Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases.

With an established role in cystic fibrosis and bronchiectasis, nebulized antibiotics are increasingly being used to treat respiratory infections in critically ill invasively mechanically ventilated adult patients. Although there is limited evidence describing their efficacy and safety, in an era when there is a need for new strategies to enhance antibiotic effectiveness because of a shortage of new agents and increases in antibiotic resistance, the potential of nebulization of antibiotics to optimize therapy is considered of high interest, particularly in patients infected with multidrug-resistant pathogens. This Position Paper of the European Society of Clinical Microbiology and Infectious Diseases provides recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology regarding the use of nebulized antibiotics in invasively mechanically ventilated adults, based on a systematic review and meta-analysis of the existing literature (last search July 2016). Overall, the panel recommends avoiding the use of nebulized antibiotics in clinical practice, due to a weak level of evidence of their efficacy and the high potential for underestimated risks of adverse events (particularly, respiratory complications). Higher-quality evidence is urgently needed to inform clinical practice. Priorities of future research are detailed in the second part of the Position Paper as guidance for researchers in this field. In particular, the panel identified an urgent need for randomized clinical trials of nebulized antibiotic therapy as part of a substitution approach to treatment of pneumonia due to multidrug-resistant pathogens.

Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines.

Nebulized antimicrobial agents are increasingly administered for treatment of respiratory infections in mechanically ventilated (MV) patients. A structured online questionnaire assessing the indications, dosages and recent patterns of use for nebulized antimicrobial agents in MV patients was developed. The questionnaire was distributed worldwide and completed by 192 intensive care units. The most common indications for using nebulized antimicrobial agent were ventilator-associated tracheobronchitis (VAT; 58/87), ventilator-associated pneumonia (VAP; 56/87) and management of multidrug-resistant, Gram-negative (67/87) bacilli in the respiratory tract. The most common prescribed nebulized agents were colistin methanesulfonate and sulfate (36/87, 41.3% and 24/87, 27.5%), tobramycin (32/87, 36.7%) and amikacin (23/87, 26.4%). Colistin methanesulfonate, amikacin and tobramycin daily doses for VAP were significantly higher than for VAT (p < 0.05). Combination of parenteral and nebulized antibiotics occurred in 50 (86%) of 58 prescriptions for VAP and 36 (64.2%) of 56 of prescriptions for VAT. The use of nebulized antimicrobial agents in MV patients is common. There is marked heterogeneity in clinical practice, with significantly different in use between patients with VAP and VAT. Randomized controlled clinical trials and international guidance on indications, dosing and antibiotic combinations to improve clinical outcomes are urgently required.

Oral clearance and pathogenic oropharyngeal colonization in the elderly.

The elderly have an increased incidence of oropharyngeal colonization with respiratory pathogens, a well-known risk factor for the development of pneumonia. Changes in the oral milieu may occur secondary to decreased salivary production and abnormalities in swallowing. These abnormalities, common in the elderly, may result in impaired clearance of organisms, allowing pathogenic colonization. To test this hypothesis, we performed a prospective cross-sectional analysis of 75 elderly institutionalized patients and measured oral clearance using (99m)Tc-human serum albumin (HSA) administered to the oropharynx. Oropharyngeal cultures, salivary cell populations, elastase activity, and clinical parameters were measured simultaneously. Retention of radiolabel ranged from 100% to 2.3% over 120 min of observation. Clearance in the oropharynx was significantly decreased in those patients who had oropharyngeal colonization with gram-negative bacilli (GNB), Staphylococcus aureus (SA), or yeast compared with those demonstrating normal flora by 95% confidence intervals. Decreased clearance was also seen in patients on antidepressants by 95% confidence levels. The absolute number of salivary lymphocytes/ml and buccal cells/ml was increased in colonized patients versus noncolonized persons (mean +/- SEM, 128 x 10(3) +/- 49 x 10(3), 25.4 +/- 11.6 x 10(3)). Elastase activity was elevated in patients who had GNB compared with patients without GNB (mean +/- SEM, 10.6 nM +/- 5.7, versus 2.2 nM +/- 1.2, p = 0.036). We conclude that a decrease in salivary clearance of potentially pathogenic organisms may be a major risk factor for the development of colonization in the elderly.

