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Enterobacter meningitis: organism susceptibilities, antimicrobial therapy and related outcomes
Surgical Neurology 63 (2005) 533 – 537 www.surgicalneurology-online.com
Infection
Enterobacter meningitis: organism susceptibilities, antimicrobial therapy and related outcomes David R. Foster, PharmDa, Denise H. Rhoney, PharmDb,c,* a
Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA Departments of bPharmacy Practice, Colleges of Pharmacy and Allied Health Professions, and c Neurology, College of Medicine, Wayne State University, Detroit, MI 48201 USA Received 17 February 2004; accepted 24 June 2004
Abstract
Background: Meningitis due to Enterobacter species is an uncommon infection in adults; however, when present, treatment is frequently complicated by resistance of many Enterobacter isolates to third-generation cephalosporins and poor central nervous system penetration of other antibiotics. The aim of this study was to retrospectively review cases of meningitis caused by Enterobacter species at our institution, to better characterize patient factors, pathogen characteristics, and treatment options for this infection. Methods: We reviewed all cases of Enterobacter meningitis in a 12-year period at a tertiary care center. Data collected included patient demographics, antibiotic sensitivities of Enterobacter isolates, antimicrobial therapy, and patient outcomes. Results: Nineteen cases were identified, primarily in patients with neurotrauma and in neurosurgical patients. Enterobacter cloacae was the most frequent Enterobacter species isolated followed by Enterobacter aerogenes and Enterobacter agglomerans (50%, 34%, and 16% of cultures, respectively). Overall, clinical cure/improvement was achieved in 47% of patients, and the mortality rate was 21%. Antibiotic treatment varied substantially and included third-generation cephalosporins, intravenous and intrathecal aminoglycosides, trimethoprim-sulfamethoxazole (TMP-SMX), piperacillin, ciprofloxacin, and other miscellaneous antibiotics. Treatment with TMP-SMX was associated with a high rate of clinical cure/improvement, whereas third-generation cephalosporins were less efficacious. Conclusions: Enterobacter meningitis is an infrequent complication of neurological insult. Treatment is often complicated by resistance of Enterobacter species to third-generation cephalosporins. Our results indicate that while third-generation cephalosporins are not the most appropriate choice of agents to treat Enterobacter meningitis, TMP-SMX may yield satisfactory results. D 2005 Elsevier Inc. All rights reserved.
Keywords:
Enterobacter; Gram-negative bacillary meningitis; Meningitis; Postneurosurgery
1. Introduction Meningitis due to Enterobacter species is an uncommon infection in adults, primarily observed in neurosurgical patients and those with neurotrauma. Many Enterobacter species contain chromosomally mediated, depressed type I b-lactamases, and treatment is frequently complicated by * Corresponding author. Tel.: +1 313 993 7742; fax: +1 313 577 5396. E-mail address: [email protected] (D.H. Rhoney). 0090-3019/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2004.06.018
resistance of many Enterobacter isolates to third-generation cephalosporins and poor central nervous system (CNS) penetration of other antibiotics [3,10]. This may necessitate the use of agents uncommonly used to treat gram-negative bacillary meningitis. Trimethoprim-sulfamethoxazole (TMP-SMX) has excellent CNS penetration and antimicrobial activity against Enterobacter spp and is an option for the treatment of such infections [5]. Other potential treatment options include fluoroquinolones and intrathecally administered aminoglycosides, although there is less
534
D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537
Table 1 Patient characteristics Patients, n Age (y), median (range) Admitting diagnosis, n (%) Subdural hematoma Subarachnoid hemorrhage Intracranial hemorrhage Seizures Trauma Meningitis AIDS-related CNS infection CNS tumor Contusion/concussion Stroke Other Invasive CNS procedures, n (%) Positive Enterobacter from non-CNS sites, n (%) Length of hospitalization (d), median (range) Length of staya (d), median (range) a
19 39 (25-69) 4 (21) 3 (16) 3 (16) 3 (16) 3 (16) 2 (11) 2 (11) 1 (5) 1 (5) 1 (5) 6 (32) 16 (84) 8 (42) 28.0 (2-109) 21 (4-109)
ICU indicates intensive care unit, (n = 17).
experience with these modalities. In an effort to describe the treatment patterns used to treat Enterobacter meningitis at our institution and to determine clinical and microbiological outcomes associated with various treatment alternatives, we reviewed all cases of Enterobacter meningitis in a 12-year period.
