825 e2 Antibiotic (Total Daily Dose) Neonates 0–7 d, 2000 ga Neonates 7 d, 2000 g Infants and Children Maximum Daily Adult Dose Ampicillin (mg/kg/day) 300 300 300–400 12 g Cefepime (mg/kg/day) 100 100[.]
825.e2 eTABLE Antimicrobial Therapy for Specific Meningeal Pathogens 67.2 Pathogen Therapy Streptococcus agalactiae Penicillin G gentamicin or ampicillin gentamicin Haemophilus influenzae, b-lactamase-negative Ampicillin H influenzae, b-lactamase-positive Third-generation cephalosporina Streptococcus pneumoniae, penicillin-susceptible Penicillin G or ampicillinb S pneumoniae, penicillin-resistant, cephalosporin-susceptible Third-generation cephalosporina S pneumoniae, drug-resistant (multiply resistant) Vancomycin plus third-generation cephalosporina rifampin Neisseria meningitidis Third-generation cephalosporina N meningitidis, penicillin-susceptible Penicillin G or ampicillinb Escherichia coli, other aerobic enteric gram-negative bacilli (not including Pseudomonas aeruginosa) Cefotaxime or ceftriaxone (if mo old) plus aminoglycosidec E coli may produce extended-spectrum b-lactamases that require use of carbapenems (i.e., meropenem) Pseudomonas aeruginosa Meropenem plus aminoglycoside or cefepime plus aminoglycoside or ceftazidime plus aminoglycosided Coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus Vancomycin rifampin Methicillin-susceptible S aureus Nafcillin a Cefotaxime or ceftriaxone Some clinicians prefer ampicillin because of less frequent dosing c The choice of aminoglycoside will depend on the institution’s susceptibility patterns d The choice of antipseudomonal regimen is influenced by the institution’s susceptibility patterns b eTABLE Dosages for Antimicrobial Agents for Bacterial Meningitis 67.3 Antibiotic (Total Daily Dose) Neonates 0–7 d, 2000 ga Neonates d, 2000 g Infants and Children Ampicillin (mg/kg/day) 300 300 300–400 12 g Maximum Daily Adult Dose Cefepime (mg/kg/day) 100 100 150 6g Cefotaxime (mg/kg/day) 150 200 200–300 12 g Ceftriaxone (mg/kg/day) — — 100 4g Gentamicin (mg/kg/day) 7.5 7.5 mg/kg Meropenem (mg/kg/day) 120 120 120 6g Penicillin G (U/kg/day) 300,000 400,000 250,000–400,000 Rifampin (mg/kg/day) — 10–20 10–20 Vancomycin (mg/kg/day) 30 45 60 a Dosages of agents for neonates ,2000 g can be obtained from Lexi-Comp, Inc From Bradley JS, Nelson JD 2017 Nelson’s Pocket Book of Pediatric Antimicrobial Therapy 23rd ed Elk Grove Village, IL: American Academy of Pediatrics; 2017 24 million U 600 mg 45 mg/kg 826 S E C T I O N V I Pediatric Critical Care: Neurologic effective as ceftriaxone or cefotaxime as empiric therapy for bacterial meningitis It can be considered for use in nosocomial meningitis either as a single agent or in combination with vancomycin Linezolid, a member of the oxazolidinone class, readily enters the CSF and is active against gram-positive organisms Accumulating evidence suggests that shorter durations may be effective and safe in some cases A 2009 meta-analysis on duration of therapy in pediatric meningitis that focused on the three most common pathogens and compared short-course (4–7 days) versus long-course (7–14 days) therapy found no significant difference in clinical success or long-term neurologic complications.47 Subsequently, a multinational trial enrolled over 1000 children with meningitis caused by Hib, S pneumonia, or N meningitidis who were stable after days of IV ceftriaxone therapy and randomized them to receive placebo or an additional days of ceftriaxone.48 Again, there were no significant differences in bacteriologic failures, clinical failures, or clinical sequelae in survivors Patients with persistent seizures, bacteremia, brain abscesses, other infections, or who were judged to be severely ill at the 5-day mark were excluded A 2017 study of 263 children and adults with meningococcal meningitis found that a 4-day course was noninferior in all outcomes compared with days.49 Supportive Care The correction of hyponatremia and hypotension (key to maintaining adequate cerebral perfusion) when present and the treatment of cerebral edema may be just as important as the selection of an effective antimicrobial regimen In patients with altered mental status, airway protection and assisted ventilation may be required Patients who present in septic shock may require vasoactive-inotropic support Anticonvulsant therapy is indicated in patients with seizures Rapid placement of an external ventriculostomy may be indicated in patients with radiographic or clinical evidence of obstructive hydrocephalus with risk for impending herniation Consultation with infectious disease and pharmacy