- Email: [email protected]
Spontaneous adult Gram-negative bacillary meningitis in Soweto, South Africa
International Journal of Infectious Diseases 30 (2015) 38–40
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Short Communication
Spontaneous adult Gram-negative bacillary meningitis in Soweto, South Africa Gloria Teckie, Alan Karstaedt * Division of Infectious Diseases, Department of Medicine, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of the Witwatersrand, PO Bertsham, 2013 Johannesburg, South Africa
A R T I C L E I N F O
Article history: Received 5 July 2014 Received in revised form 23 October 2014 Accepted 25 October 2014 Corresponding Editor: Eskild Petersen Keywords: Gram-negative bacillary meningitis Adults Africa HIV
S U M M A R Y
Background: Gram-negative bacillary (GNB) meningitis is a rare cause of meningitis in adults and can occur as a spontaneous infection or as a complication of a neurosurgical procedure or trauma. We aimed to describe the characteristics and outcomes of adults with spontaneous GNB meningitis. Methods: A retrospective cohort analysis was performed of 26 patients with GNB meningitis seen at a single hospital in Soweto, South Africa. Results: A predisposing condition was found in 24 (92%) patients. The 19 (73%) HIV-infected patients had a median CD4 count of 24/mm3. Chronic renal disease, diabetes mellitus, myeloma, and alcoholism were other underlying conditions. The HIV-infected had a median cerebrospinal fluid (CSF) neutrophil count of 2/mm3 compared to the HIV-non-infected of 560/mm3. Common organisms were Escherichia coli, Klebsiella pneumoniae, and non-typhoidal Salmonella in HIV-positive patients and K. pneumoniae in the HIV-negative group. Ten (38%) isolates were resistant to third-generation cephalosporins. Mortality was 65%. Conclusions: A disproportionate burden of GNB meningitis fell on the HIV-infected, among whom absent or low CSF white cells was common. Management was complicated by high rates of resistance to thirdgeneration cephalosporins. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction
2. Methods
Gram-negative bacillary (GNB) meningitis is a rare though increasing cause of meningitis in adults.1 Spontaneous GNB meningitis, as distinct from neurosurgical GNB meningitis, is commonly community-acquired, is associated with underlying disease, particularly diabetes mellitus, alcoholism, malignancy and other immunocompromised states, and has a higher mortality.2–6 This study was undertaken to describe adults with spontaneous GNB meningitis in Soweto, South Africa, an area with high HIV seroprevalence, and to compare those patients with HIV infection to the HIV-non-infected.
2.1. Study site
* Corresponding author. Tel.: +27 11 933 8940; fax: +27 11 938 1454. E-mail address: [email protected] (A. Karstaedt).
Chris Hani Baragwanath Hospital, a 2700-bed public sector university hospital, is the main hospital serving Soweto. 2.2. Patient population A retrospective cohort study was performed of adult patients (18 years of age) hospitalized with spontaneous GNB meningitis between January 2007 and December 2009. A case of GNB meningitis was based on the culture of Gram-negative bacilli in cerebrospinal fluid (CSF) together with a compatible clinical presentation and appropriate CSF findings. Patients were excluded who were post-neurosurgery or who had a traumatic head injury. One HIV-negative patient without records and six patients not tested for HIV infection were also excluded.
http://dx.doi.org/10.1016/j.ijid.2014.10.006 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
G. Teckie, A. Karstaedt / International Journal of Infectious Diseases 30 (2015) 38–40
CSF pleocytosis referred to the presence of any neutrophils or >5 lymphocytes/mm3. Nosocomial infection was defined as an infection that was not present on admission to hospital and that subsequently developed more than 48 h after initial hospitalization. Clinical information not documented was considered not to be present. Appropriate antibiotic therapy was based on in vitro susceptibility testing. 2.3. Microbiology Gram-negative bacilli in CSF were obtained from routine cultures and were identified by standard methods. Antibiotic susceptibility was tested by disk diffusion and minimum inhibitory concentrations (MICs) were determined by Etest (AB Biodisk, Solna, Sweden) where appropriate. Extended-spectrum beta-lactamase-producing organisms were identified using Clinical and Laboratory Standards Institute breakpoints.7 2.4. Statistical analysis The Chi-square test or Fisher’s exact test was used to compare categorical variables and the Wilcoxon rank-sum test to compare continuous variables. A p-value of <0.05 was considered to be statistically significant.
