Part K: Infectious Disease

EVALUATION

Septic neonates can have dramatic clinical presentations characterized by respiratory failure, persistent pulmonary hypertension of the newborn (PPHN), disseminated intravascular coagulation (DIC), hypotension, or multiorgan failure. More challenging for health care providers, however, are more commonly encountered patients with subtle and nonspecific signs and symptoms or risk factors for sepsis. Considering the deleterious consequences of a missed or delayed diagnosis, a high index of suspicion is warranted when undertaking evaluation of neonates for potential sepsis.

Maternal History

Careful history is essential for determining key risk factors associated with early-onset sepsis (EOS). Clinicians should confirm the following:

1. Maternal group B streptococci (GBS) status.

2. Use of GBS-specific intrapartum antibiotic prophylaxis vs broad-spectrum intrapartum antibiotic use.

3. Duration of time between rupture of membranes and birth.

4. Length of time of intrapartum antibiotic administration (>4 hours).

5. Intrapartum maternal fever.

6. Gestational age of the newborn.

Labor and Delivery

The clinical presentation of a septic infant can start as early as labor and delivery. Signs and symptoms may include the following:

1. Intrapartum fetal tachycardia.

2. Meconium staining of amniotic fluid.¹

3. Low Apgar scores (newborns with an Apgar score ≤ 6 at 5 minutes had a 36-fold higher likelihood of sepsis than those with Apgar scores ≥ 7).²

Clinical Signs and Physical Findings

After birth, clinical signs of sepsis present in a range from nonspecific and subtle to severe multisystem dysfunction. More commonly presenting signs include the following:

1. Neurological: Temperature instability (fever or hypothermia, with fever more common in term newborns and hypothermia more likely in preterm neonates³); apnea; lethargy or irritability; hypotonia; weak cry; poor suck; seizures.

2. Respiratory: Tachypnea; respiratory distress (flaring, grunting, retractions, or decreased breath sounds); and pulmonary hemorrhage.

3. Cardiovascular: Tachycardia or bradycardia; cyanosis; hypotension; prolonged capillary refill time; mottled appearance; cool and clammy skin.

4. Hematological: Jaundice, petechiae, purpura, and pallor.

5. Gastrointestinal: Abdominal distension, feeding intolerance, emesis, diarrhea, bloody stools, and hepatomegaly.

6. Renal: Oliguria, anuria.

Diagnostic Tests/Laboratory Testing

Several tests are almost universally obtained for the evaluation of EOS; others are still limited by the lack of evidence to support widespread use:

1. Blood culture: This remains the gold standard for diagnosis of EOS. Although there is a considerably high incidence of false-negative cultures^4,5 obtained from neonates, a culture absent of bacterial growth at 36–48 hours from a newborn with no other signs of EOS is reassuring. One small prospective cohort study has also examined utilizing cord blood for blood culture sampling in asymptomatic term newborns evaluated for sepsis based on the presence of risk factors.⁶ The authors concluded it may be a reasonable consideration, but additional studies are needed before a practice recommendation can be made. For those neonates who fail to demonstrate improvement after initiating empiric antibiotic therapy, repeating blood cultures is recommended, with expansion to other sites (cerebrospinal fluid [CSF], respiratory, and urine). If the initial blood culture is positive, blood culture(s) should be repeated 24 hours after antibiotics were initiated.⁵

2. CSF culture/studies: Meningitis in the newborn can be difficult to diagnose clinically. Although the decision to perform a lumbar puncture (LP) remains controversial, guidelines have been provided by the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn for obtaining LP and CSF studies in a clinically unstable newborn or a newborn with a positive blood culture.⁷ Consideration for “holding” CSF stored in the laboratory in case additional studies are later needed should always be included in the discussion for performing the procedure. Serial LPs in the absence of an initial positive culture are not recommended because they are unlikely to yield additional benefit that outweighs potential risks and complications.

3. Complete blood cell count (CBC) with (manual) differential count: A CBC is the most readily available and commonly utilized test for EOS. It is typically done as a screening tool between 2 and 12 hours of life. However, values may range widely and be influenced by the timing of the sample acquisition. Serial studies at 6-, 12-, or 24-hour intervals are useful and, in conjunction with other laboratory results and clinical findings, can be recommended to influence the decision to discontinue antibiotic therapy.^8,9 In sick neonates, thrombocytopenia is frequently observed, but it has no consistent predictive value. For a subset of patients, development of (worsening) thrombocytopenia may signal progression to septic shock or invasive gram-negative or fungal infection (premature infants).

4. Immature neutrophils (band cells + myelocytes + metamyelocytes) to total neutrophils ratio (I/T) 70.20 warrants a greater level of suspicion for EOS, especially in conjunction with other abnormal findings.¹⁰ Values less than 0.2 are usually considered within normal limits. An I:T ratio that “normalizes” within 24–48 hours, particularly in an otherwise-asymptomatic infant, can be considered a reassuring laboratory finding.

5. C-reactive protein (CRP): As an acute phase reactant, any inflammatory condition can elevate CRP. However, abnormally elevated CRPs obtained serially after birth can support a diagnosis of EOS. Furthermore, serial CRP values within normal range, particularly in the absence of other signs of EOS, may provide reassurance for discontinuing empiric antibiotic therapy.¹¹ Serial CRP values are used by some centers to guide duration of empiric antibiotic therapy. Such protocols typically require at least two CRP levels, obtained 24 hours apart, with results below the laboratory’s designated cutoff to identify infants unlikely to be infected.^12,13 We would caution against using this as a singular approach because there are still many unanswered questions about the value of CRP in managing neonatal sepsis. Research is ongoing and includes the intriguing possibility for point-of-care testing.¹⁴

6. Neutrophil CD64: Neutrophils have been shown to express CD64 when activated. Several studies have found CD64 determination to have high sensitivity and specificity for the determination of EOS when an appropriate cutoff value is selected. Advantages include small blood volume for sampling and rapid results. It is also considered advantageous when used in conjunction with CRP testing for EOS laboratory evaluations.^{15, 16, and 17}

7. Blood gas monitoring: Patients with sepsis often have metabolic or respiratory acidosis, hypoxemia (especially in PPHN), and hypercarbia. Frequent blood gas monitoring can alert the clinician to acute changes in the patient’s status that warrant urgent intervention. Arterial blood gas sampling is preferred for its accuracy.

8. Imaging studies: Imaging is helpful when respiratory symptoms predominate (chest x-ray) or there is a concern for intracranial bleeding as a complication of sepsis (cranial ultrasound). An echocardiogram is useful for ruling out congenital cardiac disease, assessing myocardial dysfunction, or determining the presence and severity of PPHN.

9. Electroencephalogram (EEG): For infants with an abnormal neurological status, including persistent lethargy, hypotonia, and seizure activity, in addition to a LP, an EEG evaluation in consultation with pediatric neurology may be warranted because neonates may have significant subclinical seizure activity requiring anticonvulsant therapy.

Differential Diagnosis/Diagnostic Algorithms

The differential diagnosis for EOS is broad (Table 113-1). However, given that EOS can mimic the presentation of other severe diagnoses, it is important to keep a complete differential in mind when evaluating a newborn. Figure 113-1 represents a diagnostic algorithm for EOS.

MANAGEMENT

When presented with an acutely ill neonate, it is important to promptly administer appropriate supportive measures and initiate clinical investigations into the cause. Management includes broad-spectrum antibiotics as well as supportive therapy. Asymptomatic newborns with risk factors for infection should be carefully monitored for early signs and symptoms of sepsis. For symptomatic infants, full cardiopulmonary monitoring is crucial as a neonate’s clinical condition can deteriorate rapidly.

Antibiotic Therapy for EOS

In suspected sepsis, the initial antibiotic therapy is empirical, targeted against the most likely EOS pathogens. Antibiotics need to be initiated as soon as possible, preferably after cultures have been obtained. Once a pathogen is identified, antibiotic therapy should be adjusted and ideally narrowed based on the susceptibilities of the organism(s). Decisions for duration of therapy will be dictated by the source and type of organism(s) isolated as well as the clinical course.

Recommended Empiric Antibiotic Therapy for EOS

The antibiotics recommended for the neonate with suspected EOS are ampicillin and gentamicin.¹⁸ These antibiotics have the additional benefit of intramuscular (IM) or intravenous (IV) administration. A National Institute of Child Health and Human Development (NICHD) network study and other reports have shown the efficacy of this combination.^19,20 Our recommendation is to start meningitic doses of ampicillin if the suspicion for meningitis is strong enough to warrant an LP in the evaluation process, even if the patient is not symptomatic. This also applies to the critically sick infant when the LP is deferred. If treatment is continued longer than 48 hours, meningitis was excluded, and the clinical status is improving, ampicillin can be changed to nonmeningitic dosing.

Use of Third-Generation Cephalosporins/Alternative Antibiotics for Empiric Therapy

An alternative regimen of ampicillin and a third-generation cephalosporin (eg, cefotaxime, ceftriaxone) is not more effective than ampicillin and gentamicin. Routine use of cefotaxime is discouraged because of the emergence of cephalosporin-resistant bacterial strains (eg, Enterobacter cloacae, Klebsiella, and Serratia species).¹⁸ A large study found that in patients receiving ampicillin, the concurrent use of cefotaxime during the first 3 days after birth was associated with an increased risk of death, compared with patients treated with ampicillin and concurrent use of gentamicin.²¹ Third-generation cephalosporins have also been linked to invasive candidiasis infections in extremely premature neonates. Ceftriaxone administration is completely avoided in infants less than 28 days old because of several adverse effects, including hyperbilirubinemia as a result of displacement from albumin and cardiovascular collapse from coadministration with calcium-containing intravenous solutions.²² Increasingly, piperacillin/tazobactam (Zosyn) is being utilized as a single agent or added to an aminoglycoside for empiric antibiotic therapy in neonatal sepsis.^23,24

Supportive Therapy

The main goal of supportive therapy is to increase delivery of substrates to meet tissue demand that has been compromised during a septic episode. Necessary therapies may involve the following:

1. Respiratory support: Provide oxygen and, if respiratory distress is present, provide adequate support (from nasal cannula to endotracheal intubation and mechanical ventilation).

2. Volume/fluid/blood pressure support: Initiate rapid fluid resuscitation with crystalloid or colloid parenteral solutions as needed to correct circulatory derangements. An adequate circulating blood volume is necessary to maintain right ventricular filling and cardiac output. However, repeated bolus administration of crystalloid and colloid solutions will not provide additional benefit. Correcting underlying vascular derangements, such as peripheral vasodilation, must be promptly addressed through the use of pressor support (dopamine, dobutamine, epinephrine, etc).

