Epidemiology, Risk Factors, and Presentation
The fetus and the newborn are extremely susceptible to infections. This susceptibility stems from maternal risk factors, obstetrical complications, the postnatal environment, and the immature host defenses of the newborn. Neonatal sepsis is defined as a systemic inflammatory response syndrome secondary to infection. The age of onset of sepsis reflects the likely mode of acquisition, microbiologic features, mortality rate, and presentation of the infection. Meningitis is usually a sequela of sepsis. The incidence of neonatal sepsis ranges from 1 to 8 cases per 1000 live births, whereas meningitis may occur in 1 of every 6 septic infants. Epidemiologically, neonatal sepsis is divided into the following categories: early-onset sepsis, late-onset sepsis, and very late-onset sepsis.
Early-onset sepsis (EOS) is a systemic, multiorgan disease that presents in the first week of life and usually on the first day of life. Infection is most often acquired before delivery. Obstetrical complications contribute to the development of infection and include rupture of membranes prematurely (before onset of labor) or a prolonged period (>18 hours) before delivery, chorioamnionitis, maternal fever, maternal urinary tract infection, and infant prematurity or low birth weight. These infants have a fulminant onset of respiratory symptoms, usually due to pneumonia; shock or poor perfusion; and temperature instability. Mortality may be as high as 30% to 50%. The microbiologic features of EOS reflect maternal genitourinary and gastrointestinal colonization. Before the adoption of intrapartum antibiotic prophylaxis (IAP) against group B Streptococcus (GBS), this pathogen caused the overwhelming majority of EOS. Today, GBS still causes most cases of EOS; however, enteric bacilli such as Escherichia coli have become more prevalent in term infants and are as likely as GBS to cause EOS in very low-birth-weight premature infants. Although GBS and enteric bacilli cause the preponderance of EOS, a third pathogen, Listeria monocytogenes, can cause EOS. Unlike GBS and the gram-negative pathogens, which usually are acquired through asymptomatic maternal colonization, L. monocytogenes generally causes a flulike or gastrointestinal illness in the mother. This organism is mostly acquired from animal products: unpasteurized milk, cheese, delicatessen meats, and hot dogs. The importance of this organism will become clear in the discussion of empiric antibiotic therapy.
Late-onset sepsis is defined as the infections that occur beyond the first week of life but before 30 days of life. Very late-onset sepsis occurs beyond 30 days of life. Although obstetrical complications may be identified, these are not typical. Late-onset disease is more likely to reflect infection with gram-positive organisms acquired in the nursery: coagulase-positive staphylococci, Staphylococcus aureus, and enterococci. Very late-onset disease includes infections caused by GBS, gram-negative bacilli, and Streptococcus pneumoniae.
The high incidence of gram-positive infection in the hospitalized infant reflects the combination of usually lower gestational age and low-birth-weight, and the consequent need for the insertion of central venous catheters for supportive care. Although many of these infants will manifest poor feeding, temperature instability, and lethargy, they are more likely to have localized disease: urinary tract infection, osteoarthritis, or soft tissue infection. Meningitis is common. Presentation may be slowly progressive or fulminant. Mortality is lower than with EOS but may still be 20% to 40%.
The widespread use of IAP in the United States has been shown to have decreased the incidence of EOS by 70%, to 0.44 cases per 1000 live births, an incidence equivalent to that of late-onset sepsis. Of importance is that the improved survival of very low-birth-weight infants has put them at increased risk of systemic nosocomial infection. In a multicenter trial of prophylactic intravenous immunoglobulin administration involving more than 2400 very low-birth-weight infants, 16% of the infants developed sepsis at a median age of 17 days. Compared with the infants who did not develop sepsis, these infants not only had increased morbidity, but their mortality rose from 9% to 21% (not always directly due to sepsis) and their average length of hospital stay increased from 58 to 98 days.
