Rosalie Sagraves, Pharm.D., FCCP
Spring 1998

Pediatric Infectious Diseases: Part III
Sepsis and Meningitis

  1. Neonatal Infections
  2. Neonatal Sepsis (Sepsis Neonatorum)
  3. Neonatal Meningitis
  4. Childhood Meningitis

Please see Pediatric Infectious Diseases Part II for the goals, objectives, and readings for Part III.

I. Neonatal Infections

The number and severity of bacterial infections are greater in the newborn period than at any time thereafter. Newborn infants do not manifest the classic clinical signs of infection usually observed in children and adults. Systemic bacterial infections occur in < 1% of newborns, and viral disease may occur in 6-8% of all neonates. Nosocomial bacterial infections have been reported in 2-25% of newborns in intensive care nurseries. The mortality from infections varies, but it has been reported as 20-50% for early-onset sepsis and 10-20% for late-onset sepsis. Mortality may even be higher for premature infants. These percentages may vary with the source of information, but they show that, even in this antibiotic era, the morbidity and mortality from neonatal infections is still very high.

A. Definitions:

1. Fetus: week eight of gestation to birth

2. Neonate: birth to 28 days of age

3. Infant: 1 month to 1 year

4. Early-onset neonatal infection: occurs within the first 5 days of life; usually caused by organisms acquired during intrauterine or intrapartum stages.

B. Perinatal environments (infection noted in a newborn may depend on where the exposure occurred ù which perinatal environment):

1. Intrauterine infection can result from:

a. Transplacental passage of pathogens including viral infections (e.g., rubella, cytomegalovirus [CMV], herpes simplex, hepatitis, mumps), bacterial infections (e.g., syphilis, tuberculosis, Listeria, Salmonella infections) and protozoal infections (e.g., toxoplasmosis, malaria).

b. Infection may also ascend through the cervix.

2. Intrapartum

a. The infant is colonized with organisms that reside in the maternal cervicovaginal canal.

b. Common organisms include streptococci, Escherichia coli, and other aerobic and anaerobic enteric pathogens.

c. The neonate may be exposed to Chlamydia, gonococci, herpes simplex viruses and CMV, if mother infected.

3. Postpartum

a. Infection may occur secondary to contact with hospital nursery personnel and equipment after birth or with household members.

b. Organisms in hospital nurseries include enteroviruses, herpes simplex, respiratory syncytial virus and parainfluenza viruses.

C. Ontogeny of the immune system

1. Remember that the fetus is considered a "compromised host" because of the immaturity of his/her immune system.

2. Microorganisms that cause disease in neonates are different from those seen later in childhood or in adults.

D. Antibiotic/antimicrobial agents

1. In Table 1 are listed recommended doses, by age and weight, for selected antibiotics/ antimicrobials. Doses are listed per dose NOT per day. Please note that dosing intervals shorten with increasing maturity. These doses represent generally accepted recommended doses. Because of the wide individual variation among infants in the elimination of certain antimicrobial agents (e.g., aminoglycosides) their use should be guided by serum concentrations to avoid toxic or subtherapeutic concentrations.

Table 1. Recommended doses of selected antibiotics/antimicrobials for neonates

(From Applied Therapeutics: The Clinical Use of Drugs 1997; 96-18)

2. Special limitations for the use of antibiotics/antimicrobials in neonates

a. Sulfonamides are not FDA approved for infants < 2 mo. of age. They may cause kernicterus by competing with bilirubin for albumin-binding sites. Kernicterus is the deposition of bilirubin in the brain which can cause mental retardation.

b. Tetracyclines bind to bone and teeth by chelation with calcium, cause decreased bone growth and permanent discoloration of teeth. The use of tetracyclines should typically be avoided from the second trimester of gestation to year eight of life.

c. Cephalosporins. First-generation agents (e.g., cephalothin and cefazolin) as well as older second-generation agents (e.g., cefoxitin) do not adequately penetrate cerebrospinal fluid (CSF). Another second generation agent cefuroxime penetrates into the CSF but not as well as third-generation cephalosporins which are active against many gram-negative bacilli.

 


II. Neonatal Sepsis (Sepsis Neonatorum)

A. Bacteriology. Organisms that most commonly cause neonatal sepsis and meningitis:

1. E. coli - maternal enteric organism that colonizes the gastrointestinal tract of the newborn and then invades blood and meninges.