3. Correction of metabolic abnormalities (hypoglycemia, hypocalcemia, etc): Management of fluid and electrolytes is extremely important. Metabolic and respiratory acidosis require timely correction. When glucose abnormalities are present (hypo- or hyperglycemia), they can be important diagnostic evidence and contributors to neonatal morbidity and mortality,²⁵ therefore, judicious correction is necessary.

4. DIC: Evidence of abnormal blood clotting should be corrected with transfusions and drugs. However, reversal of DIC often poses considerable challenges despite repletion with blood products. It is important to remember that reversal will not occur until the underlying cause or organism has been effectively treated. Use of factor VII has not been investigated sufficiently to recommend administration to septic neonates in DIC.

5. Provide thermoregulatory support: Hypothermia is a frequent finding in neonatal sepsis. When present, patients’ temperature is artificially controlled, and the ability to wean thermoregulatory support should be monitored.

6. Inhaled nitric oxide (iNO): In patients with severe hypoxic respiratory failure unable to maintain the arterial pressure of oxygen (PaO₂) greater than 80 mm Hg despite maximal respiratory support or in a ventilated patient with a significant (>50%) O₂ requirement and echocardiographic evidence of pulmonary artery pressures close to or above systemic pressure, especially if there is evidence of poor cardiac output, iNO may provide some benefit. The appropriate starting dose is 20 ppm. Increasing to levels above 20 ppm has no additional positive impact and increases the likelihood of adverse effects, including methemoglobinemia.

7. Extracorporeal membrane oxygenation (ECMO): Consider this modality if other means of respiratory and cardiovascular support fail to be sufficient. For centers without ECMO support, transfer to a neonatal intensive care unit (NICU) with a higher level of care should be considered and initiated early.

8. Monitoring of renal function: This is particularly important for patients treated with nephrotoxic medications, including aminoglycosides (eg, gentamicin) and vancomycin. Renal injury is typically acute and reversible. However, intravenous fluids and medication administration should be reviewed daily and tailored to the level of renal function present.

9. Sedation/pain control considerations: Measures to provide comfort with procedures (LP, blood draws, etc) should be provided. Newborns do not necessarily need sedation or pain control for ventilator management. However, those patients who are difficult to ventilate/oxygenate because of agitation may benefit from adequate sedation. Continuous infusion with benzodiazepines (eg, midazolam) should be avoided given concerns for adverse neurodevelopmental outcomes. Recognition of rapid tolerance development/neonatal abstinence syndrome is important as patients recover from sepsis, so timely weaning off continuous analgesic infusions when they are used as a part of clinical management should be initiated as soon as appropriate.

10. Alternative treatment options: Routine use of adjunctive immunotherapeutics, such as white cell transfusions, intravenous immunoglobulin, granulocyte and granulocyte-macrophage colony-stimulating factor administration, activated protein C and lactoferrin, is not recommended as studies have failed to demonstrate an improvement in outcomes for neonatal sepsis.²⁶

Indications for Discontinuation of Antibiotic Therapy

By far, the greatest controversy in neonatal sepsis involves the decision to discontinue empiric antibiotic therapy. There is appropriate concern for the adverse effects of prolonged antibiotic therapy in the setting of sterile cultures, as retrospective cohort studies have indicated an increased risk for morbidity and mortality.^27,28 Recent studies have attempted to create predictive models that go beyond assessing infants who are “at risk” or “not at risk” and consider timing of laboratory findings in addition to clinical acumen for determining duration of antibiotic therapy.¹¹ Unfortunately, current studies are still inadequate and unable to provide final guidance on appropriate testing and timing of testing to cover the range of circumstances necessitating initiation of empiric antibiotic therapy.

Consent/Ethical Considerations

For newborns who require admission to the NICU, appropriate consents from parents or guardians will be necessary. Ethical considerations for investigations and treatment in cases of extreme prematurity or suspected genetic syndromes with known mortality should be undertaken with the family as soon as feasible, ideally before the infant’s clinical deterioration.

CONCLUSION/FOLLOW-UP

Aftercare Monitoring

Neonates with resolution of their septic episode should demonstrate the ability to maintain their temperature without thermoregulatory assistance and consume adequate nutrition for growth by oral feeding unless secondary diagnoses preclude the ability to attain these milestones.

Follow-up Tests

For neonates with additional morbidities associated with sepsis, additional evaluation should be performed prior to discharge. This may include repeating head ultrasound, chest x-ray (determine resolution of pneumothorax but not resolution of pneumonia as those findings lag behind evidence of clinical improvement), echocardiogram to assess myocardial function/contractility, or cultures to demonstrate clearance of infection. Patients should be examined carefully for evidence of thrombus formation as well as any evidence of persistent neurological deficits that would necessitate outpatient follow-up in consultation with appropriate subspecialists. Because of potential ototoxicity associated with certain infections and as a recognized side effect of aminoglycoside use, hearing screening should be performed prior to discharge.

Clinical Follow-up

For patients with severe sepsis/septic shock (pressor support, ECMO support, etc), follow-up in 3 to 6 months after discharge with a neonatal/developmental specialist is warranted. Continued follow-up through the first 3 years of life, including regular neurodevelopmental assessments, is also recommended. Should evidence of developmental delay manifest, prompt referral to appropriate services (speech therapy, occupational therapy, physical therapy, etc) is important.

Long-Term Outcome/Implications for Patient/Family

Multiple confounders exist that significantly hamper the ability to definitively predict long-term outcomes for neonates diagnosed with sepsis. The extremely premature infants who had sepsis have a higher incidence of cerebral palsy as compared to those who did not have sepsis during their NICU stay.^29,30 Similarly, infants with bacterial sepsis associated with meningitis have worse neurodevelopmental outcomes, as well as patients who required ECMO support.

REFERENCES

EVALUATION

Health care-associated infection (HCAI), also referred to as nosocomial or hospital acquired, is an infection that a patient acquires and (a) becomes evident 48 hours or more after admission, (b) was not present or incubating at the time of admission to the hospital, and (c) develops while the patient is receiving treatment of other conditions. Neonates admitted to the neonatal intensive care unit (NICU) frequently contract HCAIs¹ and may present with a wide range of symptoms, including fulminant sepsis, particularly late-onset sepsis (LOS). A significant number of HCAIs are preventable, even in the high-risk and vulnerable NICU population. Therefore, any discussion of HCAI management must also emphasize the role of preventive measures (refer to chapter 53).

Risk Factors

Recognition of risk factors for HCAIs is important when evaluating an acutely ill/decompensating patient for a possible HCAI.

1. Patient related: These risk factors are strongly influenced by the gestational age or weight at birth.² With decreasing gestational age and birth weight, the more likely it is that an HCAI can occur as there is an underdeveloped immune response, increased hospital length of stay, severity of illness, exposure to NICU-related risk factors (see next item), and development of chronic and exacerbating medical conditions such as chronic lung disease (CLD) or necrotizing enterocolitis (NEC).

2. NICU related: These risk factors include the following:

   1. indwelling intravascular or transmucosal catheters,

   2. mechanical ventilation,

   3. total parenteral nutrition (TPN) and intralipids,

   4. broad-spectrum antibiotic therapy,

   5. treatment with histamine₂ receptor antagonists (H₂ blockers),

   6. steroid administration, and

   7. exposure to the endemic microbial flora of the NICU environment as well as its health care workers.^{3, 4, and 5}

Clinical Signs and Symptoms

The clinical presentation can range from nonspecific and subtle to severe, multisystem organ dysfunction. Common presenting findings are the following:

1. Neurological:

   1. temperature instability (fever or hypothermia);

   2. apnea (unrelated to/distinct from apnea of prematurity);

   3. lethargy or irritability, hypotonia, poor suck; and

   4. seizures.

2. Respiratory:

   1. Tachypnea;

   2. grunting, flaring, retracting, or decreased breath sounds;

   3. worsening gas exchange by blood gas, increased oxygen requirement, pulse oximetry, etc;

   4. change in chest x-ray findings, and

   5. new onset or change in character of sputum and increased respiratory secretions and suctioning requirements (for ventilated patients).

3. Cardiovascular:

   1. tachycardia or bradycardia;

   2. arrhythmia;

   3. cyanosis; and

   4. hypotension, prolonged capillary refill time, mottled appearance, cool and clammy skin.

4. Hematological:

   1. leukopenia or leukocytosis,

   2. anemia, and

   3. thrombocytopenia,

5. Skin:

   1. jaundice,

   2. petechiae,

   3. purpura, and

   4. pallor or cyanosis.

6. Gastrointestinal:

   1. abdominal distension, feeding intolerance, emesis;

   2. diarrhea or bloody stools; and

   3. ileus or absent bowel sounds.

7. Renal:

   1. oliguria or anuria and

   2. pyuria or malodorous urine.

Diagnostic Tests/Laboratory Testing

Testing should always include consideration of the patient’s risk factors for HCAIs with the caveat that not all “positive” cultures signify the presence of an infection (warranting treatment). Clinicians should also follow available diagnostic guidelines where available (see chapter 53).

1. Blood cultures: At least 1 mL of blood is recommended for each culture.

   1. Draw from all intravascular catheters and a peripheral source.

   2. Fungal cultures should also be considered, particularly in extremely low birth weight (ELBW) infants who are at greater risk for invasive fungal infections.

   3. Repeat cultures and expand to other potential sources (urine, CSF, etc.) if no clinical improvement is seen after initiating empiric antibiotic therapy.

   4. If the blood culture is positive, blood cultures from all lines and a peripheral source should be repeated at least every 24 hours after antibiotics/antifungals are initiated until cultures become negative.

