Health Care–Associated Infections in the Nursery

Incidence

The incidence of HAIs varies markedly by birth weight, gestational age, underlying conditions, and exposure to medical devices. Reported rates of specific infections in similar patient populations differ dramatically by institution. In the past, much of this variation likely arose from differences in patient populations and clinical practices. As noted above, however, the patient safety movement has resulted in marked reductions in the rates of many specific HAIs in numerous NICU settings.

In 1999, a nationwide multicenter surveillance study, the Pediatric Prevention Network (PPN) Point-Prevalence Survey, was undertaken to determine the point prevalence of and to define risk factors associated with nosocomial infections in NICU patients. This study included data from 29 NICUs and found that 11.4% of infants had an active nosocomial infection on the day of the survey. Bacteremia was the most common infection (53%). Lower respiratory tract infections; ear, nose, or throat infections; and urinary tract infections accounted for 13%, 9%, and 9% of infections, respectively. A more recent nationwide point-prevalence survey conducted in Canada in 2009 found that the overall rate of HAI in NICUs was 6.6% (95% confidence interval (CI), 4.68 to 9.19) and that bacteremia accounted for 60% of all infections.

In contrast to the NICU setting, the frequency of nosocomial infection in well-infant nurseries has been estimated to be 0.3% to 1.7%. In general, non–life-threatening infections such as conjunctivitis account for most infections in the well-infant population. The remainder of this chapter focuses on nosocomial infections in NICUs.

Maternally Acquired Infections

Differentiating maternally acquired and hospital-acquired infections can be difficult. Surveillance definitions typically describe nosocomial infections as infections that arise 2 or more days after initial admission to a nursery or NICU. No precise time point or definition perfectly discriminates infections that clinically were likely attributable to vertical transmission from infections transmitted within the NICU. Approximately 90% of hospitalized neonates with an infection presumed to be of maternal origin had onset of symptoms within 48 hours of birth. Maternally acquired bloodstream infections were more likely to be caused by group B streptococci, other streptococci, and Escherichia coli and were rarely caused by CoNS.

Nonmaternal Routes of Transmission

Nonmaternal routes of transmission generally can be divided into three categories: contact (from either direct or indirect contact from an infected person or a contaminated source), droplet (from large respiratory droplets that fall out of the air at a maximum distance of 3 feet), and airborne (from microscopic droplet nuclei, which can remain suspended in air for long periods and as a result travel longer distances). Specific microorganisms can be spread by more than one mechanism; however, in most instances, a single mode of spread predominates. The U.S. Centers for Disease Control and Prevention (CDC) has developed a system of precautions to prevent the spread of HAIs that is based on these modes of transmission.

Most neonatal HAIs are caused by the infant’s own flora. The “abnormal flora” of the neonate residing in the NICU is determined at least in part by the NICU environment and the hands of health care workers. Contact transmission of bacteria, viruses, and fungi on the hands of health care workers is arguably the most important, yet seemingly preventable, mechanism by which potentially pathogenic organisms are spread. Poor compliance with hand hygiene has been repeatedly shown as a cause of outbreaks and transmission of resistant microorganisms. In a study of infants with CoNS bloodstream infections, investigators used pulsed-field gel electrophoresis to demonstrate a high rate of concordance between the isolates that caused invasive infection in hospitalized neonates and those carried on the hands of nurses who cared for them. In contrast, gram-negative organisms isolated from neonatal bloodstream infections differed from those cultured from the clean hands of their nurses.

Transmission via contaminated inanimate objects also occurs and has been described as a potential mechanism of spread of pathogens in multiple NICU outbreaks. Implicated items have included linens, medical devices, soap dispensers, and breast pumps. These observations highlight the need for careful attention to disinfecting items shared among infants.

Spread of infection through large respiratory droplets is an important mode of transmission for pertussis and certain respiratory viruses. The early identification and appropriate use of precautions for suspected cases are particularly important for nurseries that admit infants from the community. Recent reports of NICU-based outbreaks of pertussis have highlighted both the morbidity and cost associated with these outbreaks. Parents and health care workers with unrecognized infection have been found to be the source of NICU-based pertussis outbreaks. Measles, varicella, and pulmonary tuberculosis are usually spread via the airborne route by means of microscopic droplet nuclei but are not typical risks in a nursery or NICU.

