Listeria monocytogenes meningitis in an immunocompetent 18-year-old patient as a possible diagnostic and therapeutical problem Meningitis prouzrokovan bakterijom Listeria monocytogenes kod imunokompetentnog 18-godišnjeg bolesnika kao mogu dijagnosti ki i terapijski problem

Introduction. Listeria monocytogenes is the third most frequent cause of bacterial meningitis in adults. It commonly affects persons with defective cell-mediated immunity or advanced age, and only a few patiens with no underlying predisposition have been reported. Case report. We presented an previously healthy, 18-year-old man with typical clinical features of meningitis. On the account of earlier treatment with ceftriaxone and cerebrospinal fluid finding, an assumption of partially treated bacterial meningitis was made. The initial treatment with vancomycin and ceftriaxone, substituted on day 4 with meropenem, did not produce any clinical effect. On day 6 Listeria monocytogenes was isolated and, even as late as that, the administration of ampicillin was followed by complete recovery of the patient. Conclusion. In younger, immunocompetent individuals, in spite of the existent diagnostic and therapeutic problems, the subacute course of Listeria monocytogenes meningitis provides enough time for appropriate treatment and favorable disease outcome.


Introduction
Listeria monocytogenes (L.monocytogenes) is a Grampositive intracellular bacterium widespread in the natural environment.Nevertheless, it is not common human pathogen.It commonly causes infections in neonates and patients with defective cell-mediated immunity due to hematologic malignancy, organ transplatation, pregnency, chronic corticosteroid therapy, alcoholism and/or cirrhosis, renal diseases, advanced age, AIDS etc 1 .
Listeriosis in adults usually presents as meningitis (in over 30%) or meningoencephalitis (especially as rhombencephalitis) and occasionally as isolated cerebritis 2,3 .It is the third most common cause of acute bacterial meningitis, after Streptococcus pneumoniae and Neisseria meningitidis, with the frequency of 4% to 12% in different countries of the Northern hemisphere 1,[4][5][6] .However, among the immunocompetent persons below 50 years of age, L. monocytogenes meningitis is rare and has been reported only in a few patiens, but never in Serbia and neighboring countries 7,8 .

Case report
A previously healthy 18-year-old man with a 3-day history of fever, severe headache and vomiting was admitted to the clinic.For two days before, he was treated with ceftriaxone (2 g IV q24 h).
On examination, he was febrile (38.4 o C), adynamic, dehydrated, with heart rate of 95/min.There were neck stiffness, and positive signs of Kernig's and Brudzinski's.Other physical findings were normal.Initial laboratory investigations showed an elevated white blood cells (WBC) count of 21,600/mm 3 with 85% neutrophils and elevated C-reactive protein (CRP) content of 126.3 mg/L.Additional blood data were unremarkable.
The patient was initially treated with ceftriaxone (2 g IV, q12 h) and vancomycin (1 g IV, q12 h).On day 4 after admission the patients was still febrile.Marked meningeal syndrome was present, and computed tomography (CT) scan showed diffuse cerebral edema, in spite of already administered dexamethasone and mannitol.Ceftriaxone was replaced with meropenem (2 g IV, q8 h), without any significant clinical improvement in the next two days.
At the same time, the initial CSF was inoculated onto Columbia agar, chocolate agar and MacConkey agar plates and tube of thioglycolate broth.After incubation, only thioglycolate broth culture was positive.Broth was subcultured to Columbia and chocolate agar plates and bacterial growth was seen on both media.Gram stain of the isolate demonstrated Gram-positive rods with coryneform appearance.The microorganism was identified as L. monocytogenes by Vitek 2 System (BioMerieux, France).It was sensitive to ampicillin minimum inhibitory concentration (MIC 0.125 g/mL), cotrimoxazole (MIC 0.125 g/mL), meropenem (MIC 0.064 g/mL), chloramphenicol (MIC 0.125 g/mL), gentamicin (MIC 0.064 g/mL), and vancomycin (MIC 0.73 g/mL).
After L. monocytogenes isolation on day 6, the treatment with ampicillin was initiated (2 g IV, q4 h).The day after, the patient was afebrile and the signs of meningeal syndrome started to resolve.A week after the treatment with ampicillin started, CSF analysis revealed 40 WBC per mm 3 (12.5% neutrophils and 87.5% lymphocytes), proteins of 0.34 g/L and glucose of 3.2 mmol/L (glycemia 5.7 mmol/L).Control CT scan was normal.After three weeks of the treatment with ampicillin, the patient was fully recovered and discharged from the clinic.
In addition, the result of the serum human immunodeficiency virus test was negative.CD4 lymphocyte count was 685 per mm 3 with CD4/CD8 ratio of 1.35.Further laboratory investigations failed to confirm any immunological abnormalities in the course of hospitalization and subsequent 6month follow-up.