39
was found in 24 (92%) patients. The 19 (73%) HIV-infected patients had a median CD4 count of 24/mm3. Compared to the HIV-noninfected, the HIV-infected patients were more likely to be female and to have concurrent tuberculosis and less likely to have another underlying disease, but these differences did not reach statistical significance. Underlying medical conditions, other than HIV infection, which affected eight patients, were chronic renal disease (four patients), diabetes mellitus, myeloma, and alcoholism (two patients each), and systemic lupus erythematosus (one patient). The HIV-infected had significantly fewer patients with CSF neutrophil counts >20/mm3 (p = 0.048). Four HIV-positive patients had CSF lymphocyte predominance. Five (26%) HIVpositive patients had acellular CSF, but all had abnormal chemistry. The peripheral blood white cell count was significantly higher in the HIV-negative group compared to those with HIV infection (Wilcoxon sum of ranks p = 0.0024). Common organisms were Escherichia coli, Klebsiella pneumoniae, and non-typhoidal Salmonella in the HIV-positive group and K. pneumoniae in the HIV-negative group. Three K. pneumoniae specimens and one E. coli had extended-spectrum beta-lactamases. Sixteen (62%) organisms were susceptible to ceftriaxone or cefotaxime. Nine of these patients died. The other 10 isolates (eight were nosocomially acquired) were susceptible to meropenem. Eight in this group died. Overall mortality was 65%, with 13 deaths in the first week after diagnosis. 4. Discussion
3. Results The characteristics of 26 patients with spontaneous GNB meningitis are summarized in Table 1. A predisposing condition
Table 1 Characteristics of 26 patients with spontaneous Gram-negative bacillary meningitis comparing the HIV-infected to the HIV-non-infected HIV-infected
HIV-non-infected
19 7 Categories Age, years, median (range) 41 (24–60) 43 (23–68) Male, n (%) 9 (47%) 5 (71%) Nosocomial, n (%) 7 (37%) 3 (43%) Underlying disease other than HIV, n (%) 3 (16%) 5 (71%) Tuberculosis, n (%) 10 (53%) 0 Fever, n (%) 6 (32%) 2 (29%) Meningism, n (%) 17 (89%) 5 (71%) Decreased level of consciousness, n (%) 13 (68%) 6 (86%) Seizure, n (%) 3 (16%) 5 (71%) White cell count, 109/l, median (range) 6.7 (1.06–9.17) 13.3 (4.82–32.4) CD4 cell count/mm3, median (range) 24 (8–276) On ART, n (%) 1 (5%) CSF characteristics 3 Neutrophils/mm , median (range) 2 (0–4960) 560 (1–2458) Lymphocytes/mm3, median (range) 17 (0–2640) 12 (0–160) Protein, g/l, median (range) 1.75 (0.22–>5) 2.59 (0.12–5) Glucose, mmol/l, median (range) 1.7 (<0.3–6.3) 0.5 (<0.3–6.0) Gram stain positive, n (%) 5 (26%) 4 (57%) CSF culture, n (%) Escherichia coli 8 (42%) 1 (14%) Klebsiella pneumoniae 5 (26%) 3 (43%) Non-typhoidal Salmonella 3 (16%) 0 Salmonella typhi 1 (5%) 0 Pseudomonas aeruginosa 1 (5%) 1 (14%) Proteus mirabilis 1 (5%) 0 Haemophilus influenzae 0 1 (14%) Enterobacter spp 0 1 (14%) Blood or pus culture, n (%) Same organism 5 (26%) 4 (57%) Different organism 2 (11%) 0 Treatment Appropriate antibiotics, n (%) 14 (74%) 6 (86%) Died, n (%) 13 (68%) 4 (57%) ART, antiretroviral therapy; CSF, cerebrospinal fluid.
