appear in the exudative process of neonatal meningitis.6. Etiology. Over the last 40 years there has been a continual flux in the bacteria responsible for neonatal ...
Acquired Bacterial Infection in the Newborn W. T. BINGHAM
SUMMARY Sepsis in the neonatal period constitutes a major diagnostic and therapeutic challenge for the physician involved in the care of newborn infants. The paucity of definitive clinical symptoms and signs necessitates a comprehensive knowledge of the pathogenesis and clinical findings of septicemia. Early commencement of appropriate antimicrobial therapy is of utmost importance if inroads are to be made into the high morbidity and mortality rates of this disease entity. (Can Fam Physician 25:716-719, 1979). Dr. Bingham is completing a clinical fellowship in neonatology at the University of Manitoba. Reprint requests to: Children's Centre, Dept. of Pediatrics, 700 William Avenue, Winnipeg, MB. R3E OZ3. SEPSIS NEONATORUM, a generalized bacterial infection, is a severe manifestation of acquired bacterial infection in the newborn period. Due to the immaturity of the neonate's defense mechanisms, septicemia is a major problem: the incidence is one to four per 1000 live births' and mortality ranges from 13%-45% 2 In order to confirm a case of neonatal sepsis, a positive blood culture is mandatory. Positive documentation may not be possible and clinical criteria, combined with a high index of suspicion, must be applied. Early diagnosis and treatment are of paramount importance, since delay is associated with increased morbidity and mortality.
Pathogenesis Infection may be acquired during the prenatal or postnatal period. In utero, the infant may be exposed to bacteria via the maternal-fetal vascular route or as an ascending infection when amniotic integrity is disrupted. During a vaginal delivery the infant is exposed to potential pathogens of the maternal genitourinary tract. Postnatally, the neonate may be exposed to resuscitative equipment (suction catheters, endotracheal tubes), respirators and humidified incubators; all of which should be considered fomites.3 Invasive life-supporting measures allow introduction of pathogens into areas that were sterile or previously 716
protected by physiologic barriers to infection. The immaturity of the infant's inflammatory and immunologic reaction to pathogenic organisms also predisposes him to disseminated infection. Polymorphonuclear leukocytes in the normal newborn are less able to chemotax and form chemotactic factors. Factor B, an integral serum factor in the alternate route of complement fixation, is deficient in approximately 15% of newborn cord sera. IgM levels are low in the neonate; therefore, classic activation of the complement system is impaired.4 IgG antibodies are low in molecular weight and are transmitted transplacentally to the fetus, conferring in-
complete passive antibody protection; however, IgG antibodies are less efficient in bactericidal and opsonic activities against gram negative bacteria than the antibodies of the IgM class which are not able to cross the placenta. The phagocytic activity of the newborn's leukocytes is reduced, especially in the preterm and sick infant, and bactericidal ability5 is questionably impaired. Plasma cells and lymphocytes, which play an important part in antibody formation, are late to appear in the exudative process of neonatal meningitis.6
been a continual flux in the bacteria responsible for neonatal sepsis. In the pre-antibiotic era, gram positive bacteria, particularly group A Beta hemolytic streptococci, were predominant pathogens. In the 1 950s Escherichia coli emerged as a leading cause of sepsis and has remained a major therapeutic problem due to its variance of sensitivity to aminoglycosides. Bacteriologic surveillance in the 1 970s has revealed group B Beta hemolytic streptococcus to be a common yet devastating neonatal pathogen with two clinical expressions. Early group B streptococcal disease presents within the first few days of life as a fulminating septicemia with a prediliction for the respiratory system (group B streptococcal pneumonia).7 Late onset group B streptococcal disease (serotype III) manifests as neonatal meningitis,'usually at two to three weeks of age. At the present time, E. coli and group B streptococci are responsible for approximately 70% of infections.' The invasiveness of E. coli is related to the K capsular antigen and that of group B streptococci to the capsular polysaccharides. 8 Baker and Kasper suggest that maternal antibodies to type III streptococci may protect the infant.9 This hypothesis is substantiated by the fact that infants are less reactive than older children to polysaccharide antigens. Table 1 lists several of the common bacterial pathogens associated with neonatal sepsis. Recent improvements in anaerobic techniques have shown that organisms such as Bacteroides, Clostridia and anaerobic streptococci can be identified in cases of neonatal sepsis. Onset of disease may be related to the source of the pathogen. If infection develops within the first few days of life, acquisition is probably from the maternal genitourinary tract. The neonate who develops an infection later in his nursery stay likely acquired it from the hospital equipment and nursery staff.