The most important risk factors for the development of neonatal sepsis are low birth weight and prematurity. Sepsis conversely is also the most common cause of death in infants under 1500 g. The incidence of sepsis is inversely proportional to the gestational age or birth weight of the infant. Other risk factors include immature immune function, exposure to invasive procedures, hypoxia, metabolic acidosis, hypothermia, and low socioeconomic status—all factors associated with low birth weight and prematurity. In a multicenter survey of GBS disease carried out by the Centers for Disease Control and Prevention (CDC), 13.5 cases per 1000 live births were diagnosed among black infants compared with 4.5 cases among 1000 white infants, and EOS was twice as common among black infants as among white infants. Although males have a higher incidence of sepsis, once respiratory distress syndrome is accounted for, they are not at a significantly higher risk of sepsis, contrary to the results of older studies. It is generally felt that sepsis is more common among the firstborn of twins. Infants with galactosemia are more likely to become infected with gram-negative organisms, in particular E. coli. The administration of iron for anemia appears to increase risk because iron may be a growth factor for a number of bacteria. Finally, the widespread use of broad-spectrum antibiotics may cause a shift in the nursery to a higher prevalence of resistant bacteria that are also more invasive.
Evaluation and Management of Neonatal Sepsis
Definitive diagnosis of bacterial infection is predicated on the recovery of a pathogen from a normally sterile body site such as blood, urine, or cerebrospinal fluid (CSF). Although many indirect indices of infection have been identified and studied, including total white blood cell count, absolute neutrophil count, C-reactive protein level, procalcitonin level, and levels of a variety of inflammatory cytokines, these tests are nonspecific and are not adequately sensitive to confirm or exclude systemic infection.
In any infant with suspected EOS cultures of blood should be drawn and, if the infant is in hemodynamically stable condition, spinal fluid should be obtained, and the infant should be started on intravenous antibiotics. The need for lumbar puncture in the first 24 to 72 hours of life has been a topic of some controversy. Data suggesting that lumbar puncture is unnecessary in these infants comes primarily from retrospective studies of asymptomatic infants. The poor correlation between the results of neonatal blood cultures and CSF cultures underscores the need for lumbar puncture. Several studies report that bacterial meningitis would be missed in approximately one third of neonates on the basis of blood culture results alone. Antibiotic regimens should cover GBS, gram-negative bacilli, and L. monocytogenes. The most commonly used regimens are ampicillin and cefotaxime or ampicillin and gentamicin. Both regimens are quite effective against GBS. Unfortunately, E. coli has increasingly become resistant to ampicillin. In many institutions, more than half of the E. coli isolates are resistant to ampicillin. A search of the Cochrane database for evidence suggesting that one regimen is superior to another does not yield a conclusion. Regardless of the regimen used, ampicillin should be included, because the cephalosporins have no activity against L. monocytogenes, and gentamicin monotherapy would be ineffective.
The data for empirical therapy in late- and very late-onset disease are not definitively in favor of any one regimen. Given the prevalence of staphylococcal species, many clinicians would include vancomycin in the empiric treatment of a hospitalized neonate with signs of sepsis beyond the seventh day of life. If the infant is being admitted from the community, the regimen should include coverage for GBS, E. coli, and S. pneumoniae. Commonly cited guidelines for the evaluation of febrile children without a focus of infection who are between 30 and 60 days of life include obtaining blood and urine samples for culture and performing a lumbar puncture before administration of antibiotics.
Group B Streptococcus Infection
Streptococcus agalactiae, or group B Streptococcus (GBS), is the most common cause of vertically transmitted neonatal sepsis, a significant cause of maternal bacteriuria and endometritis, and a major cause of serious bacterial infection in infants up to 3 months of age. Nine serotypes of GBS have been identified on the basis of differing polysaccharide capsules: Ia, Ib, II, and III through VIII. Traditionally, neonatal disease is considered early onset (EOGBS) if it occurs in the first 7 days of life and late onset if it occurs from 8 days through 3 months of life. Epidemiologically, the serotypes responsible for neonatal disease shifted significantly in the 1990s. Type Ia, type III, and type V cause 35% to 40%; 25% to 30%; and 15% of cases of EOGBS, repectively. Type III still causes the majority of late-onset disease and neonatal meningitis. Antibodies against specific serotypes of GBS are protective but not cross-reactive.