Aerosolized antibiotics: current and future.

Aerosolized antibiotic therapy appears to have potential for targeted therapy to the airways and deep lung to prevent VAP in patients at high risk for this disease. The definition of that high-risk population is important if this model is to be successful. We are attempting to define susceptible patients by measuring the volume of airway secretions, which mirrors the inflammation milieu of the central airways. Elevated sputum volume is marked by heavy growth of pathogenic organisms and high levels of inflammatory cytokines. Large-scale clinical trials are necessary to define the usefulness of these surrogates in defining a targeted population and for assessing the potential of aerosolized antibiotic prophylactic therapy for preventing pneumonia and mortality. If successful, the aerosol approach may avoid systemic therapy and its associated complications.

Aerosolized antibiotics in mechanically ventilated patients: delivery and response.

OBJECTIVES: To determine whether aerosolized antibiotics can be delivered efficiently to the lower respiratory tract in mechanically ventilated patients and to define possible clinical responses to these agents. DESIGN: Prospective serial study with cases as their own control. SETTING: A 10-bed respiratory care unit for patients with chronic respiratory failure in a tertiary university hospital. PATIENTS: Ventilator dependent patients who are otherwise medically stable. All subjects had a tracheostomy in place, were colonized with gram-negative organisms, and produced purulent secretions which could be sampled daily. INTERVENTIONS: Six patients received nine courses of nebulized therapy, which consisted of treatments every 8 hrs of gentamicin (80 mg) or amikacin (400 mg) for 14 to 21 days. MEASUREMENTS AND MAIN RESULTS: Doses to the lung were measured using radiolabeled aerosols and antibiotic concentrations in sputum. The response was assessed by a) changes in the volume of respiratory secretions; b) effect on bacterial cultures; and c) changes in the inflammatory cells and mediators of inflammation of the respiratory secretions (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha], soluble intercellular adhesion molecule-1 [sICAM-1], and human leukocyte elastase). On average, patients inhaled 35.4 +/- 5.08% (SD) of the initial drug placed in the nebulizer (neb-charge). Of this neb-charge, 9.50 +/- 2.78% was found on the respirator tubing and tracheostomy tube and 21.9 +/- 7.15% was actually deposited in the lungs. The remainder of the neb-charge was sequestered in the nebulizer or exhaled. Trough sputum concentrations averaged 4.3 +/- 3.2 microg/mL/mg neb-charge (range 234 to 520 microg/mL) and increased to 16.6 +/- 8.1 microg/mL/mg neb-charge (range 1005 to 5839 microg/mL) immediately after therapy (p = .011). Serum concentrations were undetectable in most determinations except for a single patient who was in renal failure (8.7 microg/mL amikacin). Treatment caused a significant reduction in the volume of secretions (p = .002). Weekly cultures revealed eradication of Pseudomonas species, Serratia marcescens, and Enterobacter aerogenes in most of the trials. Before antibiotic treatment, concentrations of IL-1beta were higher than those reported in acute respiratory distress syndrome. Throughout the duration of the study, IL-1beta correlated significantly with the absolute number of macrophages, neutrophils, and lymphocytes, respectively (r2 = .55, p = .002; r2 = .50, p < .0004, r2 = .36, p = .005). TNF-alpha concentrations correlated with lymphocytes and neutrophils, respectively (r2 =.27, p = .013, r2 = .21, p = .033). sICAM-1 concentrations increased two-fold (p < .001) during treatment and then returned to baseline. The volume of secretions was related to neutrophil and IL-1beta concentrations, respectively (r2 = .25, p = .008, r2= .35, p = .006). CONCLUSIONS: Nebulizer delivery of aerosolized aminoglycosides is efficient and predictable. In our clinical model, aerosolized antibiotics can make a significant impact on respiratory secretions. Their efficacy in treatment of critically ill patients remains to be determined.

RhDNase I aerosol deposition and related factors in cystic fibrosis.