Other sources of HAIs include contaminated infusions, medications, and feeding powders or solutions, which can be either intrinsically or extrinsically contaminated, and have been reported as the source of outbreaks caused by a variety of different pathogens. It is important, when possible, to mix infusions in a controlled environment (usually the pharmacy), to avoid multiuse sources of medication, and to use bottled or sterilized feeding solutions when breast milk is unavailable.

Risk Factors for Health Care–Associated Infections

Coagulase-Negative Staphylococci

Since the early 1980s, CoNS have been the most common cause of HAIs, particularly bloodstream infections, in the NICU. Data from 2006 to 2008, reported to the National Healthcare Safety Network (NHSN), estimate that 28% of bloodstream infections are caused by these organisms. Although an infrequent cause of fatal infection, bacteremia caused by CoNS has been associated with prolonged NICU stay and increased hospital charges, even after adjustment for birth weight and severity of illness on admission. Molecular techniques suggest that infections caused by Staphylococcus epidermidis can result from clonal dissemination and that there is often concordance between the strains infecting infants and strains carried on the hands of health care workers. Several studies have demonstrated that a small number of CoNS clones accounted for the isolates from both infected infants and the health care workers that cared for them. These findings suggest that a significant proportion of CoNS infections may be preventable by strict adherence to appropriate hand hygiene practices.

Other Gram-Positive Bacteria

Enterococcus accounts for approximately 10% of all neonatal HAIs, 6% to 15% of bloodstream infections, 0% to 5% of cases of pneumonia, 17% of urinary tract infections, and 9% of surgical site infections. Sepsis and meningitis are common manifestations of enterococcal infection during NICU outbreaks. The presence of a nonumbilical CVC, prolonged presence of a CVC, and bowel resection all have been identified as independent risk factors for enterococcal infections in NICU patients, whereas prolonged antibiotic exposure and low birth weight (LBW) were found to be risk factors for colonization with vancomycin-resistant enterococci. Because Enterococcus colonizes the gastrointestinal tract and can survive for long periods on inanimate surfaces, the patient’s environment may become contaminated and, along with the infant, serve as a reservoir for ongoing spread of the organism.

Historically, before the recognized importance of hand hygiene and the availability of antimicrobial agents, group A streptococci were a major cause of puerperal sepsis and fatal neonatal sepsis. Although less common now, group A streptococci remain a cause of outbreaks in nurseries and NICUs. Early-onset infections caused by group A streptococci are often characterized by severe sepsis and respiratory distress, whereas clinical manifestations of late-onset infections typically include meningitis and soft tissue infections. Molecular techniques have enhanced the ability to define outbreaks, and use of these techniques has suggested that transmission can occur between mother and infant, between health care worker and infant, and between infants—probably indirectly via the hands of health care workers. In one recurring outbreak, inadequate laundry practices seemed to have been a contributing factor.

Data from the CDC and the Neonatal Research Network have shown that group B streptococcal infections account for less than 2% of non–maternally acquired nosocomial bloodstream infections and pneumonia. Numerous studies from the 1970s and 1980s showed nosocomial colonization of infants born to women negative for group B streptococci. These studies suggested a rate of transmission to infants born to seronegative mothers of 12% to 27%. A case-control study evaluating risk factors for late-onset infection caused by group B streptococci showed that premature birth was a strong predictor. In that study, 50% of the infants with late-onset infection caused by group B streptococci were born at less than 37 weeks of gestation compared with 15% of control subjects, and only 38% of the mothers of these infants were colonized with group B streptococci, suggesting possible nosocomial transmission of group B streptococci during the NICU stay.

Gram-Negative Bacteria

Organisms from the Enterobacteriaceae family have long been recognized as an important cause of HAIs, including sepsis, pneumonia, urinary tract infections, and soft tissue infections; morbidity and mortality rates are frequently high. Enterobacter species, Klebsiella pneumoniae, and E. coli are the members of the Enterobacteriaceae family that are most commonly encountered in the NICU. Many outbreaks caused by gram-negative bacteria have been reported. Underlying causes of these outbreaks include contaminated equipment, formula or breast milk, and intravenous fluids, understaffing, overcrowding, and poor hand hygiene practices. Risk factors for endemic bloodstream infections caused by gram-negative organisms include LBW, gastrointestinal tract pathology, and proton-pump inhibitors. The origins of these organisms are often unclear, although many authors hypothesize that at least some episodes of gram-negative bacteremia are a consequence of intestinal translocation. This hypothesis is consistent with the observation that enteric feedings have been associated with a reduced risk of gram-negative infections but awaits future studies for confirmation.

