of antifungal prophylaxis and to evaluate whether combination prophylactic regimens (e.g., fluconazole and nystatin) improve neonatal outcomes.

C. Stockmann et al.

3.3 Immunoprophylaxis Prophylaxis with immune-modulating agents has been proposed as an adjunctive method to prevent neonatal sepsis [111]. The most studied example has involved enteral lactoferrin immunoprophylaxis [112]. Lactoferrin is a member of the transferrin family of iron-binding glycoproteins, which form a critical component of the innate immune response [113]. Broad-spectrum antimicrobial activity has been attributed to lactoferrin, such that development of resistance has been shown to require multiple simultaneous mutations [114, 115]. Due to the delay in initiating enteral feeding, pre-term infants often have low lactoferrin concentrations in the blood [116]. Enteral lactoferrin supplementation has been suggested as a means of compensating for innate and adaptive immunodeficiencies during the neonatal period [112]. Manzoni et al. [117] reported the results of a multicenter randomized controlled trial in which prophylactic lactoferrin, alone or in combination with the probiotic Lactobacillus rhamnosus GG, decreased the incidence of late-onset sepsis by 69 % among a cohort of 472 neonates. This protective effect was strongest for extremely low birthweight neonates (\1,000 g) and was not significant for neonates 1,000–1,500 g. However, the authors used a fixed dose of 100 mg/day, which may not have been adequate for larger infants. As a consequence of this finding and the decreased incidence of neonatal sepsis among larger infants, a recent Cochrane review concluded that there is insufficient evidence to support the routine use of lactoferrin supplementation to prevent neonatal sepsis [118]. To meet this need, several international trials are currently being conducted or are in active planning stages. In the UK, the ELFIN (Enteral LactoFerrin In Neonates) trial group is conducting a pragmatic randomized controlled trial that aims to recruit 2,200 pre-term infants and evaluate the incidence of late-onset neonatal sepsis [119]. These data will be evaluated in a planned meta-analysis that will incorporate results from similar trials being planned in Australia and the USA [112]. 3.4 Breastfeeding Human breast milk features potent antibacterial and antiviral activity [120]. Neonates who are breast fed have been reported to have a lower incidence of respiratory illness, gastroenteritis, and otitis media than neonates who were exclusively fed formula [120–122]. Studies since the 1970s have reported that breastfeeding decreases the risk of neonatal sepsis and gram-negative meningitis [121]. Even partial breastfeeding appears to have a significant effect in reducing the incidence of neonatal sepsis [122]. It has been

Pharmacologic Treatment of Neonatal Sepsis

suggested that breast milk provides direct protection against pathogens by arresting infectious agents at the mucosal membranes, preventing their entrance into tissues [123]. Human milk also contains billions of granulocytes, macrophages, lymphocytes, and epithelial cells during early lactation [123]. The primary antibodies featured in breast milk are secretory IgA, which are found in high concentrations in the intestinal mucosa [124]. Neonates are particularly susceptible to infections caused by microbes that colonize the gut after birth and then translocate through the intestinal mucosa to the Peyer’s patches and lymph glands [125]. Immune responses, particularly those accompanied by large quantities of secretory IgA have been hypothesized to effectively constrain bacterial translocation, thereby limiting the bacteria to the intestinal lumen [126]. Additionally, Hasselbalch et al. [127] found that the thymus of exclusively breast-fed children is double the size of the thymus of non-breastfed children and speculated that this may reflect the action of breast milk in actively stimulating the immune system. Cumulatively, there is substantial evidence supporting the role of breast milk in reducing the risk of neonatal sepsis; however, the mechanisms underlying this protective effect are incompletely understood and are likely to be multifactorial. 3.5 Epidemiologic Surveillance and Decontamination Measures Infection prevention measures, including the decontamination of fomites, are vital components of neonatal care [128]. Equipment that is not disposable must be cleaned regularly, as these have been implicated in many neonatal intensive care unit epidemics [129]. Prevention of epidemic outbreaks requires a team effort, including clinicians, nursing staff, infection preventionists, and environmental services. Infections in previously healthy neonates in the absence of predisposing risk factors should be viewed with suspicion. Additionally, temporal or geographic clusters of cases with a common etiological agent should also spark concern. Detailed methods for managing infectious disease outbreaks in neonatal intensive care units have been described elsewhere [130].

