Infection on the Neonatal and Pediatric Intensive Care Units

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Infection on the Neonatal and Pediatric Intensive Care Units

A.J. PETROS, V. DAMJANOVIC, A. PIGNA, J. FARIAS

Current Concept of Infections on Neonatal and Pediatric Intensive Care Units

Neonatal Intensive Care Unit

Infections in neonates requiring intensive care are unique in each of the essen- tial elements of the pathogenesis of infection, i.e., the potential pathogen and its source, the mode of transmission, and the susceptible host. The pathogen, e.g., hepatitis B virus, or potential pathogen, e.g. Escherichia coli, is closely related to its source and mode of transmission. Many micro-organisms are present in the maternal birth canal (the source). They are most commonly Streptococcus agalactiae, E. coli, Herpes simplex virus, Listeria monocytogenes, and Candida albicans. One or more of these micro-organisms can be vertically transmitted from the mother to the neonate. When this type of infection occurs the infection will always be present in the 1st week of the neonate’s life (early onset).

Different micro-organisms are acquired on the neonatal intensive care unit (NICU). In general, these are coagulase-negative staphylococci (CNS), aerobic Gram-negative bacilli (AGNB) (mainly Klebsiella species and Pseudomonas aeruginosa), Staphylococcus aureus, and Candida species. The sources of these micro-organisms acquired on the NICU are mainly other neonates who carry the micro-organisms and/or who are infected with them. Staff on the NICU, mothers, contaminated materials, and equipment (environment) constitute uncommon sources. Although these micro-organisms can be transmitted from one neonate to another via equipment, the hands of healthcare workers are the main mode of transmission on the NICU [1]. Infections due to micro-organisms acquired on the unit are usually of late onset, following an episode of carriage.

The incidence of infection is higher in the neonatal period than at any time in life. Neonates, particularly preterm, are extremely susceptible to infection.

Low birth weight is the single most important risk factor for infection in neonates [2].

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The reasons for this increased susceptibility include immaturity of the immune system, poor surface defenses, lack of resistance to colonization [3, 4], invasive devices, and usage of broad-spectrum antibiotics. Increased susceptibility to carriage and infection in preterm neonates is the main factor that facil- itates transmission of potential pathogens and subsequent outbreaks of infection on the NICU [1]. Moreover, preterm neonates can be susceptible to new and unknown potential pathogens such as Hansenula anomala, a saprophytic yeast known as a contaminant in the brewing industry. This newly recognised potential pathogen caused an outbreak of carriage and infection that lasted for 13 months on the Mersey regional NICU [5].

Pediatric Intensive Care Unit

The identical concept of three elements, including potential pathogen, its source, mode of transmission, and susceptible host, applies to the patients admitted to the pediatric intensive care unit (PICU). Recent epidemiological studies in children who required a prolonged PICU admission demonstrated that two-thirds of all infections diagnosed were due to micro-organisms present in the patient’s admission flora [6, 7, 9]. These infections were practically all within a week of PICU admission. Infections due to micro-organisms acquired on the unit, and subsequently carried, invariably occurred after 1 week. The three main micro-organisms causing infections within the 1st week are CNS, S.

aureus, and C. albicans. After 1 week the two main micro-organisms are S.

aureus and P. aeruginosa. Unlike neonates, maternal flora is not the source of micro-organisms acquired on a PICU. It is invariably the other patients who function as a major source.

The length of stay in the NICU is substantially longer than that on the PICU (median of 13 versus 6.5 days) [4, 7, 8]. An extensive literature search showed that outbreaks are more common in NICU than PICU (Chapter 13). Finally, lower overall mortality rates of 5% [9] support the observation that children on a PICU are less susceptible hosts compared with the 10% mortality in neonates requiring intensive care on the NICU [4].

Magnitude of the Problem

Neonatal Intensive Care

The overall infection rates in neonates whilst on intensive care vary between 15% and 20%. This is equal to rates reported for adult medical and surgical units and higher than most pediatric units [10]. The main site of infection is the bloodstream, followed by the lower airways.

