Gram-negative bacilli are rare causes of meningitis in adults. However, the incidence of GNBM seems to be increasing and accounts for 15–20% of cases of meningitis in adults . Primary GNBM is a rare complication of bacteremia. The predisposing factors are mainly chronic alcoholism and an immunocompromised status. The severity of predisposing underlying disease might explain the poor prognosis despite appropriate antimicrobial therapy in these patients . Secondary GNBM has been documented after disruption of the dura arachnoid barrier, mainly because of trauma or surgery . The overall mortality in patients with GNBM ranges from 2.5  to 36  and 38% . In children and infants, the causative organisms of GNBM in developing countries are mainly Salmonella and Klebsiella species and the underlying associated conditions are diarrheal diseases and malnutrition, whereas in developed countries the main causative organism is Escherichia coli and the associated underlying conditions are urinary tract anomalies and neurosurgical anomalies or operations .
Third-generation cephalosporins have been found to be safe, effective, and well-tolerated in the treatment of GNBM [7,8]; however, an increase in resistance has been detected [4,9].
The aim of this retrospective study was to study the causes, clinical presentation, mortality, and morbidity in patients with primary and secondary GNBM and to evaluate the efficacy, safety, and tolerability of ceftriaxone (a third-generation cephalosporin) in the treatment of the disease and the rate of resistance of these organisms to the drug.
Patients and methods
This retrospective study included 95 patients with GNBM and was carried out in Egypt to study the causes and outcome of GNBM. Data from the files of all the patients admitted to the Abbassia and Imbaba fever hospitals, the two main fever hospitals in Egypt, during the period from 1993 to the end of 2009, were transferred to a computer database for analysis.
Ninety-five patients with GNBM are the basis of this study. The criteria for diagnosis of GNBM were as follows: clinical picture suggestive of meningitis, isolation of Gram-negative bacilli from the cerebrospinal fluid (CSF) and CSF picture compatible with bacterial meningitis, cloudy or turbid CSF, leukocytic pleocytosis (>10 white blood cells/mm2 mainly polymorphs), elevated CSF protein more than 0.8 g/l, and CSF glucose/blood ratio less than 50% . As a routine, on admission, a lumber puncture was performed on all patients under strict aseptic conditions. The CSF samples were examined to determine the level of CSF glucose and protein and stained with Gram stain for the presence of Gram-negative bacilli and cultured on chocolate and McConkey agar media.
The data collected from records of patients confirmed as having GNBM by isolation of the organism from the CSF were analyzed to identify age, sex, duration of symptoms before hospitalization, predisposing factors, clinical presentation, causative organisms, and outcome.
According to the presence or absence of a predisposing factor, patients with GNBM were divided in two groups: primary and secondary GNBM. Primary GNBM was characterized by an abrupt onset with no apparent causes of meningitis. Secondary GNBM was characterized by an insidious onset and the presence of predisposing cause for meningitis.
Initially, all patients admitted to both hospitals during the period of this study received ceftriaxone 100 mg/kg/day for children or 3 g/day for adults intravenously for 10 days. Patients with ceftriaxone-resistant strains (according to culture and sensitivity results) were shifted to an antibiotic to which the organism was sensitive. In addition, dexamethasone (0.2 mg/kg) intravenously, divided into 12 hourly, was given to all patients for the first 3 days of treatment.
This study was subjected to an expedited review by the Faculty of Medicine, Beni Suef University Research Ethics Committee. Request for waiving of informed consent form was applied and approved by the Research Ethics Committee on the basis of classifying the study as a noninterventional study and because obtaining informed consent to review patient record was not feasible.
Some demographic data in patients with Gram-negative bacillary meningitis
In primary GNBM, there were 49 patients (29 male and 20 female) ranging in age from 3 to 52 years (mean 13±6.5 years). The duration of symptoms before hospital admission ranged from 2 to 6 days (mean 3.5±1.1 days). In secondary GNBM, there were 46 patients (32 male and 14 female) ranging in age from 15 to 64 years (mean 32±7.5 years). The duration of symptoms ranged from 7 to 16 days (mean 9±3.2 days) before hospital admission. The mean age and duration of symptoms in patients with secondary GNBM were significantly higher than in those with primary GNBM (Table 1).
Clinical presentation of 95 patients with Gram-negative bacillary meningitis
The clinical presentation in patients with GNBM was similar to that of patients with meningitis because of common organisms. Patients with primary GNBM had a significantly higher frequency of signs of meningeal irritation (84%) than patients with secondary GNBM (26%). The frequency of unarousable coma in patients with secondary GNBM (76%) on admission was significantly higher than in patients with primary GNBM (18%) (Table 2).
Causative organisms of Gram-negative bacillary meningitis
In patients with primary GNBM, the causative organisms responsible for the disease were Salmonella typhi in 16 (33%) patients, E. coli in 15 (31%), Klebsiella pneumoniae in nine (18%), Enterobacter spp. in five (10%), and Proteus mirabilis in four (8%) patients. In patients with secondary GNBM, the causative organisms were P. mirabilis in 17 (37%), Pseudomonas aeruginosa in 16 (35%), E. coli in nine (20%), and K. pneumoniae in four (9%) patients (Table 3).
Predisposing factors and causative organisms of secondary Gram-negative bacilliary meningitis
Otitis media was the most common predisposing factor for the disease and occurred in 26 (57%) patients. The organisms isolated from these patients were P. mirabilis in 15 (33%) patients, P. aeruginosa in seven (15%), and E. coli in four (9%) patients.
