Keywords

antibiotics, bacteremia, bacterial infections, early onset sepsis, immunity, meningitis, neonatal sepsis, pneumonia

 

Authors

  1. Rubarth, Lori Baas PhD, APRN, NNP-BC
  2. Christensen, Carla M. PharmD
  3. Riley, Cheryl DNP, RN, NNP-BC

Abstract

Abstract: Neonatal bacterial infections leading to sepsis occur frequently in the first few days or weeks of life. NPs must be able to recognize the early signs of sepsis and understand the need for rapid evaluation and treatment. This article discusses antibiotic treatments for various types and locations of bacterial infections and sepsis in the neonate.

 

Article Content

Bacterial infections leading to sepsis in the neonate can occur from exposure to bacteria in the intrauterine environment or in the immediate postnatal environment. Infection and sepsis are not differentiated in neonates, as most infections develop into sepsis in neonates due to their weaker immune systems, poor responsiveness to bacteria, and immaturity (see Deficiencies in newborn immune systems). If a neonate gets an infection, it almost always results in sepsis; this is why any neonate brought into the ED with a fever receives an immediate workup for sepsis and meningitis.

  
Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

An infection can cause pneumonia, septicemia, urosepsis, or meningitis. Early onset sepsis is defined as a life-threatening infection that occurs within the first week of a newborn's life, with late-onset sepsis occurring after the first week of life.

 

Most early onset infections in neonates are either pneumonia or overwhelming sepsis and present with signs and symptoms within the first 24 hours after birth.1,2 Meningitis is often associated with late-onset sepsis but can also occur with early onset sepsis.2 This article provides a broad overview of bacterial sepsis in the neonate, including pathogens, clinical manifestations, diagnosis, and antimicrobial treatment.

 

The incidence of early onset neonatal sepsis is less than one case per 1,000 live births.3 The incidence in preterm infants is higher at about 3.7 per 1,000 live births if less than 37 weeks' gestation and about 11 per 1,000 live births for very low-birth-weight infants (less than 1,500 g [53 oz]).3

 

Immunity

Overall, premature and term infants have a diminished immune response. Passive immunity occurs prior to birth by the active transport of immunoglobulin G (IgG) antibodies across the placenta. These antibodies help protect the infant from viruses, bacterial toxins, and encapsulated pyogenic bacteria.4 However, infants lack IgA, IgE, and IgM antibodies because they do not readily cross the placenta. This leaves the infant vulnerable to Gram-negative organisms, some viruses, and blood-group antigens that cause blood-group incompatibilities with maternal antibodies.

 

Additional deficiencies include decreased white blood cells (WBCs), complement, fibronectin, cytokines, and antibodies, particularly in preterm infants.4 Therefore, neonates are more susceptible to bacterial sepsis.

 

Major pathogens

The two most common pathogens responsible for early onset sepsis are group B streptococcus (GBS) and Escherichia coli, despite the use of intrapartum GBS prophylaxis in the United States.1,3 Occasionally, other streptococci, enterococci, coagulase-negative staphylococci, Haemophilus influenzae, and Listeria monocytogenes can cause early onset sepsis.3,5Listeria is seen more frequently in western European countries but can also occur in the United States.6Listeria is present in raw meats, fish, raw milk, raw vegetables, and processed meats such as hot dogs and lunchmeat.

 

The most common pathogens responsible for late-onset infections are coagulase-negative staphylococci and Staphylococcus aureus as well as those previously mentioned.2Candida albicans is also a major pathogen for hospital-acquired infections in the neonatal ICUs along with Klebsiella and Pseudomonas.2

  
Table Deficiencies i... - Click to enlarge in new windowTable Deficiencies in newborn immune systems

Routes of infection

There are four routes of infection for the neonate: ascending, descending, transplacental, and hospital-acquired. The ascending route allows bacteria from the maternal vaginal tract and cervix to enter the uterus prior to delivery, usually due to ruptured membranes or through the maternal-fetal vasculature. This is the most common route of infection in neonates. In the descending route, the fetus acquires the pathogen as the neonate descends through the vagina at birth. These infections are usually caused by common flora in the maternal vagina or gastrointestinal (GI) tract. This can result in herpes virus infection, GBS, or yeast infections. Transplacental infections usually occur when viruses cross the placenta from mother to fetus. Hospital-acquired infections occur after birth with contamination from an environmental source or from parents and healthcare providers.