4 Conclusions The treatment of neonatal sepsis is challenging owing to complex developmental and environmental factors that contribute to inter-individual variability in the pharmacokinetics of many antimicrobial agents. Clinicians caring for septic neonates should consider the influence of growth and development upon the safety and efficacy of antibiotic, antifungal, and immunomodulatory adjuvant therapies.

77

Additionally, underlying pathologies have the potential to alter drug absorption, distribution, metabolism, and elimination. We have taken the opportunity to highlight recommended antimicrobial regimens for the empiric and definitive management of neonatal sepsis. As our knowledge of antimicrobial pharmacokinetics and pharmacodynamics expands, in the short-term, further research will be needed to characterize clinically relevant and age-appropriate biomarkers and endpoints for the treatment of neonatal sepsis. Active prevention efforts, including universal screening and intrapartum chemoprophylaxis, have led to a dramatic decrease in the incidence of early-onset sepsis attributable to group B streptococcus. In the long-term, further work is needed to develop safe and effective pharmacologic therapies and immunoprophylactic agents, which hold the promise of treating and preventing lifethreatening neonatal infections. Conflict of interest None. No sources of funding were used to support the writing of this manuscript.

References 1. Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG. Seventyfive years of neonatal sepsis at Yale: 1928–2003. Pediatrics. 2005;116(3):595–602. 2. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292(19):2357–65. 3. Klein J. Bacterial sepsis and meningitis. Philadelphia: WB Saunders; 2001. 4. Cohen-Wolkowiez M, Moran C, Benjamin DK, Cotten CM, Clark RH, Benjamin DK Jr, et al. Early and late onset sepsis in late preterm infants. Pediatr Infect Dis J. 2009;28(12): 1052–6. 5. Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP, et al. Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817–26. 6. Andrews WW, Schelonka R, Waites K, Stamm A, Cliver SP, Moser S. Genital tract methicillin-resistant Staphylococcus aureus: risk of vertical transmission in pregnant women. Obstet Gynecol. 2008;111(1):113–8. 7. Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev. 2004;17(3):638–80. 8. Vergnano S, Menson E, Kennea N, Embleton N, Russell AB, Watts T, et al. Neonatal infections in England: the NeonIN surveillance network. Arch Dis Child Fetal Neonatal Ed. 2011;96(1):F9–14. 9. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Remington JS, Klein JO, Wilson CB, et al., editors. Infectious diseases of the fetus and newborn infant. 7th ed. Philadelphia: Elsevier Saunders; 2011. p. 222–75. 10. Johnson PJ. Neonatal pharmacology–pharmacokinetics. Neonatal Netw. 2011;30(1):54–61. 11. Yaffe S, Aranda JV. Neonatal and pediatric pharmacology: therapeutic principles in practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2010.