2. Patients and methods Adult patients with cerebrospinal fluid (CSF) cultures positive for Enterobacter species in a 12-year period (1989-2001) were identified from the records of the clinical microbiology laboratory at Detroit Receiving Hospital, a 340-bed teaching hospital and level 1 trauma center. Meningitis was confirmed by the presence of clinical and laboratory signs suggestive of bacterial meningitis. Data collected included antibiotic sensitivities, choice of therapy, and both clinical and microbiological outcomes. Clinical outcomes were defined as follows: cure (complete resolution of signs and symptoms upon discontinua-
tion of therapy), improvement (resolution or lack of progression in most signs and symptoms upon discontinuation of therapy), failure [characterized by (a) persistence or progression of all signs and symptoms after 5 days of therapy or (b) death due to infection], or indeterminate (unable to classify as any of the other categories). Microbiological outcomes were defined as follows: cure [either (a) elimination of the causative organism from the site of infection (ie, CSF) during or upon completion of therapy or (b) absence of appropriate material for culture (ie, CSF) because the patient has improved clinically and repeated sampling is no longer justified], failure/persistence [failure to eradicate the original causative organism from the site of infection (ie, CSF)], or indeterminate (cannot be evaluated because of death, withdrawal of agent before follow-up cultures are available, and/or incomplete microbiological data). Data were coded and entered to a spreadsheet (SPSS 11.0, SPSS Inc, Chicago, Ill). Descriptive statistics were used to describe the data. 3. Results 3.1. Patients Nineteen patients with Enterobacter meningitis were identified. The majority of patients either had experienced a neurological insult (84%) and/or had undergone an invasive neurological procedure (84%), as described in Table 1. Eight of the 19 patients (42%) had Enterobacter cultured from other (non-CNS) sites; all of these patients had positive sputum cultures and 2 patients had Enterobacter cultured from multiple non-CNS sites (urine and skin). No patients had blood cultures positive for Enterobacter. Other patient characteristics are summarized in Table 1. 3.2. Infecting organisms Enterobacter cloacae was the most frequent Enterobacter species isolated (50% of cultures), followed by Enterobacter aerogenes (34% of cultures) and Enterobacter agglomerans (16% of cultures). Antibiograms of the
Table 2 Antibiograms of infecting organisms Agent c
TMP-SMX Gentamicin Tobramycin Amikacin Ceftriaxone Ceftazidime Ceftizoxime Imipenem-cilastin Piperacillin Ciprofloxacin a b c
MIC a (lg/mL)
E cloacae b
E aerogenes b
E agglomerans b
b 2/38 b4 b4 b 16 b8 b8 b8 b4 b 16 b1
88 88 100 100 54 65 47 87 53 100
77 77 77 77 100 77 69 91 69 82
100 100 100 100 100 100 100 100 100 100
Minimum inhibitory concentration required for organism to be deemed susceptible. Expressed as percentage of susceptible isolates. Trimethoprim-sulfamethoxazole.
D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537
infecting organisms are shown in Table 2. Overall, E cloacae and E aerogenes isolates tended to be susceptible to TMP-SMX, aminoglycosides, ciprofloxacin, and imipenem, whereas susceptibilities to third-generation cephalosporins and other agents were less predictable. In contrast, E agglomerans isolates were susceptible to all antimicrobial agents tested. 3.3. Antimicrobial therapy and outcomes Third-generation cephalosporins (ceftizoxime and ceftazidime) were the most common agents chosen for empirical therapy (68%), followed by intravenous aminoglycosides (tobramycin and gentamicin, 36.8%) and piperacillin (26%); combination therapy was used in many patients (73% of treated patients). Specific antibiotic regimens and outcomes
535
are shown in Fig. 1. As is evident from Fig. 1, many patients were treated with multiple overlapping courses of antibiotics. After identification of infecting organisms and corresponding antibiotic sensitivities, antibiotics were changed in 11 patients; in these cases, TMP-SMX was most commonly used (55%), followed by intrathecal aminoglycosides (46%), third-generation cephalosporins (36%), intravenous aminoglycosides (27%), ciprofloxacin (9%), and cephadrine (9%). Overall, clinical cure/improvement was achieved in 47% of patients. Microbiological cure was achieved in 52% of patients, while 5% were classified as microbiological failure, and microbiological outcome was said to be indeterminate in the remaining 42% of patients. The overall mortality rate was 21%, although in the majority of cases, it
Fig. 1. Choice of antibiotic therapy and patient outcomes. 1AG indicates intravenous aminoglycoside; AMP, ampicillin; C1, first-generation cephalosporin; C2, second-generation cephalosporin; C3, third-generation cephalosporin; CIP, ciprofloxacin; IMI, imipenem-cilastin; ITAG, intrathecal aminoglycoside; PIP, piperacillin; TMP-SMX, trimethoprim-sulfamethoxazole. 2Impr. indicates improvement; Indet., indeterminate.