Although GBS can cross the placenta, the primary mode of transmission is after rupture of membranes and during passage through the birth canal. Approximately 20% to 40% of women are colonized in their genital tract, but the primary reservoir of GBS is the lower gastrointestinal tract. High genital inoculum at delivery increases the likelihood of transmission and the consequent rate of EOGBS. Half of infants born to colonized women will themselves be colonized with GBS. Before the use of IAP targeted against GBS, the incidence of EOGBS ranged from 1 to 3 cases per 1000 live births. By definition, EOGBS presents in the first 6 days of life, and close to 90% of cases present within 24 hours of life. The vast majority of these infants demonstrate systemic illness by 12 hours.
In 1986 Boyer and Gotoff published the first randomized controlled trial showing the effectiveness of IAP in reducing neonatal colonization and EOGBS. In 1996 the CDC published the first set of guidelines for the prevention of perinatal GBS disease. The guidelines endorsed two approaches to IAP: (1) women with vaginal or rectal cultures positive for GBS should receive IAP; or (2) women with any of the following risk factors—delivery before 37 weeks’ gestation, membrane rupture 18 hours or longer before delivery, or maternal fever of 38° C or higher—should receive IAP. In addition, any woman who had a history of GBS bacteriuria or who had previously delivered an infant with EOGBS was to receive IAP. In addition to the administration of IAP, the guidelines provided for the evaluation of the infant after delivery. These strategies reduced the incidence to 0.6 cases per 1000 live births in 1998. Ongoing active surveillance of GBS demonstrated that the screening-based approach was superior to the risk-based approach in preventing EOGBS. In 2002 the CDC published revised guidelines that promoted the universal screening of all pregnant women between 35 and 37 weeks’ gestation using rectovaginal cultures and recommended that all women with positive culture results receive IAP. The guidelines also recommended IAP for mothers who had any history of GBS bacteriuria during the pregnancy, who had suspected amnionitis, or who had previously delivered an infant with EOGBS. These guidelines also clarified the antibiotic dosages for IAP, alternatives for mothers with penicillin allergy, and the management of an exposed newborn ( Fig. 14-1 ).
As of 2003, the incidence of EOGBS was down to 0.3 cases per 1000 live births. Although effective, the screening-based approach incurs the costs of testing, IAP, and management of the exposed infant. Although, to date, no studies have shown an association between penicillin and ampicillin IAP and the emergence of antibiotic resistance in other bacteria, this risk remains a concern. An immunization-based strategy targeting pregnant women has the potential to prevent EOGBS, late-onset disease, and some maternal disease and to be more cost effective. A multivalent protein conjugate vaccine has proved effective in a murine model, and several human trials of individual serotype conjugate vaccines have shown promise.
For documented GBS infection, penicillin is the drug of choice and is the most narrow-spectrum agent. Ampicillin is an acceptable alternative agent. No penicillin resistance has been reported to date. The dosages and intervals depend on the postgestational age of the infant. The duration of therapy is 10 days for bacteremia without a focus, 14 days for uncomplicated meningitis, and up to 4 weeks for septic arthritis, endocarditis, or ventriculitis.
Coagulase-Negative Staphylococcus Infection
For several decades, coagulase-negative staphylococci have been the most common cause of nosocomial blood stream infections in the neonatal intensive care unit and are responsible for the majority of cases of late-onset sepsis in preterm neonates. Infections with these gram-positive bacteria are most often associated with indwelling central venous catheters. These bacteria are part of normal human skin flora. Staphylococcus epidermidis is the most common species of coagulase-negative staphylococci recovered from human skin and mucous membranes. Most infants are colonized within the first week of life from passage through the birth canal and repeated exposure from colonized caregivers.
The major virulence factor for coagulase-negative staphylococci is its ability to adhere to plastic and other foreign bodies by producing a biofilm. The biofilm consists of multiple layers of bacteria surrounded by an exopolysaccharide matrix or slime. This biofilm protects the bacteria from host phagocytic cells and interferes with the ability of many antimicrobial agents to effectively eliminate infection. This affinity for plastic foreign bodies explains the high recovery rate of these organisms from infected catheters, ventricular shunts, endotracheal tubes, and artificial vascular grafts and cardiac valves.
Neonatal infections with coagulase-negative staphylococci typically present without localizing signs with fever, new-onset respiratory distress, or a deterioration in respiratory status. Other common nonspecific signs of coagulase-negative staphylococcus sepsis include apnea, bradycardia, poikilothermia, poor perfusion, poor feeding, irritability, and lethargy. Indolent infection is more common than fulminant disease, with mortality generally under 15%. Coagulase-negative staphylococci infections, however, are a major source of morbidity leading to increased antibiotic exposure, length of stay, and hospital costs.