78 12. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67. 13. Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics. 1961;28:169–81. 14. Anderson GD, Lynn AM. Optimizing pediatric dosing: a developmental pharmacologic approach. Pharmacotherapy. 2009;29(6):680–90. 15. Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, et al. Pharmacokinetics–pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis. 2007;44(1):79–86. 16. Paap CM, Nahata MC. Clinical pharmacokinetics of antibacterial drugs in neonates. Clin Pharmacokinet. 1990;19(4): 280–318. 17. Ljungberg B, Nilsson-Ehle I. Pharmacokinetics of antimicrobial agents in the elderly. Rev Infect Dis. 1987;9(2):250–64. 18. Neely MN, Reed MD. The pharmacokinetic–pharmacodynamic basis of optimal antibiotic dosing. In: Long S, Pickering L, Prober C, editors. Principles and practices of pediatric infectious diseases. 4th ed. Philadelphia: Elsevier Saunders; 2011. 19. Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Brunton L, Chabner B, Knollman B, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGrawHill; 2011. p. 17–39. 20. van den Anker JN. Developmental pharmacology. Dev Disabil Res Rev. 2010;16(3):233–8. 21. Gupta M, Brans YW. Gastric retention in neonates. Pediatrics. 1978;62(1):26–9. 22. Koren G. Therapeutic drug monitoring principles in the neonate. National Academy of Clinical Biochemistry. Clin Chem. 1997;43(1):222–7. 23. Huang NN, High RH. Comparison of serum levels following the administration of oral and parenteral preparations of penicillin to infants and children of various age groups. J Pediatr. 1953;42(6):657–8. 24. Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet. 2009;48(2):71–88. 25. Kadambari S, Heath PT, Sharland M, Lewis S, Nichols A, Turner MA. Variation in gentamicin and vancomycin dosage and monitoring in UK neonatal units. J Antimicrob Chemother. 2011;66(11):2647–50. 26. Siber GR, Echeverria P, Smith AL, Paisley JW, Smith DH. Pharmacokinetics of gentamicin in children and adults. J Infect Dis. 1975;132(6):637–51. 27. Windorfer A, Kuenzer W, Urbanek R. The influence of age on the activity of acetylsalicylic acid-esterase and protein-salicylate binding. Eur J Clin Pharmacol. 1974;7(3):227–31. 28. Ehrnebo M, Agurell S, Jalling B, Boreus LO. Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults. Eur J Clin Pharmacol. 1971;3(4):189–93. 29. Lees P, Shojaee Aliabadi F. Rational dosing of antimicrobial drugs: animals versus humans. Int J Antimicrob Agents. 2002;19(4):269–84. 30. Cuzzolin L. Drug metabolizing enzymes in the perinatal and neonatal period: differences in the expression and activity. Curr Drug Metab. 2013;14(2):167–73. 31. Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver—evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997;247(2):625–34.

C. Stockmann et al. 32. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37(6):485–505. 33. Rakhmanina NY, van den Anker JN. Pharmacological research in pediatrics: from neonates to adolescents. Adv Drug Deliv Rev. 2006;58(1):4–14. 34. Sonntag J, Prankel B, Waltz S. Serum creatinine concentration, urinary creatinine excretion and creatinine clearance during the first 9 weeks in preterm infants with a birth weight below 1500 g. Eur J Pediatr. 1996;155(9):815–9. 35. Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24(1):67–76. 36. Allegaert K, Anderson BJ, van den Anker JN, Vanhaesebrouck S, de Zegher F. Renal drug clearance in preterm neonates: relation to prenatal growth. Ther Drug Monitor. 2007;29(3):284–91. 37. Nierenberg DW. Drug inhibition of penicillin tubular secretion: concordance between in vitro and clinical findings. J Pharmacol Exp Ther. 1987;240(3):712–6. 38. Hayton WL. Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS PharmSci. 2000;2(1):E3. 39. Gilman JT. Therapeutic drug monitoring in the neonate and paediatric age group. Problems and clinical pharmacokinetic implications. Clin Pharmacokinet. 1990;19(1):1–10. 40. de Hoog M, Mouton JW, van den Anker JN. New dosing strategies for antibacterial agents in the neonate. Semin Fetal Neonatal Med. 2005;10(2):185–94. 41. Waites KB, Sims PJ, Crouse DT, Geerts MH, Shoup RE, Hamrick WB, et al. Serum concentrations of erythromycin after intravenous infusion in preterm neonates treated for Ureaplasma urealyticum infection. Pediatr Infect Dis J. 1994;13(4):287–93. 42. Healy CM, Hulten KG, Palazzi DL, Campbell JR, Baker CJ. Emergence of new strains of methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit. Clin Infect Dis. 2004;39(10):1460–6. 43. Dotis J, Iosifidis E, Ioannidou M, Roilides E. Use of linezolid in pediatrics: a critical review. Int J Infect Dis. 2010;14(8): e638–48. 44. Deville JG, Adler S, Azimi PH, Jantausch BA, Morfin MR, Beltran S, et al. Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates. Pediatr Infect Dis J. 2003;22(9 Suppl):S158–63. 45. Clissold SP, Todd PA, Campoli-Richards DM. Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1987;33(3):183–241. 46. Blumer JL, Reed MD, Kearns GL, Jacobs RF, Gooch WM 3rd, Yogev R, et al. Sequential, single-dose pharmacokinetic evaluation of meropenem in hospitalized infants and children. Antimicrob Agents Chemother. 1995;39(8):1721–5. 47. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death. Pediatrics. 2006;117(1):67–74. 48. Cotten CM, McDonald S, Stoll B, Goldberg RN, Poole K, Benjamin DK Jr. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birthweight infants. Pediatrics. 2006;118(2):717–22. 49. Mustafa MM, McCracken GH Jr. Antimicrobial agents in pediatrics. Infect Dis Clin N Am. 1989;3(3):491–506. 50. National Institute of Health and Clinical Excellence (NICE) Clinical Guideline. Antibiotics for early-onset neonatal infection: antibiotics for the prevention and treatment of early-onset