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D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537
was impossible to determine the precise role of the infection in causing death (ie, due to the underlying conditions of the patients). Clinical cure or improvement occurred in 83% of patients in whom TMP-SMX was used, compared with 54% in those treated with a third-generation cephalosporin, 60% in those treated with intrathecal aminoglycosides, and 57% in those treated with intravenous aminoglycosides. As is evident in Fig. 1, it was oftentimes difficult to determine clinical outcome; 47% of cases were classified as indeterminate. Of note, these categories are not mutually exclusive, and these data should be viewed as descriptive in nature. The inherent complexity of the treatment regimens and the small sample size make meaningful statistical comparisons of outcomes associated with different therapeutic choices impossible.
4. Discussion Enterobacter meningitis is an uncommon form of gramnegative bacillary meningitis. Unfortunately, when present in neurosurgical (and other critically ill) patients, Enterobacter meningitis is a challenging infection that may be associated with serious consequences. In a 12-year period, we identified 19 cases of such infections, predominantly as a complication of neurotrauma and/or neurological surgery. Both the relative infrequency of Enterobacter meningitis and the predominance of the infection in patients with neurological insult are consistent with a limited number of other reviews of this phenomenon [4,10]. Third-generation cephalosporins are often a preferred means of therapy for gram-negative bacillary meningitis, because of their broad spectrum of activity and excellent CNS penetration. Unfortunately, Enterobacter species commonly contain chromosomally mediated, depressed type I b-lactamases, rendering third-generation cephalosporins ineffective. Predictably, we observed a high incidence of resistance of E cloacae and E aerogenes to third-generation cephalosporins. This proved to be problematic in the treatment of these patients; ceftizoxime and ceftazidime were chosen as part of an empirical regimen in almost 70% of the patients identified. Moreover, this resulted in the use of agents that are less commonly used in the treatment of serious CNS infections. Surprisingly, TMP-SMX was the most commonly used agent after organism identification and determination of antibiotic sensitivities. Because TMP-SMX is generally regarded as a bacteriostatic agent and has generally been replaced by newer bactericidal agents in the treatment of severe infections, we found the favorable success rate observed with the use of TMP-SMX compared with other antibiotics equally surprising; clinical cure/ improvement was observed in 83% of patients in whom TMP-SMX was used, compared with 53% in those treated with a third-generation cephalosporin and 60% in those treated with intrathecal aminoglycosides. In some cases in
our series, several Enterobacter isolates that were initially susceptible to third-generation cephalosporins appeared to develop resistance during treatment with a third-generation cephalosporin, although, because of the retrospective design used, we were unable to determine this conclusively (ie, development of resistance vs emergence of a second species). Wolff et al [10] observed similar results in a review of 13 cases of Enterobacter meningitis; all of the patients in their series who were treated with TMP-SMX were cured, compared with a 70% cure rate in patients treated with b-lactam antibiotics. This may, in part, be attributed to the fact that TMP-SMX has good CNS penetration and excellent activity against Enterobacter species [9]. Of interest, in a smaller series (10 patients), Huang et al [4] reported successfully treating Enterobacter meningitis with carbepenems. Others have reported successfully treating cases of Enterobacter meningitis with cefepime, intracisternal/intrathecal gentamicin, imipenem plus intrathecal amikacin, TMP-SMX plus gentamicin, and ciprofloxacin [1,2,6-8]. The design of our study may be subject to several criticisms. Most importantly, our results may be limited by the retrospective nature of the study. Unfortunately, however, the infrequent nature of this infection makes prospective evaluation very difficult, if not impossible. In addition, we are able to report only descriptive statistics; the small number of subjects in our study, in conjunction with the inherent complexity of the treatment regimens used in our subjects made meaningful statistical comparisons of outcomes associated with different therapeutic choices impossible. Finally, our results may reflect practice patterns and organism susceptibilities at our institution only. Each of these limitations is inherent in the study of an infrequent problem in a complex patient population. In summary, our study illustrates that Enterobacter meningitis is an infrequent complication of neurological insult. Treatment is often complicated by resistance of Enterobacter species to third-generation cephalosporins. Our results indicate that while third-generation cephalosporins are not the most appropriate choice of agents to treat Enterobacter meningitis, TMP-SMX may yield satisfactory results. References [1] D’Antuno VS, Brown I. Successful treatment of enterobacter meningitis with ciprofloxacin. Clin Infect Dis 1998;26:206 - 7 [letter]. [2] De Champs C, Guelon D, Joyon D, Sirot D, Chanal M, Sirot J. Treatment of a meningitis due to an Enterobacter aerogenes and a Klebsiella pneumoniae producing an extended spectrum b-lactamase. Infection 1991;19:181 - 3. [3] Heusser MF, Patterson JE, Kuritza AP, Edberg SC, Baltimore RS. Emergence of resistance to multiple beta-lactams in Enterobacter cloacae during treatment for neonatal meningitis with cefotaxime. Pediatr Infect Dis J 1990;9:509 - 12. [4] Huang CR, Lu CH, Chang WN. Adult Enterobacter meningitis: a high incidence of coinfection with other pathogens and frequent association with neurosurgical procedures. Infection 2001;29:75 - 9.