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In a multicenter study of NICUs in Oakland, New Haven in 1994 Beck-Sague et al. [11] reported that nosocomial bloodstream infection occurred at a rate of 5% when surveillance cultures were performed and was actually half that reported in studies reporting the rate of all infections. Bloodstream infections can account for 50% of all infections on the NICU. Lower airway infections occur in approximately 3% of neonates whilst on the NICU [12]. The main organisms are viruses, S. aureus, and AGNB.

The survival benefit of intensive care in neonates has significantly increased over the last 25 years. In a 2-year study from New York (1977–1978), the mortality for early onset sepsis in neonates of less than 1,000 g was 53.4%; mortality was 20.3% for late-onset sepsis [13]. Ten years later, a 5-year study from Oxford (1982–1986) reported mortality figures of 28% and 4% for early and late-onset sepsis in neonates, respectively [2]. Recent data from a Dutch NICU show a mortality of less than 10% in a 1-year study (1997) in 436 neonates of about 2,000 g [4].

Pediatric Intensive Care

Nosocomial infection in the PICU is an important cause of morbidity and mortality in ventilated children. Bloodstream and lower airway infections are most common and are almost always due to prolonged use of devices. The incidence of bloodstream infection is reported at 10.6–46.9/1,000 catheter-days [14]. The incidence of lower airways infection is 6.5–20.2/1,000 ventilation-days.

Bloodstream infections. In a recent report from a mixed PICU in Birmingham United Kingdom [15], where all children admitted were included, the incidence of bloodstream infection was 10.6/1,000 patient-days. Consequently the group as a whole was less ill and stayed for a median of 3 days. The larger denomina- tor of >12,000 patient-days also dilutes the real infection rate. Of the micro- organisms causing positive blood cultures, 62% were Gram-positive bacteria, mainly CNS, S. aureus, and enterococci, 32% were AGNB, and the remainder were yeasts.

In a recent study from Liverpool (UK) comprising 1,241 children requiring a median of 8 days’ ventilation, the overall infection rate was 41.9% [9]. Viral infection accounted for 14.5% and bacterial/yeast infections for 33%. The incidence of bloodstream infection was 20.1/1,000 patient-days. The infection rate due to microorganisms acquired while on the PICU was 13.3%; 4% of admitted children developed infections due to resistant micro-organisms. The causative micro-organisms were CNS, enterococci, Pseudomonas spp., S. aureus, and yeasts.

A study from London (UK) reported an incidence of bloodstream infection of 46.9/1,000 patient-days in a subset of 103 children with a median time of 6

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days of line in situ [16]. The causative organisms were CNS, S. aureus, Candida albicans, and Klebsiella species.

Lower airway infections. In a pediatric trauma unit the rate of lower airway infections was 5.5% [17]. The most common organisms were S. aureus, Haemophilus influenzae, Enterobacter, and Pseudomonas spp. [17]. In the Liverpool study the overall airway infection rate was 10.6%, with a rate of 9.1 episodes/1,000 patient-days [9]. The three main organisms were S. aureus, P.

aeruginosa, and H. influenzae.

The magnitude of the problem can be assessed in a different way, based upon the carrier state (Chapter 5). Endogenous infection must be distinguished from exogenous infection. Endogenous infection is one caused by potential pathogens previously carried by the patient. If the potential pathogen was present on admission then the infection due to this potential pathogen is called primary endogenous. This type of infection tends to occur early, within the 1st week. If the infection is due to a potential pathogen acquired on the unit, after going through the carriage phase, then the infection is termed secondary endogenous. Infections caused by micro-organisms not carried by the patient are termed exogenous. Obviously surveillance cultures are indispensable for this classification [6, 9].

Some micro-organisms cause more serious clinical disease than others. This differential pathogenic effect can be used to develop a pathogenicity index for an individual micro-organism, in a specific organ system, in a particular homo- geneous population for which surveillance cultures are useful [18]. The ratio of the number of ICU patients infected by a particular micro-organism and the number of patients simply carrying that organism in their throat and/or gut is defined as the intrinsic pathogenicity index for a particular micro-organism.