Pseudomonas aeruginosa , an opportunistic pathogen that can persist in relatively harsh environments, has frequently been associated with HAIs and outbreaks in NICUs. Nosocomial P. aeruginosa infections vary in their clinical presentation, but the most common manifestations are respiratory; ear, nose, or throat; and bloodstream infections. P. aeruginosa infections, particularly bloodstream infections, have been associated with a very high mortality rate. Risk factors for infection include feeding intolerance, prolonged parenteral alimentation, and long-term intravenous antimicrobial therapy. Outbreaks caused by P. aeruginosa have been linked to contaminated hand lotion, respiratory therapy solutions, a water bath used to thaw fresh-frozen plasma, a blood gas analyzer, and bathing equipment.

Health care workers and their contaminated hands have also been linked with Pseudomonas infections in the NICU. In a study of a New York outbreak, recovery of Pseudomonas species from the hands of health care workers was associated with older age and history of use of artificial nails. This and other studies suggest that the risk of transmission of Pseudomonas to patients is higher among health care workers with onychomycosis or who wear long artificial or long natural nails. As a result of these and other findings, the CDC revised its 2002 hand hygiene recommendations to include a recommendation against the presence of health care workers with artificial fingernails in intensive care units.

Multidrug-Resistant Organisms

Staphylococcus aureus has frequently been identified as a cause of nosocomial infection and outbreaks in well-infant nurseries and NICUs. Methicillin-resistant S. aureus (MRSA) has become a serious nosocomial pathogen, and outbreaks have been reported in many areas of hospitals, including nurseries. Recent data from the NHSN demonstrated that approximately one third of NICU infections caused by S. aureus were due to MRSA. With the emergence of community strains of MRSA, nosocomial transmission of MRSA with the molecular phenotype of either community-associated or hospital-associated strains has been shown. In addition to the usual manifestations of neonatal nosocomial infection, S. aureus HAIs (caused by methicillin-sensitive strains or MRSA strains) can manifest as skin infections, bone and joint infections, parotitis, staphylococcal scalded skin syndrome, toxic shock syndrome, and disseminated sepsis. No significant differences in clinical manifestations have been noted between infections caused by methicillin-sensitive S. aureus compared with MRSA.

Direct contact is the presumed mechanism of most instances of S. aureus transmission. Several distinct reservoirs of MRSA have been identified and associated with MRSA outbreaks, including parents, visitors, and health care workers. Understaffing and overcrowding have been associated with S. aureus outbreaks in NICUs. The potential for airborne transmission has been suggested by “cloud babies,” described by Eichenwald and colleagues, in which the respiratory secretions or desquamated skin from a colonized infant carry S. aureus over relatively long distances. “Cloud” health care workers also have been described; in such cases, the point source of an outbreak was determined to be a colonized health care worker with a viral respiratory infection. Parents can also transmit MRSA to their newborn infants on passage through a colonized birth canal or postpartum handling.

The emergence of vancomycin-resistant enterococci (VRE) is a concern in all hospital settings, and several VRE outbreaks have been reported in NICUs. In neonates, VRE seem to cause clinical syndromes indistinguishable from syndromes caused by susceptible enterococci. Vancomycin use, which is especially prevalent in the NICU, has increased markedly and has probably contributed to the growing prevalence of resistant gram-positive organisms in neonatal patients. More recent observations suggest that clinical infections caused by VRE may signal the presence of a larger reservoir of VRE among asymptomatic colonized infants, and some authors have suggested that active surveillance may be required to interrupt ongoing transmission.

Over the past decade, the array and prevalence of resistant gram-negative organisms have expanded rapidly. Extended-spectrum β-lactamases (ESBLs) are plasmid-mediated resistance factors produced by members of the Enterobacteriaceae family. ESBLs inactivate third-generation cephalosporins and aztreonam. K. pneumoniae and E. coli are the organisms most commonly recognized as ESBL-producing organisms, but other ESBL-producing gram-negative bacilli are being increasingly reported in both NICU outbreaks as well as endemic infections in NICUs in some settings. Transfer of ESBL-carrying plasmids to other Enterobacteriaceae organisms has been shown in several NICU outbreaks. Two mechanisms of acquisition of resistant gram-negative organisms have been shown through molecular epidemiologic investigations: patient-to-patient transfer (presumably via contaminated health care worker hands or medical equipment) and de novo emergence as a consequence of antibiotic exposure.