D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537 [5] Levitz RE, Quintilani R. Trimethoprim-sulfamethoxazole for bacterial meningitis. Ann Int Med 1984;100:881 - 90. [6] Ralph ED, Behme RJ. Enterobacter meningitis—treatment complicated by emergence of mutants resistant to cefotaxime. Scand J Infect Dis 1987;19:577 - 9. [7] Rousseau JM, Soullie´ B, Villevielle T, Koeck JL. Efficacy of cefepime in postoperative meningitis attributable to Enterobacter aerogenes. J Trauma 2001;50:971 - 2 [letter]. [8] Saad AF, Farrar WE. Intracisternal and intrathecal injections of gentamicin in Enterobacter meningitis. Arch Intern Med 1974; 134:738 - 40. [9] Salter AJ. Trimethoprim-sulfamethoxazole: an assessment of more than 12 years of use. Rev Infect Dis 1982;4:196 - 236. [10] Wolff MA, Young CL. Antibiotic therapy for enterobacter meningitis: a retrospective review of 13 episodes and review of the literature. Clin Infect Dis 1993;16:772 - 7.
Commentary Gram-negative rod meningitis often results from head trauma or craniotomy that requires neurosurgical intervention. It is also seen in neonates. Enterobacter infection is also an uncommon cause of gram-negative bacterial meningitis in adult patients. Before the introduction of third-generation cephalosporins, successful therapy was difficult because of the absence of adequate CSF concentrations of the antibiotic being used. This fact resulted in the concomitant use of intrathecal antimicrobial therapy with aminoglycosides. With the effectiveness of third-generation cephalosporins, these problems appeared to have been overcome. However, as this article by Foster and Rhoney demonstrates, many species from the Enterobacteriaceae family contain chromosomally mediated inducible (class I) blactamases, which often cannot be detected by routine susceptibility testing. These include Enterobacter sp, Serratia sp, Citrobacter sp, indole-positive Proteus and Pseudomonas aeruginosa. These organisms contain class I enzymes that can be rapidly induced by second- or thirdgeneration cephalosporins, resulting in the production of large amounts of b-lactamase and consequent inactivation of the antimicrobial activity. This problem can be obviated by using such agents as imipenem, meropenem, chloramphenicol, TMP-SMX, ciprofloxacin, and cefepime, which are not susceptible to class I b-lactamases. The study by Foster and Rhoney supports this conclusion. The use of
537
aminoglycosides in combination therapy may also prevent the overgrowth of resistant organisms. Finally, if a cephalosporin is selected to treat gramnegative rod meningitis, the disk approximation test can be helpful in screening isolates for the production of inducible class I b-lactamases. Lawrence A. Cone, MD, FACP Eisenhower Medical Center Rancho Mirage, CA 92270, USA The study by Foster and Rhoney sheds some light on the difficult subject of Enterobacter meningitis. They were able to gather, although in a retrospective study, a significant number of patients (n = 19) with an uncommon neurological infection. From their experience, adequate recommendations can be made on diagnostic and therapeutic procedures. Perhaps the most important contribution of this analysis is the high rate of therapeutic success using a quite old bacteriostatic agent, TMP-SMX. Interestingly, this drug is rarely used as a first-choice empirical treatment before bacterial identification; third-generation cephalosporins are usually used first. However, by far, the best results were obtained with TMP-SMX, as compared with cephalosporins and intrathecal aminoglycosides, which are the commonly used therapeutic agents in most centers. The results obtained by the authors are welcomed for two main reasons: first, because TMP-SMX seems to be equally effective against the three most frequent Enterobacter species that cause meningitis; thus, this drug can be proposed as the first choice for empirical treatment in suspected cases of Enterobacter meningitis; second, the low cost of TMP-SMX in comparison with newer antibiotics is not a trivial issue. Nowadays, most studies on therapeutic improvements imply a simultaneous skyrocketing increase in monetary costs, and it is refreshing to hear that occasionally, an old and cheaper drug works better than the new and expensive ones. A blind, prospective study comparing these drugs is desirable, although difficult to perform. Julio Sotelo, MD (General Director) Instituto Nacional de Neurologia y Neurocirugia Mexico City, 14269 Mexico
Infection