2. Group B Streptococcus (GBS) is currently the most common cause of neonatal bacteremia and sepsis.

a. Acquisition

1) Intrapartum

2) Postpartum

b. Syndromes

1) Early-onset disease

2) Late-onset disease

3. Listeria monocytogenes is a gram-positive rod that may cause congenital disease resulting in abortion or stillbirth. It can cause early- or late-onset disease.

4. Anaerobes may cause sepsis with approximately 10-25% of all neonatal bacteremias caused by anaerobes.

5. Miscellaneous organisms associated with disease include Group D streptococci, H. influenzae (usually nontypable), and, in the high-risk newborns, Staphylococcus epidermidis

B. Clinical features:

1. Factors associated with neonatal sepsis are listed in Table 2. When any of these factors associated with early-onset sepsis are present, a screening CBC must be performed and the neonate observed for the development of sepsis.

2. Signs and symptoms of neonatal sepsis are listed in Table 3. When any of these signs or symptoms are present, a complete septic work-up (including LP) should be performed because neonatal meningitis is a common complication of sepsis.

Table 2. Factors and Clinical Signs/Symptoms Associated with Neonatal Sepsis

Factors Information
Early-Onset Sepsis  
Maternal infection during the Maternal fever, pyuria and foul smelling
perinatal period amniotic fluid
Prolonged rupture of the membranes If > 24 hrs since ruptured or amnionitis noted
Difficult or prolonged labor Infant hypoxia and staining of the meconium as a sign of fetal/neonatal stress
Prematurity and/or low birth weight Increased risk of infection
Low Apgar score or the need for resuscitation at birth Hypoxia, hypoperfusion, aspiration or the need for intubation
Late-Onset Sepsis  
Sex Male > Females
Congenital anomalies Routes for infections are provided by e.g., meningomyelocele or sinus tracts
Prolonged stay in neonatal intensive care unit Increase the risk for infection
Procedures Use of monitoring electrodes, umbilical catheters, chest tubes, etc. increase infection risk

 

Table 3. Signs and Symptoms of Sepsis in the Neonate

- Hyperthermia

- Hypothermia

- Lethargy

- Irritability

- Seizures

- Cyanosis

- Dyspnea

- Periodic breathing

- Tachycardia or bradycardia

- Hypotension

- Shock

- Abdominal distention

- Anorexia

- Vomiting

- Diarrhea

- Hepatomegaly

- Jaundice

C. Diagnosis:

1. History and physical examination

2. Blood, urine and CSF samples should be obtained, examined and cultured.

3. Laboratory tests useful in making the diagnosis include:

a. Peripheral WBCs

Table 4. Range of White Blood Cells (x 1000/mm3) for normal infants

 

Age Total neutrophils Immature neutrophils Ratio of immature
    (bands) to total neutrophils
Birth 1.8 - 6 0 - 1.1 < 0.16
1 day 7.2 - 14.5 0 - 1.3 < 0.15
5 days 1.8 - 5.4 0 - 0.5 < 0.12
28 days 1.8 - 5.4 0 - 0.5 < 0.12

 

b. Counterimmunoelectrophoresis (CIE) or latex agglutination (LA)

c. Other tests, when used individually, are unreliable indicators of neonatal sepsis. A combination of a complete leukocyte count, microerythrocyte sedimentation rate, and C-reactive protein may be more accurate than any single test.

D. Therapy

1. Antibiotics

Table 5. Initial Empirical Therapy for Neonatal Sepsis and Meningitis

 

Clinical problem Recommendation
Early-onset sepsis and/or meningitis Ampicillin and aminoglycoside
Late-onset sepsis and/or meningitis Ampicillin and cefotaxime

 

2. Duration of therapy:

a. If initial cultures are negative and the infant is asymptomatic, usually stop antibiotics after 3-5 days and observe closely.

b. If initial blood cultures are positive and meningitis is not present, usually a 7-10 day course of treatment with an appropriate antibiotic, based on susceptibility data.