Fungi

Candida species are the third most common pathogen identified in patients with late-onset sepsis and are associated with morbidity and mortality rates similar to those observed with sepsis from gram-negative bacteria. More recent reports have also linked neonatal candidiasis to increased neurodevelopmental impairment in infancy, retinopathy of prematurity, and death. In addition, investigators have quantified the cost of an episode of candidemia in the NICU to be $28,000 to $39,000.

Chitnis and colleagues reported on data from the National Nosocomial Infections Surveillance (NNIS) network, including 128 NICUs covering 130,523 patients over a 10-year period ending in 2004. Of 1997 cases of candidemia in these patients, 57.9% were Candida albicans , 33.7% were Candida parapsilosis , 3.8% were Candida tropicalis , 2% were Candida glabrata , and 0.2% were Candida krusei . Over time, there was an overall decrease in candidemia in neonates weighing less than 1000 g, but there was variability in the incidence of candidemia in different NICUs, ranging from 2.4% to 20.4%. During this time period, there was no change in the distribution of Candida species. The combined mortality rate for neonates with candidemia was 13%, which did not significantly differ among infecting species.

A retrospective cohort study of neonatal candidiasis using the 2003 Kids Inpatient Database reported the incidence of candidiasis at 15 per 10,000 NICU admissions. Two thirds of the cases occurred in neonates with a birth weight of less than 1000 g. Of these patients, neonates with extremely LBW were twice as likely to die as propensity-matched neonates with extremely LBW without candidiasis. The overall mortality attributable to candidiasis in neonates with extremely LBW was 11.9%.

Many risk factors have been associated with neonatal candidemia. Colonization likely precedes infection, and this can occur either vertically (via the maternal genitourinary tract) or horizontally (nosocomial spread). The relative roles of gastrointestinal tract colonization and enteric translocation versus skin surface colonization and catheter-related infection are unclear and not mutually exclusive. Studies have identified gestational age 32 weeks or younger, APGAR score less than 5, shock, disseminated intravascular coagulation, delayed enteral feeding, intralipid use, parenteral nutrition, CVCs, H2 blockers, intubation, and prolonged length of stay as risk factors for neonatal candidemia. Use of broad-spectrum antibiotics has also been associated with an increased risk of candidemia.

Fluconazole prophylaxis at dosage of 3 mg/kg or 6 mg/kg twice weekly reduces rates of candidemia in premature neonates in NICUs that have a high incidence of candidemia. Recent data suggest the risk of invasive candidiasis in infants is decreasing. At present, fluconazole prophylaxis is only recommended for infants with extremely LBWs in nurseries that have a moderate (5%-10%) or high (>10%) incidence of invasive candidiasis. A long-term follow-up study of surviving infants who had participated in a randomized controlled trial of fluconazole prophylaxis revealed no difference in neurodevelopmental outcomes at 8 to 10 years of life.

Malassezia species, which are lipophilic yeasts, frequently colonize NICU patients. In one French study, 30 of 54 preterm neonates (56%) became colonized with Malassezia furfur . Malassezia pachydermatis , a zoonotic organism present on the skin and in the ear canals of healthy dogs and cats, has also been associated with nosocomial outbreaks in NICUs. In one report, the outbreak seemed to be linked to colonization of health care workers’ pet dogs.

Invasive mold infections are a rare cause of nosocomial infection in neonates, but when they occur, they are associated with a high mortality rate. Aspergillus infections may manifest as pulmonary, central nervous system, gastrointestinal, or disseminated disease. A cutaneous presentation, with or without subsequent dissemination, seems to be the most common presentation for hospitalized premature infants without underlying immunodeficiency. Often, skin maceration is the presumed portal of entry. In a series of four patients who died of disseminated Aspergillus infection that started cutaneously, a contaminated device used to collect urine from the male infants was implicated. Investigation of a recent cluster of Aspergillus infections implicated contaminated humidity chambers of incubators as a source. Contaminated wooden tongue depressors, used as splints for intravenous and arterial cannulation sites, were associated with cutaneous infection caused by Rhizopus microsporus in four premature infants. In addition to preterm birth, use of broad-spectrum antimicrobial agents, steroid therapy, and hyperglycemia are thought to be risk factors for mold infection.

Viral Pathogens

Nosocomial viral infections can be a significant problem for neonates. Introduction of common viral pathogens into the NICU can be associated with (1) admission of infants from the community, (2) health care workers who work while ill or infectious, and (3) visitors.