Gram Negative Bacillary Meningitis

Meningitis caused by enteric gram-negative bacilli is an important cause of morbidity and mortality in populations at risk, including those with diabetes, malignancy, cirrhosis, immunosuppression, advanced age, parameningeal infection, and/or a defect allowing communication from skin to CNS (such as neurosurgery, congenital defects, or cranial trauma).10

The optimal treatment for gram-negative bacillary meningitis is not well defined. The introduction of extended-spectrum cephalosporins has improved patient outcomes significantly. While the third-generation cephalosporins ceftriaxone and cefotaxime provide good coverage for most enterobacteriaceae, these antibiotics are not active against P. aeruginosa. Ceftazidime, cefepime, and carbapenems are effective

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in pseudomonal meningitis. Addition of an aminoglycoside may improve treatment results; however, CNS penetration of aminoglycosides is extremely poor, even in the setting of inflamed meninges. Intrathecal or intraventricular administration of aminoglycosides may be useful, but intraventricular antibiotics have been associated

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with increased mortality in neonates. Intrathecal therapy is accomplished by administering the antibiotic into the CSF via LP, whereas intraventricular therapy is usually administered into a reservoir implanted in the ventricles of the brain.

Initial therapy of suspected or documented pseudomonal meningitis should include an extended-spectrum ^-lactam (e.g., ceftazidime, cefepime, or meropenem) plus an aminoglycoside (preferably tobramycin or amikacin). Although the carbapenem imipenem-cilastatin has similar activity to these ^-lactams, its use is not recommended in meningitis because of the risk of seizures. Aztreonam, high-dose ciprofloxacin, and colistin are alternative treatments for pseudomonal meningitis. Local therapy (i.e., intrathecal or intraventricular therapy) may be indicated in patients with gramnegative bacillary meningitis (especially infections caused by multidrug-resistant P aeruginosa) or in patients who fail to improve on IV antibiotics alone. In cases of multidrug-resistant pathogens, alternative pharmacodynamic dosing strategies such as continuous or extended infusion of ^-lactam antimicrobials may be considered to optimize target attainment (time greater than minimum inhibitory concentration). Given the differences in local hospital resistance patterns, administration of pathogen-directed treatment is very important after microbiology results become available. Therapy for gram-negative bacillary meningitis should be continued for at least 21 days.

Postoperative Infections in the Neurosurgical Patient and Shunt Infections

Patients who undergo neurosurgical procedures or have invasive or implanted foreign devices (such as CSF shunts, intraspinal pumps or catheters, or epidural catheters) are at risk for CNS infections. Key pathogens in postneuro-surgical infections include coagulase-negative staphylococci, S. aureus, streptococci, propionobacteria, and gram-negative bacilli, including P. aeruginosa. Clinical signs and symptoms may be similar to those of other CNS infections, and there also may be evidence of malfunction of implanted hardware or visible signs of a postoperative wound infection.

Empirical therapy for postoperative infections in neurosurgical patients (including patients with CSF shunts) should include vancomycin in combination with either ce-fepime, ceftazidime, or meropenem. Linezolid reaches adequate CSF concentrations and resolves cases of meningitis refractory to vancomycin. 5,38 However, data with linezolid are limited. The addition of rifampin should be considered for treatment of shunt infections. When culture and sensitivity data are available, pathogen-directed antibiotic therapy should be administered. Removal of infected devices is desirable; aggressive antibiotic therapy (including high-dose IV antibiotic therapy plus intraventricular vancomycin and/or tobramycin) may be effective for patients in whom hardware removal is not possible.39 If methicillin-resistant S. aureus is identified as the causative organism, daptomycin may be considered an alternative therapy.40

The use of prophylactic antibiotics against meningitis postcraniotomy remains controversial. A meta-analysis suggests that prophylaxis reduces rates of postoperative meningitis by nearly one-half.4 Other studies have demonstrated no benefit and there is limited data on organism-specific reductions in infection rate.43,44 Additionally, breakthrough meningitis that does occur may be a result of drug-resistant patho-43

gens.

Brain abscesses are localized collections of pus within the cranium. These infections are difficult to treat due to the presence of walled-off infections in the brain tissue that are hard for some antibiotics to reach. In addition to appropriate antimicrobial therapy (a discussion of which is beyond the scope of this chapter), surgical debridement is of ten required as an adjunctive measure. Surgical debridement may also be required in the management of neurosurgical postoperative infections.