Pharmacologic Treatment of Neonatal Sepsis

51.

52.

53. 54.

55. 56. 57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

neonatal infection. 2012. http://www.ncbi.nlm.nih.gov/ pubmedhealth/PMH0051825/. Accessed 1 Sept 2013 Schelonka RL, Chai MK, Yoder BA, Hensley D, Brockett RM, Ascher DP. Volume of blood required to detect common neonatal pathogens. J Pediatr. 1996;129(2):275–8. Kellogg JA, Ferrentino FL, Goodstein MH, Liss J, Shapiro SL, Bankert DA. Frequency of low level bacteremia in infants from birth to two months of age. Pediatr Infect Dis J. 1997;16(4):381–5. Polin RA. The ‘‘ins and outs’’ of neonatal sepsis. J Pediatr. 2003;143(1):3–4. Kumar Y, Qunibi M, Neal TJ, Yoxall CW. Time to positivity of neonatal blood cultures. Arch Dis Child Fetal Neonatal Ed. 2001;85(3):F182–6. Pichichero ME, Todd JK. Detection of neonatal bacteremia. J Pediatr. 1979;94(6):958–60. Red Book. 2012 Report of the committee on infectious diseases. Elk Grove: American Academy of Pediatrics; 2012. El Desoky ES, Sheikh AA, Al Hammadi AY. Aminoglycoside and vancomycin serum concentration monitoring and mortality due to neonatal sepsis in Saudi Arabia. J Clin Pharm Ther. 2003;28(6):479–83. de Hoog M, Schoemaker RC, Mouton JW, van den Anker JN. Vancomycin population pharmacokinetics in neonates. Clin Pharm Ther. 2000;67(4):360–7. Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82–98. Richardson MD. Changing patterns and trends in systemic fungal infections. J Antimicrob Chemother. 2005;56(Suppl 1):i5–11. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110(2 Pt 1):285–91. Langan EA, Agarwal RP, Subudhi CP, Judge MR. Aspergillus fumigatus: a potentially lethal ubiquitous fungus in extremely low birthweight neonates. Pediatr Dermatol. 2010;27(4):403–4. Roilides E, Zaoutis TE, Walsh TJ. Invasive zygomycosis in neonates and children. Clin Microbiol Infect. 2009;15(Suppl 5):50–4. Benjamin DK Jr, DeLong ER, Steinbach WJ, Cotton CM, Walsh TJ, Clark RH. Empirical therapy for neonatal candidemia in very low birth weight infants. Pediatrics. 2003;112(3 Pt 1):543–7. Benjamin DK Jr, Stoll BJ, Gantz MG, Walsh MC, Sanchez PJ, Das A, et al. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics. 2010;126(4):e865–73. Procianoy RS, Eneas MV, Silveira RC. Empiric guidelines for treatment of Candida infection in high-risk neonates. Eur J Pediatr. 2006;165(6):422–3. van den Anker JN, van Popele NM, Sauer PJ. Antifungal agents in neonatal systemic candidiasis. Antimicrob Agents Chemother. 1995;39(7):1391–7. Juster-Reicher A, Leibovitz E, Linder N, Amitay M, FlidelRimon O, Even-Tov S, et al. Liposomal amphotericin B (AmBisome) in the treatment of neonatal candidiasis in very low birth weight infants. Infection. 2000;28(4):223–6. Baley JE, Meyers C, Kliegman RM, Jacobs MR, Blumer JL. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr. 1990;116(5):791–7.