Skull surgery or trauma was responsible for the disease in 14 (31%) patients, and the isolated organisms were P. aeruginosa in six (13%), E. coli in four (9%), and K. pneumoniae in four (9%) patients.
Spinal anesthesia or myelography was the precipitating cause in 6 (13%) patients and the isolated organisms were P. aeruginosa in 3 (7%) patients, P. mirabilis in 2 (4%), and E. coli in one (2%) patient (Table 4).
Treatment of patients with Gram-negative bacilliary meningitis
The protocol for the treatment of GNBM in both hospitals was done by ceftriaxone given intravenously once daily for 10 days. Once the sensitivity tests were available, organisms resistant to ceftriaxone were given the appropriate drug to which the organism was sensitive. The organisms isolated from 91 (96%) patients were sensitive to ceftriaxone and only four (4%) were resistant to ceftriaxone but were sensitive to aztreonam, which was given in a dose of 2 g for adults and 50 mg/kg for children every 8 h intravenously for 2 weeks. The organisms resistant to ceftriaxone were K. pneumoniae in one patient with primary GNBM and P. aeruginosa in two patients and P. mirabilis in one patient with secondary GNBM.
Outcome of patients with Gram-negative bacilliary meningitis
In the 49 patients with primary GNBM, 12 (24%) patients died, 11 (22%) developed neurological sequalae, and 26 (53%) were cured. In the 46 patients with secondary GNBM, 16 (35%) patients died, 15 (33%) developed neurological sequalae, and 15 (33%) were cured (Table 5). Primary GNBM was significantly associated with a higher cure rate than secondary GNBM.
The clinical picture of GNBM is similar to that seen with other types of septic meningitis; however, it carries a poorer prognosis . To the best of our knowledge, the data compiled in this study are the largest series of patients with GNBM reported from Egypt and one of the largest studies worldwide.
In this study, primary GNBM was associated with an abrupt onset of fever and signs and symptoms of meningeal irritation, whereas secondary GNBM had a gradual onset with unarousable coma. This agrees with that reported by Rahal and Simberkoff  and Hsu et al. . The mean age of patients with secondary GNBM was significantly higher than in patients with primary GNBM, which may be because of the low prevalence of neurosurgical procedures in them.
The most common causative organisms in primary GNBM were S. typhi in 16 (33%) patients and E. coli in 15 (31%) patients, which is similar to that reported by Akpede et al. , whereas in the study by Bouadma et al.  E. coli (57%) and K. pneumoniae (17%) were the most common causative organisms. The difference between their results and ours may be attributed to the endemicity of S. typhi in Egypt as compared with France.
In our patients with secondary GNBM, P. mirabilis (37%) and P. aeruginosa (35%) were the main causative organisms, whereas in the other studies the most common causative organisms of secondary GNBM were Enterobacter spp. and E. coli as reported by O'Neill et al.  and K. pneumoniae, Enterobactrer spp., and E. coli in the study conducted by Briggs et al. .
The high incidence of P. mirabilis and P. aeruginosa in our patients with secondary GNBM can be explained by the fact that the most common predisposing factor in these patients was chronic otitis media, which was found in 26 (57%) patients. These are the common causative organisms in chronic otitis media compared with developed countries in which neurosurgical operations and skull injuries were the most common predisposing factors of GNBM [3,14].
In our patients with primary GNBM, the mortality rate was 24%, which is much lower than that (83%) reported by Jang et al.  and that (38%) reported by Bouadma et al.  This difference may be because of the fact that the most common causative organism in our patients was S. typhi (33%), which is much more susceptible to treatment than K. pneumoniae (72%) was the main pathogen in patients in the study by Jang et al.  and E. coli (57%) and K. pneumoniae (17%) were the main pathogens in patients in the study by Bouadma et al. . In addition, all their patients had severe predisposing underlying disease that needed intensive care unit admission.
The mortality rate in our patients with secondary GNBM was 35%, which is similar to that reported by Jang et al.  but much higher than the 15% reported by Briggs et al.  and the 2.5% reported by O'Neill et al. . Good nursing facilities and intraventricular antibiotics may be the causes of lower mortality rates in these two studies. An intraventricular antibiotic ensures a high concentration of antibiotics at the site of infection. Vancomycin, gentamicin, and colistin are the commonly used intraventricular agents .
Third-generation cephalosporins have been widely used in the treatment of patients with GNBM over the past 20 years because these antibiotics penetrate well into the CSF after intravenous administration and this has resulted in a dramatic decrease in meningitis-related mortality [15,16]. Increased resistance to third-generation cephalosporins has been detected in GNBM patients by many researchers, which are as follows: 9% by Lu et al. ; 25% by O'Neill et al. ; and 30% by Tiskumara et al.  In our series, the rate of resistance to ceftriaxone (third-generation cephalosporin) was 4%, which was much lower than the other studies. Therefore, it is still a good drug for treatment of GNBM patients in Egypt.
From this study, we conclude that, although GNBM is a rare disease, it has a high mortality rate and should be managed as a medical emergency. GNBM should be suspected in patients with otitis media, neurosurgical, and head trauma or who underwent spinal anesthesia and have disturbance in their level of consciousness, even if there are no signs of meningeal irritation.
Ceftriaxone is still an effective drug in the treatment of GNBM and had a low rate of resistance in our study. Studies should be carried out to evaluate its use intravenously in combination with intraventricular antibiotics as a few studies suggested a marked decrease in mortality rate with the use of intaventricular drugs in neurosurgical patients.
The authors thank Dr Nabil Iskander Girgis, former consultant NAMRU-3, Cairo, and Dr Yehia Sultan, Abbassia Fever Hospital, for their great help in collecting the data of this study.
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