colleagues is often valuable When a child with suspected bacterial meningitis is admitted, droplet precautions should be implemented immediately in addition to standard precautions until 24 hours of effective antimicrobial therapy against N meningitis has been administered.14,50 Droplet precautions are not required for confirmed pneumococcal infections In patients who present in shock or dehydration, administration of IV fluids is critical for the maintenance of normal blood pressure, adequate cerebral perfusion, and reducing the risk of central venous thrombosis In the absence of shock and dehydration, there has been disagreement regarding IV fluid management in patients with meningitis There are potential risks from giving too much fluid (especially brain swelling) as well as too little fluid (especially shock) In a recent Cochrane review, the authors evaluated differing volumes of fluid given in the initial management of bacterial meningitis in three pediatric trials, only one of which was considered high quality.51 They concluded that low-quality evidence showed no difference between maintenance versus restricted fluid regimens regarding death or severe acute neurologic complications However, there was low-quality evidence supporting maintenance therapy over fluid restriction to reduce severe neurologic events at months following infection Adjunctive Therapy The search for therapeutic adjuncts to improve outcomes in bacterial meningitis often has been hampered by the difficulty in conducting randomized clinical trials due to the acuity of the disease, narrow time frame in which adjuncts can influence outcome, and the increasingly small number of cases in the postvaccine era Immunomodulation, hypothermia, free radical scavengers, C5 monoclonal antibodies, neutrophil proapoptosis agents, and TLR antagonists have all shown benefit in experimental models of meningitis, but no large clinical trials have been conducted to date The use of dexamethasone (DXM) in meningitis has been studied for over decades In early studies in children with Hib meningitis, DXM-treated children had a lower incidence of moderate-to-severe hearing deficits when compared with placebo.52 However, one of the study antimicrobial agents, cefuroxime, was later shown to be associated with increased neurologic sequelae In adults with pneumococcal meningitis, the early administration of DXM, 15 to 20 minutes before or with first dose of antibiotic, was associated with a reduction in mortality and unfavorable outcomes.53,54 There is no evidence that corticosteroid use is beneficial in neonatal bacterial meningitis.55 A Cochrane database review of the effect of adjuvant corticosteroid therapy on meningitis found no effect on overall mortality.56 This study pooled 25 randomized clinical trials from adults and children Subgroup analyses for causative organisms showed that corticosteroids reduced mortality in S pneumoniae meningitis (a finding potentially driven by adult data) but not in meningitis caused by Hib or N meningitidis The rate of hearing loss was reduced in children with Hib meningitis but not when caused by other bacteria Patients with TB meningitis treated with steroids have improved survival compared with nonrecipients owing to reduction in cerebral vasculitis associated with this infection However, the severity of neurologic disability observed with TB meningitis is not altered.43 When DXM is administered, clinicians should be cognizant that fever associated with the infection may be suppressed and then rebound when the agent is discontinued.56 Such rebounds may occur in time frames when complications such as subdural effusions or empyema begin to emerge, which also can generate new or higher temperature elevations Thus, beyond the apparent reduction in hearing loss associated with Hib meningitis when DXM is administered shortly before antimicrobial therapy, studies of adjuvant corticosteroid therapy in children have not unequivocally demonstrated beneficial effects The decision to use DXM thus remains an individualized, case-by-case decision that involves balancing potential benefits and risks that are often difficult to quantify Outcomes With aggressive support and timely and appropriate antimicrobial therapy, the overall mortality rate of bacterial meningitis remains low, at about 2% to 7% overall Unfortunately, neurologic sequelae still occur in about 50% of survivors.7,15,57 Prognosis can vary by age (worse in young infants), progression of illness before effective antimicrobial therapy is initiated, causative microbe, bacterial burden in the CSF at the time of