Clinical Presentation
The hallmark of neonatal sepsis is the infant's relatively undifferentiated response to septicemia, being either subtle, vague or nonspecific in the early stages of the disease. The clinical presentation of sepsis (Table 2) is virtually the same for most disorders Etiology affecting the newborn; therefore, Over the last 40 years there has placing the onus on the physician to CAN. FAM. PHYSICIAN Vol. 25: JUNE 1979
TABLE 1 Drugs of Choice for Common Etiologic Agents of Neonatal Sepsis Etiologic Agent Gram-positive Group B beta hemolytic
Drug(s) of Choice Duration of Treatment
streptococcus Alpha streptococcus Pneumococcus Listeria monocytogenes
Penicillin G Penicillin G Penicillin G Ampicillin
Staphylococcus Enterococcus
aminoglycoside Meningitis-14-21 days Methicillin Ampicillin + aminoglycoside
Gram-negative Escherichia coli Klebsiella Pseudomonas aeruginosa Enterobacter Salmonella, shigella Hemophilus influenzae Beta-lactamase positive Beta-lactamase negative Serratia Unknown
Gram-positive organisms Sepsis-7-1 0 days
±
Aminoglycoside Aminoglycoside Gram-negative organisms Carbenicillin + aminoglycoside Sepsis-i 0-14 days Aminoglycoside Meningitis-21-28 days Ampicillin
Chloramphenicol Ampicillin Aminoglycoside "Suspect" sepsisAmpicillin + 7-10 days. aminoglycoside
TABLE 2 Findings Suggesting Neonatal Sepsis
Early "Not doing well"
Lethargy/irritability/hypoglycemia Hyperthermia/hypothermia Poor feeding/vomiting Abdominal distension Diarrhea
Apnea/dyspnea/tachypnea Tachycardia/hypotension rapidly rule in or out any possibility of sepsis and treat accordingly.
Diagnosis The diagnosis of neonatal sepsis is based on historical factors predisposing the infant to infection in combination with physical findings and results of laboratory investigations (Table 3). The presence of malodorous amniotic fluid suggests amnionitis and the likelihood of bacterial aspiration by the fetus. Endometritis, defined as pyrexia with excessive uterine tenderness, indicates possible fetal exposure to infection. The risk of neonatal bacteremia is significantly increased if the time between rupture of the membranes and delivery is greater than 24 hours.10 The significant historical factors should be correlated with the clinical findings and if the index of suspicion is high for sepsis, the appropriate laboratory investigations CAN. FAM. PHYSICIAN Vol. 25: JUNE 1979
Late
Jaundice
Convulsions/bulging fontanel Coagulopathy Petechiae HepatospIenomegaly
TABLE 3 Workup for Neonatal Sepsis HISTORICAL FACTORS Maternal infrequent antenatal care pyrexia premature/prolonged rupture of membranes
amnionitis/endometritis fetal distress dystocia Neonatal low Apgar score resuscitation indwelling catheters/tubes congenital anomalies surgical manipulation PHYSICAL FINDINGS Refer to Table 2.