 

Predisposing risk factors

Risk factors for infection in the neonate include premature or prolonged rupture of the fetal membranes, premature labor, or maternal infection. Chorioamnionitis results from bacteria invading the uterus causing inflammation of the fetal membranes. Clinical signs of chorioamnionitis include maternal fever and foul-smelling amniotic fluid.7

 

Neonates are more susceptible to pneumonia, septicemia, or meningitis if they are born prematurely with decreased immunity or are low birth weight. Intrauterine growth restriction or small-for-gestation-age infants may be the result of poor maternal nutrition, poor prenatal care, drug use, or maternal illnesses such as preeclampsia.2

 

Clinical manifestations

There is no single set of symptoms that are reliable and specific indicators of infection or sepsis, making it difficult to diagnose in the neonatal period.2 The neonate may show subtle changes in color, tone, activity, and/or feeding. Parents or healthcare providers often describe the neonate as "not doing well." Temperature instability is a common early sign of sepsis, with hypothermia being more common than fever, especially in a premature neonate.

 

Additional early clinical manifestations of sepsis include apnea and signs of respiratory distress. Neonates may also become lethargic, hypotonic, and may not eat or breastfeed. Signs and symptoms of sepsis in a neonate can be difficult to differentiate from other disorders. As sepsis progresses, symptoms of shock (such as pale color, gray color, duskiness, tachycardia, and/or hypotension) may be present. Neonates with GBS sepsis can develop apnea and shock quickly.5,7

 

Neonates with meningitis may be irritable, jittery, and have seizures, abnormal eye movements, or hypertonia. Neonates with prolonged septicemia can also develop unusual bleeding times and disseminated intravascular coagulation.2,7

 

Lab evaluation

Many conditions mimic infection, so a thorough assessment of the neonate is critical. Lab evaluation should include a complete blood cell count with differential and blood culture. Initially, WBC counts may be normal or elevated, but as the sepsis progresses, the WBC count may drop to less than 5,000 cells/mm3 of blood; therefore, neonates with infection (pneumonia, septicemia, or meningitis) may present with either a very high or low WBC count.2,7

 

Because there is wide variation of normal WBC values in neonates, a normal WBC count does not rule out infection and could be temporary. This makes interpretation of the differential much more critical in neonates than in adults. Infection is probably present in the neonate with neutropenia or shift of neutrophils. Neonates with sepsis quickly deplete their neutrophils and eventually lack the WBCs needed to fight infection.7

 

The bone marrow of the neonate will deliver immature neutrophils to the systemic circulation when there are no further mature neutrophils available; therefore, a low number of neutrophils (absolute neutrophil count [ANC] less than 2,000/mm3) or many immature neutrophils (high immature: total [I:T] ratio) can indicate an infection (see Possible indicators of infection and sepsis).7 If the ANC is extremely low (less than 1,000/mm3), very few neutrophils remain in the neonate's system.

  
Table Possible indic... - Click to enlarge in new windowTable Possible indicators of infection and sepsis

Blood culture is still the gold standard for diagnosis of infection or sepsis.7 If the neonate has a definite bacterial infection in the bloodstream, most blood cultures will grow the bacteria within the first 24 to 48 hours. Infection evaluations in neonates over age 1 week should include a urine culture.8 Neonates at birth will rarely have bladder infections, but older neonates may.

 

Neonates under age 1 month who develop a fever should have a lumbar puncture to investigate for meningitis, even with a negative blood culture.2 Cerebrospinal fluid (CSF) with a large number of WBCs (more than 30) is also indicative of meningitis. A CSF Gram stain may provide information as to the specific pathogenic bacteria present. High protein levels (more than 180 mg/dL) or low glucose levels (less than half of the serum level) can also be indicators of meningitis.