As in other studies, the vast majority of patients had a predisposing disease.2–6 The most striking finding was the disproportionate burden in patients with advanced HIV infection. In France, three (7.5%) of 40 patients with spontaneous GNB meningitis were HIV-infected.6 In Gabon, all 16 patients with GNB meningitis (nine with E. coli and seven with Pseudomonas aeruginosa) were HIV-infected.8 If GNB meningitis is caused by systemic bacteraemia,2 the organisms should mirror those in the community. In Africa, Salmonella typhi and Salmonella spp are by far the commonest causes of adult community-acquired Gram-negative bacteraemia, followed by E. coli and Klebsiella spp.9 The findings in Soweto did not accurately reflect this order. The spectrum of organisms in Soweto was similar to that in the West, with E. coli and Klebsiella spp predominating, rather than to the preponderance of K. pneumoniae in Taiwan.1–3,5 The HIV-infected had a significantly reduced proportion with a CSF pleocytosis >20/mm3, largely due to the absence of CSF white cells in five (26%) patients. These patients did not have repeat CSF examinations to assess for a delayed rise in neutrophils. An absence of CSF pleocytosis has been described in patients with GNB meningitis; this has to be distinguished from pseudomeningitis, in which a positive CSF culture is not matched by the clinical findings and CSF parameters.10 Except for fewer patients with documented fever than in some other reports, the clinical features of meningitis were similar to those published.2–6 The choice of antibiotics for the treatment of GNB meningitis has become more difficult as resistance to cefotaxime and ceftriaxone has increased.11 In eight of the 10 isolates resistant to cefotaxime and ceftriaxone in this series, nosocomial acquisition was a clue for meropenem treatment. Combination therapy with intraventricular aminoglycosides shows promise for resistant organisms and for suboptimal response to monotherapy.11 The mortality was higher than the 38–61% in equivalent studies.2–6 There were limitations to this study as it was a retrospective record review and was dependant on the adequacy of documentation provided by the attending practitioners. Unmeasured confounders may have impacted the results.
40
G. Teckie, A. Karstaedt / International Journal of Infectious Diseases 30 (2015) 38–40
In conclusion, GNB meningitis in Soweto, an area with a high HIV seroprevalence, was distinguished by the disproportionate representation of the HIV-infected, in whom there was often an absence or low number of cells in the CSF. Management was complicated by the high rates of resistance to third-generation cephalosporins. Acknowledgements We thank Jeannette Wadula, Sharona Seetharam, and Mani Khoosal (Department of Microbiology and Infectious Diseases, National Health Laboratory Service) for their assistance, as well as Karine Scheuermaier for statistical help. Ethical approval: This study was approved by the Committee for Research on Human Subjects of the University of the Witwatersrand, Johannesburg, South Africa. Funding: There was no outside funding of this study. Conflict of interest: Neither author reports any conflict of interest. References 1. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness Jr VS, et al. Acute bacterial meningitis in adults: a review of 493 episodes. N Engl J Med 1993;328:21–8.
2. Berk SL, McCabe WR. Meningitis caused by Gram-negative bacilli. Ann Intern Med 1980;93:253–60. 3. Lu CH, Chang WN, Chang HW. Klebsiella meningitis in adults: clinical features, prognostic factors and therapeutic outcomes. J Clin Neurosci 2002;9:533–8. 4. Bouadma L, Schortgen F, Thomas R, Wutke S, Lellouche F, Regnier B, et al. Adults with spontaneous aerobic Gram-negative bacillary meningitis admitted to the intensive care unit. Clin Microbiol Infect 2006;12:287–90. 5. Chang WN, Lu CH, Chuang YC, Tsai NW, Chang CC, Chen SF, et al. Clinical characteristics of post-neurosurgical Klebsiella pneumoniae meningitis in adults and a clinical comparison to the spontaneous form in a Taiwanese population. J Clin Neurosci 2010;17:334–8. 6. Pomar V, Benito N, Lopez-Contreras J, Coll P, Gurgui M, Domingo P. Spontaneous Gram-negative bacillary meningitis in adult patients: characteristics and outcome. BMC Infect Dis 2013;13:451. 7. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved Standard M7A7. Wayne, PA: Clinical and Laboratory Standards Institute; 2007. 8. Nkoumou MO, Betha G, Kombila M, Clevenbergh P. Bacterial and mycobacterial meningitis in HIV-positive compared with HIV-negative patients in an internal medicine ward in Libreville, Gabon. J Acquir Immune Defic Syndr 2003;32:345–6. 9. Reddy EA, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:417– 32. 10. Chen HP, Lai CH, Chan YJ, Chen TL, Liu CY, Fung CP, et al. Clinical significance of Acinetobacter species isolated from cerebrospinal fluid. Scand J Infect Dis 2005;37:669–75. 11. Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, et al. Management of meningitis due to antibiotic-resistant Acinetobacter species. Lancet Infect Dis 2009;9:245–55.