Enterobacter meningitis: organism susceptibilities, antimicrobial therapy and related outcomes David R. Foster, PharmDa, Denise H. Rhoney, PharmDb,c,* a
Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA Departments of bPharmacy Practice, Colleges of Pharmacy and Allied Health Professions, and c Neurology, College of Medicine, Wayne State University, Detroit, MI 48201 USA Received 17 February 2004; accepted 24 June 2004
Abstract
Background: Meningitis due to Enterobacter species is an uncommon infection in adults; however, when present, treatment is frequently complicated by resistance of many Enterobacter isolates to third-generation cephalosporins and poor central nervous system penetration of other antibiotics. The aim of this study was to retrospectively review cases of meningitis caused by Enterobacter species at our institution, to better characterize patient factors, pathogen characteristics, and treatment options for this infection. Methods: We reviewed all cases of Enterobacter meningitis in a 12-year period at a tertiary care center. Data collected included patient demographics, antibiotic sensitivities of Enterobacter isolates, antimicrobial therapy, and patient outcomes. Results: Nineteen cases were identified, primarily in patients with neurotrauma and in neurosurgical patients. Enterobacter cloacae was the most frequent Enterobacter species isolated followed by Enterobacter aerogenes and Enterobacter agglomerans (50%, 34%, and 16% of cultures, respectively). Overall, clinical cure/improvement was achieved in 47% of patients, and the mortality rate was 21%. Antibiotic treatment varied substantially and included third-generation cephalosporins, intravenous and intrathecal aminoglycosides, trimethoprim-sulfamethoxazole (TMP-SMX), piperacillin, ciprofloxacin, and other miscellaneous antibiotics. Treatment with TMP-SMX was associated with a high rate of clinical cure/improvement, whereas third-generation cephalosporins were less efficacious. Conclusions: Enterobacter meningitis is an infrequent complication of neurological insult. Treatment is often complicated by resistance of Enterobacter species to third-generation cephalosporins. Our results indicate that while third-generation cephalosporins are not the most appropriate choice of agents to treat Enterobacter meningitis, TMP-SMX may yield satisfactory results. D 2005 Elsevier Inc. All rights reserved.
Keywords:
Enterobacter; Gram-negative bacillary meningitis; Meningitis; Postneurosurgery
1. Introduction Meningitis due to Enterobacter species is an uncommon infection in adults, primarily observed in neurosurgical patients and those with neurotrauma. Many Enterobacter species contain chromosomally mediated, depressed type I b-lactamases, and treatment is frequently complicated by * Corresponding author. Tel.: +1 313 993 7742; fax: +1 313 577 5396. E-mail address: [email protected] (D.H. Rhoney). 0090-3019/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2004.06.018
resistance of many Enterobacter isolates to third-generation cephalosporins and poor central nervous system (CNS) penetration of other antibiotics [3,10]. This may necessitate the use of agents uncommonly used to treat gram-negative bacillary meningitis. Trimethoprim-sulfamethoxazole (TMP-SMX) has excellent CNS penetration and antimicrobial activity against Enterobacter spp and is an option for the treatment of such infections [5]. Other potential treatment options include fluoroquinolones and intrathecally administered aminoglycosides, although there is less
534
D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537
Table 1 Patient characteristics Patients, n Age (y), median (range) Admitting diagnosis, n (%) Subdural hematoma Subarachnoid hemorrhage Intracranial hemorrhage Seizures Trauma Meningitis AIDS-related CNS infection CNS tumor Contusion/concussion Stroke Other Invasive CNS procedures, n (%) Positive Enterobacter from non-CNS sites, n (%) Length of hospitalization (d), median (range) Length of staya (d), median (range) a
19 39 (25-69) 4 (21) 3 (16) 3 (16) 3 (16) 3 (16) 2 (11) 2 (11) 1 (5) 1 (5) 1 (5) 6 (32) 16 (84) 8 (42) 28.0 (2-109) 21 (4-109)
ICU indicates intensive care unit, (n = 17).
experience with these modalities. In an effort to describe the treatment patterns used to treat Enterobacter meningitis at our institution and to determine clinical and microbiological outcomes associated with various treatment alternatives, we reviewed all cases of Enterobacter meningitis in a 12-year period.