79 70. Grant SM, Clissold SP. Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs. 1990;39(6):877–916. 71. Fasano C, O’Keeffe J, Gibbs D. Fluconazole treatment of neonates and infants with severe fungal infections not treatable with conventional agents. Eur J Clin Microbiol Infect Dis. 1994;13(4):351–4. 72. Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49(11):4536–45. 73. Hope WW, Seibel NL, Schwartz CL, Arrieta A, Flynn P, Shad A, et al. Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother. 2007;51(10):3714–9. 74. Smith PB, Walsh TJ, Hope W, Arrieta A, Takada A, Kovanda LL, et al. Pharmacokinetics of an elevated dosage of micafungin in premature neonates. Pediatr Infect Dis J. 2009;28(5): 412–5. 75. Hope WW, Smith PB, Arrieta A, Buell DN, Roy M, Kaibara A, et al. Population pharmacokinetics of micafungin in neonates and young infants. Antimicrob Agents Chemother. 2010;54(6): 2633–7. 76. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, et al. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38(2):161–89. 77. Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Immune status in very preterm neonates. Pediatrics. 2012;129(4):e967–74. 78. Ballow M, Cates KL, Rowe JC, Goetz C, Desbonnet C. Development of the immune system in very low birth weight (less than 1500 g) premature infants: concentrations of plasma immunoglobulins and patterns of infections. Pediatr Res. 1986;20(9):899–904. 79. Locksmith G, Duff P. Infection, antibiotics, and preterm delivery. Semin Perinatol. 2001;25(5):295–309. 80. Hill HR. Intravenous immunoglobulin use in the neonate: role in prophylaxis and therapy of infection. Pediatr Infect Dis J. 1993;12(7):549–58 (quiz 59). 81. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev. 2004;(1):CD001239. 82. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev. 2004;(1):CD000361. 83. Baley JE. Neonatal sepsis: the potential for immunotherapy. Clin Perinatol. 1988;15(4):755–71. 84. Christensen RD, Brown MS, Hall DC, Lassiter HA, Hill HR. Effect on neutrophil kinetics and serum opsonic capacity of intravenous administration of immune globulin to neonates with clinical signs of early-onset sepsis. J Pediatr. 1991;118(4 Pt 1):606–14. 85. Mohan PV, Tarnow-Mordi W, Stenson B, Brocklehurst P, Haque K, Cavendish V, et al. Can polyclonal intravenous immunoglobulin limit cytokine mediated cerebral damage and chronic lung disease in preterm infants? Arch Dis Child Fetal Neonatal Ed. 2004;89(1):F5–8. 86. Alejandria MM, Lansang MA, Dans LF, Mantaring JB. Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database Syst Rev. 2002;(1):CD001090. 87. Brocklehurst P, Farrell B, King A, Juszczak E, Darlow B, Haque K, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med. 2011;365(13):1201–11. 88. al-Mulla ZS, Christensen RD. Neutropenia in the neonate. Clin Perinatol. 1995;22(3):711–39.

