Sheila M. Hickey

Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.

Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

Treatment of pneumococcal meningitis has become problematic because of the emergence of penicillin- and cephalosporin-resistant strains and because of the concern that dexamethasone therapy might reduce penetration of antibiotics into the cerebrospinal fluid (CSF). We addressed these issues with our rabbit meningitis model by studying two pneumococcal isolates that were resistant to penicillin and ceftriaxone and susceptible to vancomycin and rifampin. Ceftriaxone, vancomycin, and rifampin were given alone or in combination, with or without coadministration of dexamethasone. Treatment was started 12 to 14 h after intracisternal inoculation of approximately 10(4) CFU of one of the organisms. Rifampin concentrations in serum and CSF were similar, regardless of whether dexamethasone was given, whereas those of ceftriaxone were somewhat lower at each time point in animals given dexamethasone. The penetration of vancomycin into CSF was consistently and substantially reduced with dexamethasone treatment, which resulted in a delay in CSF sterilization not observed in non-dexamethasone-treated animals. When rifampin was used with ceftriaxone for treatment of meningitis caused by the more resistant strain, bacteriologic cure occurred promptly, with or without dexamethasone therapy. In areas with high rates of occurrence of resistant pneumococcal strains, we believe initial empiric therapy of bacterial meningitis should include two antibiotics: ceftriaxone and either rifampin or vancomycin. When dexamethasone is used, the combination of ceftriaxone and rifampin is preferred for therapy.

Clinical utility of the polymerase chain reaction for diagnosis of enteroviral meningitis in infancy

OBJECTIVE To determine the utility of polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF), serum, and urine for rapid diagnosis of enteroviral meningitis in infants 3 months of age and younger. STUDY DESIGN We identified prospectively infants 3 months of age and younger coming to the emergency department with fever whose examination included a lumbar puncture, blood culture, or both. Samples of CSF, serum, urine, throat, and stool specimens were collected for viral culture and, with the exception of stool, for PCR assay. Those infants who had not received prior antibiotic therapy and had sterile bacterial cultures of CSF, blood, and urine were selected for the present analysis. RESULTS A total of 259 specimens for viral culture and 203 specimens for PCR assay were collected from 64 infants. Comparison of results of PCR assay of CSF with viral culture, the gold standard for diagnosis of enteroviral meningitis, demonstrated a sensitivity of 100% and a specificity of 90%. Because enteroviruses are not always detectable by culture, the following modified standard was established to define enteroviral meningitis: either CSF pleocytosis, sterile bacterial cultures and detection of an enterovirus in stool culture or positive viral culture of CSF, or both. With this modified definition, the sensitivity and specificity of the PCR assay of CSF were 92% and 94%, respectively. PCR assay of serum and urine offered no benefit over PCR assay of CSF alone for diagnosis of meningitis. CONCLUSION PCR assay of CSF is useful for the rapid and reliable diagnosis of enteroviral meningitis. Application of this technique in the clinical setting can potentially diminish unnecessary hospitalization and use of antibiotics.

Cerebrospinal fluid values in the term neonate

BACKGROUND Cerebrospinal fluid (CSF) values in the noninfected neonate are not well-delineated. Studies analyzing these values are inconsistent in the criteria used to define the noninfected population. The purpose of our study was to examine CSF values in neonates in the first 30 days of life in whom infection was more thoroughly excluded than in previous reports. Stringent inclusion criteria defined the noninfected population, and the recently available polymerase chain reaction (PCR) for enteroviruses was used in addition to cultures to help exclude viral disease. Results were also stratified by age in weeks to evaluate for any variability that occurs in CSF values during the first month of life. METHODS Neonates were selected from subjects enrolled in two studies on aseptic meningitis. Noninfected infants were identified by the following criteria: (1) atraumatic lumbar puncture (< or = 1000 red blood cells/mm3); (2) no antibiotic therapy before lumbar puncture; (3) sterile blood, CSF and urine bacterial cultures; (4) negative CSF viral culture; and (5) negative CSF PCR for enteroviruses. RESULTS The mean +/- SD total CSF white blood cell count for 108 noninfected neonates was 7.3 +/- 14/mm3 (95% confidence interval 6.6 to 8.0/mm3) with a median of 4/mm3 and a range of 0 to 130/mm3. There were no significant differences in the mean CSF white blood cell counts among age categories. CONCLUSIONS The application of stringent inclusion criteria and the use of the PCR yielded a population of infants that better represents the noninfected neonate than earlier reports. These values can be used for reference in evaluating the febrile or ill neonate.