Viral Encephalitis and Meningitis

Viral encephalitis and meningitis may mimic bacterial meningitis on clinical presentation but often can be differentiated by CSF findings (Table 70-2). The most common viral pathogens are enteroviruses, which cause approximately 85% of cases of viral CNS infections.10 Other viruses that may cause CNS infections include arboviruses, HSV, cytomegalovirus, varicella-zoster virus, rotavirus, coronavirus, influenza viruses A and B, West Nile virus, and Epstein-Barr virus. Viral CNS infections are acquired through hematogenous or neuronal spread.10 Most cases of enteroviral meningitis or encephalitis are self-limiting with supportive treatment.41 However, arbovirus, West

Nile virus, and Eastern equine virus infections are associated with a less favorable prognosis.

In contrast to other viral encephalitides, HSV type 1 and 2 encephalitis are treatable. Although rare (1 case per 250,000 population per year in the United States), HSV encephalitis is a serious, life-threatening infection.45 Over 90% of HSV encephalitis in adults is due to HSV type 1, whereas HSV type 2 predominates in neonatal HSV encephalitis (greater than 70%)46 HSV encephalitis is the result of reactivation of a latent infection (two-thirds of cases) or a severe case of primary infection (one-third). Without effective treatment, the mortality rate may be as high as 85% and survivors often have significant residual neurologic deficits. In accordance with 2008 IDSA guidelines, high-dose IV acyclovir is the drug of choice, given for 2 to 3 weeks at a dose of 10 mg/kg intravenously every 8 hours in adults, based on ideal body weight and for 3 weeks at a dose of 20 mg/kg intravenously every 8 hours in neonates. 7 8 Patients receiving acyclovir should maintain adequate hydration (consider continuous IV hydration in those receiving high-dose acyclovir) to help prevent

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acute kidney injury secondary to crystal nephropathy. ' Foscarnet 120 to 200 mg/

kg/day divided every 8 to 12 hours for 2 to 3 weeks is the treatment of choice for

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acyclovir-resistant HSV isolates. ' Adjunctive Dexamethasone Therapy

The adjunctive agent dexamethasone improves outcomes in selected patient populations with meningitis. Dexamethasone inhibits the release of proinflammatory cytokines and limits the CNS inflammatory response stimulated by infection and antibiotic therapy.

Clinical benefit in reducing neurologic deficits (primarily by reducing hearing loss) has been observed in infants and children with H. influenzae meningitis, as well as other pathogens causing meningitis, if dexamethasone is initiated prior to antibiotic

therapy. ' The American Academy of Pediatrics recommends dexamethasone (0.15 mg/kg IV every 6 hours for 2-4 days) for infants and children at least 6 weeks of age with Hib meningitis and consideration of dexamethasone in pneumococcal meningitis.17,49 In contrast to this recommendation, a large multicenter cohort study failed to show any mortality benefit of adjunctive dexamethasone therapy regardless of age or responsible pathogen (S. pneumoniae or N. meningitidis)5 Dexamethasone should be initiated 10 to 20 minutes before or no later than the time of initiation of antibiotic therapy; it is not recommended for infants and children who have already received antibiotic therapy because it is unlikely to improve treatment outcome in these patients.

There are insufficient data to make a recommendation regarding the use of adjunctive dexamethasone therapy in neonatal meningitis.

In adults, a significant benefit was observed with dexa-methasone over placebo in reducing meningitis complications, including death, particularly in patients with pneumococcal meningitis.51 The IDSA recommends dexamethasone 0.15 mg/kg intravenously every 6 hours for 2 to 4 days (with the first dose administered 10 to 20 minutes before or with the first dose of antibiotics) in adults with suspected or proven pneumococcal meningitis.17 Dexamethasone is not recommended for adults who have already received antibiotic therapy. Some clinicians would administer dexamethasone to all adults with meningitis pending results of laboratory tests. Benefit of dexamethasone in bacterial meningitis in a HIVpositive population has not been clearly established.52

There is some controversy regarding the administration of dexamethasone to patients with pneumococcal meningitis caused by penicillin- or cephalosporin-resistant strains, for which vancomycin would be required. Animal models indicate that concurrent steroid use reduces vancomycin penetration into the CSF by 42% to 77% and

delays CSF sterilization due to reduction in the inflammatory response. A prospective evaluation in patients with pneumococcal meningitis receiving vancomycin and adjunctive dexa-methasone demonstrated that adequate concentrations of vancomycin, nearly 30% of serum concentrations, were achievable in the CSF, provided ap-

propriate vancomycin dosage was utilized. Treatment failures have been reported in adults with resistant pneumococcal meningitis who were treated with dexamethasone, but the risk-benefit of using dexamethasone in these patients cannot be defined at this time. Animal models indicate a benefit of adding rifampin in patients with resistant pneumococcal meningitis whenever dexamethasone is used.25, 7

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