Indigenous flora, including anaerobes, will rarely cause infections in the lower airways of patients requiring ventilation for more than 3 days, despite being carried in high concentrations. This is because they have intrinsic pathogenicity index values of between 0.01 and 0.03. Low-level pathogens, including viridans streptococci, enterococci, and CNS, are also carried in high concentrations in the oropharynx by a substantial percentage of ICU patients and are unable to cause lower airway infections. High-level pathogens such as S. pyogenes and Salmonella have an intrinsic pathogenicity index approaching 1.0, and disease manifests itself in virtually all oropharyngeal and gut carriers. The concept of carriage recognizes about 15 potentially pathogenic micro-organisms with intrinsic pathogenicity indices of between 0.1 and 0.3. These consist of the 6

“community” or “normal” micro-organisms S. pneumoniae, H. influenzae, Moraxella catarrhalis, E. coli, S. aureus, and C. albicans, present in previously healthy individuals, and 9 “hospital” or “abnormal” bacteria carried by patients with either an acute or chronic underlying condition, namely Klebsiella,

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Proteus, Morganella, Enterobacter, Citrobacter, Serratia, Pseudomonas, Acinetobacter spp., and methicillin-resistant S. aureus (MRSA). The overall mortality on our PICU is in the range of 5%, but the mortality rate rises to 10%

in the subset of children who require prolonged mechanical ventilation [9].

Pathogenesis

Figure 1 describes the pathogenesis of infection in neonates and children requiring intensive care. Practically all infections in these two groups are endogenous in origin. Therefore patients infect themselves with micro-organisms that they carry. A recent study in 400 children, requiring ventilation on a PICU, demonstrated that 90% of all lower airway infections were endogenous;

80% of lower airway infections were primary endogenous, 10% secondary endogenous, and the remaining 10% were exogenous [6].

Bloodstream infections occur due to translocation. Micro-organisms in the terminal ileum in overgrowth (≥10⁵ micro-organisms/ml) migrate into the bloodstream [19]. This mechanism applies to S. agalactiae, S. aureus, and

Fig. 1.Schematic representation of the digestive tract, illustrating that the throat and gut are the major internal sources of potential pathogens causing endogenous infections of blood, lower airways, bladder, and wounds (CNS, coagulase-negative staphylococci, S. agal, Streptococcus agalactiae)

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Candida species. Recently it has been demonstrated that in neonates and chil- dren staying longer that 1 week on the NICU or PICU, CNS and AGNB cause septicemia due to translocation [20].

Lower airway infections are caused by micro-organisms carried in the oropharynx that then migrate into the lower airways. In a previous healthy child, S. pneumoniae, H. influenzae, and S. aureus cause bacterial lower airway infections. Whilst AGNB and MRSA are causative organisms in children with conditions that require intensive care for longer than 1 week.

Bladder infections are, in general, endogenous due to migrating fecal bacteria. Wound infections of the head, neck, and thorax are, in general, caused by oral bacteria, whilst wound infections between the waist and knee are caused by gut bacteria.

Exogenous infections, defined as infections caused by micro-organisms not carried by the patient, vary between 5% and 25%. They are a particular problem in patients with tracheostomies, leading to lower airway infections of exogenous pathogenesis [21]. Children with wounds, particularly burns, are at high risk of exogenous colonization and infection [9]. Up to 16% of bloodstream infections have an exogenous pathogenesis following contamination of an indwelling intravascular device [19]. Gastrostomies can also be considered as a wound and recurrent exogenous colonization/infection is not uncommon in children with such devices [9]. To identify an exogenous infection, surveillance samples of throat and rectum are indispensable. Blood cultures or lower airway secretions are positive for a potential pathogen that is not present in throat and or rectal cultures.