   5. For persistently positive cultures caused by an intravascular or indwelling device, removal is necessary.

   6. Sending additional cultures of a removed device (eg, catheter tip) rarely aids management in the setting of known positive blood cultures.⁶

2. Cerebrospinal fluid (CSF) culture/analysis: Meningitis in a sick NICU patient can be difficult to diagnose. In a 2004 study by Stoll et al, approximately one-third of patients with meningitis did not have evidence of sepsis.⁷ Further complicating the issue are those patients with posthemorrhagic hydrocephalus who have had placement of either a ventricular reservoir or a shunt because they are at increased risk for infection.⁸ A decision to evaluate CSF (via either lumbar puncture [LP] or sampling of a reservoir/shunt) should be made prior to initiating empiric antibiotic therapy. The treatment should not be postponed in an ill neonate who is too unstable for CSF evaluation. CSF studies to be obtained include Gram stain, cell count with differential, evaluation of protein and glucose concentrations, and CSF culture(s). However, only the CSF culture is the gold standard for diagnosis.⁹ Additional potentially useful diagnostic studies include the following:

   1. CSF lactate: There are reference ranges available for CSF lactate in neonates¹⁰; however, we are unaware of studies specific to neonates suspected of CSF infection, so any results obtained should be interpreted with caution. Studies involving use of CSF lactate in pediatric patients are available.^11,12

   2. Polymerase chain reaction (PCR) analysis: This is an excellent test for rapid diagnosis, particularly when viral infection is strongly suspected.¹³ It is currently the standard for identification of herpes simplex virus (HSV) and enterovirus in CSF. PCR analysis has good sensitivity and specificity; however, if blood is present in the CSF, results should be cautiously interpreted.

3. Tracheal culture/analysis: Consideration for ventilator-associated pneumonia (VAP) is an important part of the evaluation for an HCAI. When presenting signs or symptoms are consistent with respiratory tract infection, culture and studies are recommended but should be interpreted with caution. Identifying an organism can indicate a pathogen but may just represent colonization. Tracheitis is a diagnostic possibility that may require treatment, but studies are limited in their ability to differentiate it from pneumonia. Gram stains demonstrating the presence of polymorphonuclear leukocytes (PMNs) with bacteria or fungi support the use of empiric therapy but cannot dictate targeted therapy or duration of treatment.¹⁴ Viral studies (respiratory syncytial virus (RSV), metapneumovirus, influenza, enterovirus, rhinovirus, etc) are important as viral nosocomial infections do occur.¹⁵ Testing (including PCR analysis) for pertussis, mycoplasma, and ureaplasma may also be considered.

4. Urine culture/studies: Compared to early-onset sepsis, the incidence of urinary tract infections (UTIs) is higher in neonates experiencing prolonged hospitalization.^16,17 Premature neonates are particularly susceptible.¹⁸ The presence of an indwelling (Foley) catheter increases the likelihood of a UTI. For diagnosis, urinalysis plus bacterial cultures are recommended. Obtaining fungal cultures is encouraged as clinically indicated.

5. Viral cultures/studies: As previously mentioned, viral studies are important (CSF, blood, urine, nasopharyngeal and tracheal aspirates, skin swabs) because viruses can cause NICU-related HCAIs. PCR analysis is a valuable and rapid diagnostic tool for diagnosing viral infections and can aid in management decisions while awaiting culture results.

6. Complete blood cell count (CBC) with (manual) differential count: A CBC is readily available and frequently obtained from patients hospitalized in the NICU. Results can be trended and used to support or rule out a diagnosis of infection.

   1. Platelets: In sick neonates, thrombocytopenia is frequently observed, but it has no consistent predictive value. Development of new-onset thrombocytopenia (>30% decline from prior baseline value), however, may signal progression to septic shock or invasive gram-negative bacterial or fungal infection.¹⁹

   2. White blood cells: Either leukocytosis or leukocytopenia heightens a clinician’s concern for infection.

   3. Immature/total (I:T) neutrophil ratio: This is calculated as a secondary data point from the differential of the CBC by dividing the total immature neutrophil forms by the total immature plus mature neutrophils. Values less than 0.2 are usually considered within normal limits and not indicative of the presence of an infection.²⁰ Higher I:T ratios support a diagnosis of infection, especially in conjunction with other abnormal clinical signs and symptoms. An I:T ratio as an isolated index, however, lacks sensitivity and specificity for determining the presence of HCAIs.

   4. Eosinophils: Eosinophilia is also associated with infection in sick infants,^21,22 although there is still debate on the timing of its appearance and potential correlation with other inflammatory conditions (eg, CLD).²³ For more information on the use of the CBC, please see chapter 128.

7. C-reactive protein (CRP): Elevated CRPs obtained serially in conjunction with clinical concern for infection can support a diagnosis of HCAI associated with late-onset sepsis. A clinician should exercise caution when utilizing this test result as a singular index to confirm evidence of infection because there are still many unanswered questions about the value of CRP in managing neonatal sepsis. However, diagnostic accuracy may be improved when used in combination with laboratory indices such as the white blood cell count, I:T ratio, or CD64 count.^24,25 Research into improved application of CRP values is ongoing and includes the intriguing possibility for point-of-care testing.²⁶

8. Neutrophil CD64 (nCD64): Neutrophils have been shown to express CD64 when activated. Several studies have found nCD64 determination to have high sensitivity and specificity for the determination of infections when an appropriate cutoff value is selected.²⁷ Advantages to its use include small blood volume for sampling and rapid results. It is also considered particularly advantageous when used in conjunction with CRP testing for laboratory evaluations of sepsis.^{28, 29, and 30}

9. Other inflammatory markers: Measurements of interleukin (IL) 6, IL-8, tumor necrosis factor α (TNF-α), procalcitonin,^31,32 Neutrophil gelatinase-associated lipocalin (NGAL), and hepcidin³³ have all been examined as additional values providing more accurate diagnosis of infection/sepsis. Norobust studies definitively demonstrated that these are superior to current testing modalities. Because there are insufficient data to guide their use for identifying HCAIs in sick neonates, no recommendations are currently made.

10. Blood gas monitoring: Unexplained metabolic acidosis can often indicate infection, and respiratory acidosis, hypoxemia, and hypercarbia may point to new-onset pneumonia or systemic infection. In a sick patient, blood gas monitoring can alert the clinician to acute changes in the patient’s status that warrant urgent intervention. Arterial blood gas (ABG) sampling is preferred for its accuracy, although venous or capillary samples may suffice.

11. Imaging studies: Imaging is helpful when respiratory (chest x-ray) or gastrointestinal (abdominal x-ray or ultrasound) symptoms predominate. There may also be concern for intracranial bleeding as a complication of sepsis (cranial ultrasound). An echocardiogram is useful for ruling out worsening cardiac disease (patent ductus arteriosus, persistent pulmonary hypertension of the newborn [PPHN], myocardial dysfunction, etc). Serial imaging is often required.

12. Electroencephalography (EEG): The presence of seizures in premature and sick infants can challenge the clinician caring for NICU patients because seizures can be subclinical or atypical. In addition to a LP, an EEG evaluation in consultation with a pediatric neurologist may be warranted, as neonates can have significant subclinical seizure activity requiring initiation of anticonvulsant therapy to manage the seizures.

Differential Diagnosis/Diagnostic Algorithms

The differential diagnostic list is not extensive for HCAIs, but they can mimic the presentation of other severe diagnoses, including late-onset sepsis associated with perinatally acquired infections (Table 114-1).

MANAGEMENT

Asymptomatic neonates in the NICU with risk factors for HCAI may unexpectedly and rapidly develop symptoms and signs of infection/sepsis. Hence, these patients warrant vigilant monitoring for evidence of developing issues. Once symptomatic, prompt initiation of broad-spectrum antimicrobials and supportive therapy, and clinical investigations into the cause, are critical as a neonate’s clinical condition can deteriorate rapidly.

Antibiotic Therapy for HCAIs

When an HCAI is suspected, the initial antibiotic therapy is empirical but targeted against the most likely pathogens. As such, the choice of initial antibiotic therapy may also be guided by previous microorganisms isolated from the patient, as well as the patterns of antibiotic resistance in pathogens causing infections in the patient’s NICU. Empiric therapy needs to be initiated promptly, but preferably after cultures have been obtained. If a likely pathogen (not colonizer or contaminant) is identified, then therapy should be tailored and ideally narrowed based on the susceptibilities of the organism(s). Decisions for duration of therapy will be dictated by the source and type of organism(s) isolated as well as the patient’s overall clinical course.

1. Intravascular catheter-associated bloodstream infection (CABSI): For infants with suspected CABSI, vancomycin and gentamicin should be initiated to provide empiric coverage for coagulase-negative staphylococci, Staphylococcus aureus, and gram-negative bacteria. Linezolid may also be appropriate in units with Staphylococcus capitis infections and/or Vancomycin-resistant enterococci.

2. Gram-negative sepsis: In a patient with severe acute deterioration likely caused by a gram-negative organism (eg, Serratia, Enterobacter, Klebsiella, or Pseudomonas), double gram-negative coverage may be indicated. For example, both a β-lactam antimicrobial agent (eg, ampicillin or piperacillin-tazobactam) and an aminoglycoside should be initiated in a patient with severe and acute decompensation consistent with gram-negative sepsis. Infections caused by extended-spectrum β-lactamase-producing organisms (or hyperproduction of β-lactamase) need to be treated with meropenem and should be considered in patients with poor response to therapies, even while awaiting susceptibility reports.

3. Anaerobic infection: If there is suspicion that infection can be caused by anaerobic bacteria found in the gastrointestinal tract (eg, necrotizing enterocolitis), clindamycin, metronidazole, or another appropriate antibiotic should be added to the regimen.

4. Consideration of antifungal and antiviral empiric therapy should also be stressed when risk factors are present, particularly when there is a lack of reasonable improvement after initiating broad-spectrum empiric antibiotic therapy.

Supportive Therapy

The main goal of supportive therapy is to increase delivery of substrates to meet tissue demand that has been compromised during an HCAI and prevent recurrent infections. Necessary therapies may involve the following:

1. Remove indwelling intravascular/transmucosal devices: As mentioned, any discussion of HCAIs includes consideration for their prevention. Indwelling foreign bodies are frequently associated with biofilm production. The formation of biofilm can complicate treatment of an HCAI and impede the clearance of pathogenic organisms, as evidenced by repeatedly positive cultures despite appropriate therapeutic interventions. Removal of indwelling foreign bodies typically facilitates successful eradication of the infection.

2. Administer Oxygen: If necessary (eg, worsening respiratory distress persists), provide adequate support (from nasal cannula to endotracheal intubation and mechanical ventilation).

3. Volume, fluid, and blood pressure support: Initiate rapid fluid resuscitation with crystalloid or colloid parenteral solutions as needed to correct circulatory derangements. An adequate circulating blood volume is necessary to maintain right ventricular filling and cardiac output. However, repeated bolus administration will not provide additional benefit. Correcting underlying vascular compromise, such as peripheral vasodilation and decreased cardiac output, must be promptly addressed through the use of pressor support (dopamine, dobutamine, epinephrine, etc).