2. Patients and methods Adult patients with cerebrospinal fluid (CSF) cultures positive for Enterobacter species in a 12-year period (1989-2001) were identified from the records of the clinical microbiology laboratory at Detroit Receiving Hospital, a 340-bed teaching hospital and level 1 trauma center. Meningitis was confirmed by the presence of clinical and laboratory signs suggestive of bacterial meningitis. Data collected included antibiotic sensitivities, choice of therapy, and both clinical and microbiological outcomes. Clinical outcomes were defined as follows: cure (complete resolution of signs and symptoms upon discontinua-
tion of therapy), improvement (resolution or lack of progression in most signs and symptoms upon discontinuation of therapy), failure [characterized by (a) persistence or progression of all signs and symptoms after 5 days of therapy or (b) death due to infection], or indeterminate (unable to classify as any of the other categories). Microbiological outcomes were defined as follows: cure [either (a) elimination of the causative organism from the site of infection (ie, CSF) during or upon completion of therapy or (b) absence of appropriate material for culture (ie, CSF) because the patient has improved clinically and repeated sampling is no longer justified], failure/persistence [failure to eradicate the original causative organism from the site of infection (ie, CSF)], or indeterminate (cannot be evaluated because of death, withdrawal of agent before follow-up cultures are available, and/or incomplete microbiological data). Data were coded and entered to a spreadsheet (SPSS 11.0, SPSS Inc, Chicago, Ill). Descriptive statistics were used to describe the data. 3. Results 3.1. Patients Nineteen patients with Enterobacter meningitis were identified. The majority of patients either had experienced a neurological insult (84%) and/or had undergone an invasive neurological procedure (84%), as described in Table 1. Eight of the 19 patients (42%) had Enterobacter cultured from other (non-CNS) sites; all of these patients had positive sputum cultures and 2 patients had Enterobacter cultured from multiple non-CNS sites (urine and skin). No patients had blood cultures positive for Enterobacter. Other patient characteristics are summarized in Table 1. 3.2. Infecting organisms Enterobacter cloacae was the most frequent Enterobacter species isolated (50% of cultures), followed by Enterobacter aerogenes (34% of cultures) and Enterobacter agglomerans (16% of cultures). Antibiograms of the
Table 2 Antibiograms of infecting organisms Agent c
TMP-SMX Gentamicin Tobramycin Amikacin Ceftriaxone Ceftazidime Ceftizoxime Imipenem-cilastin Piperacillin Ciprofloxacin a b c
MIC a (lg/mL)
E cloacae b
E aerogenes b
E agglomerans b
b 2/38 b4 b4 b 16 b8 b8 b8 b4 b 16 b1
88 88 100 100 54 65 47 87 53 100
77 77 77 77 100 77 69 91 69 82
100 100 100 100 100 100 100 100 100 100
Minimum inhibitory concentration required for organism to be deemed susceptible. Expressed as percentage of susceptible isolates. Trimethoprim-sulfamethoxazole.
D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537
infecting organisms are shown in Table 2. Overall, E cloacae and E aerogenes isolates tended to be susceptible to TMP-SMX, aminoglycosides, ciprofloxacin, and imipenem, whereas susceptibilities to third-generation cephalosporins and other agents were less predictable. In contrast, E agglomerans isolates were susceptible to all antimicrobial agents tested. 3.3. Antimicrobial therapy and outcomes Third-generation cephalosporins (ceftizoxime and ceftazidime) were the most common agents chosen for empirical therapy (68%), followed by intravenous aminoglycosides (tobramycin and gentamicin, 36.8%) and piperacillin (26%); combination therapy was used in many patients (73% of treated patients). Specific antibiotic regimens and outcomes
535
are shown in Fig. 1. As is evident from Fig. 1, many patients were treated with multiple overlapping courses of antibiotics. After identification of infecting organisms and corresponding antibiotic sensitivities, antibiotics were changed in 11 patients; in these cases, TMP-SMX was most commonly used (55%), followed by intrathecal aminoglycosides (46%), third-generation cephalosporins (36%), intravenous aminoglycosides (27%), ciprofloxacin (9%), and cephadrine (9%). Overall, clinical cure/improvement was achieved in 47% of patients. Microbiological cure was achieved in 52% of patients, while 5% were classified as microbiological failure, and microbiological outcome was said to be indeterminate in the remaining 42% of patients. The overall mortality rate was 21%, although in the majority of cases, it
Fig. 1. Choice of antibiotic therapy and patient outcomes. 1AG indicates intravenous aminoglycoside; AMP, ampicillin; C1, first-generation cephalosporin; C2, second-generation cephalosporin; C3, third-generation cephalosporin; CIP, ciprofloxacin; IMI, imipenem-cilastin; ITAG, intrathecal aminoglycoside; PIP, piperacillin; TMP-SMX, trimethoprim-sulfamethoxazole. 2Impr. indicates improvement; Indet., indeterminate.