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Short Communication
Spontaneous adult Gram-negative bacillary meningitis in Soweto, South Africa Gloria Teckie, Alan Karstaedt * Division of Infectious Diseases, Department of Medicine, Chris Hani Baragwanath Hospital and Faculty of Health Sciences, University of the Witwatersrand, PO Bertsham, 2013 Johannesburg, South Africa
A R T I C L E I N F O
Article history: Received 5 July 2014 Received in revised form 23 October 2014 Accepted 25 October 2014 Corresponding Editor: Eskild Petersen Keywords: Gram-negative bacillary meningitis Adults Africa HIV
S U M M A R Y
Background: Gram-negative bacillary (GNB) meningitis is a rare cause of meningitis in adults and can occur as a spontaneous infection or as a complication of a neurosurgical procedure or trauma. We aimed to describe the characteristics and outcomes of adults with spontaneous GNB meningitis. Methods: A retrospective cohort analysis was performed of 26 patients with GNB meningitis seen at a single hospital in Soweto, South Africa. Results: A predisposing condition was found in 24 (92%) patients. The 19 (73%) HIV-infected patients had a median CD4 count of 24/mm3. Chronic renal disease, diabetes mellitus, myeloma, and alcoholism were other underlying conditions. The HIV-infected had a median cerebrospinal fluid (CSF) neutrophil count of 2/mm3 compared to the HIV-non-infected of 560/mm3. Common organisms were Escherichia coli, Klebsiella pneumoniae, and non-typhoidal Salmonella in HIV-positive patients and K. pneumoniae in the HIV-negative group. Ten (38%) isolates were resistant to third-generation cephalosporins. Mortality was 65%. Conclusions: A disproportionate burden of GNB meningitis fell on the HIV-infected, among whom absent or low CSF white cells was common. Management was complicated by high rates of resistance to thirdgeneration cephalosporins. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction
2. Methods
Gram-negative bacillary (GNB) meningitis is a rare though increasing cause of meningitis in adults.1 Spontaneous GNB meningitis, as distinct from neurosurgical GNB meningitis, is commonly community-acquired, is associated with underlying disease, particularly diabetes mellitus, alcoholism, malignancy and other immunocompromised states, and has a higher mortality.2–6 This study was undertaken to describe adults with spontaneous GNB meningitis in Soweto, South Africa, an area with high HIV seroprevalence, and to compare those patients with HIV infection to the HIV-non-infected.
2.1. Study site
* Corresponding author. Tel.: +27 11 933 8940; fax: +27 11 938 1454. E-mail address: [email protected] (A. Karstaedt).
Chris Hani Baragwanath Hospital, a 2700-bed public sector university hospital, is the main hospital serving Soweto. 2.2. Patient population A retrospective cohort study was performed of adult patients (18 years of age) hospitalized with spontaneous GNB meningitis between January 2007 and December 2009. A case of GNB meningitis was based on the culture of Gram-negative bacilli in cerebrospinal fluid (CSF) together with a compatible clinical presentation and appropriate CSF findings. Patients were excluded who were post-neurosurgery or who had a traumatic head injury. One HIV-negative patient without records and six patients not tested for HIV infection were also excluded.
http://dx.doi.org/10.1016/j.ijid.2014.10.006 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
G. Teckie, A. Karstaedt / International Journal of Infectious Diseases 30 (2015) 38–40
CSF pleocytosis referred to the presence of any neutrophils or >5 lymphocytes/mm3. Nosocomial infection was defined as an infection that was not present on admission to hospital and that subsequently developed more than 48 h after initial hospitalization. Clinical information not documented was considered not to be present. Appropriate antibiotic therapy was based on in vitro susceptibility testing. 2.3. Microbiology Gram-negative bacilli in CSF were obtained from routine cultures and were identified by standard methods. Antibiotic susceptibility was tested by disk diffusion and minimum inhibitory concentrations (MICs) were determined by Etest (AB Biodisk, Solna, Sweden) where appropriate. Extended-spectrum beta-lactamase-producing organisms were identified using Clinical and Laboratory Standards Institute breakpoints.7 2.4. Statistical analysis The Chi-square test or Fisher’s exact test was used to compare categorical variables and the Wilcoxon rank-sum test to compare continuous variables. A p-value of <0.05 was considered to be statistically significant.
