|Year : 2012 | Volume
| Issue : 2 | Page : 242-245
Fatal meningitis caused by vancomycin-resistant enterococci: Report of two cases from south India
I Praharaj, S Sujatha, SC Parija, MS Gopalakrishnan
Department of Microbiology and Neurosurgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
|Date of Submission||07-Jan-2012|
|Date of Acceptance||15-Mar-2012|
|Date of Web Publication||28-May-2012|
Department of Microbiology and Neurosurgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006
Source of Support: None, Conflict of Interest: None
Vancomycin-resistant enterococci rarely cause meningitis and present a therapeutic challenge. Antimicrobial susceptibility testing was done for strains of Enterococcus species isolated from CSF samples of patients with meningitis by phenotypic methods. Multiplex polymerase chain reaction was performed to determine the genetic basis of vancomycin resistance of such isolates. We report here two cases of enterococcal meningitis caused by vancomycin-resistant Enterococcus species. One of the isolates was identified as Enterococcus faecalis and the other as Enterococcus gallinarum. We also report the simultaneous presence of vanC1 and vanA resistance genes in the strain of E. gallinarum. To the best of our knowledge, this is the first report of vanA resistance gene in an isolate of E. gallinarum from the Indian subcontinent. This is also the first Indian report of vancomycin-resistant Enterococcus causing meningitis.
Keywords: Enterococcus, multiplex PCR, meningitis, resistance, vancomycin
|How to cite this article:|
Praharaj I, Sujatha S, Parija S C, Gopalakrishnan M S. Fatal meningitis caused by vancomycin-resistant enterococci: Report of two cases from south India. Indian J Med Microbiol 2012;30:242-5
|How to cite this URL:|
Praharaj I, Sujatha S, Parija S C, Gopalakrishnan M S. Fatal meningitis caused by vancomycin-resistant enterococci: Report of two cases from south India. Indian J Med Microbiol [serial online] 2012 [cited 2019 Sep 19];30:242-5. Available from: http://www.ijmm.org/text.asp?2012/30/2/242/96713
| ~ Introduction|| |
Enterococcus species are unusual etiologic agents of bacterial meningitis and are responsible for 0.3%-4% of all meningitis cases.  Most cases of enterococcal meningitis have been reported in adults who have undergone some neurosurgical procedure. However, a few cases of spontaneous meningitis have also been reported in patients with some comorbid conditions such as diabetes, malignancies, or immunosuppression. Enterococcus meningitis has been described in the setting of Strongyloides stercoralis hyperinfection.  The commonest species of Enterococcus isolated from cases of meningitis is Enterococcus faecalis. Other species such as E. faecium, Enterococcus casseliflavus and Enterococcus gallinarum e also been reported from CSF samples. , Meningitis caused by vancomycin-resistant Enterococcus (VRE) is quite rare and is a therapeutic challenge as there are very few antimicrobials effective against these organisms. Optimal therapy for VRE and meningitis due to VRE has not yet been established. Antimicrobial agents such as chloramphenicol and linezolid have been used to treat patients with VRE meningitis. Zeana et al. described a case of VRE meningitis in a patient with Strongyloides stercoralis hyperinfection which was successfully managed with linezolid.  Linezolid is an oxazolidinone with good CSF penetration and has the advantage of being available in oral formulations. It has been used in quite a few cases of VRE meningitis although there have been a few reports of clinical failure of linezolid treatment in cases of postneurosurgical meningitis. ,
| ~ Case Reports|| |
A 48-year-old lady who had undergone retromastoid craniotomy and total excision of a right vestibular schwannoma presented with high-grade fever, vomiting, and headache 1 week after being discharged. In the immediate postoperative period, the patient had developed a CSF leak which was managed with resuturing and lumbar CSF drainage. Multiple lumbar punctures were done and the CSF analysis revealed a high polymorphonuclear cell count, low glucose, and increased protein levels. However, no organism could be isolated on gram staining and bacteriological culture. A diagnosis of chemical meningitis was made, and the patient was discharged on a dose of steroids which was to be later tapered. One week after she was discharged, the patient presented with headache, vomiting, and high grade fever. On examination, the patient was found to have an oral temperature of 39°C and was disoriented to time, place, and person. Pulse rate was 90/min and blood pressure was 110/80 mmHg. A computed tomography (CT) scan of the brain showed a small area of enhancement posterior to the petrous bone but no definite abscess or empyema formation. A lumbar puncture was done and the CSF analysis revealed a white cell count of 560 cells/μl with 95% neutrophils and 5% lymphocytes. Gram staining of the CSF showed plenty of pus cells but no bacteria. Bacteriological culture showed no growth after 48 hours. On the third day, turbidity was observed in the brain heart infusion (BHI) broth inoculated with the CSF sample. Subculture onto solid media such as blood agar and chocolate agar yielded E. faecalis which was identified following the Facklam and Collins scheme of identification.  The isolate was found to be resistant to ampicillin, ciprofloxacin, gentamicin, vancomycin. and teicoplanin. Minimum inhibitory concentration (MIC) testing was performed for vancomycin and teicoplanin by agar dilution method and the particular isolate was found to have MIC of more than 128 μg/ml for both vancomycin and teicoplanin. The isolate was, however, found to be sensitive to linezolid, tetracycline, and chloramphenicol by disk diffusion. A repeat sample received from the patient also grew E. faecalis with a similar susceptibility pattern. This isolate was obtained directly from the CSF sample and not from the BHI subculture.