diagnosis, and host factors that may impair the immune response Infants younger than 90 days may have sequelae in more than two-thirds of cases.15 Overall, hearing loss is the most common long-term neurologic deficit associated with bacterial meningitis in children Hearing loss is often associated with fibrosis and even ossification CHAPTER 67 Central Nervous System Infections and Related Conditions of the cochlea with destruction of the organ of Corti.58 Seizure disorders; motor deficits, including hemiparesis and hypertonicity; cognitive impairments of various types, including disorders of speech and language development; communicating and noncommunicating hydrocephalus; visual disturbances and other cranial nerve deficits; and ataxia can occur as a result of brain injuries from bacterial meningitis.7 Children without apparent permanent neurologic sequelae at discharge are at low risk for future epilepsy related to their meningitis.59 When compared with other pathogens, pneumococcal, TB, and gram-negative enteric meningitis are most commonly associated with neurologic sequelae Among the most common bacterial etiologies, S pneumoniae is associated with highest mortality and with hearing loss rates of 20% to 30% Antimicrobial resistance in pneumococcal meningitis does not appear to be associated with increased mortality or neurologic sequelae compared with strains susceptible to penicillin or ceftriaxone, though this may be due to routine use of vancomycin as part of initial empiric therapy.60 Individual outcomes upon initial admission to the PICU are difficult to predict, and no single factor is entirely predictive In a retrospective study of 15 PICUs in the United States, patients with both bacterial and nonbacterial meningitis had an unadjusted mortality rate of 7% Nonsurvivors had a significantly higher Pediatric Risk of Mortality (PRISM) III score Mortality was threefold higher in patients with bacterial-confirmed meningitis The presence of coma upon initial presentation to the PICU was associated with 10-fold increased mortality.61 In another study evaluating only pneumococcal meningitis, the presence of shock, hyponatremia, or coma on admission to the ICU was associated with a higher use of invasive medical devices and higher mortality.62 A third pediatric study of all-cause meningitis reported risk factors associated with increased mortality, including low Glasgow Coma Scale score, respiratory distress at presentation, seizures at any point during admission, and—in resourcelimited countries—malnutrition.63 Among laboratory findings, the presence of low WBC and platelet counts was associated with increased mortality.64,65 The hippocampus, which is important to information processing, is frequently affected in bacterial meningitis.66 As such, meningitis survivors may demonstrate neuropsychological problems and cognitive issues later in life An educational outcomes evaluation showed that children recovering from CNS infections significantly underperformed on neuropsychological evaluations in areas of memory function and teacher-rated academic performance in comparison with healthy controls.67 827 antimicrobial prophylaxis with ceftriaxone, ciprofloxacin, or rifampin.14 Rifampin also is recommended for prophylaxis of close contacts of patients with Hib (or H influenzae type a) who meet selected criteria.50 Subdural Empyema A subdural empyema (SDE) is a purulent fluid collection outside the brain parenchyma contained between the dura and the arachnoid layers of the CNS SDEs can occur anywhere in the subdural space, but the majority are in the supratentorial compartment They are usually encapsulated and often loculated Multiple predisposing etiologies are responsible, including extension of local infections (i.e., sinuses, otitis, mastoiditis) and hematologic spread from distant sites In younger patients, an SDE frequently accompanies acute bacterial meningitis wherein the infection extends through the arachnoid and into the subdural space.69 In the pediatric population, extraaxial CNS infections are most common in two distinct age groups, corresponding to known etiologies Subdural empyemas following meningitis are more common in infants, while sinus-related infections are most common in those older than years.70 In addition to meningitis, otorhinolaryngeal infections are an important predisposing factor for development of an SDE in older children In a retrospective study conducted over 24 years at a single children’s hospital, 70 children developed SDEs Sinusitis was the most common etiology, followed by bacterial meningitis.71 In this study, all