4. Treat refractory hypotension/use of corticosteroids: For patients with refractory hypotension, septic shock, or acute adrenal insufficiency not responsive to volume and pressors, the use of hydrocortisone has been reported to have some efficacy in correcting severe hypotension.³⁴ Short-term adverse effects appear minimal, but many questions remain about long-term consequences. Randomized trials are lacking.

5. Correct metabolic abnormalities (hypoglycemia, hyperkalemia, hypocalcemia, etc.): Management of fluid and electrolytes is extremely important. Both metabolic and respiratory acidosis require timely correction.

6. Provide thermoregulatory support: Temperature instability may frequently occur with HCAI and neonatal sepsis. When hypothermia is present, a patient’s temperature is artificially regulated. If hyperthermia/fever occurs, pharmacologic cooling measures are appropriate (Nonpharmacologic interventions may also provide benefit.).

7. Reverse disseminated intravascular coagulopathy (DIC): Evidence of abnormal blood clotting should be corrected with transfusions and drugs. However, reversal of DIC often poses considerable challenges despite repletion with blood products. It is important to remember that reversal will not occur until the underlying cause has been effectively treated. Use of factor VII has not been investigated sufficiently to recommend administration to neonates in DIC, although off-label use is anecdotally reported and described in the literature.^35,36

8. Start inhaled Nitric Oxide (iNO) Therapy: Use of iNO is recommended in infants older than 34 weeks’ gestational age³⁷ with severe hypoxic respiratory failure and inability to maintain the arterial pressure of oxygen (PaO₂) above 80 mm Hg despite maximal respiratory support (in premature infants 34 weeks or less it has equivocal effects on pulmonary outcomes, survival, and neurodevelopmental outcomes). It may also provide support to ventilated infants with a significant (>50%) O₂ requirement and echocardiographic evidence of pulmonary artery pressures close to or above systemic pressure, especially if there is evidence of poor cardiac output. The appropriate starting dose is 20 ppm. Concentrations greater than 20 ppm have no additional positive impact and increase the likelihood of adverse effects, including methemoglobinemia.

9. Initiate extracorporeal membrane oxygenation (ECMO): Consider this modality in neonates older than 34 weeks or 2.5 kg if other means of respiratory and cardiovascular support fail and the patient has a reversible condition. For centers without ECMO support, transfer to a NICU with a higher level of care should be considered and initiated early to optimize the likelihood of a positive outcome for the patient. Long-term follow-up of ECMO survivors demonstrated concerns over neurodevelopmental outcomes, so ethical considerations are important in making the decision to proceed with ECMO support.

10. Monitor renal function closely: This is particularly important for patients treated with nephrotoxic medications, including aminoglycosides (eg, gentamicin) and vancomycin. Renal injury is typically acute and reversible. However, intravenous fluids and medication administration should be reviewed daily and tailored to the level of renal function present. Although typically reversible, infants with confirmed UTI may warrant later follow-up to reassess renal function¹⁸ and genitourinary anatomy. Consultation with pediatric nephrology and/or urology may assist in determining the necessity of additional post-UTI evaluations.

11. Sedation/pain control considerations: Measures to provide comfort with procedures (LP, blood draws, etc) should be undertaken. Neonates do not necessarily require sedation or pain control for ventilator management. However, those patients with PPHN who are difficult to ventilate or oxygenate because of agitation will benefit from adequate sedation. Continuous infusion with benzodiazepines (eg, midazolam) should be avoided given concerns for adverse neurodevelopmental outcomes. Recognition of rapid tolerance development or neonatal abstinence syndrome is important. Patients already receiving continuous analgesic infusions may require a significantly higher basal infusion rate during an acute episode of HACI. However, as patients recover, timely weaning off or to previous baselines should be initiated as soon as appropriate.

12. Alternative treatment options: Routine use of adjunctive immunotherapeutics, such as white cell transfusions, intravenous immunoglobulin, granulocyte and granulocyte-macrophage colony-stimulating factor administration, activated protein C,³⁸ pentoxyphylline, and lactoferrin are not recommended as studies were either insufficient to draw adequate conclusions or simply failed to demonstrate an improvement in outcomes for serious infections in neonates.

Prevention

Any discussion regarding the evaluation and management of HCAIs must emphasize prevention, and there are multiple areas to address. Proper hand hygiene and stringent techniques for the handling of invasive catheters yield high-impact results (reductions in HCAIs). The use of prophylactic antifungal therapy continues to be debated and is beyond the scope of this discussion. Please see chapter 53 for additional details on prevention of HCAIs.

Consent/Ethical Considerations

Public disclosure of adverse events and specific disclosure to patients and family members is quickly becoming a legal requirement in many states. Ethically, physicians are expected to discuss adverse events with their patients or patients’ families. Given that HCAIs are mostly preventable and inextricably tied to hospital admission, clinicians must consider the legal and ethical ramifications of HCAIs.

CONCLUSION/FOLLOW-UP

Aftercare Monitoring

Neonates with resolution of their HCAI episode should ideally return to their prior baseline or a higher baseline function unless secondary diagnoses or associated complications of the HCAI preclude the ability to attain these goals.

Follow-up Tests

For neonates with additional morbidities associated with HCAIs, additional evaluations should be performed prior to discharge. These may include repeat head ultrasound, brain magnetic resonance imaging (MRI), chest x-ray (determine baseline evidence of CLD at discharge), echocardiography to assess myocardial function/contractility, and cultures to demonstrate clearance of infection (if discharge < 72 hours after resolution of HCAI). Patients should be examined carefully for evidence of thrombus formation as well as for any evidence of persistent neurological deficits that would necessitate outpatient follow-up in consultation with appropriate subspecialists. Because of the potential ototoxicity associated with certain infections and as a recognized side effect of aminoglycoside use, hearing screening has to be performed prior to discharge.

Clinical Follow-up

Neonatal patients with HCAIs were typically sicker and have longer lengths of stay during their hospitalization period. Given that they are considered fragile and at risk, follow-up appointments in 3 to 6 months after discharge with a neonatal/developmental specialist are warranted. Continued follow-up through the first 3 years of life, including regular neurodevelopmental assessments, is also recommended. Should evidence of developmental delay manifest, prompt referral to appropriate services (speech therapy, occupational therapy, physical therapy, etc) is important.

Long-Term Outcome/Implications for Patient/Family

Multiple confounders can significantly hamper the ability to definitively predict long-term outcomes for neonates diagnosed with the infections. The extremely premature infants who had sepsis have a higher incidence of cerebral palsy as compared to those who did not have sepsis during their NICU stay.^39,40 Similarly, infants with bacterial sepsis associated with meningitis have worse neurodevelopmental outcomes, as well as patients that required ECMO support.

REFERENCES

THE ORGANISM

Staphylococci are aerobic or facultative anaerobic gram-positive cocci in clusters or, less often, chains, pairs, or tetrads. Staphylococcus aureus produces coagulase. Staphylococci that do not produce coagulase are reported as coagulase-negative staphylococci (CONS) and include S. epidermidis, S. lugdenensis, S. haemolyticus, and S. saprophyticus. Both S. aureus and certain species of CONS can cause serious infection in the newborn period. This chapter deals only with infections caused by S. aureus.

Staphylococcus aureus became resistant to penicillin shortly after penicillin was introduced in the 1940s by producing penicillinase, which inactivates the β-lactam ring in penicillin. Penicillinase-stable β-lactam antibiotics (methicillin, nafcillin, and oxacillin) were developed to overcome this resistance. However, in 1961, a strain of methicillin-resistant S. aureus (MRSA) was identified that was resistant to these newer β-lactam antibiotics.¹ Methicillin resistance occurs as a result of a modified drug target, penicillin-binding protein (PBP2a), encoded by the mecA gene² on a staphylococcal cassette chromosome (SCCmec types I–V).³ SCCmec types II–III typically carry multiple resistance determinants. SCCmec types IV–V carry fewer resistance determinants but may be associated with virulence factors such as Panton-Valentine leucocidin (PVL).

Initially, most strains of MRSA were health care or hospital associated (HA-MRSA) and were SCCmec types I–III. Now, MRSA can be acquired in the community (CA-MRSA) and colonizes or infects patients who have neither been hospitalized nor had recent access to health care. CA-MRSA is associated with SCCmec types IV and V. CA-MRSA tends to be susceptible to more antibiotics compared to HA-MRSA. However, resistance patterns are variable, depending on which strains are circulating in a community.

EPIDEMIOLOGY

Staphylococcus aureus has a propensity to colonize the anterior nares, and many studies evaluating colonization rely on nasal cultures.⁴ In infants, other body sites are likely to be colonized, including the throat, umbilicus, skin (groin and axillae), vagina, and rectum.^{5, 6, and 7} Approximately 25%–50% of the population is colonized with S. aureus, either methicillin-sensitive strains (MSSA) or MRSA.^{8, 9, and 10} Colonization with MSSA is more common than with MRSA. Children are more likely to be colonized than adults. Some patients are never colonized, some only intermittently, and some persistently. The rate of MRSA colonization in the United States is reported to be low (<2%)⁸ but varies depending on the population studied. For example, the following holds:

• Newborns: Fewer than 1% to 40% (colonization rates higher during neonatal intensive care unit [NICU] outbreaks)^{11, 12, 13, and 14}

• Healthy children less than 5 years old: Fewer than 1%–6.7%^{15, 16}

• Pregnant women: Fewer than 1%–10% (anogenital cultures)^{17, 18, 19, and 20}

  • – There are conflicting reports regarding the association of MRSA genital colonization and group B streptococcus genital colonization.²⁰

• Homeless in San Francisco: 2.8%

• Veterinarians: 6.5%²¹

• Pediatric patients in Texas: 22%²²

It is common for infants to become colonized with S. aureus after exposure to their mothers, other family members and friends, or hospital and home environmental surfaces. In most cases, colonization occurs after discharge from the nursery.²³ Transmission of MRSA is reported through the following:

• Infected breast milk and colonized caregivers to neonates²⁴

• Health care workers to neonates²⁵

• NICU patients to health care workers and their families²⁶

• Interinstitutional transfer of MRSA from one nursery to another²⁷

Neonatal colonization with S. aureus increases with age. Most infants are unlikely to be colonized in the first 3 days of life.^{11, 28} Transmission of MRSA from mother to infant during delivery is rare but reported (proven when isolates are matched by pulsed field gel electrophoresis).²³ Most infants colonized with MSSA or MRSA do not develop infection. However, in some studies, 4%–26% of MRSA-colonized infants developed MRSA infection.^{11, 12, 28} Risk factors for developing infection with MRSA in the newborn period include^{12, 13, 29, 30, 31, 32, 33, 34, and 35}

• MRSA chorioamnionitis

• Prematurity or very low birth weight

• Cesarean section

• Presence of a central venous or umbilical catheter

• Previous antibiotic use

• Prolonged hospitalization

• Surgical procedures

• Male gender (independent of circumcision)

• Circumcision

Colonization with MRSA clears over time in most infants without specific topical or oral antibiotics for eradication.¹¹

CLINICAL FINDINGS:

MRSA Colonization: Colonized infants are asymptomatic.