The patient was started on ampicillin and gentamicin and was subsequently administered linezolid after the susceptibility test results. Patient was treated with 600 mg of i.v. linezolid every 12 hours. Steroids, which were started initially for a presumed diagnosis of chemical meningitis, were stopped. The febrile spikes subsided and the patient showed considerable clinical improvement. CSF sample sent after 21 days of treatment with linezolid, ampicillin, and gentamicin was also found to be sterile. The patient was discharged after 1 month of antimicrobial treatment.
However, the patient was again admitted after 1 month with chief complaint of paroxysmal headache. A clinical diagnosis of postmeningitis hydrocephalus was made and she underwent lumboperitoneal shunt after ensuring that lumbar CSF was sterile. However, she again developed fever, headache, and drowsiness. Fearing CSF infection, the lumboperitoneal shunt was exteriorized. CSF was initially turbid with pus cells, but there were no bacteria. Culture was sterile. Partial blockade of the shunt with reactive CSF pleocytosis was considered to be the reason for the symptoms and the drainage tube was removed. CSF was tested multiple times to rule out partially treated meningitis. During this period, the patient was also empirically treated with linezolid, metronidazole, amikacin, and ceftriaxone. Unfortunately, while waiting for emergency ventriculoperitoneal shunt surgery, she had sudden neurological deterioration and expired.
A 70-year-old man presented with fever, headache, and vomiting. The patient had no history of any intracranial or neurosurgical interventions in the past. He, however, had a history of left subtotal chronic suppurative otitis media (CSOM) which had been treated with topical antibiotics (ciprofloxacin and gentamicin ear drops). The patient was disoriented to time, place, and person and had a Glasgow Coma Score of 4. On admission, the patient had an axillary temperature of 38°C, pulse rate 88/min, BP 110/70 mmHg, and was tachypneic (respiratory rate 42/min).There was no neck stiffness or any other signs of neck rigidity. The patient had no history of prior hospitalization for any considerable period of time. A presumptive diagnosis of meningitis was made and the patient was hospitalized. The patient deteriorated rapidly and bilateral crepitations were heard on auscultation of the chest. The patient was put on ventilator and was treated with vancomycin, metronidazole, and ceftriaxone in the intensive care unit. After about 10 days of treatment, the patient developed features of sepsis and the condition of the patient rapidly deteriorated in spite of the antibiotics being administered. However, blood culture was found to be sterile. CSF culture yielded E. gallinarum which was identified based on bile-esculin hydrolysis, 6.5% NaCl tolerance, heat tolerance, PYR test, motility. and the absence of yellow pigment. This particular isolate was found to be resistant to ampicillin, ciprofloxacin, tetracycline. and gentamicin (high-level resistance). The isolate was also found to be resistant to the glycopeptides vancomycin and teicoplanin. The patient died within one day of isolation of VRE from CSF before the antibiotics could be changed based on the susceptibility report. The isolate was found to have high-level resistance to vancomycin and teicoplanin. MIC of both vancomycin and teicoplanin was found to be more than 128 μg/ml by the agar dilution method. Later, multiplex polymerase chain reaction (PCR) was carried out on the isolate to detect vancomycin resistance genes using appropriate primers.  Rapid alkaline lysis method was used followed by phenol chloroform extraction for DNA extraction. 
The primers used for the genotypic characterization of the vancomycin-resistant strain of Enterococcus were the ones from Dutka-Malen et al., 1995.  Primers were supplied by Sigma Aldrich.
The following pairs of primers were used.
vanA A1 5´-GGGAAAACGACAATTGC-3´
vanB B1 5´-ATGGGAAGCCGATAGTC-3´
vanC-1 C1 5´-GGTATCAAGGAAACCTC-3´
vanC2/C3 D1 5´-CTCCTACGATTCTCTTG-3´
The set of primers used for detecting the 16S rRNA in the extracted DNA was included in order to have an internal control. The sequence used was taken from Kariyama et al., 2000.  Multiplex PCR was carried out and the PCR products were resolved by agarose gel electrophoresis followed by gel documentation. A negative control was included containing all the constituents of the reaction except the DNA.