Treatment of coagulase-negative staphylococci often requires the use of vancomycin. More than 80% of strains acquired in the hospital are resistant to β-lactam antibiotics. Resistance is typically attributable to altered penicillin-binding proteins and β-lactamase production. Unfortunately, these types of resistance can be inducible and therefore may not be detected by routine microdilutional methods. If a strain is reported as penicillin sensitive, consultation with the hospital microbiologist is recommended to confirm testing for inducible resistance. More than 50% of coagulase-negative staphylococci are resistant to clindamycin, trimethoprim-sulfamethoxazole, gentamicin, and ciprofloxacin. Coagulase-negative staphylococci isolated from hospitalized patients show varying rates of resistance to the tetracyclines, chloramphenicol, rifampin, and newer-generation quinolone antibiotics. Some S. epidermidis isolates have been recovered that show resistance to vancomycin; however, these species have been susceptible to the newer agents for gram-positive organisms: linezolid, quinupristin-dalfopristin, and daptomycin. Pharmacokinetic data and clinical experience with these agents in neonates are limited, and these drugs should be used only in consultation with a physician with expertise in infectious diseases.
The most effective management of coagulase-negative staphylococci infections is the combination of systemic antimicrobial therapy and, whenever possible, the removal of the foreign body. When a foreign body cannot be feasibly removed, the combination of vancomycin with rifampin, and/or an aminoglycoside, may be used. In the case of ventricular shunt infections, antibiotics may be administered both systemically and intraventricularly. If an attempt is made to manage an infection without foreign body removal, consultation with an infectious disease expert would be advised to determine the best antimicrobial agents and duration of therapy.
Although many groups have proposed different strategies to prevent neonatal catheter infections, few studies have yielded promising results. Several groups have studied the use of prophylactic antibiotics in neonates with indwelling catheters. The Cochrane Neonatal Group found no evidence to support this practice for neonates with umbilical arterial or venous catheters, nor did they find evidence to support routine use of vancomycin in preterm infants to prevent nosocomial sepsis. The use of a vancomycin-heparin lock solution to prevent nosocomial blood stream infection showed promise in a small randomized, controlled, double-blinded study in critically ill neonates with peripherally inserted central venous catheters ; however, larger studies are needed. The use of antibiotic- or silver-impregnated catheters has not been studied in neonates. In 2002, the CDC recommended against the routine use of antimicrobial prophylaxis for patients with central venous catheters. In 2006, the Cochrane Neonatal Group began a systematic review of the use of systemic antibiotics to reduce morbidity and mortality in neonates with central venous catheters. Results are not yet available.
Staphylococcus Aureus Infection
Staphylococcus aureus is a gram-positive bacteria that is morphologically indistinguishable from the coagulase-negative staphylococci by light microscopy. S. aureus is part of normal skin flora. This organism causes a much wider and potentially more invasive spectrum of disease than that caused by coagulase-negative species. This pathogen is a common cause of superficial pustular disease and localized cellulitis, and is the most frequent cause of surgical site infection in infants and adult patients. The production of numerous toxins, enzymes, and binding proteins facilitates its ability to establish aggressive, life-threatening pyogenic infection. Small-inoculum colonization or infection can produce catastrophic, toxin-mediated disease such as scalded skin syndrome or toxic shock.