80 89. Rodwell RL, Taylor KM, Tudehope DI, Gray PH. Hematologic scoring system in early diagnosis of sepsis in neutropenic newborns. Pediatr Infect Dis J. 1993;12(5):372–6. 90. Davies EG. The immunology of neonates and children and its relation to susceptibility to infection. London: Springer; 2008. 91. Sachs UJ, Reiter A, Walter T, Bein G, Woessmann W. Safety and efficacy of therapeutic early onset granulocyte transfusions in pediatric patients with neutropenia and severe infections. Transfusion. 2006;46(11):1909–14. 92. Pammi M, Brocklehurst P. Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia. Cochrane Database Syst Rev. 2011;(10):CD003956. 93. Saez-Llorens X, McCracken GH Jr. Bacterial meningitis in children. Lancet. 2003;361(9375):2139–48. 94. Goldmann DA, Durbin WA Jr, Freeman J. Nosocomial infections in a neonatal intensive care unit. J Infect Dis. 1981;144(5):449–59. 95. Sande MA, Tauber MG, Scheld WM, McCracken GH Jr. Pathophysiology of bacterial meningitis: summary of the workshop. Pediatr Infect Dis J. 1989;8(12):929–33. 96. Saravolatz LD, Manzor O, VanderVelde N, Pawlak J, Belian B. Broad-range bacterial polymerase chain reaction for early detection of bacterial meningitis. Clin Infect Dis. 2003;36(1):40–5. 97. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267–84. 98. El Bashir H, Laundy M, Booy R. Diagnosis and treatment of bacterial meningitis. Arch Dis Child. 2003;88(7):615–20. 99. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336(10):708–16. 100. Renier D, Flandin C, Hirsch E, Hirsch JF. Brain abscesses in neonates. A study of 30 cases. J Neurosurg. 1988;69(6):877–82. 101. Graham DR, Band JD. Citrobacter diversus brain abscess and meningitis in neonates. JAMA. 1981;245(19):1923–5. 102. Schrag SJ, Zywicki S, Farley MM, Reingold AL, Harrison LH, Lefkowitz LB, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med. 2000;342(1):15–20. 103. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep. 2002;51(RR-11):1–22. 104. Van Dyke MK, Phares CR, Lynfield R, Thomas AR, Arnold KE, Craig AS, et al. Evaluation of universal antenatal screening for group B streptococcus. N Engl J Med. 2009; 360(25):2626–36. 105. Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1–36. 106. Jordan HT, Farley MM, Craig A, Mohle-Boetani J, Harrison LH, Petit S, et al. Revisiting the need for vaccine prevention of lateonset neonatal group B streptococcal disease: a multistate, population-based analysis. Pediatr Infect Dis J. 2008;27(12):1057–64. 107. Baker CJ, Edwards MS. Group B streptococcal conjugate vaccines. Arch Dis Child. 2003;88(5):375–8. 108. Benjamin DK Jr, Stoll BJ, Fanaroff AA, McDonald SA, Oh W, Higgins RD, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117(1):84–92. 109. Kaufman DA, Manzoni P. Strategies to prevent invasive candidal infection in extremely preterm infants. Clin Perinatol. 2010;37(3):611–28. 110. Manzoni P, Jacqz-Aigrain E, Rizzollo S, Franco C, Stronati M, Mostert M, et al. Antifungal prophylaxis in neonates. Early Hum Dev. 2011;87(Suppl 1):S59–60.