LABORATORY INVESTIGATIONS Hematologic hemoglobin WBC differential platelets Urologic urinalysis urine for countercurrent
immunoelectrophoresis Biochemical blood sugar, calcium, electrolytes, bilirubin, leukocyte LDH
Bacteriologic Cultures
nose, throat, external auditory canal, rectum, secretions, tracheal Scierema aspirate, gastric axilla, Cyanosis supra cord, umbilical Bradycardia/shock pubic urine, CSF, peripheral venous blood should be undertaken immediately. Gram stain Hematologic investigations may re- CSF, buffy coat, gastric veal a decreased hemoglobin and he- aspirate, other secretions matocrit secondary to hemolysis. The RADIOLOGIC INVESTIGATIONS total WBC count may be either ele- Chest and abdominal radiographs vated (>30,000 / mm3) or decreased (2,500 / mm3). The platelet count evidence of amnionitis; however, remay be reduced in the presence of a cent studies have shown the gastric consumptive coagulopathy; in this aspirate to be of no value in predictcase, further coagulation studies ing serious infection."1 Biochemical investigations are useshould be performed. in elucidating the differential diagful Examination of the urine may yield Leukocyte LDH may be signinosis. evidence of pyuria; countercurrent imelevated in the newborn ficantly the of (CIE) munoelectrophoresis urine can be used for the assay of He- infant with neonatal sepsis. The modimophilus influenzae, E. coli and fied nitroblue tetrazolium test (NBT) has demonstrated that the absolute group B streptococcal antigens. Bacteriologic investigations include number of NBT-positive cells are culture and gram stain of the speci- greater in infected infants. A radiograph of the chest may remens and sites mentioned in Table 3. The gastric aspirate should be exam- veal radiodensities suggesting a pneuined microscopically for neutrophils. monic process and a radiograph of the 717
abdomen may display air-fluid levels evidence of pneumotosis intestinalis which would raise the possibility of necrotizing enterocolitis. Examination of the CSF should include cell count, sugar and protein level and CIE if available. or
Treatment Following the attainment of appropriate cultures, antimicrobial therapy must be initiated as rapidly as possible. Do not wait for results of cultures and sensitivities. Commonly used antibiotics are listed in Table 4, where the values are approximations derived from currently available published material."2 If the infant is found to have meningitis, repeat examinations of the CSF should be carried out after 24 hours of antibiotic therapy. If CSF cultures remain positive after 24 hours of therapy, ventricular fluid should be examined for the presence of ventriculitis. Evidence now indicates that aminoglycosides (gentamicin) administered intravenously do not reach
therapeutic levels within the ventricular fluid. McCracken13 recommends drainage of the ventricles and direct instillation of gentamicin (one to two mg daily) into the ventricles in confirmed ventriculitis. When aminoglycosides are used via the intrathecal or intraventricular route, levels should be monitored in order to ensure therapeutic and safe concentrations. The Neonatal Meningitis Cooperative Study Group completed a protocol examining the effects of intrathecal gentamicin. They were unable to demonstrate a significant improvement in morbidity or mortality rates for the infants treated with lumbar intrathecal gentamicin (one mg daily). 13 The mortality rate for neonatal meningitis is approximately 20-50%; nearly 50% of the survivors will have evidence of neurologic damage. 13, 14 The septic infant often needs supportive treatment which includes an isothermal environment, adequate ambient oxygen level, normal hydration and physiologic blood sugar levels.
Prophylactic Antibiotics Prophylactic use of antimicrobial agents is rarely indicated in the newborn period. Prophylactic antibiotics should not be used for the premature infant unless there are specific indications such as clinical evidence of infection. Prophylactic antibiotics are not of proven efficacy in preventing infectious complications when used with indwelling umbilical vessel catheters. Routine administration of antibiotics to infants born after prolonged rupture of membranes has not shown conclusive benefits. Prophylactic antibiotic administration for control of nosocomial staphylococcal infection should be strongly discouraged. The application of triple dye to the umbilical area has been associated with low nasal and cord colonization rates of staphylococci and other organisms. 15 The routine instillation of one percent silver nitrate solution into the conjunctival sac (Crede's prophylaxis) is now common practice for control of gonococcal ophthalmia. Post-instilla-
TABLE 4
Dose and Frequency of Antimicrobials Used in the Newborn Period Antibiotic
Dose / kg / day >7 days days -2 kg >2 kg s2 kg >2 kg
-7
Penicillin G (crystalline) -septicemia
50,000 units
75,000 units
Route
Frequency
Comments
s7 days >7 days s2 kg >2 kg s2 kg >2 kg
qi 2h
q8h
*IV IM
>250,000 units / kg / day be associated with
may
IM
-meningitis
100,000-150,000 150,000-250,000 units units
q6h
q6h
*lv IM
Ampicillin -septicemia
50 mg
75 mg
q12h
q8h
*IV *IV
-meningitis
100 mg
200 mg
q6h
q6h
*IV
50 mg
50 mg
ql2h q8h
ql2h q8h
*IV
CNS toxicity
IM
IM
Methicillin
IM
Carbenicillin
200 mg
300 mg 400 mg
ql2h
q8h q6h
*IV
Cephalothin
40 mg
60 mg
ql2h
q8h
*IV
Kanamycin
15 mg 20 mg
ql2h
q8h
*IV
IM
IM
20 mg
30 mg
IM
Gentamicin
Chloramphenicol**
*
**
5 mg
7.5 mg
ql 2h
q8h
25 mg
25 mg
q24h
q24h
Monitor renal function. >14 days of age, increase dose by 25 mg / kg / day. Monitor serum electrolytes Limited efficacy and safety data in neonates. If IV, give over 30 minutes. Possible nephrotoxicity and ototoxicity. If IV, give over 1-2 hrs. Possible nephrotoxicity and ototoxicity. If >14 days and >2000 g, increase dosage to 50 mg / kg / day, and give q 12h. Also q 12h for meningitis.