Risk factor analysis invariably includes low birth weight, the administration of total parenteral nutrition, the presence of invasive indwelling devices, including endotracheal tubes, mechanical ventilation, length of stay, and prior use of antibiotics [2, 22, 23]. All these factors reflect the severity of illness and are dif- ficult to modify in order to control infection. Risk factor analysis cannot easily contribute to infection control.

Diagnosis of Infection

Infection is a microbiologically proven, clinical diagnosis of local and/or general inflammation. The signs of generalized infections in neonates, e.g., septicemia, are often non-specific and may be clinically indistinguishable from those of non-infectious conditions [2]. For instance, the clinical picture of res- piratory distress in early onset sepsis may be identical to hyaline membrane disease. Furthermore, the clinical diagnosis of local infection such as meningi- tis may not differ from that of systemic sepsis without meningeal involvement.

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However, infections in the PICU are more specific and further description of local and general infection is related to pediatric patients.

Pneumonia

Microbiologically proven pneumonia requires (1) the presence of new or pro- gressive pulmonary infiltrates on a chest X-ray for ≥48 h and (2) purulent tra- cheal aspirate and (3) fever ≥38.5^oC and (4) leukocytosis (WBC >12,000/ml) or leukopenia (WBC <4,000/ml) and (5) tracheal aspirate ≥10⁵colony forming units (CFU) of potentially pathogenic micro-organism/ml or bronchoalveolar lavage (BAL) yielding ≥10⁴CFU/ml.

Clinical diagnosis only requires criteria 1-4 above and sterile BAL or tra- cheal aspirate.

Tracheitis/Bronchitis

Diagnosis of tracheitis/bronchitis requires (1) purulent tracheal aspirate and (2) fever ≥38.5^oC and (3) leukocytosis (WBC >12,000/ml) or leukopenia (WBC

<4,000/ml) and (4) tracheal aspirate yielding ≥10⁵CFU/l. Most importantly, the chest X-ray is normal.

Systemic Inflammatory Response Syndrome

The diagnosis of systemic inflammatory response syndrome (SIRS) requires clinical signs of generalized inflammation caused by micro-organisms and/or their products, including at least three of the following: fever, temperature instability, lethargy, poor perfusion, and hypotension.

Bloodstream Infections

The diagnosis of bloodstream infections requires SIRS with a positive blood culture from either a peripheral vein or an intravascular device.

Intra-abdominal infection

This is defined as an infection of an abdominal organ and of the peritoneal cavity (peritonitis), with local signs such as abdominal tenderness and generalized symptoms including fever and leukoyctosis. Peritonitis can be a localized or a generalized infection of the peritoneal cavity. Following ultrasonography and/or computed tomography and/or laparotomy, the diagnosis is confirmed by the isolation of micro-organisms of≥3+ or ≥10⁵CFU/ml and ≥2+ leukoyctes in the diagnostic sample [24].

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Urinary Tract Infection

Infection of the urinary tract most often involves the bladder. The common fea- tures of dysuria, supra-pubic pain, frequency, and urgency, are often not assess- able in PICU patients. Therefore the diagnosis of cystitis is based upon freshly obtained catheter urine containing ≥10⁵ CFU/ml of urine and ≥5 WBC/high- power light microscopy field.

Wound Infection

Wound infection is diagnosed by purulent discharge from wounds, a culture yielding ≥3+ or ≥10⁵CFU/ml of pus, and signs of local inflammation. The isolation of skin flora is considered to be contamination.

Prevention

Beside the five infection control interventions (Chapter 10), there is only evidence of effectiveness for two antibiotic maneuvers that prevent infection on the NICU and PICU; surgical prophylaxis [25–27] and selective decontamination of the digestive tract (SDD) (Table 1) [28–32].