patients were older than years at diagnosis However, another study that included infants demonstrated that only 10% of SDEs were related to otorhinolaryngeal infection The drop in SDEs from sinus infections is presumed to be due to increased antibiotic use In this study, meningitis, head trauma, and recent neurosurgery were identified as common predisposing factors for SDE development.72 A more recent pediatric prevalence study for SDE reported that neurosurgical procedures were the most commonly associated factor.73 Initial symptoms may be vague, but a history of sinus infections is common As an example, Pott puffy tumors are found frequently among patients with prior sinusitis and can have associated empyema development (Fig 67.1) Fever, headaches, eye pain, and altered Prevention The best means of prevention of bacterial meningitis is receipt of recommended vaccinations in childhood and adolescence, especially the recommended capsular polysaccharide-protein conjugate vaccines against Hib, pneumococci, and meningococci Two protein antigen-based vaccines effective against many N meningitidis serogroup B strains are available but are considered optional based on patient preference at this time.14 Vaccines against GBS have been developed; future maternal vaccination against GBS could further reduce early-onset and potentially impact lateonset GBS infections of all types.68 Prevention also involves family members Individuals (family or hospital staff) with significant, prolonged, or close exposures to children with N meningitidis meningitis should receive • Fig 67.1 Sagittal noncontrast head computed tomography scan showing Pott puffy tumor with abscess 828 S E C T I O N V I Pediatric Critical Care: Neurologic level of consciousness are common presenting features in SDE Prolonged fever (90%), seizures (70%), and focal neurologic signs (60%) are the most common clinical signs noted in children.72 Though often a source of fever, these fluid collections can be sterile Focal neurologic deficits are frequently observed Seizures and cerebral edema from cortical vein thrombosis are common complications among patients presenting with SDEs.74 Before recent changes in vaccination strategies, SDE was often secondary to Hib Currently, Streptococcus species (particularly viridans, pneumoniae, or milleri) and S aureus are the most common pathogens identified.71,73,75 The most common pathogen in infants less than months old is GBS.72 Abscess fluid cultures are positive in almost two-thirds of cases, with 15% demonstrating polymicrobial growth.76 The diagnosis of SDE is often made with radiologic assistance Patients with sinus infections, progressive headaches, and new neurologic deficits should be evaluated with CT or MRI It is often difficult to distinguish an SDE from a sterile reactive subdural effusion (RSE).77 SDEs can be differentiated from epidural empyemas, as they not cross the midline and tend to layer along the convexity of the brain in a crescent shape SDEs appear as isodense to low-dense extraaxial collections with rim enhancement on CT MRI is superior to CT in the demonstration of both the extraaxial fluid and enhancement of the inner membrane with contrast medium (Fig 67.2) Diffusion-weighted imaging (DWI) is increasingly used to distinguish SDE from nonpurulent RSE.78 While SDEs appear bright with a low apparent diffusion coefficient (ADC), SDEs have a low signal and ADC values similar to CSF Serial cranial ultrasounds may be considered for the evaluation of response to antibiotics in infants when repeated imaging is indicated.79 The goal of treatment is evacuation of purulence and eradication of the source of infection Medical management alone may be adequate if the empyema is small, but most cases require surgical evacuation of the purulent material Craniotomy is the preferred procedure in most cases Drainage through a burr hole may be considered in the unstable patient In a retrospective review of 699 patients treated for SDE, performance of a craniotomy was associated with a mortality of 8% compared with 23% for • Fig 67.2 Contrast-enhanced brain magnetic resonance image showing diffuse leptomeningeal enhancement and focal collections of subdural empyemas near the sylvian fissures bilaterally patients who received burr hole drainage.80 In young infants, a subdural tap through the anterior fontanel may be considered for intracranial purulent exudate evacuation because of ease of access Many of these patients required repeated surgical aspirations owing to empyema recurrence Following surgical drainage, broad-spectrum antibiotics should be initiated