One of the greatest hazards encountered by the premature infant is neonatal sepsis.20,25 This is defined as symptomatic infection of the bloodstream which frequently seeds the meninges. The term neonatal septicemia is reserved for these primary cases of disease and is contracted with bacteremia secondary to an obvious primary focus of infection elsewhere in the body.29 Various estimates have been made as to the incidence of septicemia in the newborn. The available data suggests the risk of septicemia in the premature is about one in 230 live births, whereas in a full-term baby the risk is approximately one in 1,200 live births.25
At present the agents most commonly responsible for septicemia in the premature are the gram negative organisms, particularly E. coli. 5 Other common coliform organisms responsible for neonatal septicemia are Klebsiella, Enterobacter and Pseudomonas. Occasionally encountered organisms include various members of the Proteus species, Paracolon bacillus, Salmonella and H. influenzae.5,25 Other gram negative organisms found in the disease are the "water bugs," Achromobacter and Flavobacterium. Mimea and Bacteroides species and Serratia marcescens are also agents that are involved.
Most frequently encountered gram positive organisms are coagulase positive staphylococci. Reduction in staphylococcal nursery epidemics has lowered but not eliminated the importance of this organism as an agent in neonatal septicemia. Staphylococcus epidermidis, a normal skin inhabitant, and Listeria monocytogene may be pathogens in the premature.11 Recently, an increased incidence of neonatal septicemia associated with group B betahemolytic Streptococcus has been noted.9 On occasion Streptococcus fecalis which is a normal inhabitant of the intestinal tract and perineum is an offending agent. D. pneumoniae has also been encountered in this condition. In one recent case of a newborn who become ill within the first 24 hours after birth, identical Pneumococcal types were isolated from the infant's bloodstream and the maternal cervix.
Maternal, infant and environmental factors are involved in the pathogenesis of neonatal septicemia.
A. Maternal Factors: Probably one of the most widely discussed and least understood of maternal factors associated with neonatal septicemia is the "amniotic sac infection syndrome."3 This consists of infections of the placenta, chorion, amnion and sometimes the umbilical cord vessels. The route of infection is an ascending one beginning with a localized focus at the internal cervical os. The ascending infection results in invasion of the amniotic sac with or without premature rupture of the membranes. Bacteria may then be swallowed and aspirated with amniotic fluid by the fetus or may have access to the bloodstream through the skin, ears or mucous membranes of the eyes or intestinal tract. Alternatively, the bacteria in the amniotic sac may directly invade the umbilical cord of the fetus and thus cause a bloodstream infection. There is also some evidence that maternal perinatal complications such as premature rupture of the membranes, placenta previa and premature separation of the placenta may also be associated with neonatal septicemia particularly in those infants who become sick before they are 10 days old.25 Most often, however, these maternal complications result in the delivery of a healthy, noninfected infant.
Maternal infection, particularly of the urinary tract, may also play a role in neonatal septicemia. In one series of 29 infants with septicemia and purulent meningitis, six mothers had urinary tract infections.1 In five instances, the bacteria isolated from the maternal urinary tract were identical to those isolated from the infant's spinal fluid. Maternal cervical infection may also be associated with septicemia in the newborn. It is believed that infant contamination occurs during delivery and results in disease in these cases. Listeria monocytogenes and group B beta hemolytic Streptococcus have been associated with such maternal cervical infections.
B. Infant Factors: Premature infants represent compromised hosts to a greater degree than full-term babies. Fragile skin of the premature may afford less protection than the integument of a full-term infant. The normal protective action of the mucosal lining of orifices and organs is also more readily compromised in the premature. For example, immature infants tend to develop functional ileus in the first few days of life. Malfunction of the bowel results in stasis and bacterial overgrowth.18 Secondary bowel wall edema and increased permeability of the intestinal tract may permit bloodstream invasion of organisms by a bacteria laden gut.
Premature infants tend to have more problems in establishing respiration and therefore require considerable suction and resusdtative efforts. Abrasion of the mucosa of the nasopharynx affords direct access to the bloodstream for bacteria colonizing the nasopharynx or by bacteria present on contaminated equipment used in the care of these infants. Prematures tend to have greater need for supportive therapy which necessitates placement of various indwelling catheters which are easily contaminated.