3. Supportive care:

a. Intensive care

b. Vital signs and blood gases monitored

c. Ventilatory support often required because of hypoxia and hypercapnia

d. Fluid and electrolytes monitored for acidosis, hypoglycemia and electrolyte imbalances

e. Blood transfusions may be necessary to improve intravascular volume and oxygen-carrying capacity

f. Fresh-frozen plasma has been advocated to improve low serum complement and opsonic activity. White cell transfusions useful in infants with depleted bone marrows. Intravenous immune globulin (IVIG) for treatment or prophylaxis is currently being investigated.

E. Prevention. Immunoprophylaxis (vaccine or IVIG) against GBS is in the investigational stage. Administration of penicillin to colonized mothers before delivery is not effective in reducing colonization rates. Furthermore, preliminary studies indicate no clear benefit of a single dose of penicillin to mothers prior to delivery or to newborns within 1 hour of delivery. Some investigators have shown that intrapartum treatment of colonized mothers reduces colonization and the risk of disease in their infants.


III. Neonatal Meningitis

A. Clinical features:

1. May be similar those seen with sepsis (see Table 3).

2. Convulsions, irritability or lethargy may also occur. Rarely will a neonate with meningitis exhibit a bulging fontanelle or nuchal rigidity.

B. Diagnosis:

1. Blood, CSF and urine samples obtained, examined and cultured

2. CIE and the LA

3. Table 6 lists mean and ranges for normal values for CSF analysis in newborns. Normal CSF values for WBCs and protein in neonates may be higher and CSF glucose lower than for normal adults

C. Bacteriology. E. coli and GBS cause approximately 70% of neonatal meningitis while L. monocytogenes accounts for another 5%. Other pathogens known to cause meningitis, especially in low-birth-weight infants, include Staphylococcus aureus, S. epidermidis and Candida.

D. Therapy:

1. Antibiotics.

a. Initial therapy - parenteral ampicillin and an aminoglycoside or ampicillin and a third generation cephalosporin (e.g., cefotaxime). Please see Tables 1 and 7.

b. If gram-negative bacilli are seen on CSF Gram stain, some experts recommend adding a third-generation cephalosporin (e.g., cefotaxime) while awaiting culture results. Once sensitivities are known, appropriate antibiotic therapy can be selected.

c. GBS (suspected or proven). Because of the relative resistance of GBS organisms to penicillin, aqueous penicillin can be used but should be given at doses of 400,000 units/kg/day (see Table 1). Some experts recommend treatment with penicillin and an aminoglycoside until CSF cultures are negative; therapy should be continued for a least 14 days after negative CSF cultures have been documented by repeat LP.

d. L. monocytogenes should be treated with parenteral ampicillin or penicillin. Duration of therapy is as recommended for GBS above. Some experts add a parenteral aminoglycoside (e.g., gentamicin) for synergy.

e. Enteric gram-negative bacteria are more difficult to eradicate from the CSF than gram-positive bacteria, in part because of the low levels of aminoglycosides achieved therein. In general, repeat LP may be done to document sterilization of the CSF, and therapy is generally continued for 14 days after sterilization or for a total of 21 days.

2. Supportive care. It is particularly important to reduce free water intake to avoid hyponatremia due to inappropriate secretion of antidiuretic hormone (SIADH) associated with meningitis.


IV. Childhood Meningitis

A. Clinical Features:

1. Triad of symptoms includes fever, headache and stiff neck

2. Children < 2 yrs of age may not have a stiff neck or other signs of meningeal irritation (e.g., positive Kernig's and Brudzinski's signs)

3. 90% will have an altered level of consciousness

4. Most will present with lethargy, irritability or confusion

5. 10-15 % present in coma which is a very poor prognostic sign

6. Infants may have a bulging fontanelle, high pitched cry or feeding difficulties

B. Diagnosis:

1. LP is needed

2. MRI or CT scan done before an LP in patients in whom cerebral edema or a high ICP is suspected

3. CSF is examined for appearance, cell count, chemistry (glucose, protein), gram stain and culture and CIE

C. Bacteriology

Beyond the neonatal period, the most common pathogens are H. influenzae type B (up to 6 years of age), Neisseria meningitidis (meningococcus) and Streptococcus pneumoniae (pneumococcus).

Meningitis develops as a result of bacterial entry into the subarachnoid space through hematogenous seeding, direct extension from a contiguous focus (e.g., otitis media, mastoiditis, sinusitis, cranial bone or vertebral osteomyelitis) or as a result of congenital, traumatic or surgical disruption of normal anatomical barriers (e.g., basilar skull fracture, neurosurgical procedures, congenital dermal sinuses along the craniospinal axis).