A third- or fourth-generation cephalosporin plus vancomycin is a reasonable initial antibiotic option Metronidazole may be added to cover anaerobic organisms, especially if an infected sinus is suspected as the source of the SDE.81 Duration of IV antibiotics varies from to weeks, with longer courses recommended for patients with bone involvement.75 The keys to an optimal outcome are early accurate diagnosis, timely intervention, and appropriate antibiotic therapy Among adults, reported mortality rates of SDE are 10% following meningitis and up to 20% following untreated sinus infections.82 Germiller and Sparano reported a 4% mortality rate in a pediatric series of intracranial suppurative infections.83 Survivors often had significant long-term morbidity with persistent seizures, hemiparesis, or residual neurologic deficits Age, initial level of consciousness, initiation of treatment, and the rapidity of disease progression all influence outcome The sequelae of SDE may be more severe in young infants than in any other age group.79 Brain Abscess The brain parenchyma itself is remarkably resistant to microbial infections Despite the relative frequency of occult bacteremia in the pediatric patient, cerebral abscess formation is rare Brain abscesses typically begin with a localized area of cerebritis, evolve through various stages, and finally organize into a collection of encapsulated purulent material Among intracranial masses, the incidence of brain abscess is 8% in developing countries and 1% to 2% in Europe and North America.84 Most abscesses occur in the first decades of life, but this associative factor is changing with improvement in treatment of sinus and otologic infections.85 Incidence of brain abscesses in children is cases/1,000,000 with a peak age of presentation between and years.86 Certain medical conditions predispose patients for brain abscess formation These include a history of congenital heart disease with intracardiac or intrapulmonary shunting, otologic infections, immunodeficiencies, prolonged corticosteroid use, diabetes mellitus, and alcoholism.87 At a single children’s hospital over a 19-year period, congenital heart disease and sinus/otologic infections were the most common predisposing factors to development of cerebral abscesses.88 CNS abscesses can occur from a number of different etiologies and in different locations In a large series examining brain abscesses in adults and children, almost 90% were in supratentorial locations Associated infections or factors included otorhinogenic (38.6%), traumatic (32.8%), pulmonary (7.0%), cryptogenic (4.6%), postsurgical (3.2%), meningitis (2.8%), cardiac (2.7%), and “other” (8.6%).89 In children, the most common origin of brain abscesses is direct or indirect extension from the middle ear, paranasal sinus, or dental infections.90 Brain abscesses are sequelae in 6% to 8% of untreated sinusitis cases and up to 10% of mastoiditis cases.86 Abscesses in the temporal lobe or cerebellum are typically linked to ear or mastoid air cell points of entry and tend to be solitary Frontal lobe abscesses are often due to ethmoid sinus or dental infections Sphenoid sinusitis is associated with abscesses in the temporal lobes as well as the pituitary gland Abscesses caused by hematogenous origin are often noted in specific areas of the brain, especially in the middle cerebral artery CHAPTER 67 Central Nervous System Infections and Related Conditions 829 distributions, including the parietal and occipital regions.91 These abscesses tend to be multiple and of varying sizes The etiology of these abscesses is often from distant sources, such as endocarditis or pulmonary infections Not surprisingly, cyanotic heart disease increases the risk of brain abscess formation.86,92 In one study, over 30% of patients with brain abscesses were found to have an underlying heart defect.93 Tetralogy of Fallot, transposition of the great vessels, atrial septal defects, ventricular septal defects, and pulmonary arteriovenous fistulas are all reported to predispose children to brain abscesses.94 This increased predisposition may be due to the presence of areas of brain ischemia caused by decreased arterial oxygen saturation and increased viscosity from an elevated hematocrit Right-to-left shunting likely also predisposes to brain abscess formation, as the removal of organisms from the systemic circulation by the pulmonary capillaries is bypassed Hematogenous spread can also occur from venous drainage into the cavernous sinus, resulting in frontal lobe abscesses that correlate with infections of the facial tissues or