39
was found in 24 (92%) patients. The 19 (73%) HIV-infected patients had a median CD4 count of 24/mm3. Compared to the HIV-noninfected, the HIV-infected patients were more likely to be female and to have concurrent tuberculosis and less likely to have another underlying disease, but these differences did not reach statistical significance. Underlying medical conditions, other than HIV infection, which affected eight patients, were chronic renal disease (four patients), diabetes mellitus, myeloma, and alcoholism (two patients each), and systemic lupus erythematosus (one patient). The HIV-infected had significantly fewer patients with CSF neutrophil counts >20/mm3 (p = 0.048). Four HIV-positive patients had CSF lymphocyte predominance. Five (26%) HIVpositive patients had acellular CSF, but all had abnormal chemistry. The peripheral blood white cell count was significantly higher in the HIV-negative group compared to those with HIV infection (Wilcoxon sum of ranks p = 0.0024). Common organisms were Escherichia coli, Klebsiella pneumoniae, and non-typhoidal Salmonella in the HIV-positive group and K. pneumoniae in the HIV-negative group. Three K. pneumoniae specimens and one E. coli had extended-spectrum beta-lactamases. Sixteen (62%) organisms were susceptible to ceftriaxone or cefotaxime. Nine of these patients died. The other 10 isolates (eight were nosocomially acquired) were susceptible to meropenem. Eight in this group died. Overall mortality was 65%, with 13 deaths in the first week after diagnosis. 4. Discussion
3. Results The characteristics of 26 patients with spontaneous GNB meningitis are summarized in Table 1. A predisposing condition
Table 1 Characteristics of 26 patients with spontaneous Gram-negative bacillary meningitis comparing the HIV-infected to the HIV-non-infected HIV-infected
HIV-non-infected
19 7 Categories Age, years, median (range) 41 (24–60) 43 (23–68) Male, n (%) 9 (47%) 5 (71%) Nosocomial, n (%) 7 (37%) 3 (43%) Underlying disease other than HIV, n (%) 3 (16%) 5 (71%) Tuberculosis, n (%) 10 (53%) 0 Fever, n (%) 6 (32%) 2 (29%) Meningism, n (%) 17 (89%) 5 (71%) Decreased level of consciousness, n (%) 13 (68%) 6 (86%) Seizure, n (%) 3 (16%) 5 (71%) White cell count, 109/l, median (range) 6.7 (1.06–9.17) 13.3 (4.82–32.4) CD4 cell count/mm3, median (range) 24 (8–276) On ART, n (%) 1 (5%) CSF characteristics 3 Neutrophils/mm , median (range) 2 (0–4960) 560 (1–2458) Lymphocytes/mm3, median (range) 17 (0–2640) 12 (0–160) Protein, g/l, median (range) 1.75 (0.22–>5) 2.59 (0.12–5) Glucose, mmol/l, median (range) 1.7 (<0.3–6.3) 0.5 (<0.3–6.0) Gram stain positive, n (%) 5 (26%) 4 (57%) CSF culture, n (%) Escherichia coli 8 (42%) 1 (14%) Klebsiella pneumoniae 5 (26%) 3 (43%) Non-typhoidal Salmonella 3 (16%) 0 Salmonella typhi 1 (5%) 0 Pseudomonas aeruginosa 1 (5%) 1 (14%) Proteus mirabilis 1 (5%) 0 Haemophilus influenzae 0 1 (14%) Enterobacter spp 0 1 (14%) Blood or pus culture, n (%) Same organism 5 (26%) 4 (57%) Different organism 2 (11%) 0 Treatment Appropriate antibiotics, n (%) 14 (74%) 6 (86%) Died, n (%) 13 (68%) 4 (57%) ART, antiretroviral therapy; CSF, cerebrospinal fluid.