D. Therapy of bacterial meningitis. Antibiotics should be given IV in high doses. The choice of antibiotics will be determined by the organism that is seen on Gram stain, identified by CIE or LA, subsequently isolated, or likely to be present based on the clinical setting and age of the patient (see Table 7).

Table 7.

In children therapy is empirical for H. influenzae, N. meningitides, and S. pneumoniae (Rx: ceftriaxone or cefotaxime or chloramphenicol and ampicillin). After the CSF has been fully examined, therapy can be modified, if necessary.

1. Presumed bacterial meningitis. In some cases, despite the negative Gram stain, CSF findings may suggest a bacterial etiology (i.e., low glucose level, elevated WBC with polymorphonuclear leukocyte predominance). These patients are treated for bacterial meningitis of unclear etiology.

2. Specific therapy. The initial therapy when the Gram stain is suggestive of a certain bacteria or when the identity of the organism is definitely known. Once sensitivities are known, optimal antibiotic regimens can be instituted.

E. Adjunctive therapy of bacterial meningitis:

1. Dexamethasone therapy in children.

a. Recent studies suggest that hearing loss is a sequela of bacterial meningitis which may be reduced in children who receive dexamethasone early in the therapy. This is especially true for patients with H. influenzae type b infections.

b. Dexamethasone decreases the meningeal inflammatory response in meningitis. Although mechanisms are unclear, components of the bacterial cell wall elaborated in infection, especially with H. influenzae type b and S. pneumonia infections, stimulate cytokines (e.g., interleukin-1 and cachectic or tumor necrosis factor) which adversely affect capillary endothelial cell function and cerebral blood flow.

c. Dexamethasone doses typically used are 0.15 mg/kg/dose IV given q6h for the first 4 days of therapy (beginning with the first dose of antibiotics).

d. Recommendations on when to use dexamethasone

e. Other constraints:

1) Gastrointestinal bleeding

2) Patients with aseptic meningitis or nonbacterial meningitis should not receive dexamethasone

2. Reduction of intracranial pressure (ICP):

a. Some experts suggest that patients with fulminant meningitis and altered consciousness should have ICP monitored by intracranial device

b. ICPs > 20 mm Hg are abnormal, and patients treated for ICPs > 15 mm Hg may have a better outcome

3. Fluid restriction: Since SIADH occurs in 30% of patients with meningitis, fluid intake may need to initially be restricted to 2/3 maintenance to help prevent SIADH. Fluids can go to maintenance if SIADH does not develop or if the patient is dehydrated.

4. Removal of foreign bodies (reservoirs, shunts):

a. Remove foreign bodies such as reservoirs and shunts or treat with antibiotic therapy both systemically and intraventricularly for varying lengths of time.

b. Failure to respond is an indication for removing a shunt or reservoir.

5. An Ommaya reservoir may be necessary for intraventricular instillation of antibiotics, particularly when an aminoglycoside or vancomycin is used.

F. Duration of therapy.

Table 8. Guidelines for the Duration of Therapy for Various Types of Meningitis

Meningococcal 7 to 10 days
Pneumococcal 10 to 14 days
Staphylococcal 14 to 21 days
H. influenzae type b 10 to 14 days (some data suggest a 7 day course)
Gram-negative bacilli 10 to 14 days after CSF culture is negative
Listeria 2 to 3 weeks (4 to 6 weeks is preferred by some experts)

G. Monitoring response to therapy. Response is usually evaluated by clinically monitoring the patient's signs and symptoms, mental status, neurolgic signs and temperature.

H. Follow-up LP studies. Repeat CSF examination is not necessary if the child responds appropriately to therapy.

I. Mortality. Despite therapy, H. influenzae meningitis carries a mortality of 3-5% in children, and at least 30% of survivors have neurologic sequelae.

J. Prophylaxis of meningitis:

1. Meningococcal meningitis. Prophylaxis indicated only in certain circumstances.

a. Prophylaxis indicated for several groups of patients. It is not necessary to perform nasopharyngeal cultures to determine whether contacts are colonized with N. meningitides. Once the index case has been diagnosed, the following groups should be treated immediately:

1) Household contacts of the index case (i.e., those residing in the residence of the index patient or nonresidents who spent 4 or more hours with the index patient for 5 of 7 days preceding hospital admission of the index patient).