ethmoidal sinuses Extensions from cranial osteomyelitis, scalp infections, endocarditis, and meningitis are other known causes of CNS abscess formation Several studies examined the etiology of brain abscesses in noncardiac patients Antecedents include endocarditis in 10% of patients, bacteremia in 8%, immunodeficiency in 12%, pulmonary anomalies in 5%, and skin folliculitis in 3%.95,96 Infants and toddlers are more susceptible than other age groups to brain abscesses arising from sequelae of bacterial meningitis or bacteremia.97 Penetrating head trauma and neurosurgery represent a small proportion of the predisposing causes of CNS abscess, but the proportion is increasing, possibly as other predisposing factors such as middle ear infection become less important In roughly one-quarter of brain abscess cases, no identifiable route or predisposing factors are identified.98 CNS abscess formation can occur in any area of the brain The most frequent areas are frontal, temporal, and frontal-parietal.99 Occipital lobes are least frequently involved Histologically, brain abscesses begin as regions of cerebritis (Fig 67.3) They evolve into discrete collections of encapsulated pus over a series of stages (early cerebritis, late cerebritis, early capsular, and late capsular) This evolution takes to days as the center of the lesion undergoes liquefaction necrosis.100 By 10 to 14 days, a well-vascularized collagenous capsule with peripheral gliosis or fibrosis is typically present (Fig 67.4) The clinical presentation of brain abscesses varies depending on the size, multiplicity, and location of the lesion The initial presentation can be relatively nonspecific and occur due to focal mass expansion, intracranial hypertension, or destruction of the CNS parenchyma Most patients are symptomatic during the early cerebritis phase Symptoms include headache (70%), fever (60%), vomiting (50%), focal neurologic deficits (45%), and seizures (40%).90,100 Clinical symptoms occur less commonly in pediatric cases The triad of fever, headache, and focal deficits occurs in roughly one-third of patients, while meningeal signs occur in less than 25%.101 Over half of cases will have papilledema The sudden worsening of a preexisting headache can indicate rupture of the brain abscess into the ventricular space or impending herniation from the lesion’s mass effect Significant alteration in mental status is an ominous clinical finding Abscesses located within their brainstem typically present with fever, headaches, hemiparesis, and focal cranial nerve findings involving CN III, CN VI, and CN VII Since the clinical presentation of brain abscess is often nonspecific, the diagnosis is often made by CT Without imaging, it may be difficult to differentiate between brain abscess and other intracerebral pathologic processes The increased use of CT has altered the prognosis of brain abscess by improving early diagnosis Serial CT scanning may provide additional information about response to treatment CT with IV contrast can be used for determining the size and number of abscesses but cannot consistently discriminate between metastases or primary brain tumors and brain abscesses MRI is also a useful diagnostic tool and may have significant advantages in differentiating brain abscess from primary, cystic, or necrotic tumors using DWI and ADC images.102 MRI may also have a diagnostic advantage over CT by better identification of edema from liquefaction necrosis and greater sensitivity for early detection of satellite lesions (Figs 67.5 and 67.6).103 A 2014 metaanalysis of 11 studies demonstrated the value of DWI in brain abscess discrimination DWI imaging provided both sensitivity and specificity of 95% in identification or brain abscesses.104 • Fig 67.3 Axial fluid-attenuation inversion recovery magnetic resonance • Fig image showing left frontal cerebritis with developing abscess 67.4 Contrast enhanced axial T1-weighted magnetic resonance image of brain demonstrates enhancing abscess in the right frontal lobe ... effect of adjuvant corticosteroid therapy on meningitis found no effect on overall mortality.56 This study pooled 25 randomized clinical trials from adults and children Subgroup analyses for causative... survival compared with nonrecipients owing to reduction in cerebral vasculitis associated with this infection However, the severity of neurologic disability observed with TB meningitis is not... may impair the immune response Infants younger than 90 days may have sequelae in more than two-thirds of cases.15 Overall, hearing loss is the most common long-term neurologic deficit associated