Premature infants also share the hazards common to full-term infants. The umbilical stump which is moist and warm harbors a variety of bacteria and may be the source of bloodstream infection. As in the full-term infant, congenital anomalies of the urinary tract may be the source of septicemia in the newborn infant. It is of interest that urologie abnormalities are more commonly found in those infants with septicemia developing after the first 10 days of life whereas perinatal complications are more common in infants developing septicemia within the first 10 days of life.25
There are certain aspects of the immunologic system of the newborn that predispose him to infection. Although it is clear that the newborn infant and indeed the premature are not immunologically incompetent, some features of their humoral immune system may predispose them to infection in the neonatal period. The human fetus can synthesize IgG and IgM as early as twelve weeks of gestation, and by seven months of gestation it has developed a competent humoral immune system. At birth the infant inherits transplacentally a variety of antibodies of the IgG globulin class accumulated by the mother by antigenic experiences throughout her life. Included are antibodies against a variety of viruses, toxins such as tetanus and diptheria toxins and antibodies against gram positive bacteria. The IgM antibodies which are of a greater molecular weight do not readily pass the placenta, and therefore infants including prematures lack these types of antibodies. Most of the gram negative organisms are in this class of globulins, and their absence may contribute to the susceptibility of the newborn infant to gram negative septicemia.26
In the past few years a great deal of information has been accumulated on polymorphonuclear leukocyte function and its contribution to host defense. With this information has come knowledge of some additional specific deficiencies found in premature and full-term newborn infants. The migration of polymorphonuclear leukocytes to sites of infection and their ability to phagocyte offending agents is probably the most important single factor involved in host defense against bacterial disease. A compromise in the system therefore makes the host more susceptible to being overwhelmed by bacterial agents. The first step in phagocytosis is the attraction of bacteria to the polymorphonuclear leukocytes. The polymorphonuclear leukocyte of the premature has been shown to be "lazier" than that of the older infant and adult.14 In addition, attraction of the bacteria to the polymorphonuclear cell is slow in the newborn. Chemotactic factor, which mediates this attraction, is deficient in newborn serum.26 Some data suggests that there are additional heat labile serum factors probably related to the complement system that are deficient particularly in the premature infant. These factors are important in the interactions that take place with bacteria in preparation of bacteria for phagocytosis.7 Once prepared, however, there is no conclusive evidence that the polymorphonuclear leukocyte of the premature infant is less capable of phagocyting and killing bacteria than the adult leukocyte.23
Another factor absent in the premature is secretory IgA. This material is not present at birth in the human newborn and develops in the first few weeks of life at the same time immunocompetent cell populations of the alimentary tract are formed.4 The deficiency of this system may be another factor responsible for the increased susceptibility of premature infants to enteric infection.
There is no evidence that there is any other deficiency in cellular immunity in the premature infant. The ability of lymphocytes to respond to mitogens has been shown to occur as early as the 20th week of gestation.30
In summary, there are various immunologic deficiencies seen in the premature and full-term infants primarily in the heat labile and heat stable opsonins. These substances may be important determinants in deciding outcome in bacterial infections in newborns.
C. Environmental Factors: Some important factors in the increased incidence of infection in the nursery are related to the extensive use of catheters and resuscitation, oxygen and humidification equipment, all of which are easily contaminated.2,28 In addition, soap dispensing containers, medications, sink traps, aerators and breastpumps have all been involved in cases of neonatal septicemia.6,12,21,31 The organisms that contaminate the variety of fomites found in the nursery are gram negative organisms probably because they have minimal nutritional requirements and require little nutritional substrate. Extensive use of antibiotics and antiseptics have also probably been effective in reducing gram positive organisms in the environment and have contributed to an ecologie shift resulting in the emergence of gram negative bacteria as the predominant organisms found in many nurseries.
CLINICAL SIGNS AND SYMPTOMS
Septicemia may be present at birth and when it occurs in the first 10 days of life it is most frequently associated with perinatal maternal or infant complications.25 The signs and symptoms of neonatal septicemia particularly in the premature may be vague and the diagnosis extremely difficult to establish.