Over the last two decades, S. aureus has shown an increasing resistance to β-lactam antibiotics, as documented by methicillin susceptibility testing ; these methicillin-resistant strains (MRSA) are resistant to all penicillins, penicillin–β-lactamase inhibitor combination drugs, cephalosporins, and carbapenems. Most hospital-acquired strains are resistant to clindamycin. Until recently, these resistant strains were not inherently more virulent. Unfortunately, however, over the last several years community MRSA strains have acquired an additional virulence factor, Panton-Valentine leukocidin. This factor has contributed to a significant increase in invasive, pyogenic infection by MRSA. Several outbreaks in preterm and term neonates, as well as nosocomial transmission from caregivers, equipment, and toys in neonatal intensive care units, have been reported. In an ill, hospitalized neonate who develops suspected or documented infection with gram-positive cocci, vancomycin should be included in the empirical antibiotic regimen. As discussed earlier, blood stream infections caused by coagulase-negative species are much more prevalent than bacteremias from S. aureus; however, many clinicians would elect to start vancomycin for any gram-positive blood stream infection in a hospitalized neonate because of the high rate of resistance to β-lactam antibiotics in the coagulase-negative strains and the potential consequences of not treating MRSA. Other drugs are available with activity against MRSA, including older drugs like tetracyclines and trimethoprim-sulfamethoxazole, but these drugs are typically avoided in neonates. Several newer drugs—quinupristin-dalfopristin, linezolid, and daptomycin—have activity against MRSA. MRSA infections in neonates should be managed by an individual with expertise in the pharmacodynamics and pharmacokinetics of these drugs.
Candidiasis
The survival of fragile, very low-birth-weight neonates has led to increased infections due to candidiasis in the nursery. Candida species are responsible for 2.4% of early-onset infections in newborns but, more importantly, they cause 10% to 12% of late-onset infections. Overall, infections with these fungi are among the three most common infections in the neonatal intensive care unit.
Although Candida albicans once caused 75% of invasive candidal infections, infections involving non-albicans species are now becoming more common, approaching 40% to 45% of infections. The incidence of Candida parapsilosis infection, unique to the newborn, has risen more than tenfold, and this species now causes 25% of fungal infections in the newborn. Also of note, the incidence of Candida tropicalis and Candida glabrata infection has nearly doubled during the same time period. The reported mortality attributable to C. albicans infection varies widely but may be as high as 20% to 40%. The mortality from C. parapsilosis is certainly significant but tends to be lower than that attributable to C. albicans.
Vertical transmission from mother to infant usually occurs during passage through the birth canal, especially in the presence of vaginitis. This is most often seen with C. albicans and C. glabrata. Congenital infections may rarely be seen and have been attributed both to ascending infection from the vagina and transplacental infection. C. parapsilosis, however, is frequently transmitted horizontally and is the most common fungal organism isolated from the hands of health care workers. This fungus is not commonly found in the genitourinary tracts of mothers. Colonization appears to occur more readily among very low and extremely low-birth-weight infants than among term infants and occurs in up to 25% of these infants in the first week of life. One fourth of intubated infants demonstrate respiratory colonization.
A large number of predisposing factors have influenced the rate of dissemination. One of the primary factors is the prolonged and frequent use of broad-spectrum antibiotics that suppress the growth of bacteria in the gastrointestinal tract and allow candidal overgrowth. Eventually, penetration of the epithelial barrier leads to disseminated disease. Mucosal penetration and dissemination are more likely the denser the colonization, and C. albicans has been shown to adhere to the mucosa of the preterm infant better than to that of the term infant. In particular, the use of third-generation cephalosporins seems to increase the risk of gastrointestinal colonization and subsequent candidemia. Dense colonization of the gastrointestinal tract increases the chances of translocation of the yeast across the mucosa. Intestinal ischemia, necrotizing enterocolitis, and spontaneous perforation of the intestine, common in the preterm infant, are all highly associated with candidemia. Delayed enteral feeding has also been associated with infection. The use of histamine 2 blockers raises the pH of the stomach and increases colonization, particularly of C. parapsilosis. Abdominal and cardiac surgeries are greater risks in term infants. In a similar fashion, candidal organisms readily penetrate the relatively poor barrier provided by the immature skin of the preterm infant, and that skin also readily breaks down during ordinary care. Colonized infants are more likely to be delivered vaginally than by cesarian section. The use of topical petrolatum for skin care of extremely low-birth-weight infants may increase the risk. Catheters, as well as all other indwelling tubes (endotracheal, chest, urinary, ventriculoperitoneal), may become infected. The longer the duration of an indwelling catheter, particularly if used for total parenteral nutrition or infusion of intravenous lipids, the greater the risk is to the infant. Immature immune defenses provide yet another set of risk factors. Neutrophils ingest and kill Candida intracellularly, but neutropenia is also common in very low-birth-weight infants. Theophylline, frequently used in preterm infants, may inhibit the candidacidal activity of neutrophils. Steroids inhibit the immune response, induce hyperglycemia, and, in the mouse, increase the adherence of the yeast to the intestinal mucosa.