2) Nursery school or day-care contacts (i.e., young children)

3) Very close day-to-day contacts of the index case (e.g., boyfriend, girlfriend or roommate)

4) Unusual in-hospital situations with close contact (e.g., mouth-to-mouth resuscitation)

b. Prophylaxis is not indicated for:

1) Routine contacts of the hospitalized patient (i.e., nurses or physicians)

2) Casual school contacts in older children (grade school and older)

3) Casual contacts at work or home

c. Agents used in prophylaxis.

1) Rifampin is the preferred agent when susceptibility studies or serotypes are not know. It is administered for 2 days: 600 mg PO bid for adults, 10 mg/kg (maximum dose, 600 mg) bid for children _ 1 month of age, and 5 mg/kg bid for infants < 1 month of age.

2) If the organism is known to be susceptible to sulfonamides, 2 days of sulfisoxazole therapy may be given: 1 gm bid for adults, 500 mg bid for children ages 1-12 yrs and 500 mg once daily for children younger than 1 year.

3) Administration of meningococcal vaccine may be recommended by health officials under certain special circumstances.

2. H. influenzae type b meningitis. Prophylaxis for family and close contacts of a patient with H. influenzae type b meningitis is controversial. A number of family and day-care center (not school) outbreaks have been described, and nasopharyngeal carriage is known to be common among family members and intimate contacts of patients with invasive disease.

Epidemiologic studies suggest that the risk of invasive H. influenzae disease for household contacts, particularly those < 4 years of age, is similar to the risk of secondary meningococcal disease in all household contacts of a patient with meningococcal meningitis. Rifampin has been shown to eradicate H. influenzae type b carrier state. With these facts in mind, guidelines have been published that recommend the following:

a. If there is a sibling < 49 months of age in the household of an index case, all household contacts (defined as any individual residing in the residence of the index patient or nonresident who spent _4 hours with the index patient for at least 5 of the last 7 days preceding the day of hospitalization of the index patient), including the index case, should receive rifampin once daily in a dose of 20 mg/kg (maximum dose, 600 mg/day) for 4 days. For infants < 1 month of age, the dose is not established, but 10 mg/kg/day has been recommended. For adults, 600 mg daily is suggested. Prophylaxis is not recommended for pregnant women who are contacts of affected infants as the effect of rifampin on the fetus has not been established.

b. In the case of invasive H. influenzae disease in a day-care centers/nursery schools, the role of rifampin prophylaxis must be individualized.

 

PEDIATRIC INFECTIOUS DISEASES SUMMARY*

 

Disease Age Most likely bacteria Empirical Therapy
Neonatal sepsis or

Neonatal meningitis

 Neonate E. Coli

Group B Streptococcus

Listeria Monocytogenes

 IV route:

Ampicillin plus aminoglycoside

or

Ampicillin plus cefotaxime
Meningitis 1 - 3 months Same as neonatal plus H. influenza is now possible. Keep ampicillin to cover Listeria which can still occur. IV route:

Ampicillin plus cefotaxime

or

Ampicillin plus ceftriaxone
Meningitis 3 months -

6 years

 H. influenza

Neisseria Meningitides

(meningococcus)

Streptococcus pneumoniae

(pneumococcus)

 IV route:

Ceftriaxone alone

or

Cefotaxime alone

or

Ampicillin plus chloramphenicol
Meningitis Children

> 6 years

 Streptococcus pneumoniae

(pneumococcus)

Neisseria Meningitides

(meningococcus)

 IV route:

Ceftriaxone alone

or

penicillin alone, if H. influenza is not suspected
Otitis media Neonate Gram negative organisms IV route:

Ampicillin plus aminoglycoside
Otitis media non-neonate

(children all ages)

 Streptococcus pneumoniae

(pneumococcus)

H. influenza

Moraxella catarrhalis

 PO route:

1. Amoxicillin.

2. Cotrimoxazole or Pediazole

3. More expensive: cefaclor,

augmentin, cefuroxime, cefixime, etc.

 

References for the above summary table

* Some information in this table may vary from that of others in the handout because of sources used for the information.

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