As in other studies, the vast majority of patients had a predisposing disease.2–6 The most striking finding was the disproportionate burden in patients with advanced HIV infection. In France, three (7.5%) of 40 patients with spontaneous GNB meningitis were HIV-infected.6 In Gabon, all 16 patients with GNB meningitis (nine with E. coli and seven with Pseudomonas aeruginosa) were HIV-infected.8 If GNB meningitis is caused by systemic bacteraemia,2 the organisms should mirror those in the community. In Africa, Salmonella typhi and Salmonella spp are by far the commonest causes of adult community-acquired Gram-negative bacteraemia, followed by E. coli and Klebsiella spp.9 The findings in Soweto did not accurately reflect this order. The spectrum of organisms in Soweto was similar to that in the West, with E. coli and Klebsiella spp predominating, rather than to the preponderance of K. pneumoniae in Taiwan.1–3,5 The HIV-infected had a significantly reduced proportion with a CSF pleocytosis >20/mm3, largely due to the absence of CSF white cells in five (26%) patients. These patients did not have repeat CSF examinations to assess for a delayed rise in neutrophils. An absence of CSF pleocytosis has been described in patients with GNB meningitis; this has to be distinguished from pseudomeningitis, in which a positive CSF culture is not matched by the clinical findings and CSF parameters.10 Except for fewer patients with documented fever than in some other reports, the clinical features of meningitis were similar to those published.2–6 The choice of antibiotics for the treatment of GNB meningitis has become more difficult as resistance to cefotaxime and ceftriaxone has increased.11 In eight of the 10 isolates resistant to cefotaxime and ceftriaxone in this series, nosocomial acquisition was a clue for meropenem treatment. Combination therapy with intraventricular aminoglycosides shows promise for resistant organisms and for suboptimal response to monotherapy.11 The mortality was higher than the 38–61% in equivalent studies.2–6 There were limitations to this study as it was a retrospective record review and was dependant on the adequacy of documentation provided by the attending practitioners. Unmeasured confounders may have impacted the results.
40
G. Teckie, A. Karstaedt / International Journal of Infectious Diseases 30 (2015) 38–40
In conclusion, GNB meningitis in Soweto, an area with a high HIV seroprevalence, was distinguished by the disproportionate representation of the HIV-infected, in whom there was often an absence or low number of cells in the CSF. Management was complicated by the high rates of resistance to third-generation cephalosporins. Acknowledgements We thank Jeannette Wadula, Sharona Seetharam, and Mani Khoosal (Department of Microbiology and Infectious Diseases, National Health Laboratory Service) for their assistance, as well as Karine Scheuermaier for statistical help. Ethical approval: This study was approved by the Committee for Research on Human Subjects of the University of the Witwatersrand, Johannesburg, South Africa. Funding: There was no outside funding of this study. Conflict of interest: Neither author reports any conflict of interest. References 1. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness Jr VS, et al. Acute bacterial meningitis in adults: a review of 493 episodes. N Engl J Med 1993;328:21–8.
2. Berk SL, McCabe WR. Meningitis caused by Gram-negative bacilli. Ann Intern Med 1980;93:253–60. 3. Lu CH, Chang WN, Chang HW. Klebsiella meningitis in adults: clinical features, prognostic factors and therapeutic outcomes. J Clin Neurosci 2002;9:533–8. 4. Bouadma L, Schortgen F, Thomas R, Wutke S, Lellouche F, Regnier B, et al. Adults with spontaneous aerobic Gram-negative bacillary meningitis admitted to the intensive care unit. Clin Microbiol Infect 2006;12:287–90. 5. Chang WN, Lu CH, Chuang YC, Tsai NW, Chang CC, Chen SF, et al. Clinical characteristics of post-neurosurgical Klebsiella pneumoniae meningitis in adults and a clinical comparison to the spontaneous form in a Taiwanese population. J Clin Neurosci 2010;17:334–8. 6. Pomar V, Benito N, Lopez-Contreras J, Coll P, Gurgui M, Domingo P. Spontaneous Gram-negative bacillary meningitis in adult patients: characteristics and outcome. BMC Infect Dis 2013;13:451. 7. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved Standard M7A7. Wayne, PA: Clinical and Laboratory Standards Institute; 2007. 8. Nkoumou MO, Betha G, Kombila M, Clevenbergh P. Bacterial and mycobacterial meningitis in HIV-positive compared with HIV-negative patients in an internal medicine ward in Libreville, Gabon. J Acquir Immune Defic Syndr 2003;32:345–6. 9. Reddy EA, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:417– 32. 10. Chen HP, Lai CH, Chan YJ, Chen TL, Liu CY, Fung CP, et al. Clinical significance of Acinetobacter species isolated from cerebrospinal fluid. Scand J Infect Dis 2005;37:669–75. 11. Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, et al. Management of meningitis due to antibiotic-resistant Acinetobacter species. Lancet Infect Dis 2009;9:245–55.