To identify factors influencing lung dose of aerosolized recombinant human deoxyribonuclease (rhDNase I), we used gamma camera and filter techniques to measure deposition in 15 clinically stable patients with cystic fibrosis (CF) (five males and 10 females, age 6-31 yr, mean 16.9) who were on chronic daily therapy. Total and regional deposition were correlated with breathing pattern, pulmonary function, demographic factors, and disease severity. In addition, the effects of each patient's measured lung dose on pulmonary function was estimated by stopping the drug and observing changes in spirometry over a 2-wk follow-up period. After discontinuance of the drug, all patients reported worsening of dyspnea and difficulty producing sputum. There was a significant decrease in FEV1 (% predicted, mean +/- SE, 86.9% +/- 5.57 to 77.8% +/- 5.73, p < 0.005), but all patients completed the study. In some patients, as much as 48% of the deposited aerosol was found in the pharynx (range 0.0 to 0.30 mg, mean 0.089 mg +/- 0.029), and pharyngeal deposition correlated negatively with tidal volume (r = -0.696, p < 0.006) and age (r = -0.743, p < 0.005). For the lungs, deposition ranged between 0.16 mg and 0.78 mg of the 2.5 mg nebulizer dose (mean 0.47 +/- 0.04 mg) and correlated negatively with FEV1 (% predicted, r = -0.611, p = 0.0152). However, the spirometric decrements following cessation of therapy did not correlate with the lung dose of the drug. Analysis of regional deposition within the lungs indicated a wide range of distribution between central and peripheral zones. In conclusion, the deposition pattern of rhDNase I aerosols in patients with CF is largely influenced by respiratory physiology, which itself depends upon age and severity of lung disease. As the patients grow there is a decrease in upper airway deposition and more particles are presented to the lungs where those patients with more airways disease have enhanced pulmonary deposition. Upper airway deposition of rhDNase I is significant, especially in younger patients, and may be related to laryngeal side effects.

Utility of technetium-99m-DTPA in determining regional ventilation.

UNLABELLED: The goal of this study was to determine the usefulness of radiolabeled aerosols in the assessment of regional ventilation in tracheotomized patients maintained on mechanical ventilation. METHODS: Three commercially available radioaerosol nebulizer kits were studied on the bench to determine nebulizer efficiency and particle distribution of 99mTc-DTPA aerosols. We studied ventilated tracheotomized human subjects with a gamma camera and simultaneously measured regional ventilation with 81mKr gas and 99mTc-DTPA aerosol. Images were compared by analysis of radioactivity distributions in computer-generated regions of interest. RESULTS: The UltraVent nebulizing system produced the smallest particles with a mass median aerodynamic diameter of 0.9 micron compared to the AeroTech I and Venti-Scan II systems, which both produced aerosols of 1.3 microns. Despite relatively small particle sizes, 99mTc-DTPA deposition images with the UltraVent nebulizer did not accurately represent regional ventilation as measured by 81mKr equilibrium. Visual inspection of images revealed significant amounts of particle deposition in the region of the trachea which was diminished but not eliminated following replacement of the tracheotomy tube inner cannula. Based on regional analysis, correlation between radioactivity distributions of both isotopes was poor (r = 0.262, p = 0.162) with segmental analysis suggesting that the upper and middle lung regions were significantly affected by residual tracheal activity. CONCLUSION: The lungs of patients maintained on mechanical ventilation can be imaged after the inhalation of 99mTc-DTPA from commercially available delivery kits, but the correlation between aerosol deposition and regional ventilation is poor. Better definition of ventilated lung segments is obtained when using a gas such as 81mKr because tracheal activity with the radiolabeled gas is minimized.

Tracheal aspirates in long-term mechanically ventilated patients. A human model of gram-negative infection and airway inflammation.