Any infant who isn't doing well should be suspect and subjected to a work-up for possible septicemia and meningitis. The initial signs may include or be solely related to changes in feeding habits, respiratory distress or simple failure to thrive. Temperatures are often abnormally low rather than elevated. Hypothermia may be difficult to detect since prematures are frequently cared for in an incubator. The need for frequent readjustment of incubator temperature may be the first clue to septicemia in the premature. Other features such as episodes of cyanosis, apnea, pallor, convulsion, hepatosplenomegaly, enlarged kidneys, jaundice or anemia may be present.
Infants with staphylococcal sepsis may have impetiginous skin lesions. Other organisms may also be associated with skin manifestations that suggest enologie diagnosis. For example, vesicles on an indurated violacious base are lesions seen with Pseudomonas septicemia. These lesions which represent septic infarcts may on occasion be seen with Clostridia or coliform infections as well. Septicemia with Achromobacter is associated with a characteristic brawny yellowish-orange edema.12
Other organs may be seeded with bacteria and may cause localized signs and symptoms. Since the response of the premature to infection is less intense than the response of an older infant, localizing signs may easily escape notice. For example, the meninges which are frequently secondarily involved usually do not produce any of the well known signs associated with infection at this site. Infections of the bone and joints which are also relatively common produce pain and limitation of motion but they are not readily detected. An awareness of the possibilities of these complications should lead to the utilization of ancillary laboratory tests to aid in diagnosis and initiation of appropriate therapy.
Diagnosis of septicemia is made by isolation of the organisms from the blood. To avoid misleading results, cultures should be taken from peripheral veins.16 Cultures taken from the umbilical site may be falsely positive up to 25 per cent of the time.20 Contamination with skin flora can be minimized by careful preparation of the skin with an iodine containing solution. 10 Since a large number of infants with septicemia have metastatic involvement of the meninges, lumbar puncture is indicated in suspected infants. Samples of spinal fluid should be stained and cultured. Cultures should also be taken of any skin or mucosal lesion as well as the umbilical stump. The urine should be cultured as well. To avoid contamination the most reliable urine cultures are obtained by suprapubic bladder puncture since even fastidious preparation of the genital area does not preclude a high percentage of false positive voided urine specimens.
Attempts have been made to predict which newborn is likely to develop septicemia. Smears, cultures and sections of the amnion or umbilical cord of high risk pregnancies are of little value. Inflammation of these membranes does not correlate well with subsequent infection of the newborn. Cultures of various mucosal sites including the external ear canal may be of value in instances where intrauterine infection is suspected. These techniques are of little value however as a screening method for the identification of an infected infant following premature rupture of the maternal membranes. The best method for screening such infants for septicemia consists of obtaining two cultures obtained from different peripheral venous sites rather than gastric and umbilical cord blood cultures.17
Other laboratory data often is as unrevealing as the clinical signs and symptoms. In infants who are most severely infected there is often a leukopenia rather than a leukocytosis. However, peripheral blood counts of 20,000 to 40,000 may be seen. There may also be an anemia and thrombocytopenia. The direct or indirect bilirubin may be elevated. Metabolic and electrolyte abnormalities and hypoglycemia are occasionally seen as well. Urine abnormalities do not necessarily signify metastatic renal infection; may be seen as a result of debilitation, fluid and electrolyte imbalance; and usually clear rapidly in infants responding to treatment. Most often seen are albuminuria, cylindruria and pyuria. Urinary tract infection, bacteriuria, on the other hand, may point to the source of the septicemia, i.e., genitourinary tract anomaly.