Congenital candidiasis is extremely rare. In the term infant, infection results in an erythematous, macular eruption that then becomes pustular and desquamates. These same skin infections become burnlike in the preterm infant and then develop either a branlike or sheetlike desquamation, becoming superficial erosions. Intrauterine infection is highly associated with the presence of genital tract foreign bodies, in particular, cerclage, but have not been associated with maternal diabetes or urinary tract infections. The diagnosis in the newborn can be made with skin scrapings and blood and cerebrospinal fluid cultures. In the term infant with only cutaneous infection, survival is the rule. These infants do not require treatment, although many will administer topical therapy to relieve symptoms and to decrease the mass of organisms the infant has to clear. In contrast, in the preterm infant weighing less than 1500 g, or in any infant with respiratory symptoms signifying aspiration and pneumonia, mortality is the rule unless systemic treatment is begun.
Mucocutaneous infection (thrush or a monilial diaper rash) is the most likely infection after birth, seen in 4% to 6% of newborns and occurring as early as 4 to 5 days after birth but peaking at 3 to 4 months. Thrush manifests as white, curdlike, pseudomembranous plaques on the oropharynx or posterior pharynx, whereas the diaper dermatitis produces an erythematous, scaly lesion with satellite papules or pustules in the intertriginous areas. The latter may be repetitively reinfected by a gastrointestinal tract reservoir. Therapy in those areas is local. Oral nystatin may be given to treat the thrush. Gentian violet works as efficaciously, but its propensity to stain makes it less popular. For the skin lesions, topical nystatin alone works well, although occasionally it should be combined with oral nystatin to reduce the gastrointestinal tract reservoir and to prevent spillage onto the groin. Once the rash starts spreading beyond the usual area in the diaper, systemic therapy must begin.
Invasive candidiasis is a leading cause of morbidity and mortality in infants of less than 1000 g. Incidence in neonatal centers ranges from 2% to 28%. Systemic disease in these infants, unlike in adults, results in multiple foci of infection. Onset is delayed, usually occurring at several weeks of life, and the duration of candidemia, even with treatment, averages 7 days. Most infants have several positive blood culture results, and 10% experience candidemia for longer than 14 days. Infants have a multitude of signs and symptoms including, in order of frequency, respiratory deterioration, apnea and bradycardia, hyperglycemia, a necrotizing enterocolitis–like picture without pneumatosis, skin involvement, temperature instability, and hypotension. Meningitis, once reported in half of infants with systemic candidiasis, now occurs in only 5% to 9%, probably due to more aggressive diagnosis and treatment. Roughly half of infants with meningitis will have negative blood culture results and half will have normal CSF parameters. Endophthalmitis, once seen in half of infants, again is now relatively uncommon, occurring in fewer than 1%. Prognosis is excellent if the infection is treated. However, fungal sepsis in extremely low-birth-weight infants may be associated with increased frequency of threshold retinopathy of prematurity. Endocarditis, which may be the source of infected thromboemboli, is associated with the presence of central venous catheters. The prognosis for osteoarthritis or osteomyelitis is also good with treatment. Cutaneous manifestations may include a generalized erythema or subcutaneous abscesses. Infants may be neutropenic or have an extreme leukocytosis. Continued thrombocytopenia is often an indication of ongoing disease. Pneumonitis presents with respiratory deterioration and a bronchopulmonary dysplasia–like picture on chest radiograph. Other infants may develop abdominal distension, guaiac-positive stools, and feeding intolerance but no pneumatosis intestinalis. A few will have hepatic abscesses, diarrhea, or perforation. Mortality is extremely high in those with candidal peritonitis. Urinary tract involvement is found in over half of infants with systemic candidiasis and ranges from a bladder infection to renal abscesses or renal papillary necrosis to a mycetoma or fungal ball in the renal pelvis, possibly resulting in a flank mass. Disease of the urinary tract may be entirely silent or present with hypertension or acute renal failure with oliguria or anuria. Mortality is usually in the range of 20% to 50%, but death or disability ensues in as many as 73% of extremely low-birth-weight infants. Compared with age-matched controls, there is a higher incidence of periventricular leukomalacia, chronic lung disease, severe retinopathy of prematurity, and adverse neurologic outcome at 2 years corrected age.