It is well known that patients requiring long-term mechanical ventilation and tracheostomy have nearly universal airway colonization with Gram-negative organisms. However, useful parameters to objectively describe the airway inflammation associated with airway instrumentation and colonization have not been well define. In our respiratory care unit, patients who are medically stable except for ventilator dependence are readily available for longitudinal assessment of airway secretions and therefore provide a unique population for studying airway inflammation and infection. To quantitate production of respiratory secretions, we instituted a uniform protocol of suctioning over a 6-h period. Further, we devised a method of dilution and homogenization of tracheal aspirates that permits reproducible intrasample total cell counts (coefficient of variation, 4.6%). With these techniques, patients were then studied serially over a 4- to 7-week period. Total cell count, inflammatory cell differential, and two indices of airway inflammation, human neutrophil elastase (HLE) and soluble-intercellular adhesion molecule-1 (sICAM-1) studied in the sol phase of secretions were monitored. The mean total cell count was 42.2 x 10(6) cells per gram of secretions when patients were clinically stable and not receiving antibiotics. The average differential was neutrophils 69.9%, macrophages 26.9%, and lymphocytes 2.8%. Mean active HLE was 35.6 micrograms/mL and mean sICAM-1 was 83 ng/mL. Six patients during the period of observation received intravenous oral or aerosolized antibiotics for tracheobronchitis. A threefold drop in volume of secretions was measured (p < 0.018). The total cell count and percent neutrophils decreased from 76.4 x 10(6)/g of sputum to 54.9 x 10(6) and 72.2 to 54.9%, respectively. While these changes were not statistically significant, the absolute number of airway neutrophils over the 6 h decreased sevenfold (p < 0.014). Similarly sICAM-1 burden (micrograms per 6-h period) also decreased significantly (p < 0.034). These patients provide a unique human model for future studies specifically designed to assess the effect of novel modalities of anti-inflammatory and antimicrobial agents on respiratory secretions.

Gastric flora in chronically mechanically ventilated patients. Relationship to upper and lower airway colonization.

The oropharynx, stomach, and trachea are all potential reservoirs for gram-negative organisms in mechanically ventilated patients. The pathogenic importance of each site in respiratory infection may differ between mechanically ventilated patients who are medically stable and the critically ill, and these differences may be important in understanding the pathogenesis of nosocomial infection. We prospectively studied seven patients requiring chronic ventilatory assistance who were otherwise medically stable to determine the pattern of gram-negative colonization of these three sites. Serial weekly oropharyngeal, gastric, and tracheal cultures were taken over a 6-mo period in our Respiratory Care Unit for chronically ventilator-dependent patients. Pseudomonas aeruginosa (PA) was present more frequently and persistently in the trachea than the oropharynx and stomach (p < 0.01) and members of the family Enterobacteriaceae (Ent. species) were also observed more commonly in the trachea than the oropharynx (p < 0.01). PA was seen in 6.7% of gastric specimens whereas Ent. species were found in 40% of gastric specimens. Six identical strains from a total of 53 gastric isolates and 128 oropharyngeal isolates were cultured coincidentally from these two sites. Coincidental isolation of 11 strains was observed in 177 tracheal isolates and 53 gastric samples. Documented transfers from stomach to oropharynx ascertained by sequential isolation occurred in one of 118 cultures and transfer from stomach to trachea occurred in three of 134 cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Technique for measurement of oropharyngeal clearance in the elderly.

In elderly patients, gram negative bacterial colonization often preceeds nosocomial pneumonia. As we propose that a critical factor influencing this change from normal to gram negative predominance is an alteration in oral clearance, we designed this study to validate a technique for measurement of oropharyngeal clearance in a large number of nursing home residents. We modified a protocol of La Force et al who utilized an atomizer to radiolabel oropharyngeal secretions. We determined the output per spray of a DeVILBISS model 152 atomizer and found that 3 sprays of 5 mCi of 99mTc-HSA in 4 ml saline delivered 263 microCi in 0.21 ml. To measure clearance, we designed a portable, collimated ratemeter. It has a lead lined tapered aluminium frame 15 cm high, originating from a 7.5 cm rectangular base which is fitted to the scintillator. On the bench we demonstrated that this collimator, used to confine detection to the face, did not alter sensitivity and linearity of the ratemeter in our specific experimental conditions. When the ratemeter was collimated and its window off, its sensitivity was 5 times greater than the gamma camera with no loss of linearity. However, distance had a significant effect on the ratemeter's sensitivity whereas it had little effect on the gamma camera. Finally, in thirteen patients we assessed the ratemeter's accuracy in measurement of oropharyngeal clearance by comparing curves obtained simultaneously from the ratemeter and gamma camera. While each curve had its own characteristics, both devices provided remarkably similar data and there were no significant differences (r = 0.967, p < 0.0001). We conclude that oropharyngeal clearance can be conveniently and accurately studied in elderly patients at the bedside with a collimated ratemeter. The high sensitivity provides a measure of clearance with low levels of radioactivity exposure, allowing repeated studies over time.