C. Stockmann et al. 111. Speer CP. Inflammatory mechanisms in neonatal chronic lung disease. Eur J Pediatr. 1999;158(Suppl 1):S18–22. 112. ELFIN Trial Investigators Group. Lactoferrin immunoprophylaxis for very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2013;98(1):F2–4. 113. Ochoa TJ, Cleary TG. Effect of lactoferrin on enteric pathogens. Biochimie. 2009;91(1):30–4. 114. Valenti P, Antonini G. Lactoferrin: an important host defence against microbial and viral attack. Cell Mol Life Sci. 2005;62(22):2576–87. 115. Legrand D, Pierce A, Elass E, Carpentier M, Mariller C, Mazurier J. Lactoferrin structure and functions. Adv Exp Med Biol. 2008;606:163–94. 116. Scott PH. Plasma lactoferrin levels in newborn preterm infants: effect of infection. Ann Clin Biochem. 1989;26(Pt 5):412–5. 117. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA. 2009;302(13):1421–8. 118. Venkatesh MP, Abrams SA. Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2010;(5):CD007137. 119. Modi N, Dore CJ, Saraswatula A, Richards M, Bamford KB, Coello R, et al. A case definition for national and international neonatal bloodstream infection surveillance. Arch Dis Child Fetal Neonatal Ed. 2009;94(1):F8–12. 120. Isaacs CE, Kashyap S, Heird WC, Thormar H. Antiviral and antibacterial lipids in human milk and infant formula feeds. Arch Dis Child. 1990;65(8):861–4. 121. Winberg J, Wessner G. Does breast milk protect against septicaemia in the newborn? Lancet. 1971;1(7709):1091–4. 122. Ashraf RN, Jalil F, Zaman S, Karlberg J, Khan SR, Lindblad BS, et al. Breast feeding and protection against neonatal sepsis in a high risk population. Arch Dis Child. 1991;66(4):488–90. 123. Hanson LA, Korotkova M. The role of breastfeeding in prevention of neonatal infection. Semin Neonatol SN. 2002;7(4):275–81. 124. Goldman AS. The immune system of human milk: antimicrobial, antiinflammatory and immunomodulating properties. Pediatr Infect Dis J. 1993;12(8):664–71. 125. Wold A, Adlerberth I. Pathological consequences of commensalism. In: Nataro J, Blaser MJ, Cunningham-Rundless S, editors. Persistent bacterial infections. Washington: ASM Press; 2000. 126. Hanson L, Dahlman-Hoglund A, Karlsson M, et al. Normal microbial flora of the gut and the immune system. In: Hanson L, Yoken RH, editors. Probiotics, other nutritional factors, and intestinal microflora. Philadelphia: Lippincott-Raven; 1999. p. 217–28. 127. Hasselbalch H, Jeppesen DL, Engelmann MD, Michaelsen KF, Nielsen MB. Decreased thymus size in formula-fed infants compared with breastfed infants. Acta Paediatr. 1996;85(9):1029–32. 128. Lam BC, Lee J, Lau YL. Hand hygiene practices in a neonatal intensive care unit: a multimodal intervention and impact on nosocomial infection. Pediatrics. 2004;114(5):e565–71. 129. Etienne KA, Subudhi CP, Chadwick PR, Settle P, Moise J, Magill SS, et al. Investigation of a cluster of cutaneous aspergillosis in a neonatal intensive care unit. J Hosp Infect. 2011;79(4):344–8. 130. Weston D. Infection prevention and control: theory and practice for healthcare professionals. West Sussex: Wiley; 2008. 131. Edwards MS, Baker CJ. Bacterial infections in the neonate. In: Long S, Pickering L, Prober C, editors. Principles and practices of pediatric infectious diseases. 4th ed. Philadelphia: Elsevier Saunders; 2011.

Pharmacologic Treatment of Neonatal Sepsis 132. DiCenzo R, Forrest A, Slish JC, Cole C, Guillet R. A gentamicin pharmacokinetic population model and once-daily dosing algorithm for neonates. Pharmacotherapy. 2003;23(5):585–91. 133. Yoshioka H, Takimoto M, Riley HD Jr. Pharmacokinetics of ampicillin in the newborn infant. J Infect Dis. 1974;129(4):461–4. 134. Rodvold KA, Everett JA, Pryka RD, Kraus DM. Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children. Clin Pharmacokinet. 1997;33(1):32–51. 135. Wurthwein G, Groll AH, Hempel G, Adler-Shohet FC, Lieberman JM, Walsh TJ. Population pharmacokinetics of amphotericin B lipid complex in neonates. Antimicrob Agents Chemother. 2005;49(12):5092–8.

81 136. Piper L, Smith PB, Hornik CP, Cheifetz IM, Barrett JS, Moorthy G, et al. Fluconazole loading dose pharmacokinetics and safety in infants. Pediatr Infect Dis J. 2011;30(5):375–8. 137. Wade KC, Wu D, Kaufman DA, Ward RM, Benjamin DK Jr, Sullivan JE, et al. Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother. 2008;52(11):4043–9. 138. Doby EH, Benjamin DK Jr, Blaschke AJ, Ward RM, Pavia AT, Martin PL, et al. Therapeutic monitoring of voriconazole in children less than three years of age: a case report and summary of voriconazole concentrations for ten children. Pediatr Infect Dis J. 2012;31(6):632–5.