Candidal species grow readily in cultures of blood or urine or specimens from other normally sterile sites, and yeast or hyphae can be seen on urinalysis. Given the propensity for dissemination, the patient should undergo ultrasonography of the kidneys, echocardiography, and a retinal examination. Fungal stains of skin scrapings can be helpful. A complete blood count and C-reactive protein level may give indirect evidence of infection. A lumbar puncture, together with culture, gram staining and cytologic analysis, is imperative. Overall, it is important to have a high index of suspicion.
Immediate consideration should also be given to the removal of possibly contaminated medical devices, particularly central intravascular catheters. Amphotericin B has been the standard for antifungal therapy for years, but many other agents have been introduced, and few data are available to indicate the advantages of one drug over another, let alone safety, efficacy, dosages, or duration of treatment. CSF penetration of amphotericin B, while better than in adults, is highly variable. This has led a few to suggest the use of 5-fluorocytosine or fluconazole, both of which have good penetration of the CSF, in combination with amphotericin B. Others have successfully treated meningitis with amphotericin B alone. There are three lipid formulations approved by the U.S. Food and Drug Administration for use in adults: amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), and liposomal amphotericin B (AmBisome). Because higher dosages may be used without toxicity, these preparations may be appropriate for the infant with renal disease or severe nephrotoxicity. A few studies have shown fluconazole to be efficacious in the treatment of invasive disease in neonates, equivalent to treatment with amphotericin B. Unfortunately, half of Candida glabrata and Candida krusei isolates are resistant to fluconazole. Fluconazole monotherapy is only recommended in neonates after identification of the fungal organism and determination of its susceptibility. Caspofungin is fungicidal against all candidal species. However, there are only case reports of its use in neonates, and it cannot be recommended at this time.
Prevention is clearly the best treatment for neonatal systemic candidiasis, yet this is also the area of greatest controversy. Treatment of maternal candidal infections may limit vertical transmission to the neonate. Prevention of horizontal transmission is more difficult. Hand washing does not reduce the recovery of C. albicans from medical workers’ hands. Removal of artificial fingernails may help. Careful attention to central lines is of benefit, as is attention to limiting exposure to drugs that increase the risk of disease. No consensus has been reached on the use of fluconazole prophylaxis. Some studies have shown a decrease in the incidence of colonization, invasive disease, or mortality. Finally, concern remains regarding the risk of isolates developing resistance. A recent metaanalysis of three trials involving over 1600 infants found a decrease in the risk of invasive fungal infection in very low-birth-weight infants with oral-topical antifungal prophylaxis but warned about the major methodologic weaknesses in trials to date. Also, one recent trial comparing fluconazole and nystatin oral prophylaxis had to be halted early due to a significant increase in deaths not related to fungal infections among the nystatin-treated infants. Reports do exist of increased resistance among infants with C. parapsilosis infection, a rising form of candidiasis.
Congenital Cytomegalovirus Infection
Cytomegalovirus (CMV) infection is the most frequent congenital infection in humans. The virus is endemic and worldwide and has no seasonal pattern of infection. Typically, after a primary infection, virus is shed for weeks to even years before becoming latent. Periodic episodes of viral shedding occur. The virus consists of three major components: an inner icosahedral or 20-sided capsid containing double-stranded DNA that is similar to that of herpes simplex virus; an amorphous layer consisting of viral proteins and RNA; and an outer envelope. The virus does not code for thymidine kinase, which renders acyclovir ineffective.