MRSA Infection: Clinical features of infection are indistinguishable from those caused by MSSA. Infection with MRSA typically presents after the first week of life³² but may be present shortly after delivery or a few weeks after discharge from the nursery.

Skin and soft tissue infections (SSTIs): SSTIs comprise most neonatal MRSA infections.

• Superficial skin infection lesions are typical of those seen with S. aureus (eg, impetigo) and may be pustular or bullous in appearance.

• Lesions may be present anywhere, but in newborns are often in the diaper area.

• MRSA may cause cellulitis, mastitis, or omphalitis.

MRSA conjunctivitis: MRSA is an increasingly common cause of neonatal bacterial conjunctivitis.³⁰

Bacteremia:

• Staphylococcus aureus rarely causes early-onset neonatal sepsis.

• Approximately 8% of cases of late-onset sepsis (after 72 hours of life) in low birth weight infants are caused by S. aureus.^{37, 38}

• Infants with MRSA bacteremia are younger at presentation than those with MSSA bacteremia (mean age at diagnosis 23 vs 32 days).³⁹

• Blood cultures may be persistently positive, especially if catheters are not removed immediately.

• Failure to remove a central catheter in less than 4 days has been associated with complicated MRSA disease.⁴⁰

Endocarditis: MRSA endocarditis has been reported in infants and has a high mortality.⁴⁰ Premature infants and those with congenital heart disease are most often affected.

Bone and Joint Infections: MRSA bone and joint infections commonly involve multiple foci and are associated with deep vein thromboses with septic embolization to the lungs.

Respiratory: Though MRSA may colonize the respiratory tract or endotracheal tube in asymptomatic infants, it can cause pneumonia, empyema, and lung abscess.⁴¹

Deep Abscess: Deep abscesses involving the liver and retropharynx have been reported in infants.^42,43

Central Nervous System Infection:

• Meningitis or brain abscesses are rare but reported, including one case report of an extremely premature infant who succumbed to multiple brain abscesses caused by MRSA.⁴⁴

• Some infants with MRSA bacteremia have a cerebrospinal fluid (CSF) pleocytosis with negative CSF cultures.³¹

• MRSA may cause ventriculoperitoneal shunt infections.

Urinary Tract Infections: These may be seen in infants with bacteremia and disseminated MRSA infection.⁴⁵

Coinfections: Serious coinfections with MRSA and other pathogens have been reported. Infection with MRSA and influenza virus has resulted in serious illness and death.^46,47 MRSA infection occurs in conjunction with other respiratory pathogens such as respiratory synctial virus (RSV), parainfluenza virus, adenovirus, and enteroviruses.⁴¹ Staphylococcus aureus (including MRSA) has been isolated from vesiculopustular skin lesions in addition to herpes simplex virus (HSV) in patients with neonatal HSV infection.

DIAGNOSIS

Screening the Asymptomatic Infant

• There are currently no formal consensus guidelines regarding optimal screening procedures for asymptomatic infants for MRSA colonization.⁴⁸

• Many nurseries screen all infants at the time of admission to the hospital. Some screen periodically thereafter until the baby is discharged home. Samples may either be sent for culture (results available within 2–3 days) or mecA PCR (results available within 1 day).

• Caregivers of infants who screen positive for MRSA should receive education regarding MRSA.⁴⁹ The Centers for Disease Control and Prevention website has educational material for parents regarding MRSA colonization and infection (http://www.cdc.gov/mrsa/index.html).

• Estimated sensitivity of screening for identifying colonized infants^12,50:

  • – Nares: 71%

  • – Umbilicus: 60%

  • – Skin: 40%

  • – Rectum: 21%–60%

  • – Nares plus umbilicus: >90%

Evaluation of MRSA in the Symptomatic Infant

• Physical Examination: Perform a complete physical examination with particular attention to numbers of venous or arterial catheters, evidence of catheter exit site or tunnel infection, eye discharge, skin lesions, respiratory distress, areas of cellulitis, joint or limb swelling, or failure to move an extremity.

• Laboratory Testing and Imaging: Laboratories identify MRSA by determining oxacillin or methicillin resistance by disk diffusion broth microdilution techniques. Larger laboratories may have the technology to identify the mecA gene by PCR.⁵¹ Other techniques to differentiate MSSA from MRSA include minilatex agglutination, colorimetric immunoassay methodology, and fluorescence screening.⁵²

Evaluation of Specific MRSA Conditions

• Superficial skin infection in a well-appearing healthy infant:

  • – Obtain a Gram stain and bacterial culture of pus from skin lesions with full susceptibility testing.

  • – Consider testing for HSV and varicella zoster virus (VZV) by direct fluorescent antibody testing, viral culture, or HSV/VZV PCR if lesions are suspicious for HSV or varicella.

• Any infant with signs of sepsis or systemic infection: Perform a full sepsis evaluation, including

  • – Lumbar puncture for glucose and protein, complete blood cell count (CBC) with differential, Gram stain, and cultures

  • – Blood cultures

  • – Urine culture (suprapubic or straight catheterization)

  • – C-reactive protein

  • – A chest radiograph may show consolidation, pleural effusion, or lung abscess.

  • – Echocardiogram should be obtained if blood cultures are positive for S. aureus for more than 2–3 days and in patients with congenital heart disease.

  • – Plain radiographs of bone can indicate suspected osteomyelitis. Magnetic resonance imaging (MRI) is helpful if feasible. Consider technetium bone scan because multifocal osteomyelitis is seen frequently in neonates.

  • – Computed tomography or MRI of the brain should be performed if the patient has clinical or laboratory evidence of central nervous system disease.

  • – Abdominal ultrasound can be used to identify liver abscesses, particularly if the patient has had an umbilical catheter in place.⁴³

TREATMENT

Vancomycin is recommended as the initial empiric therapy for suspected neonatal MRSA infections pending susceptibility results. Vancomycin trough levels of 15–20 µg/mL are recommended for adults with MRSA infection.⁵³ Data in neonates and children are limited, but for serious infections, these trough levels may be considered.

Clindamycin can be used empirically if local susceptibility patterns show that less than 10% of isolates are resistant to clindamycin by the D test. Check your hospital antibiogram. Clindamycin can be used for most infections except endovascular or central nervous system infections if the isolate is susceptible.

Linezolid may be considered, except in cases of endovascular infection. Studies evaluating the use of linezolid in neonates with serious MRSA infections are limited. If linezolid is used for a prolonged period (>2 weeks), follow CBC and differential, electrolytes, lactic acid, and liver function studies to assess for toxicity.

Trimethoprim-sulfamethoxazole is not recommended for use in infants less than 2 months of age.

• Colonized asymptomatic infants: No treatment is necessary.

• Uncomplicated superficial skin infection in a healthy term infant:

  • – Topical 2% mupirocin

  • – Education of caregivers regarding MRSA, including information about the signs and symptoms of invasive disease and guidance concerning measures to prevent the spread of infection in the home.

• SSTI including abscess and cellulitis in well-appearing, afebrile infant:

  • – Incision and drainage of abscess

  • – No antimicrobial therapy or give an appropriate oral antibiotic. Oral antibiotic choices:

    • Clindamycin is used if susceptible; or

    • Trimethoprim-sulfamethoxazole can be given to infants older than 2 months.

    • Linezolid can be used in select circumstances, but it is costly and associated with bone marrow suppression when used for more than 2 or 3 weeks.

• Extensive SSTI, ill appearing, with temperature instability, prematurity, extremely low birth weight, or immunocompromised:

  • – Parenteral therapy with vancomycin or clindamycin (if local rate of resistance is < 10%) can be used at least until improvement is noted and bacteremia ruled out.

  • – If infection is severe, surgical consultation, vancomycin plus naficillin with or without other antimicrobials (for gram-negative and anaerobic coverage) are used until culture results are known. The optimal duration of therapy for SSTI is unknown. Courses range from 5 to 14 days and are guided by clinical response.

• MRSA conjunctivitis:

  • – Treat with ophthalmic drops (eg, Polytrim^®)

  • – Consider oral therapy if infection recurs or does not respond to treatment

• Ill-appearing infant with no focal findings who has been hospitalized for several days:

  • – Empiric therapy: intravenous vancomycin plus cefotaxime with or without aminoglycoside pending culture results

• Documented MRSA bacteremia:

  • – Intravenous vancomycin. Follow vancomcyin levels and consider aiming for trough levels between 15 and 20 µg/mL. Monitor renal function and CBC with differential. If the organism is MSSA, do not use vancomycin. Nafcillin or a first-generation cephalosporin remain drugs of choice for MSSA infection.

  • – Intravenous clindamycin (if susceptible) may be considered for non-endovascular bacteremia provided cultures clear immediately.⁵³

  • – Intravenous linezolid may be considered for nonendovascular bacteremia.

  • – Remove all central lines.

  • – Continue to obtain blood cultures until negative; MRSA bacteremia may be prolonged.

  • – Assess daily for foci of disseminated infection.

  • – Treat for a minimum of 14 days (longer if evidence of disseminated infection is present).

• MRSA endovascular infection (endocarditis)⁵⁴:

  • – Intravenous vancomycin. Adjunctive therapy with rifampin and gentamicin may be considered after consultation with a pediatric infectious disease specialist.

  • – MRSA isolates with a vancomycin MIC of 2 µg/mL or greater by broth microdilution are associated with treatment failures, despite appearing susceptible in vitro.

  • – Consultation with an infectious disease specialist in such cases is recommended.

  • – Clindamycin and linezolid are bacteriostatic drugs and should not be used as sole treatment of endovascular infections.

  • – Echocardiograms should be obtained on all children with congenital heart disease or bacteremia lasting more than 2 or 3 days.

  • – The minimum duration of therapy is 6 weeks.

  • – A patient with endocarditis must be managed in conjunction with a cardiology specialist. Infants with S. aureus endocarditis are at risk for acute heart failure, dehiscence of a valve, myocardial abscesses, and embolic events.