Table 1.Cardiac and general surgical prophylaxis and prevention protocol for selective decontamination of the digestive tract (ICU intensive care unit, MRSA methicillin-resistant Staphylococcus aureus, AGNB aerobic Gram-negative bacilli)

Surgical prophylaxis Total daily dose (mg/kg)

<7 days >7 days 1 month >12 years to 12 years

Cardiac

Teicoplanin 16 then 8 20 then 10 400 mg

then 6 then 200 mg

Netilmicin 3<2 kg 6 6 200 mg

6>2 kg General

Cefotaxime 100 150 100-200 6–12 g

Metronidazole 22.5 22.5 22.5 1.5 g

Gentamicin 3<2 kg 6<2 kg 7.5 3-5

6>2 kg 7.5>2 kg

cont.➝

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Selective decontamination Total daily dose (4 daily)

of digestive tract <5 years 5–12 years >12 years

Oropharynx

AGNB: polymyxin E 2 g of 2% paste/gel

with tobramycin

Yeasts: amphotericin B 2 g of 2% paste/gel

or nystatin (units)

MRSA: vancomycin 2 g of 4% paste/gel

Gut

AGNB: polymyxin E (mg) 100 200 400

with tobramycin (mg) 80 160 320

Yeasts: amphotericin B (mg) 500 1,000 2,000

or nystatin 2x10⁶ 4x10⁶ 8x10⁶

MRSA: vancomycin (mg) 20-40/Kg 20-40/Kg 500-2,000

Therapy Total daily dose (mg/kg)

<7 days >7 days 1 month >12 years to 12 years

1. Neonatal ICU

Ampicillin: 50 100

active against L. monocytogenes and S. agalactiae Gentamicin:

AGNB (see below) 2. Pediatric ICU

Cefotaxime: 'community' 100 150 100-200 6-12g

+ 'hospital' microbes except P. aeruginosa Ceftazidime:

P. aeruginosa 60 90 100–150 6–9 g

Gentamicin: AGNB 3<2 kg 6<2 kg 7.5 3–5

6>2 kg 7.5>2 kg

Cephradine: S. aureus 50 50 100 4g

Vancomycin: MRSA 15 then 20 15 then 30 45 2g

Amphotericin B: 1-3 1-3 1-3 1-3

yeasts, fungi (lipophilic) Table 1cont.

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Cardiac Surgical Prophylaxis

The aim of prophylactic antibiotics in cardiac surgery is to prevent infections of the heart and mediastinal incision. The main micro-organisms causing endo- carditis include CNS, viridans streptococci, and enterococci. Less common are AGNB and yeasts. S. aureus both sensitive and resistant to methicillin are the main cause of mediastinal wound infections. A commonly used combination of antimicrobials prior to cardiac surgery is a glycopeptide and an aminogylco- side. A glycopeptide such as teicoplanin covers all streptococci and staphylococci, whilst an aminoglycoside such as netilmicin is active against AGNB that may translocate following gut ischemia. Short-term prophylaxis of three doses is normally administered, one immediately prior to surgery to achieve high tis- sues levels and two further doses 8 h apart. Under certain circumstances, such as a chest splinted open because of cardiac edema, these antibiotics may be continued for 5 days, although there is no evidence to support this practice.

General Surgical Prophylaxis

The type of antimicrobial prescribed depends on the proposed surgery and the associated risk of contamination. Clean, sterile procedures do not need antibiotic cover, whereas clean procedures with the likelihood of contamination need cover with one antimicrobial, such as cefotaxime. If there is likely to be fecal contamination, then an aminoglycoside such as gentamicin is also necessary to cover AGNB and enterococci. Finally, if the surgical procedure is likely to be associated with ischemia and possible necrotic tissue, then metronidazole should be added to the prophylactic regimen. Again three doses will suffice.

Selective Decontamination of the Digestive Tract

SDD is a prophylactic intervention designed to prevent early and late infection in the critically ill child, requiring more than 1 week of intensive care (Chapter 14). There are four randomized controlled trials [28–32] that demonstrate a sig- nificant reduction in infectious morbidity. With an overall mortality of approximately 10%, a reduction in mortality is harder to demonstrate than in adults.