Preferred route Chloramphenicol is associated with 'gray baby syndrome'. Monitor serum levels and use ONLY when pathogen is resistant to the commonly used aminoglycosides. Also monitor blood count for blood dyscrasias.
718
CAN. FAM. PHYSICIAN Vol. 25: JUNE 1979
tion irrigation is not advisable. Recent changes in attitudes and social acceptance of breastfeeding are beneficial to the neonate. Breast milk contains antibodies of the IgA class which have significant activity against E. coli in the infant's gastrointestinal tract. Breast milk also has a significant number of leukocytes (macrophages and lymphocytes) which may also enhance the infant's defense mechanisms.
References
1. McCracken GH Jr, Nelson JD: Antimicrobial Therapy for Newborns. New York, Grune and Stratton, 1977, p. 81. 2. Gotoff SP, Behraman RE: Neonatal septicemia. J Pediatr 76:142, 1970. 3. Firer J, Taylor PM, Gezon HM: Pseudomonas aeruginosa epidemic traced to delivery-room resuscitators. N Engl J Med 276:991, 1967. 4. Wilson HD, Eichenwald HF: Sepsis neonatorum. Pediatr Clin North Am 2 1:571-581, 1974. 5. Forman ML, Stiehm ER: Impaired opsonic activity but normal phagocytosis in low-birthweight infants. N Engl J Med 281:296, 1969. 6. Overall JC: Neonatal bacterial meningitis. J Pediatr 75:532, 1969. 7. Ablow RC, Driscoll SC, Efflnann EL, et al: A comparison of early onset group B streptococcal neonatal infection and the respiratory-distress syndrome of the newborn. N Engl J Med 294:65, 1976. 8. McCracken Gil Jr, Sarff LD, Glode MP, et al: Relation between Escherichia coli K, capsular polysaccharide antigen and clinical outcome in neonatal meningitis. Lancet 2:246, 1974. 9. Baker CJ, Kasper DL: Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection. N Engl J Med 294:753, 1976. 10. Tyler CW, Albers WH: Obstetric factors related to bacteremia in the newborn infant. Am J Obstet Gynecol 94 :970-976, 1966. 11. Mims LC, Medawar MS, Perkins JR, Grubb WR: Predicting neonatal infections by evaluation of gastric aspirate. Am J Obstet Gynecol 114:232-238, 1972. 12. McCracken GH Jr, Nelson JD: Antimicrobial Therapy for Newborns. New York, Grune and Stratton, 1977, pp. 5-68. 13. McCracken GH Jr, Mize SH: A controlled study of intrathecal antibiotic therapy in gram negative enteric meningitis of infancy. J Pediatr 89:66-72, 1976. 14. Fitzhardinge PM, Kazemi M, Ramsay M, et al: Long-term sequelae of neonatal meningitis. Dev Med Child Neurol 16:310, 1974. 15. Katzman GH: Effects of triple dye in a staphyloccal outbreak. J Pediatr 86:313, 1975. 16. Greenberg M, Vandow JE: Opthalmia neonatorum: Evaluation of different methods of prophylaxis in New York City. Am J Public Health 5 1:836-845, 1961. 17. Powers DW, Ayoub EM: Leukocyte lactate dehydrogenase in bacterial meningitis . Pediatrics 54:2 7, 1974. CAN. FAM. PHYSICIAN Vol. 25: JUNE 1979
going down...
t
Hygrotor
(chlorthalidone)
antihypertensive - diuretic with over 15 years of clinical use.
Geigy °H9S1 iBi-[ AA
Complete prescribing information available on request.
719