• MRSA pneumonia:

  • – If empyema is present, it should be drained surgically.

  • – Antibiotic choices are vancomycin, clindamycin, or linezolid.

• MRSA bone or joint infection⁵⁵:

  • – Osteomyelitis:

    • Surgical debridement of infected bone and contiguous soft tissue or muscle abscesses should be performed.

    • Antibiotic choices are intravenous vancomycin, clindamycin, or linezolid.

    • Minimum duration of therapy is 4–6 weeks.

    • A substantial number of cases of osteomyelitis also involve the adjacent joint and multiple bones.

  • – Septic arthritis:

    • Drainage or debridement of the joint space should be performed.

    • Antibiotic choices are the same as for osteomyelitis.

    • Duration of therapy is a minimum of 3–4 weeks if bone involvement has been ruled out.

• MRSA central nervous system infections:

  • – Meningitis:

    • Intravenous vancomycin may be given for 2 weeks with or without rifampin.

    • Intravenous linezolid may also be considered.

    • If a ventricular shunt is present, it must be removed.

    • Consider head imaging to rule out focal abscess.

  • – Brain, subdural, or epidural abscess:

    • Neurosurgical consultation should be provided for abscess drainage.

    • Intravenous vancomycin is given for 4–6 weeks with or without rifampin.

    • Intravenous linezolid may also be considered.

OUTCOMES

Mortality, duration of hospitalization, and neurodevelopmental impairment for infants with MRSA bacteremia are similar to those with MSSA bacteremia.⁵⁶ Duration of positive blood cultures is often prolonged.

INFECTION CONTROL

• Excellent hand hygiene is key in preventing nosocomial spread of MRSA.⁵⁷ One study showed a negative correlation between the amount of alcohol gel used and prevalence of MRSA colonization in a neonatal intensive care nursery.⁵⁸ Hands that are visibly soiled should be washed with soap and water.

• Infants colonized or infected with MRSA should be placed in contact isolation for the duration of hospitalization and subsequent hospitalizations.⁵⁹

• Infants with MRSA pneumonia should receive droplet precautions.

• Other strategies used to prevent or halt outbreaks of MRSA infections in newborn nurseries include^{51, 60, 61}

  • – Application of 1% chlorhexidine powder, triple dye, or iodophor to the umbilical stump.

  • – Prevention of nursery overcrowding or understaffing.

  • – Cohorting of colonized or infected babies and caregivers.

  • – Use of mupiricin or other antibiotics has not been consistently shown to eradicate colonization.

• An infant who received treatment of MRSA infection and recovers will often remain colonized despite a prolonged course of intravenous or oral therapy.

MATERNAL MRSA INFECTON AND BREASTFEEDING

• A recent review discussed in detail the safety of antibiotics prescribed to lactating mothers with MRSA infections who breast-feed.⁶²

• Detailed, up-to-date information regarding safety of drugs used by lactating mothers (to the infant) is available through the United States National Library of Medicine Toxicology Data Network (see LactMed at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT).

• In general, only low concentrations of antibiotics are found in breast milk. Anticipated adverse events include alteration of infant bowel flora. Caution is recommended if the mother is receiving trimethoprim-sulfamethoxazole and the infant has glucose-6-phosphate dehydrogenase deficiency, is premature or ill, or has hyperbilirubinemia.⁶³

• The mother with MRSA mastitis may continue to breast-feed her infant unless the infant is premature or seriously ill.

REFERENCES

INTRODUCTION

Abundant and convincing evidence demonstrates that medicines block transmission of Toxoplasma gondii from the pregnant woman to her fetus, kill tachyzoites, reduce or eliminate parasite burden, reduce or eliminate eye disease, reduce or eliminate brain disease, reduce severity of disease, eliminate meningitis, treat meningoencephalitis, and lower immune markers of infection.^{1, 2, 3, and 4} Earlier, there was some controversy in the literature (discussed in Reference 4), but currently, review of data from in vitro and experimental animal studies, attention to older publications of studies that were performed meticulously (reviewed in References 1, 2, 3, and 4), and several recent studies have clarified the efficacy and benefits of proper, early, and rapid diagnosis and medical treatment.^5,6 The recent data demonstrate how important it is to establish such diagnosis and treatment as the standard for medical care to prevent the loss of productive lives to this disease. The time when the acute infection is diagnosed and treated is critical.^{1, 2, 3, 4, and 5} The earlier the infection is treated, the better the outcomes will be for fetus, infant, and congenitally infected person.^5,6 For this reason, the focus of this chapter is to make clear how diagnosis and treatment of the fetus and infant can be optimized and how this is carried out practically.

PREVENTION WITH EDUCATION DURING GESTATION

The approach to diagnose, prevent, and treat infections of the fetus is summarized in Tables 116-1, 116-2, 116-3, 116-4, 116-5, 116-6, 116-7, and 116-8 and Figures 116-1, 116-2, 116-3, and 116-4. The pregnant woman with acute acquired T. gondii infection and the mother of a congenitally infected infant may have retinal disease caused by the parasite and should have a retinal examination. Simple instructions concerning avoiding means of acquisition of the parasite provide an opportunity to prevent some fetal infections in the pregnant woman. An educational pamphlet is provided in Chapter 57, Figure 57-3. This may be downloaded from the Internet without charge or copyright (http://www.toxoplasmosis.org/pamphlet.pdf) so it can be provided to pregnant patients or those considering becoming pregnant. However, environmental contamination by oocysts is common and often unrecognized. Risk cannot be eliminated entirely by education. Infection may occur in persons with no recognized risk factors.

GESTATIONAL SCREENING: DIAGNOSIS, PREVENTION, AND TREATMENT OF THE ACUTELY INFECTED PREGNANT WOMAN AND FETUS

Figure 116-1 and Figure 57-23 in Chapter 57 summarizes an approach used universally in France, where it successfully detects seroconversion during gestation to prevent transmission to the fetus and to identify infection in the fetus. This allows treatment without delay. In this approach,^{1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21} currently utilized in some of the best obstetrical practices in the United States, serologic screening for T. gondii specific antibody to immunoglobulin G (IgG) and immunoglobulin M (IgM) is performed once a month during gestation for all pregnant women who are seronegative and is initiated by the 11th week of gestation. Ideally, such screening would, and sometimes does, begin immediately before or early in gestation at the time pregnancy is noted, even when this is earlier than 11 weeks’ gestation. Screening is continued monthly through the time the infant is born and is performed at birth and when the infant is 1 month old to detect infections acquired late in gestation. This approach presents the opportunity to confirm when a pregnant woman seroconverts (ie, newly develops specific IgG antibody to T. gondii). This is done so that acute acquired infection can be proven by more specialized testing. In the United States, this specialized testing is performed in a reference laboratory (Table 116-7). This then enables the physician to prevent transmission from the newly infected pregnant woman to her fetus through treatment of the mother with spiramycin early in gestation (Table 116-1). Fetal ultrasounds are obtained every 2 weeks until term for mothers who seroconvert. It is then possible to diagnose infection in the fetus by ultrasound or amniocentesis. It enables treatment of the infected fetus when diagnosed by amniocentesis with polymerase chain reaction (PCR) testing of the amniotic fluid for T. gondii DNA or via ultrasound. The infected fetus can then be treated by treatment of the mother with pyrimethamine and sulfadiazine (with leucovorin, folinic acid). Clindamycin, clarithromycin, and azithromycin are second-line medicines used for pregnant women with significant hypersensitivity to sulfadiazine, but there are no data concerning their efficacy. Treatment of the infant continues after birth as described in Chapter 57 and here (Table 116-1; Figure 116-4).

BIRTH: PLACENTA SAMPLES OBTAINED IN THE DELIVERY ROOM

Table 116-2 outlines how the placenta should be processed in the delivery room and afterward.²

CLINICAL EVALUATION OF THE INFANT

Clinical evaluation of the infant is summarized in Table 116-5. Figures 116-2 and 57-8 and Tables 57-4, 116-5, 116-6, 116-7, and 57-8 include common manifestations of this infection,^{1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, and 45} which should lead to prompt diagnostic evaluation. This highlights the importance of recognition by neonatologists and others caring for such an infant that these findings are manifestations of congenital toxoplasmosis. Details of diagnostic evaluation of the infant to exclude or establish manifestations of this disease are in Tables 116-2, 116-3, 116-4, 116-5, and 116-6 along with some comments about evaluation of the mother and other family members.^{2,40,42, 43, 44, 45, 46, and 47} The tables and figures in Chapter 57 also differently illustrate manifestations of this infection and diagnostic approaches.

SAMPLE AMOUNTS NEEDED FOR SPECIALIZED TESTING AND USEFUL CONTACT INFORMATION

One of the areas of confusion sometimes is which samples and how much of them should be obtained for particular tests. Therefore, Tables 116-2, 116-3, and 116-4 and 116-6 provide this information. Table 116-7 provides contact information helpful for diagnosis and treatment and counseling pregnant women and their families and families for whom this diagnosis is suspected or proven.

ANTIBODY LOAD IN SERUM AND CEREBROSPINAL FLUID

In certain circumstances (eg, birth of an infant who is completely normal with a low likelihood of transmission from an acutely infected mother, had negative amniotic fluid PCR for T. gondii infection in a reference laboratory, and had no manifestations at birth consistent with infection), a decision is made with the parents not to treat the infant but rather to follow serum antibody load. This is measured as shown in Tables 116-8 and 57-25 (Chapter 57). In this case, a physician monitors the measurement of IgG antibody specific for T. gondii each month. Serum is diluted 2-fold in parallel with the previous month’s sample and sensitivity of the dye test noted. Passively transferred maternal T. gondii-specific IgG will fall by 50% because the half-life of IgG is 30 days. At the same time, the physician monitors that and when the infant begins making his or her own IgG (quantitative immunoglobulin milligrams per deciliter measured in the local hospital’s laboratory; also see discussion in Chapter 57).

A similar equation can be used to calculate antibody load in cerebrospinal fluid (CSF) to demonstrate local production of antibody to T. gondii due to active brain infection. This is used only when the dye test titer is less than 1:1024 (~300 IU usually). A ratio of antibody produced in CSF of 4 or greater is considered indicative of local antibody production (Tables 116-4 and 57-25 [Chapter 57]).