Discussion
Bacterial meningitis is one of the most dramatic conditions in medicine, with the mortality rate of up to 30% 6 .The precondition of favorable outcome of the disease is early administration of adequate antimicrobial therapy, which usually implies an empirical treatment 9 .Recommended primary regimens for community-acquired bacterial meningitis in adults consists of ceftriaxone or cefotaxime plus vancomycin, with the addition of ampicillin 2 g IV, q4 h in the circumstances suggesting possible L. monocytogenes origin of the infection, e.g.age 50 years or alcoholism or other debilitating associated diseases or impaired cellular immunity 10,11 .
Immune suppression or advanced age were present in all 30 patients described by the first prospective study of community-acquired L. monocytogenes meningitis in adults.Otherwise, the patients presented with signs and symptoms that were not different from those found in the general population with bacterial meningitis, and the majority (77%) had at least 1 individual CSF finding indicative of acute bacterial meningitis 12 .
Furthermore, Gram-staining of CSF specimens is negative in over two-thirds of L. monocytogenes meningitis episodes, and can be misleading in many of the remaining cases (resembling pneumococci or diphtheroids).Besides, L. monocytogenes may be difficult to culture in initial isolation during the time-consuming process of its microbiologic identification 13 .
Again, in a large literature review including all case series and case reports, young previously healthy adults constitute only 6% of patients with L. monocytogenes meningitis 14 .Without any apparent underlying predisposition to infection, this group of patients represents a real diagnostic problem, especially in terms of an appropriate empiric therapy.
The presented patient was a student, with nonsignificant medical history, with excluded HIV infection or any other apparent reason for immune suppression.As usual, there were no epidemiologic clues suggesting L. monocytogenes infection, which was mostly sporadic and food-borne by numerous types of food 15,16 .
In these circumstances, the derived CSF finding (fewer WBC, lower percentage of polymorphonuclear leukocytes, lower protein concentrations and less hypoglycorrhachia), although suggestive of L. monocytogenes meningitis, was interpreted as the result of bacterial meningitis previously partially treated with ceftriaxone.Such a miscalculation in patient management could have been expected, in view of a longer prodromal phase and subacute disease course 3,14,17 .
The treatment was initiated with cephalosporin (to which L. monocytogenes was innately resistant) and vancomycin (with proven ineffectivity in vivo against listeriosis) 17,18 .Favorable results were not obtained either after the replacement (though for a short period of time) of cephalosporin with meropenem, as a possible therapeutical alternative for L. monocytogenes meningitis, though with a variable clinical experience 19,20 .Moreover, cerebral edema has been reported as a possible serious complication, and an important cause of death in bacterial meningitis.
Even with appropriate antibiotic therapy, as a predominant infection of older and immunocompromised patients, mortality due to L. monocytogenes meningitis is among the highest (28%) of all causes of acute bacterial meningitis 21 .However, in the case here reported, previously healthy, immunocompetent 18-year-old patient was successfully cured with ampicillin (the medicament of choice in the treatment of L. monocytogenes meningitis), although its administration was significantly delayed to the moment of microbiologic identification of the causal pathogen.

Conclusion
L. monocytogenes is one of the most common causes of bacterial meningitis in immunocompromised or elderly patients.In younger, previously healthy individuals, the infection is extremely rare, and presents a diagnostic and therapeutic challenge.However, in these circumstances (as in the presented case), the subacute course of L. monocytogenes meningitis provides enough time for the initial treatment correction and favorable disease outcome.