The cornerstone of treatment of septicemia of the premature is prompt institution of appropriate and adequate antibiotic therapy. Until the organism is identified, the most commonly used combination of antibiotics is penicillin or ampi ci Hi ? and kanamyán. The dose of penicillin is 100,000 units/kg./24 hours, usually given in two divided doses. Ampicillin is given in a dose of 40 mg. /kg. every eight to 12 hours. Kanamycin is used in a dose of 15 mg. /kg. given in two equally divided doses every 12 hours.® It should be remembered that these doses of penicillin and ampicillin are predicated on a prolonged half-life of these drugs due to the immaturity of the premature kidney. However, after one week of age, although kidney function of the premature is still not fully developed, the ability of the premature kidney to handle ampicillin or penicillin is considerably improved. Therefore, these drugs should be administered every six to eight hours rather than every 12 hours. These two drugs are used empirically until the organism is identified and sensitivity tests done to indicate specific therapy. Treatment is continued for a seven to 10 day period unless, of course, there is metastatic involvement of other organs. For example, if the meninges or the bones are involved, treatment for a period of two to three weeks or even longer may be necessary.
If epidemiologic or clinical evidence suggests the offending organism is a specific organism, specific therapy is indicated. For the staphylococcus, methicillin or another antistaphylococcal beta lactamase resistant penicillin should be used systemically. If the staphylococcus is sensitive to penicillin, penicillin G is the drug of choice. For Pseudomonas, polymyxin or colsitin, carbenicillin or gentamicin are the drugs of choice.
Recent investigations suggest gentamicin may be preferable to kanamycin in the treatment of neonatal septicemia.24 Gentamicin is an aminoglycoside with a broader spectrum of activity than kanamycin. This drug is effective against Pseudomonas strains as well as E. colt, Proteus species, Klebsiella and Enterobacter. In addition some nurseries have reported an in vitro resistance to kanamycin of conform organisms of 25 to 30 per cent.22 Because of a shift of antibiotic sensitivity, a broader spectrum of coverage and the accumulation of a great deal of pharmacokinetics data, it seems likely that gentamicin will receive extensive use in the treatment of septicemia and meningitis of the premature and newborn. In the first week of life, the dose of gentamicin necessary to achieve a peak serum level of four to five ug./ml. is 5 mg. /kg. /day in two divided doses.24 After the first week of life, this dose is repeated at an eight hour interval for a total dose of 7.5 mg./kg./day. Under certain circumstances intrathecal or intraventricular administration of this drug may be deemed necessary in the treatment of meningitis. In these cases the total dose of one mg. or two mg. can be injected intrathecally or intraventricularly once daily until cultures are sterile. Preliminary data shows there is no renal, hematologic or hepatic dysfunction when this dosage of gentamicin is used in the newborn.
In addition to antibiotics, recent immunologic data suggests administration of fresh adult plasma or blood may be useful in the treatment of infants with neonatal septicemia. Providing prematures or full- term newborns with septicemia with heat labile and heat stable serum factors present in fresh whole blood or plasma may be beneficial in promoting phagocytosis and eliminating invading bacteria.
Blood, plasma or other volume expanders are useful in combating shock, a complication often seen with gram negative septicemia.19 Cortico steroids in pharmacologic doses are recommended by some investigators despite questionable effectiveness. The dose is 25 to 50 mg./kg. of hydrocortisone given intravenously and if necessary repeated in one to two hours. Proper monitoring of the infant is necessary to detect this complication.
Other supportive therapy includes temperature control, oxygen to combat cyanosis, and proper fluids and electrolytes to correct hypoglycemia, hypo- or hypernatremia, metabolic acidosis or other electrolyte abnormalities. 15,27
Gamma globulin is of no value in the treatment of neonatal septicemia.
Despite in vitro susceptibility of organisms to a variety of antimicrobial agents, mortality of infants with neonatal septicemia still is in the range of 40 to 50 per cent. In addition to this high mortality rate, a large number of infants suffer from neurologic sequelae following attacks of neonatal septicemia and meningitis. Hydrocephalus, deafness, mental retardation and convulsive disorders are but a few pf the more common complications seen. Although new antibiotics may be of some help in reducing morbidity and mortality of infants with neonatal septicemia, it is doubtful that these agents alone will offer a complete resolution of the current problem.
What is needed is further elucidation of pathogenetic mechanisms in this disease, host factors involved in infant defense against bacterial invasion, elimination of nursery hazards and earlier diagnoses. It is obvious a reduction or elimination of prematurity is the most direct approach to the problem of neonatal septicemia of the premature.
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