GUIDELINES FOR TREATMENT OF GESTATIONAL AND CONGENITAL TOXOPLASMOSIS

Table 116-1 provides guidelines for the treatment of the fetus, newborn infant, and child with congenital toxoplasmosis.² A method for preparation of medicines and their administration² is shown in Figure 116-4. In the unusual circumstance of an infant too sick to be able to utilize pyrimethamine and sulfadiazine by mouth or by feeding tube, intravenous administration of trimethoprim/sulfamethoxazole with clindamycin has been an alternate, but less-satisfactory, approach. Active choriodal neovascular membranes have been treated effectively with intraocular injection of ∝ vascular endothelial growth factor (∝-VEGF³³; LUCENTIS^®) in conjunction with anti-T. Gondii medicines (Figure 57-22). This has also been safely used to treat retinopathy of prematurity in infants.⁴⁸

TOXICITIES OF MEDICINES

The major toxicity encountered in treatment of the fetus is reversible neutropenia.^24,26 Hypersensitivity to sulfadiazine appears to be much less often encountered as a serious complication in the pregnant woman and infant than in older children and adults.⁴⁹ In the infant with congenital toxoplasmosis, the major toxicity of the medicines used to treat toxoplasmosis is reversible neutropenia. Most children maintain neutrophil counts of about 1000/mL³ (800–1200/mL³) during the year of treatment. Concomitant viral infections can result in diminution of the neutrophil count. This is managed by withholding pyrimethamine if absolute neutrophil count (ANC) falls to between 500 and 700. Both pyrimethamine and sulfadiazine are withheld if the ANC is less than 500. Leucovorin is increased to 15–20 mg/day these cases. Leucovorin is always continued for 1 week after discontinuing pyrimethamine because of the relatively long half-life of pyrimethamine (60–90 hours). Granulocyte colony-stimulating factor (G-CSF) has been used to maintain normal neutrophil counts when substantial neutropenia has been a recurrent or refractory problem. Teeth are gently cleaned with a soft pediatric toothbrush or washcloth to prevent development of dental carries due to the sugar suspension agent for the medicines. Three to four months after discontinuing treatment, commonly there is a rebound (elevation) in antibody titer of T. gondii-specific IgG, IgM, or IgA, usually without any recognized symptomology.^24,26

OUTCOMES AND PROGNOSIS

Medical and adjunctive treatment, such as prompt correction of hydrocephalus with ventriculoperitoneal shunt procedures, improves the prognosis.^{1, 2, 3, 4, 5, and 6,10,11,15,21,26, 27, 28,30,50,51} The earlier treatment is initiated, the better the prognosis will be.^5,6 This infection, even when it causes hydrocephalus, is treated as expectant for excellent outcomes. Outcomes may be good, although this does not always occur.^{1, 2, 3, 4, 5, and 6,10,11,15,21,23,26, 27, and 28,30,50, 51, and 52} It is not possible to predict with certainty when outcomes will be favorable. There can be remarkable expansion and growth of cortical mantle with ventricular peritoneal shunting. Third ventriculostomies were found to fail often in this disease,¹⁶ presumably because of the associated inflammatory process, and thus are not used. When CSF protein is high, lavage of ventricles prior to placement of the shunt to prevent occlusion of the shunt has been used successfully. Figure 57-10 shows this improved prognosis as well as some of the problems that may occur. Brain calcifications often resolve or diminish in size with treatment in the first year of life.⁵²

COMPARISON OF CONGENITAL TOXOPLASMOSIS AT BIRTH IN FRANCE, AUSTRIA, GERMANY, AND THE UNITED STATES

Prenatal and postnatal treatment improve outcomes at birth and later in life.^{1, 2, 3, 4, 5, and 6,10,11,15,21,23,26, 27, and 28,30,50, 51, and 52} The more rapidly treatment is initiated to stop destruction of the fetus and infant’s eyes and to stop brain and systemic infection, the better the outcome will be. This empirical observation is supported by in vitro data and studies with experimental animals. The latter studies demonstrated that medicines used to treat the infection are effective in vitro and in vivo in killing the active tachyzoite that destroys tissue. A contrast of outcomes in France with those in the United States is informative.^1,45 Table 116-9 and Figure 116-2 shows this contrast.⁴⁵ In France, there is serologic screening monthly during gestation (Figure 116-1). This facilitates prompt diagnosis and treatment of the fetus without delay. In the United States, screening rarely occurs, and when it does, it may often be performed only once or twice in a more random manner, with consequent delays in treatment.^1,45

ANALYSIS OF COST-MINIMIZING STRATEGIES IN PERSPECTIVE

Because exposures often are unrecognized (Tables 57-1 and 57-2 and Figure 57-3),^25,29,44 although education about risk factors can help to reduce acquisition of infection during gestation, serologic screening with prompt diagnosis and treatment or a vaccine are the only means that could almost entirely successfully prevent this disease and the suffering it causes.³ A vaccine is needed but has not yet been developed for human use. Serologic screening and treatment in gestation and in infancy are predicted to be cost minimizing.³ This is with the wide range of incidences of infection likely to occur in a variety of populations throughout the world (Figure 57-4).^3,53Medicines that eliminate cysts and active infection would greatly facilitate treatment and improve outcomes, but are not available.

In 1990, Desmonts from France wrote the following:⁵⁷

“There is a parasite, Toxoplasma, which is harmless for you but which can cause severe impairment in your child if you become infected during pregnancy. You will notice nothing but we could tell you now if you are immune; if you are not, we can monitor you during pregnancy. If you become infected we can detect the infection in your infant even if he looks normal; we can even detect it in utero and treat without delay. Yet we will do nothing, since all this is too expensive. But do not worry. Perhaps you are immune—and if you are not, you will probably escape infection when pregnant. If the worst does happen your fetus might still escape. And if your infant is severely impaired, there is no risk in having another baby because you will now be immune. Nevertheless, try not to get infected. Eat well-cooked meat and wash your hands. Good luck.”

Neonatologists can help improve care by recognizing manifestations promptly at birth and considering and testing for congenital toxoplasmosis in their patients to prevent some sequelae (Figure 116-2).

In 2011, we⁴⁵ noted the following:

Congenital toxoplasmosis continues to be a tragedy for parents and children in the United States. Decades ago some countries responded to the challenge by implementing national programs for systematic serologic screening of all pregnant women. Others did so by performing routine serologic screening in all newborns. Yet, despite the fact that all studies performed in the United States continue to reveal that congenitally infected children are born severely affected each year, a national program or policy to address the threat of this disease is currently lacking.

We now have practical means to prevent and treat this infection that were outlined here. They can be easily implemented by obstetricians, perinatologists, neonatologists, and pediatricians. This will prevent suffering and loss of life, sight, cognition, motor function, and seizures from this disease. This can be accomplished by prompt diagnosis and treatment as presented in Chapter 57 and this chapter. This appears to be not only feasible but also likely cost minimizing.

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) R01 AI027530-21 and gifts from the Mann and Cornwell, Taub, Cussen-Kapnick, Rooney-Alden, Engel, Pritzker, Harris, Zucker, Samuel, and Mussilami families and NIH U01 5 U01 AI077887-05 and 2R01AI027530-18A2. We thank those families and physicians who have worked with us to help us learn more about how to diagnose, manage, and treat this disease and those who have taught us about it, especially George Desmonts, Jacques Couvreur, Philippe Thulliez, and Jack Remington.

This chapter is especially in honor of Dana, Chad, Dani Jo, Elena, Graham, Grant, Joshua, Lucky, Margaret, Miguel, Nicky, Robbie, Roxanne, and many others and their families who understand with special poignancy Edward Young’s statement “who would not give a trifle to prevent what they would give a thousand worlds to cure.”

REFERENCES

INTRODUCTION

Perinatal transmission rates in the United States are at historic lows (<2%) because of the availability of effective interventions to prevent perinatal human immunodeficiency virus (HIV) transmission.¹ However, transmission does occur in a small number of infants, primarily because of missed prevention opportunities.^{2, 3} The neonatologist plays a vital role in the prevention of perinatal HIV transmission in early identification of HIV-exposed newborns born to infected mothers who were not tested for HIV during pregnancy and in administering antiretroviral (ARV) prophylaxis to HIV-exposed infants as early as possible after birth.^4,5 The primary care physician, in conjunction with a pediatric infectious disease specialist, must ensure appropriate follow-up to confirm or exclude the diagnosis of HIV infection in early infancy and provide ongoing counseling, support, and anticipatory guidance⁶ (Table 117-1). A comprehensive review of recommendations for evaluation and treatment of the HIV-exposed infant has been published by the American Academy of Pediatrics (AAP) and other experts.^4,5,7,8 This chapter discusses the clinical evaluation, laboratory testing, and treatment of HIV-exposed infants, incorporating the recently updated Public Health Service guidelines with a focus on prevention of perinatal HIV transmission.^5,6

DIAGNOSIS/INDICATION

Universal prenatal HIV testing is the gateway to access effective antepartum, intrapartum, and postpartum interventions to prevent perinatal HIV transmission. All pregnant women must be routinely tested for HIV (“opt-out” approach) regardless of potential risk factors.⁹ Repeat testing during the third trimester of pregnancy is recommended for certain high-risk populations to identify new infections.⁹ HIV-negative women should receive counseling to maintain HIV-negative status during pregnancy and thereafter. In contrast, women with acute or recent HIV infection must be linked to care and receive a potent combination ARV drug regimen as soon as possible, with the goal of achieving viral load to undetectable levels and preventing perinatal HIV transmission.⁵ Scheduled cesarean delivery at 38 weeks’ gestation is recommended for HIV-positive women who have received ARV agents but have viral load greater than 1000 copies/mL near delivery.⁵ Care of the HIV-exposed infant must then focus on reducing the risk of transmission with ARV prophylaxis.