A huge sample size would be necessary. However, in adults, where the overall mortality is approximately 30%, it has been possible to demonstrate a signifi- cant reduction of 22% [33–35].

There is a particular indication for SDD on the NICU, namely in the control of an outbreak of infection. Ten years ago, SDD with nystatin was used to control a Candida parapsilosis outbreak on the Mersey regional NICU. Of 106 neonates who carried the outbreak strain, 76 received nystatin in the throat and gut

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during the 12-month open trial. Six neonates developed fungemias. Once the carriage rate fell from 50% to 5%, no new cases of systemic Candida infection were observed. This was the first report of the SDD intervention to control an outbreak of infection on the NICU [36].

Treatment

Neonatal Intensive Care Unit

Early onset infections that occur on the NICU maybe due to L. monocytogenes and/or S. agalactiae. Ampicillin is the most active antibiotic against these two micro-organisms, which are acquired from the mother, and is combined with gentamicin to cover AGNB and S. aureus. Late-onset infections are treated as described in Table 2.

Table 2.Flow diagram for the treatment of an infection

DAY ONE: ABSENCE OF KNOWLEDGE OF CAUSATIVE MICROORGANISM EMPIRICAL TREATMENT: CEFOTAXIME

combined with GENTAMICIN if seriously ill

DAY TWO: PRESUMPTIVE IDENTIFICATION OF CAUSATIVE MICROORGANISM

TAILORED TREATMENT:

NORMAL POTENTIAL PATHOGEN ABNORMAL POTENTIAL PATHOGEN

S. pneumoniae S. aureus Candida species Aerobic Gram- negative bacilli

Pseudomonas species STOP Gentamicin

MONOTHERAPY Cefotaxime

STOP Cefotaxime/

Gentamicin

MONOTHERAPY Cephadrine

STOP Cefotaxime/

Gentamicin MONOTHERAPY Amphotericin B

CONTINUE Cefotaxime/

Gentamicin

REPLACE Cefotaxime with Ceftazidime

DAY THREE: CLINICAL IMPROVEMENT

DAY FIVE: STOP OR CHANGE ANTIMICROBIAL TREATMENT

STOP CHANGE

Improved after careful clinical, radiological, and microbiological evaluation

Not improved after careful clinical, radiological, and microbiological evaluation

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Pediatric Intensive Care Unit

When a child is admitted to the PICU with a severe infection, a decision as to which antimicrobial is to be used has to be made. Antimicrobials are used in combination due to the severity of the child’s illness. Our experience over 20 years leads us to the choice of cefotaxime and gentamicin. This choice is empirical due to the absence of any knowledge regarding the causative micro-organism, although reasonable assumptions can be made on the presentation of the child. For example, a child with meningococcal disease requires only cefotaxime. Metronidazole can be added in case of presumed anaerobic involvement. When a presumptive identification of the micro-organism can be made, the physician can then tailor therapy. Cefotaxime/gentamicin can be replaced by cephradine in the case of an infection due to S. pneumoniae, S. pyogenes, and S. aureus. When P. aeruginosa is isolated, ceftazidime should replace cefotaxime and gentamicin should be continued. Yeast infections require liposomal amphotericin B in place of cefotaxime/gentamicin (Table 2). The efficacy of the antimicrobial treatment can be monitored using C-reactive protein levels, in addition to the clinical, radiographic, and microbiological variables. Providing the antimicrobials used are correct, the child will improve within 3 days. In our experience a short 5-day course of intravenous antibiotics is as effective as a course of 2 weeks or more (Chapter 12). After 5 days the child is monitored for signs of infection. When there are no signs of infection, antibiotics are discontinued. Should there be no improvement after 5 days, a change in antibiotic regimen is necessary.

Metronidazole is given only for 3 days. The antifungal agent, liposomal amphotericin B, is given for 3 weeks and may be discontinued once the C-reactive protein level is normal. Systemic antimicrobials are combined with enteral SDD agents to guarantee the prevention of potential pathogens becoming resistant to the systemic agents.

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