Nebulizer therapy with antibiotics in chronic suppurative lung disease.

Aerosolized antibiotics have been shown to be a useful modality of treatment in patients with cystic fibrosis. In this investigation we examined the utility of this treatment in patients with other chronic suppurative lung disorders. These included forty patients, thirty men and ten women with chronic airway infection (27 with bronchiectasis, 6 with chronic abscess and 7 with chronic suppurative bronchitis). Pathogenic organisms were isolated from the affected part of the lung by a fiberoptic bronchoscopy using a sterile disposable bronchial microbiology brush. Cultures from these specimens were used to determine the appropriate antibiotic. A second control group of 20 patients was treated with systemic antibiotics alone. Both systemic and aerosolized antibiotics were administered in 20 patients. A statistically significant improvement in clinical, and ventilatory functions was recorded in the first group compared to the second. Nebulized antibiotics used as adjunctive therapy in association with systemic antibiotics may offer a therapeutic advantage in chronic suppurative lung diseases.

Aerosol deposition in mechanically ventilated patients. Optimizing nebulizer delivery.

Previous studies have suggested that nebulizers are inefficient in delivering aerosolized medication to the lung in patients supported by mechanical ventilation. In a recent bench study, we characterized factors that may affect aerosol delivery, i.e., nebulizer type, ventilator settings (duty cycle), volume fill, and humidification as well as technical factors affecting measurement of deposition (e.g., radiolabeled compounds). Utilizing the predictions from our bench data, the present study was designed to assess nebulized aerosol delivery to ventilated patients under optimal conditions. Seven patients who were receiving mechanical ventilation (Bear II) via tracheostomy tube (TT) were studied. The humidifier was turned off. The test aerosol, a saline solution labeled with 99mTechnetium bound to human serum albumin (99mTc-HSA), was administered via a jet nebulizer (AeroTech II, 1.1 +/- 1.8 microns [mass median aerodynamic diameter, MMAD, geometric standard deviation, sigma g]), which was incorporated into the ventilator circuit and run to dryness. Inhaled and deposited radioactivity were measured by a mass balance/filter technique. TT versus lung deposition were quantified by removal of the inner cannula and direct measurement of TT deposition in a well counter. Inspiratory versus expiratory components of TT deposition were separated via bench techniques for each TT tube and breathing pattern. The regional distribution of deposited radioactivity was confirmed by gamma camera scans before and after TT removal. Measured radioactivity at each site was expressed as a percentage of nebulizer charge (i.e., the quantity of radioactivity originally placed in the nebulizer). On average, 30.6 +/- 6.3% (SD) of the charge was inhaled by the ventilated patients. Mean deposition in the TT during inspiration was 2.6 +/- 0.5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease.

Invasive pulmonary aspergillosis usually occurs in severely immunocompromised or neutropenic patients. Six patients with invasive aspergillosis are described whose only defence impairment was underlying lung disease and corticosteroid treatment. Cough, fever, and sputum production were the usual reasons for presentation and four patients developed the sepsis syndrome. Radiographic findings included de novo cavitation in three patients and rapid radiographic progression in four. Aspergillus species were isolated from respiratory secretions of all patients early in the course of the disease. Treatment was effective in only two patients and the subsequent progress of the others was consistent with a chronic necrotising process. Invasive pulmonary aspergillosis is uncommon in patients with respiratory diseases receiving corticosteroids, but should be considered when pneumonia and cavitary infiltrates occur.

Bacterial colonization: pathogenesis and clinical significance.

Bacterial colonization of the respiratory tract frequently precedes the onset of serious invasive infection. It is increasingly evident that the risk for colonization is greatest in patients with serious underlying illness. These patients have been shown to have increased bacterial binding to their respiratory mucosa. In addition to the patients' own predisposition to infection, many of our medical interventions may further compromise the respiratory tract host defenses and permit successful bacterial growth. Methods for prevention of bacterial colonization have not been very successful to date. Although methods to decrease the introduction of exogenous bacteria to patients have been developed, problems persist with the patients' endogenous enteric gram-negative bacilli. It is hoped that increased understanding of bacterial-mucosal interactions will lead to new therapeutic strategies to prevent bacterial invasion of the respiratory tract.