If maternal HIV infection status is unknown at the time of delivery or repeat testing during the third trimester has not been done in certain high-risk women as recommended, rapid HIV testing of the mother or infant is recommended as soon as possible after delivery with immediate initiation of ARV prophylaxis if the rapid test is positive.⁵ Western blot testing must be done as soon as possible to confirm positive rapid HIV antibody test on the mother or infant, but infant ARV prophylaxis must not be delayed while waiting for the confirmatory results. ARV prophylaxis can be discontinued if the confirmatory test result is negative.⁵

Clinical Findings

History

The initial assessment of the HIV-exposed infant begins in the delivery room. Prenatal history is critical in the routine evaluation and management of HIV-exposed infants. Identification of perinatal HIV exposure is the first step involved in the delivery of optimal care to the HIV-exposed infant.⁶ In most cases, the diagnosis of maternal HIV infection would have been established during the antenatal period. Medical and obstetrical history should be reviewed to determine if the risk of perinatal HIV transmission is high or low depending on whether the mother received effective interventions. Details about maternal HIV diagnosis (viral load, CD4 T-lymphocyte cell count, genotypic drug resistance testing); ARV drug regimen (timing of initiation and compliance); and maternal clinical status must be elicited.^6,8 Maternal history should include history of sexually transmitted infections (such as syphilis, hepatitis B, or herpes simplex virus) or coinfections such as tuberculosis (TB), toxoplasmosis, or hepatitis C. Infants exposed to 1 or several of these pathogens should undergo further evaluation. In addition, history should include obstetric details (including duration of ruptured membranes, mode of delivery), use of invasive intrapartum monitoring, birth weight, and gestational age.⁶

Physical Examination

Infants with perinatally acquired HIV infection are often asymptomatic, and physical examination is usually normal in the neonatal period.¹⁰ The common features of HIV infection in early infancy are lymphadenopathy, hepatomegaly, and splenomegaly, often noted at around 3 months of age.¹⁰ Other commonly encountered findings in the first year of life include failure to thrive and neurodevelopmental delay.^10,11 HIV-exposed infants must be closely monitored for signs and symptoms of early HIV infection before definitive virologic tests become available.⁶

Baseline Tests

A complete blood cell count (CBC) with differential should be obtained on HIV-exposed infants before initiating ARV prophylaxis.⁵ Some experts recommend virologic testing (HIV DNA or RNA polymerase chain reaction [PCR] assay) at birth for diagnosis of intrauterine HIV infection, especially in HIV-infected women who have suboptimal viral suppression during pregnancy or near delivery or there is a concern about infant follow-up.⁵

TREATMENT

Neonatal ARV Prophylaxis

All HIV-exposed infants must receive ARV prophylaxis as soon as possible after birth, preferably at 6–12 hours of life, to reduce the risk of perinatal HIV transmission (Table 117-2).⁵ When the mother has received combination ARV therapy (ART) during pregnancy, neonatal zidovudine (ZDV) at gestational age-appropriate dosing for 6 weeks is the recommended ARV prophylaxis regimen of choice.

When the mother has not received antepartum ARV during pregnancy, combination ARV prophylaxis, including ZDV for 6 weeks plus 3 doses of nevirapine (NVP) during the first week of life (birth, 48 hours, and 96 hours of life), is recommended for HIV-exposed infant (Tables 117-2 and 117-3).^5,12 In these scenarios, a pediatric HIV specialist should be consulted and mothers should be counseled regarding the potential benefits and risks of combination ARV prophylaxis. In premature infants, only ZDV and NVP are recommended for ARV prophylaxis because data on pharmacokinetic, dosing, and safety of alternative ARV drugs are lacking. Infant ARV prophylaxis initiated after 48 hours of birth is not effective.¹³

Physicians can contact the Perinatal HIV/AIDS (acquired immunodeficiency syndrome) Hotline (1-888-448-8765) and seek free clinical consultation services on all issues related to perinatal HIV, including infant care.⁵ Social services should be involved before the mother and baby are discharged from the hospital to ensure compliance regarding follow-up visits. Newborns should be discharged with a supply of oral ZDV syrup.

Tests

Laboratory Testing

A repeat CBC is recommended at 4 weeks of age after starting infant ZDV prophylaxis to monitor for potential hematologic toxicity (anemia and neutropenia).³ Anemia is the most frequently encountered adverse event related to ZDV. If there is evidence of hematologic adverse events in infants receiving ARV prophylaxis, a pediatric infectious disease specialist must be consulted to guide decisions regarding early discontinuation of prophylaxis.⁵ Serum lactate level measurements are not routinely recommended but may be indicated if an infant experiences severe clinical symptoms of unknown etiology, especially neurologic symptoms.⁵ In addition to CBC, some experts recommend serum chemistry and liver function tests at birth and when HIV PCR testing is done in infants exposed to combination ARV drug regimes during pregnancy or during the neonatal period.⁵

Infant HIV Testing

Virologic tests (HIV DNA or RNA assays) are needed for early infant HIV diagnosis and should be performed at 14–21 days of life, at 1–2 months of age, and at 4–6 months of age (Figure 117-1).⁵ An infant is diagnosed with HIV infection if 2 separate blood samples test positive for HIV DNA or RNA PCR.¹⁴ HIV DNA PCR is the preferred virologic test for detection of subtype B HIV virus, the predominant viral subtype prevalent in the United States. For suspected non-subtype B virus detection, HIV RNA PCR should be used for early infant diagnosis.

Infection with HIV can be presumptively excluded in non-breast-feeding HIV-exposed children younger than 18 months of age with 2 or more negative virologic tests at age greater than 14 days and at greater than 1 month.⁵ HIV infection can be definitively excluded in non-breast-feeding HIV-exposed children younger than 18 months of age with 2 or more negative virologic tests at age greater than 1 month and at more than 4 months.⁵ In children with 2 negative virologic tests, many experts confirm HIV-negative status by documenting a negative HIV antibody test result at 12 to 18 months of age (“seroreversion”).^{5, 14} Documentation of negative HIV serology at age 18 months is recommended when non-subtype B HIV is suspected based on maternal origins.^{4, 5}

For any positive HIV DNA PCR result, the infant should be retested immediately for confirmatory PCR testing. If infection is confirmed by 2 positive virologic tests, ARV prophylaxis must be discontinued and a pediatric infectious disease consultation should be requested for confirming the diagnosis and initiation of combination ART if the infant is found to be HIV infected.¹⁵

Pneumocystis jiroveci Pneumonia Prophylaxis

Starting at 6 weeks of age after completion of an infant ARV prophylaxis regimen, all HIV-exposed infants with indeterminate HIV status should receive trimethoprim-sulfamethoxazole (TMP-SMX) to prevent Pneumocystis jiroveci pneumonia (PCP).^5,16 HIV-infected infants are at high risk of developing PCP between 3 and 6 months of life, which can result in high mortality.¹⁷ Prophylaxis for PCP need not be initiated or can be stopped when infant HIV infection is presumptively or definitely excluded.

Infant Feeding

Mothers who are HIV infected should be advised not to breast-feed their infants in the United States because infant formulas are safe and readily available.^4,5,8 Postnatal transmission of HIV is prevented by complete avoidance of breast-feeding.^4,5,8 In addition, physicians must ask mothers about premastication of foods for infant feeding, counsel HIV-infected caregivers to avoid this practice, and discuss safe feeding options.^5,18

FOLLOW-UP

Figure 117-1 provides a diagram outlining the initial evaluation and the necessary follow-up tests for an asymptomatic infant born to an HIV-positive mother, as recommended by the AAP.^{8, 14, 19}

Online resources are available for physicians and other health care workers involved in perinatal HIV prevention programs (Table 117-4). In addition, postpartum follow-up care for HIV-positive mothers must be carefully planned at discharge using a multidisciplinary approach. Several issues must be addressed, including contraceptive counseling, decisions regarding continuing ART postpartum, psychosocial support, and prompt linkage to HIV care and treatment of women diagnosed with HIV during labor (Table 117-5).

Long-Term Follow-up of HIV-Exposed Infants

The long-term carcinogenic effect of ARV drug (especially nucleoside analogue) exposure during the in utero/neonatal period is unknown. Therefore, HIV-exposed infants must be closely followed into adulthood. In addition, ARV-exposed neonates who develop significant organ, especially neurologic or cardiac, disease may need evaluation for mitochondrial dysfunction.⁵

Provision of Counseling and Psychosocial Support

Mothers infected with HIVs often face multiple physical, emotional, and social issues, including coping with the diagnosis, HIV illness or death in other family members, lack of health care, financial challenges, substance abuse, depression, and fear of loss of existing support and services. Mothers must be informed about the serial infant HIV-testing schedule during follow-up visits and informed about the delay in the definite exclusion of HIV infection status for the first several months of life.

Counseling, education, and support for mothers and other caregivers is critical and should include a discussion of all issues in the management of the HIV-exposed infant, including education and counseling regarding adherence to prescribed ARV prophylaxis to prevent perinatal HIV transmission and the administration of TMP-SMX prophylaxis to prevent PCP if indicated, avoidance of breast-feeding, infection control measures, schedule of follow-up visits, importance of maintaining confidentiality of test results, and planning for future child care if the parents are seriously ill from HIV/AIDS.^{8, 20} Recommendations on the care of HIV-exposed infants in foster care have previously been published.²¹ HIV-exposed and HIV-infected infants should not be excluded from day care.²²

HIV Testing of Family Members

Testing for HIV should be offered to the infant’s father and all siblings. Because perinatally acquired HIV-infected children may remain asymptomatic for several years, all siblings should be tested regardless of age.⁸

Anticipatory Guidance and Primary Care for HIV-Exposed Infants

Age-appropriate anticipatory guidance must be provided to all HIV-exposed infants, similar to the guidance provided for non-HIV-exposed infants. In addition, mothers and caregivers of HIV-exposed infants must receive anticipatory guidance around all components of care for the HIV-exposed infant.⁶ Mothers must be counseled at every follow-up visit to completely avoid breast-feeding and against premastication of food for older infants.⁴ In addition, HIV education related to modes of transmission must be provided to mothers and other caregivers, stressing the fact that touching, hugging, or kissing their infants is safe.⁶

Immunizations

Infants exposed to HIV should receive all routine childhood immunizations, including hepatitis B vaccine, inactivated polio vaccine, diphtheria and tetanus toxoids and acellular pertussis vaccine, Haemophilus influenza type b vaccine, pneumococcal conjugate vaccine, and Rotavirus vaccine.⁴ If infant HIV infection is confirmed, then recommendations for the HIV infected must be followed. Readers are referred to the 2012 edition of the Red Book for guidance regarding immunization practices in HIV-infected children.⁴

CONCLUSION

In conclusion, management of the infant born to an HIV-positive mother must take into considerations several unique aspects specific to these infants, including avoidance of breast-feeding, timely initiation of optimal ARV prophylaxis, serial HIV PCR testing within the first 4 months of life to determine infant HIV status, careful monitoring for toxicity related to ARV prophylaxis and clinical signs and symptoms of HIV infection, appropriate anticipatory guidance, and ongoing education and counseling of parents. Care of the HIV-exposed infant warrants a close partnership between the neonatologist, primary care pediatrician, and the pediatric infectious disease specialist.

REFERENCES