The Effect of Interleukin-10 on Meningeal Inflammation in Experimental Bacterial Meningitis

Interleukin-10 (IL-10) is a cytokine with antiinflammatory effects. In a rabbit model of meningitis, IL-10 was given intracisternally or intravenously to evaluate the impact on inflammation induced by lipooligosaccharide (LOS), Haemophilus influenzae type b (Hib), or Listeria monocytogenes. Intracisternal IL-10 in concentrations >1 microg significantly reduced tumor necrosis factor-alpha (TNF-alpha) and lactate values in cerebrospinal fluid (CSF). Intravenous IL-10 (1 mg/kg) in two doses after intracisternal LOS significantly reduced CSF TNF-alpha and lactate. When Hib was used, animals were treated with ceftriaxone and dexamethasone with or without IL-10 (1 mg/kg). TNF-alpha was significantly reduced in animals treated with IL-10, dexamethasone, or both compared with levels in rabbits receiving ceftriaxone alone. Comparable results were obtained when L. monocytogenes was inoculated and animals were treated with ampicillin with or without IL-10, dexamethasone, or nothing. In conclusion, IL-10 modulates CSF TNF-alpha concentrations in experimental LOS, Hib, or L. monocytogenes meningitis. The maximal inhibitory effect was seen when IL-10 and dexamethasone were combined.

Evaluation of CP-99,219, a new fluoroquinolone, for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

CP-99,219 is a new fluoroquinolone that has excellent activity against gram-positive organisms including penicillin- and cephalosporin-resistant Streptococcus pneumoniae strains. In our well-established rabbit model of meningitis, we conducted experiments to determine the concentrations of CP-99,219 in cerebrospinal fluid (CSF) after intravenous administration and its ability to eradicate two penicillin-resistant pneumococcal isolates. The peak and trough concentrations of CP-99,219 in the CSF were from 19 to 25% of the concentrations simultaneously obtained in serum and were unaffected by concomitant dexamethasone administration. Compared with untreated (control) animals, three doses of CP-99,219 given 5 h apart significantly reduced the bacterial count in CSF by 5 to 6 log10 CFU at 10 h. Although 47% of the dexamethasone-treated animals and 18% of those not given the steroid had positive cultures at 24 h (14 h after administration of the last antibiotic dose), the mean bacterial counts did not change from those observed at 10 h. Additionally, only results for animals infected with one of the two pneumococcal strains appeared to be affected by concomitant dexamethasone therapy.

Modulation of expression of genes involved in the inflammatory response by lipopolysaccharide and temperature in cultured human astroglial cells.

In bacterial sepsis and meningitis, large concentrations of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) correlate directly with morbidity and mortality. This laboratory has reported previously that elevated temperature in the physiologic range is associated with down regulation of IL-1 beta and TNF alpha expression in cultured astroglia after lipopolysaccharide (LPS) stimulation. To further investigate the role of elevated temperature in the CNS inflammatory response, the effects of LPS and elevated temperature on the expression of genes that participate in the inflammatory response were determined in cultured transformed human fetal astrocytes and in an astrocytoma cell line. The effect of physiologic temperature elevation on cytokine concentrations in cerebrospinal fluid (CSF) was also investigated in a rabbit meningitis model. The findings indicate that astrocytes express a wide variety of cytokines, growth factors, growth factor receptors, and other genes that could play important roles in CNS inflammation. Furthermore, temperature elevation in the febrile range can lead to alterations in the patterns of expression of many genes involved in the inflammatory response of these cells.

CLINICAL UTILITY OF POLYMERASE CHAIN REACTION (PCR) IN DIAGNOSIS OF ENTEROVIRAL MENINGITIS. † 975

CLINICAL UTILITY OF POLYMERASE CHAIN REACTION (PCR) IN DIAGNOSIS OF ENTEROVIRAL MENINGITIS. † 975