The isolate was found to possess both the vanC1 gene (822 bp genetic element) as well as the vanA gene (732 bp genetic element).  PCR amplicons were custom sequenced to confirm the identity of the vanA gene cluster and the vanC1 gene responsible for glycopeptide resistance (Macrogen Inc, Seoul, South Korea).
| ~ Discussion|| |
Enterococcal infections of the central nervous system are quite rare. Most of the cases of enterococcal meningitis reported till date have been in patients with some underlying disorders. Many of these patients have history of some neurosurgical procedures, immunosuppression, or prolonged antibiotic therapy. ,,
The first case of VRE meningitis described here is a case of postoperative meningitis in a patient who underwent craniotomy for excision of an acoustic schwannoma and had a postoperative CSF leak. Vancomycin-resistant E. faecalis was isolated on two separate occasions from the CSF of this patient. The patient was managed with linezolid and showed considerable improvement after starting therapy. Of the various antimicrobial agents used for the treatment of VRE meningitis, chloramphenicol and linezolid have been shown to have good CSF penetration and concentration even in the absence of inflamed meninges.  However, chloramphenicol is not commonly used because of the side effects associated with it. There have been case reports in which i.v. chloramphenicol has not been able to sterilize the CSF and has resulted in poor clinical outcome.  A recent report from Germany. however, demonstrated a beneficial outcome after using combination of i.v. and intrathecal chloramphenicol in a pediatric case of VRE ventriculitis after failure of i.v. linezolid therapy.  Linezolid, due to its excellent bioavailability in CSF and the fact that it can be administered orally also, has emerged as a good choice for treatment of cases of VRE meningitis. Our patient responded to linezolid therapy which was started after the initial culture reports and all subsequent CSF cultures were found to be sterile. However, the patient was later admitted for postmeningitis hydrocephalus and succumbed to sudden neurological deterioration while waiting for emergency surgery. Hydrocephalus developed most probably as sequelae of postoperative meningitis. About 17% of all meningitis cases due to Enterococcus result in neurological sequelae. Hydrocephalus, stroke, and brain abscesses have been reported as sequelae of enterococcal meningitis.  Our patient presented with postmeningitis hydrocephalus and that is the most probable cause of death in this case. Since none of the CSF cultures in this period yielded VRE and all were found to be sterile, this was most probably not a case of treatment failure with linezolid. Failure of linezolid treatment for postneurosurgical enterococcal meningitis has been described even when the Enterococcus strain showed in vitro susceptibility to linezolid.  Such cases of treatment failure are most probably due to inadequate penetration of linezolid into CSF.
The second case of VRE meningitis described was a 70-year-old man with no evident predisposing factors for VRE meningitis. The patient had not undergone any neurosurgical procedure and was not on any antibiotic therapy at the time of admission to the hospital. VRE was isolated after 10 days of stay in the medicine intensive care unit. Although most cases of meningitis due to motile enterococci have been reported in patients with some history of neurosurgical procedures, there are a few reports of meningitis due to E. gallinarum in patients with no predisposing factors.  The isolate was identified as E. gallinarum based on biochemical tests and showed high-level resistance to the glycopeptides, vancomycin, and teicoplanin. Motile Enterococcus species such as E. gallinarum and E. casseliflavus usually show low degree of intrinsic resistance to vancomycin (MIC≤16 μg/ml) and are sensitive to teicoplanin. The high degree of glycopeptide resistance seen in the particular strain of E. gallinarum could be explained after the detection of vanA gene along with the vanC1 gene in the strain by multiplex PCR. There are very few reports of meningitis caused by motile Enterococcus species and most of these strains show low level intrinsic resistance to vancomycin. ,
The presence of both vanA and vanC1 genes in the strain of E. gallinarum changed its phenotype and conferred high-level glycopeptide resistance to it. Motile enterococci such as E. gallinarum show intrinsic low-level vancomycin resistance which is not transferable. Their detection in a patient is usually not considered an indication for strict isolation precautions for the patient. However, the evidence that these organisms can take up other resistance genes (vanA gene in this case) which not only make them highly resistant to glycopeptides but also make them capable of spreading this resistance to other Enterococcus strains, makes the detection and control of these organisms important. To the best of our knowledge, this is the first report of coexistence of vanA and vanC1 genes in an isolate of VRE from the Indian subcontinent.
The overall mortality rate for VRE meningitis has been found to approach 20%.  Both the patients of VRE meningitis described here expired. The patient with postneurosurgical meningitis showed improvement with intravenous linezolid therapy but eventually succumbed to postmeningitis hydrocephalus. The second case expired most probably due to lack of appropriate treatment for VRE in time. Such high mortality rates for VRE meningitis have been described only in the presence of other poor prognostic factors such as advanced age, respiratory failure, and seizures.
In conclusion, VRE meningitis is a relatively uncommon clinical condition associated with significant mortality and postmeningitis sequelae if not detected and treated in time. Most cases of VRE meningitis are seen in patients who have undergone neurosurgical procedures. Apart from the common species of E. faecalis and E. faecium, motile species of Enterococcus like E. gallinarum and E. casseliflavus can also cause meningitis. It is important to keep these species of Enterococcus in mind while dealing with cases of enterococcal meningitis as these species are intrinsically vancomycin-resistant and vancomycin will not be effective against them in vivo even if in vitro tests indicate otherwise. Linezolid has emerged as an effective option for treatment of VRE meningitis.
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