 

The C-reactive protein level indicates inflammation and can be elevated after delivery, with meconium aspiration, intraventricular hemorrhage, or perinatal asphyxia.9 This diagnostic test may indicate infection but does not increase readily and would be most beneficial after 24 to 48 hours. Therefore, the C-reactive protein is often used as an indicator of when to discontinue the use of antibiotics (if it drops back to normal levels) instead of when to start them.7

 

Management and antibiotics

Management of the neonate with bacterial sepsis includes stabilizing the BP with inotropes and fluid boluses as needed. Hypotension often occurs with the release of bacterial toxins into the bloodstream when initiating antibiotic therapy. Keeping the blood glucose and electrolyte levels stable along with maintaining good blood flow to the kidneys is essential. Respiratory support may be necessary for neonates with pneumonia or sepsis.2

 

Prudent antimicrobial therapy requires a stepwise process of clinical patient assessment and application. The length of therapy ranges between 7 and 21 days depending on the clinical state of the patient and the identified organism.10 Certain antibiotics should be avoided due to the risk of adverse reactions specific to the neonatal or pediatric population, including trimethoprim-sulfamethoxazole, ceftriaxone, and tetracycline (see Antibiotic adverse reactions and specific considerations).

 

Although doses and intervals vary by gestational age, postnatal age, and weight, antimicrobial therapy in neonates ultimately depends on the suspected site-specific location of the infection. Particular organisms are more likely to be found at certain locations in the body under certain circumstances, which directs initial medication therapy. Some antibiotics penetrate certain tissues in the body better than others (for example, bone and central nervous system [CNS] are typically difficult to penetrate).

 

Another strong consideration in medication selection is that antibiotics have various mechanisms of action (MOA) and can be used in combination for better efficacy or for the treatment and prevention of microbial resistance.11 This information is vital for the appropriate selection of antimicrobial therapy and dosing.

 

For initial coverage, it is important to consider what type of organism is found at the site of origin. In a broad sense, antibiotics cover six major categories of bacteria: Gram-positive, Gram-negative, methicillin-resistant S. aureus (MRSA), Pseudomonas, anaerobic, and atypical (see Antibiotic coverage in neonates).1 The goal of therapy is to appropriately cover the most likely pathogens while preventing antibiotic overuse and resistance.

 

The site of microbial entry is not always easy to identify in the neonate with sepsis. When antibiotics are initiated, generally, broad-spectrum coverage is desired until therapy can be narrowed as a result of culture and sensitivity testing.7,12 At initiation, antibiotic therapy can be streamlined to include the most likely pathogens and potential source of the infection based on the patient's condition, presentation, and history.7,12 Skin, the body's largest organ, is particularly protective in the neonate. When this protective layer is compromised, Gram-positive infections, such as Streptococcus and Staphylococcus including MRSA, are possible.

 

Indwelling catheters, endotracheal tubes, and skin breakdown are just a few of the pathways that can lead to Gram-positive infections. Gram-negative organisms tend to reside within the GI tract along with anaerobes, causing these to be potential concerns if the source of the infection is an abdominal process or aspiration. In addition, Gram-negative organisms can commonly lead to urinary tract infections (UTIs). In diapered infants, Gram-positive organisms should also be considered as a potential source of a UTI. Pseudomonas is a water-loving, Gram-negative organism that consolidates in the respiratory tract, especially in ventilated infants.13 Atypical organisms such as Ureaplasma, Chlamydia, and Treponema pallidum generally enter the bloodstream of infants in utero or at delivery.14

 

When selecting an antibiotic, it is important to also know which antibiotics penetrate particular organs and where a particular antibiotic might have difficulty sustaining adequate concentrations. Two specific sites requiring good penetration for the treatment of sepsis include the meninges and respiratory tract. Cephalosporins penetrate the respiratory tract well and are considered appropriate therapy for infections involving the lung tissue.15

  
Table Antibiotic cov... - Click to enlarge in new windowTable Antibiotic coverage in neonates

For an antibiotic to cross the blood-brain barrier, it must have several properties, including low protein binding, low molecular weight, and high lipophilicity. Some antibiotics including beta-lactams will penetrate the meninges better when the meninges are inflamed. Agents with poor CNS penetration often have larger molecular weights (see Antibiotic characteristics).15,16

 

Additional considerations include bactericidal versus bacteriostatic and concentration-dependent and time-dependent eradication. In general, bactericidal agents are preferred as they kill bacteria in the absence of host defenses. Bacteriostatic antibiotics inhibit the growth of susceptible bacteria and rely on the host defenses to help kill and eradicate the infection. Bacteriostatic agents should be used with caution in premature infants due to their naturally immunocompromised state.17,18

 