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D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537
was impossible to determine the precise role of the infection in causing death (ie, due to the underlying conditions of the patients). Clinical cure or improvement occurred in 83% of patients in whom TMP-SMX was used, compared with 54% in those treated with a third-generation cephalosporin, 60% in those treated with intrathecal aminoglycosides, and 57% in those treated with intravenous aminoglycosides. As is evident in Fig. 1, it was oftentimes difficult to determine clinical outcome; 47% of cases were classified as indeterminate. Of note, these categories are not mutually exclusive, and these data should be viewed as descriptive in nature. The inherent complexity of the treatment regimens and the small sample size make meaningful statistical comparisons of outcomes associated with different therapeutic choices impossible.
4. Discussion Enterobacter meningitis is an uncommon form of gramnegative bacillary meningitis. Unfortunately, when present in neurosurgical (and other critically ill) patients, Enterobacter meningitis is a challenging infection that may be associated with serious consequences. In a 12-year period, we identified 19 cases of such infections, predominantly as a complication of neurotrauma and/or neurological surgery. Both the relative infrequency of Enterobacter meningitis and the predominance of the infection in patients with neurological insult are consistent with a limited number of other reviews of this phenomenon [4,10]. Third-generation cephalosporins are often a preferred means of therapy for gram-negative bacillary meningitis, because of their broad spectrum of activity and excellent CNS penetration. Unfortunately, Enterobacter species commonly contain chromosomally mediated, depressed type I b-lactamases, rendering third-generation cephalosporins ineffective. Predictably, we observed a high incidence of resistance of E cloacae and E aerogenes to third-generation cephalosporins. This proved to be problematic in the treatment of these patients; ceftizoxime and ceftazidime were chosen as part of an empirical regimen in almost 70% of the patients identified. Moreover, this resulted in the use of agents that are less commonly used in the treatment of serious CNS infections. Surprisingly, TMP-SMX was the most commonly used agent after organism identification and determination of antibiotic sensitivities. Because TMP-SMX is generally regarded as a bacteriostatic agent and has generally been replaced by newer bactericidal agents in the treatment of severe infections, we found the favorable success rate observed with the use of TMP-SMX compared with other antibiotics equally surprising; clinical cure/ improvement was observed in 83% of patients in whom TMP-SMX was used, compared with 53% in those treated with a third-generation cephalosporin and 60% in those treated with intrathecal aminoglycosides. In some cases in
our series, several Enterobacter isolates that were initially susceptible to third-generation cephalosporins appeared to develop resistance during treatment with a third-generation cephalosporin, although, because of the retrospective design used, we were unable to determine this conclusively (ie, development of resistance vs emergence of a second species). Wolff et al [10] observed similar results in a review of 13 cases of Enterobacter meningitis; all of the patients in their series who were treated with TMP-SMX were cured, compared with a 70% cure rate in patients treated with b-lactam antibiotics. This may, in part, be attributed to the fact that TMP-SMX has good CNS penetration and excellent activity against Enterobacter species [9]. Of interest, in a smaller series (10 patients), Huang et al [4] reported successfully treating Enterobacter meningitis with carbepenems. Others have reported successfully treating cases of Enterobacter meningitis with cefepime, intracisternal/intrathecal gentamicin, imipenem plus intrathecal amikacin, TMP-SMX plus gentamicin, and ciprofloxacin [1,2,6-8]. The design of our study may be subject to several criticisms. Most importantly, our results may be limited by the retrospective nature of the study. Unfortunately, however, the infrequent nature of this infection makes prospective evaluation very difficult, if not impossible. In addition, we are able to report only descriptive statistics; the small number of subjects in our study, in conjunction with the inherent complexity of the treatment regimens used in our subjects made meaningful statistical comparisons of outcomes associated with different therapeutic choices impossible. Finally, our results may reflect practice patterns and organism susceptibilities at our institution only. Each of these limitations is inherent in the study of an infrequent problem in a complex patient population. In summary, our study illustrates that Enterobacter meningitis is an infrequent complication of neurological insult. Treatment is often complicated by resistance of Enterobacter species to third-generation cephalosporins. Our results indicate that while third-generation cephalosporins are not the most appropriate choice of agents to treat Enterobacter meningitis, TMP-SMX may yield satisfactory results. References [1] D’Antuno VS, Brown I. Successful treatment of enterobacter meningitis with ciprofloxacin. Clin Infect Dis 1998;26:206 - 7 [letter]. [2] De Champs C, Guelon D, Joyon D, Sirot D, Chanal M, Sirot J. Treatment of a meningitis due to an Enterobacter aerogenes and a Klebsiella pneumoniae producing an extended spectrum b-lactamase. Infection 1991;19:181 - 3. [3] Heusser MF, Patterson JE, Kuritza AP, Edberg SC, Baltimore RS. Emergence of resistance to multiple beta-lactams in Enterobacter cloacae during treatment for neonatal meningitis with cefotaxime. Pediatr Infect Dis J 1990;9:509 - 12. [4] Huang CR, Lu CH, Chang WN. Adult Enterobacter meningitis: a high incidence of coinfection with other pathogens and frequent association with neurosurgical procedures. Infection 2001;29:75 - 9.