Bacterial adherence to respiratory tract cells. Relationships between in vivo and in vitro pH and bacterial attachment.

Alterations in in vitro pH have been shown to have a significant effect on the bacterial binding capacity of epithelial cells for certain organisms. We investigated the effect of in vivo pH and in vitro changes in pH on the adherence of Pseudomonas aeruginosa to buccal and tracheal cells of 19 chronic tracheostomy patients. In addition, airway pH was measured in 5 normal volunteers. Oropharyngeal and endobronchial pH were measured with a flexible electrode that could be passed through a bronchoscope under direct visualization. In vitro adherence of Pseudomonas to respiratory epithelial cells was determined at pH 6.5 and 7.2. Colonization status of the patients was determined by culture of oropharyngeal and tracheal secretions. The pH value of each site in the respiratory tract and its secretions were different in the tracheostomy patients (buccal pH 6.3; tracheal, 6.9; sputum, 7.5). No difference was noted in pH of the 2 sites in control subjects (buccal, 6.7; tracheal, 6.7). Changes in in vitro pH had a significant effect (p less than 0.004) on bacterial binding to epithelial cells from both sites. The pH had its greatest effect on tracheal cells of patients colonized with Pseudomonas. Increased in vitro binding of these organisms was noted at the more alkaline pH. The magnitude of the effect of in vitro pH alteration on bacterial binding correlated directly with the degree of binding. These results demonstrated that pH has a significant effect on in vitro Pseudomonas adherence and the effect is most marked on cells obtained from the lower respiratory tract of patients colonized with this organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutritional status and bacterial binding in the lower respiratory tract in patients with chronic tracheostomy.

Patients with chronic tracheostomy often develop tracheobronchial colonization with enteric gram-negative bacilli, especially Pseudomonas aeruginosa, but pathogenic mechanisms are largely unknown. To examine this problem, we measured in-vitro bacterial adherence to airway epithelial cells from the tracheal surfaces of 15 patients with chronic tracheostomy and 18 healthy, noncolonized controls without tracheostomy. Patients with tracheostomy had more tracheal cell adherence (7.3 +/- 0.4 [SE] bacteria/cell) than controls (4.8 +/- 0.7 bacteria/cell; p = 0.008), but patients colonized by Pseudomonas species had even more binding (9.0 +/- 0.06 bacteria/cell) than those without this finding (5.8 +/- 0.8 bacteria/cell; p = 0.008). Differences between patients in lower airway cell binding of bacteria were largely related to a multifactorial assessment of patient nutritional status, the prognostic nutritional index (r = 0.67, p = 0.005). Thus, nutritional status may account in part for the common problem of tracheobronchial colonization with gram-negative bacteria in patients with chronic tracheostomy.

Decreased cerebrospinal fluid cyclic adenosine 3',5'-monophosphate in bacterial meningitis.

The concentration of cyclic adenosine 3',5'-monophosphate (cAMP) in 16 cerebrospinal fluid samples from eight patients with bacterial meningitis due to several different organisms was determined. An age- and sex-matched control group of 12 patients with a variety of acute, noninfectious systemic and neurological diseases was also examined. To quantitate the amount of cAMP, a new, improved radioimmunoassay was used with the ability to measure 2.5 X 10(-15) mol of cAMP. The mean concentration of cAMP in the cerebrospinal fluid from patients with meningitis was 0.05 nM, and from patients in the control group it was 1.18 nM. The difference between these two values is statistically significant. The decreased cAMP concentration in the cerebrospinal fluid from patients with bacterial meningitis did not seem to be secondary to metabolism by bacteria or leukocytes, increased enzymatic degradation within the cerebrospinal fluid, or an artifact introduced by the collection and storage procedure. Since the concentration of cAMP in the cerebrospinal fluid is normally found to be within narrow limits and probably reflects intracellular cAMP levels, the results described in this study suggest that interference with cAMP metabolism in central nervous system tissue occurs in bacterial meningitis. This finding seems to be independent of the causative organism and might explain the pathogenesis of selected, neurological manifestations of this disease.