If an antibiotic is bactericidal, its pharmacodynamics are considered either time-dependent or concentration-dependent. For time-dependent antibiotics, bacterial kill is largely dependent on the duration of the exposure to the antibiotic over the bacteria's minimum inhibitory concentration (MIC) for a majority of the dosing interval. Time-dependent antibiotics do not have enhanced bacterial kill with higher serum concentrations of the antibiotic. Beta-lactam antibiotics and vancomycin are examples of time-dependent agents. For concentration-dependent antibiotics, the higher the concentration of the antibiotic, the more extensive and rapid the bacterial kill.17,18

 

This leads to a possible prolonged or postantibiotic effect, allowing for large, infrequent dosing to maximize drug concentrations and exposure while minimizing potential toxicities. Examples of concentration-dependent agents include gentamicin, tobramycin, and ciprofloxacin. For these reasons, gentamicin and tobramycin peak and trough concentrations are sometimes obtained to determine the maximum concentration impacting the degree of bacterial kill and the potential for toxicity.19-22

  
Table Antibiotic cha... - Click to enlarge in new windowTable Antibiotic characteristics

Target concentrations for gentamicin and tobramycin are generally 8 to 12 mg/L for the peak and 0.5 to 1.5 mg/L for the trough.19-22 Conversely, vancomycin is a time-dependent antibiotic. Generally, vancomycin trough serum concentrations are obtained to be certain that serum levels are above the MIC, particularly with increasing resistance. The target vancomycin trough concentration is 15 to 20 mg/L to prevent resistance and eradicate susceptible organisms.23-26

 

The impact of the patient's renal and hepatic function should not be overlooked. If it is determined that the infant's renal or hepatic function is inhibited beyond that of the typical maturity for the infant, the dose or interval may need to be adjusted, or an alternative agent should be considered that will not cause further compromise. Within this process, effective coverage and clinical outcomes should be assessed.

 

Clark and colleagues brought this to light when their research revealed that there is less mortality associated with the initial antibiotic choice for possible congenital sepsis of ampicillin and gentamicin compared with ampicillin and cefotaxime.26 Although gentamicin has more toxicity in the presence of kidney dysfunction, the switch to cefotaxime, which has less toxicity, led to more negative outcomes. Because toxicity from gentamicin can be monitored with serum concentrations, this is potentially a more effective option.26

 

The efficacy of gentamicin over cefotaxime for the initial sepsis coverage in the neonate is likely due to the MOA of these antibiotics. When gentamicin is given with ampicillin or penicillin, it has a synergistic impact. GBS is a Gram-positive organism with a cell wall. Beta-lactam antibiotics disrupt the cell wall of GBS, allowing gentamicin to cross the cell wall and enter the cell, where it can disrupt protein synthesis at the ribosomes. This is more than an additive effect of the two antibiotics individually and is also seen with Enterococcus treatment with ampicillin and gentamicin. Cefotaxime and ampicillin cover GBS, but only provide an additive effect because they have the same MOA for bacterial kill.11

 

An additional reason to utilize two antibiotics with efficacy against the same organism is to prevent an organism from developing resistance to the particular antibiotics or to treat an infection by an organism known to have highly resistant strains. This is often referred to as "double coverage." It is important to utilize two antibiotics with different MOAs so the treatment and prevention of the resistance is encouraged. The purpose is to attack the organism in two different manners, killing it prior to the organism's ability to develop resistance.11

 

Many antimicrobials are not approved by the FDA for use in infants, yet primary research and literature supports the safety and efficacy of the use of the medications mentioned in this article. NPs are encouraged to review the dosing frequently, as new research is always being done, especially with newer antibiotics. For all antimicrobial agents, doses and intervals vary with gestational age and postnatal age.27

 

Summary

Neonates are at increased risk for infection during the initial month of life. Any infant with signs of infection needs to be evaluated by a provider or brought to the ED immediately. These infants often deteriorate rapidly, making assessment, diagnosis, and treatment urgent. The possible source and location of the infection, the function of the infant's organ systems, and the MOA of the antibiotics must all be assessed when preparing for treatment.

 

The correct antibiotic can enhance efficacy and outcomes while preventing or treating resistance. Initial therapy should be broad in coverage yet appropriate for the believed origin of the infection and then de-escalated based on cultures and susceptibilities to prevent morbidity and mortality.

 

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