D.R. Foster, D.H. Rhoney / Surgical Neurology 63 (2005) 533 –537 [5] Levitz RE, Quintilani R. Trimethoprim-sulfamethoxazole for bacterial meningitis. Ann Int Med 1984;100:881 - 90. [6] Ralph ED, Behme RJ. Enterobacter meningitis—treatment complicated by emergence of mutants resistant to cefotaxime. Scand J Infect Dis 1987;19:577 - 9. [7] Rousseau JM, Soullie´ B, Villevielle T, Koeck JL. Efficacy of cefepime in postoperative meningitis attributable to Enterobacter aerogenes. J Trauma 2001;50:971 - 2 [letter]. [8] Saad AF, Farrar WE. Intracisternal and intrathecal injections of gentamicin in Enterobacter meningitis. Arch Intern Med 1974; 134:738 - 40. [9] Salter AJ. Trimethoprim-sulfamethoxazole: an assessment of more than 12 years of use. Rev Infect Dis 1982;4:196 - 236. [10] Wolff MA, Young CL. Antibiotic therapy for enterobacter meningitis: a retrospective review of 13 episodes and review of the literature. Clin Infect Dis 1993;16:772 - 7.
Commentary Gram-negative rod meningitis often results from head trauma or craniotomy that requires neurosurgical intervention. It is also seen in neonates. Enterobacter infection is also an uncommon cause of gram-negative bacterial meningitis in adult patients. Before the introduction of third-generation cephalosporins, successful therapy was difficult because of the absence of adequate CSF concentrations of the antibiotic being used. This fact resulted in the concomitant use of intrathecal antimicrobial therapy with aminoglycosides. With the effectiveness of third-generation cephalosporins, these problems appeared to have been overcome. However, as this article by Foster and Rhoney demonstrates, many species from the Enterobacteriaceae family contain chromosomally mediated inducible (class I) blactamases, which often cannot be detected by routine susceptibility testing. These include Enterobacter sp, Serratia sp, Citrobacter sp, indole-positive Proteus and Pseudomonas aeruginosa. These organisms contain class I enzymes that can be rapidly induced by second- or thirdgeneration cephalosporins, resulting in the production of large amounts of b-lactamase and consequent inactivation of the antimicrobial activity. This problem can be obviated by using such agents as imipenem, meropenem, chloramphenicol, TMP-SMX, ciprofloxacin, and cefepime, which are not susceptible to class I b-lactamases. The study by Foster and Rhoney supports this conclusion. The use of
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aminoglycosides in combination therapy may also prevent the overgrowth of resistant organisms. Finally, if a cephalosporin is selected to treat gramnegative rod meningitis, the disk approximation test can be helpful in screening isolates for the production of inducible class I b-lactamases. Lawrence A. Cone, MD, FACP Eisenhower Medical Center Rancho Mirage, CA 92270, USA The study by Foster and Rhoney sheds some light on the difficult subject of Enterobacter meningitis. They were able to gather, although in a retrospective study, a significant number of patients (n = 19) with an uncommon neurological infection. From their experience, adequate recommendations can be made on diagnostic and therapeutic procedures. Perhaps the most important contribution of this analysis is the high rate of therapeutic success using a quite old bacteriostatic agent, TMP-SMX. Interestingly, this drug is rarely used as a first-choice empirical treatment before bacterial identification; third-generation cephalosporins are usually used first. However, by far, the best results were obtained with TMP-SMX, as compared with cephalosporins and intrathecal aminoglycosides, which are the commonly used therapeutic agents in most centers. The results obtained by the authors are welcomed for two main reasons: first, because TMP-SMX seems to be equally effective against the three most frequent Enterobacter species that cause meningitis; thus, this drug can be proposed as the first choice for empirical treatment in suspected cases of Enterobacter meningitis; second, the low cost of TMP-SMX in comparison with newer antibiotics is not a trivial issue. Nowadays, most studies on therapeutic improvements imply a simultaneous skyrocketing increase in monetary costs, and it is refreshing to hear that occasionally, an old and cheaper drug works better than the new and expensive ones. A blind, prospective study comparing these drugs is desirable, although difficult to perform. Julio Sotelo, MD (General Director) Instituto Nacional de Neurologia y Neurocirugia Mexico City, 14269 Mexico