Infection with CMV largely depends on socioeconomic status, which reflects crowding. It also increases with parity and number of sexual partners. Finally, seropositivity is much higher among African American and Asian women. Seropositivity occurs in 0.5% to 2.0% of infants in the United States and Western Europe and rises to 50% to 85% among young women, but it is much more prevalent in developing countries and among lower socioeconomic groups, where seropositivity may be as high as 90%. At childbearing age, 2% of women of middle to upper socioeconomic status seroconvert yearly, compared with 6% of those of lower socioeconomic groups. Transplacental transmission of CMV from mother to infant is typical in congenital infection. A primary maternal infection results in transplacental infection in 30% to 40% of infants, with 10% to 15% of them developing symptomatic infection. The later in the pregnancy the seroconversion occurs, the more likely it will result in neonatal infection: 75% of infants are infected in the third trimester. However, the later in the pregnancy the infection occurs, the less likely the infection will be significant in the infant. Recurrent infections in the mother may also occur as a result either of reactivation or reinfection with a different strain. In either instance, transplacental infection still occurs in 1% of infants, but fewer than 1% of the infections are symptomatic. Polymerase chain reaction (PCR) methodology can detect CMV excretion in breast milk in 70% to 90% of women, particularly when the whey portion is tested, and perinatal transmission occurs to 40% to 60% of infants. Excretion occurs among these infected infants from 3 weeks to 3 months after birth. Also, transmission appears to occur readily among young children, and day care is responsible for transmission rates of over 50%, which most likely reflects contamination from saliva on toys and hands. Seroconversion may be as high as 15% to 45% among parents of children attending day care and 11% among women working in day care centers, so that subsequent pregnancies account for nearly one fourth of symptomatic congenital infections in the United States. In contrast, studies of seroconversion among health care workers do not show any risk of nosocomial transmission greater than the risk of acquiring the infection in the community. Yet nosocomial transmission to the infant may occur in the nursery, most likely via contaminated hands or fomites. Finally, infants may be infected as a result of blood transfusion or exchange transfusion. These cases may be largely prevented by using seronegative donors, leukocyte filtration, or frozen, deglycerolized packed red blood cells.
Nearly 90% of congenital infections are asymptomatic and the infants are neither growth restricted nor premature, although 10% to 15% of them are still at risk of later developmental abnormalities, which appear within the first years of life. Among asymptomatic infants, 7.2% will ultimately have hearing loss. Half of these neonates will have bilateral, progressive disease. This progressive loss, however, may be missed by routine nursery screening. A much lower risk (2%) is that of chorioretinitis, which is also usually delayed in onset. A similar number of children may also develop neurologic abnormalities, including microcephaly, neuromuscular motor defects, and mental retardation, or defects in tooth enamel. Cytomegalic inclusion disease is seen in only 5% to 10% of infected newborns and usually occurs as a result of primary infection in the mother around the time of conception ( Table 14-1 ). Mortality, which may reach 20% to 30%, results from liver failure, bleeding, disseminated intravascular coagulation (DIC), and secondary bacterial infection. Some deaths may occur after the neonatal period as a result of the complications of severe neurologic handicap. One half of symptomatic infants have intrauterine growth restriction and one third are prematurely born. Microcephaly may also be seen in half of the infants, along with intracranial calcifications. Hepatomegaly, and even more frequently splenomegaly, are among the most common findings in newborns. Two thirds of the infants develop jaundice, which often persists and becomes increasingly due to a rise in the direct component, and most infants have some rise in liver enzyme levels. Petechiae and even purpura are found in over half. Thrombocytopenia, due to suppression of the megakaryocytes in the bone marrow, may be severe (one third have platelet counts of <10,000). There may also be a Coombs-negative hemolytic anemia. Diffuse interstitial pneumonitis is rare (<1%) and is more commonly seen in perinatally acquired disease. A peculiar defect of the enamel of the primary teeth may be seen in infants. This yellow, soft enamel wears away early, leaving the teeth susceptible to rampant caries. Male infants may also have inguinal hernias. Both the defect in dental enamel and the hernias appear to be teratogenic in nature. A few infants have manifested necrotizing enterocolitis. Sensorineural hearing loss is found in over one third of the infants and, as in asymptomatic infants, may be unilateral or bilateral, profound, and progressive. Chorioretinitis, optic atrophy, and strabismus may be found in 22%, and the retinitis is more likely to present at the macula than in adults. The outcome is grim, with 90% of infants developing at least one neurologic abnormality. Although microcephaly is a strong predictor of intellectual impairment, intracranial calcifications on computerized tomographic images indicate a risk as high as 90% and are often accompanied by progressive, severe, bilateral hearing loss, optic atrophy, and neuromuscular abnormalities. Ultrasonography may accurately demonstrate calcifications, but magnetic resonance imaging may provide additional findings, such as polymicrogyri, hippocampal dysplasia, and cerebellar hypoplasia.
