Campylobacter Fetus Meningitis in Adults

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INTRODUCTION
B acterial meningitis is a severe infectious disease requiring prompt antibiotic treatment. Most cases are caused by Neisseria meningitidis and Streptococcus pneumoniae, which are both part of the commensal nasopharyngeal flora in humans. 1 Bacterial meningitis is rarely caused by bacteria having their natural reservoir in animals. One of these so-called zoonotic pathogens is Campylobacter fetus (formerly Vibrio fetus, Spirillum serpens), which is part of the commensal flora in the gastro-intestinal tracts of sheep and cattle. 2 C fetus meningitis occurs worldwide, but little is known about its clinical characteristics, predisposing factors and outcome. We report 2 cases of C fetus meningitis from a nationwide cohort of bacterial meningitis patients in the Netherlands. Additionally, we performed a review of the literature on C fetus meningitis.

METHODS
We included patients with community-acquired bacterial meningitis in a nationwide prospective cohort study in the Netherlands between January 2006 and May 2015. Methods have been described previously. 1 Patients were listed in the database of the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM), which receives > 90% of the cerebrospinal fluid (CSF) isolates of all adult patients (>16 years) with CSF culture confirmed bacterial meningitis. The NRLBM provided daily updates of the hospitals where the patients were admitted and the patients' physicians, who were subsequently contacted. Physicians could also include patients without report of the NRLBM. Written informed consent was obtained from all patients or their legally authorized representatives. The study was approved by the medical ethical review board of the Academic Medical Center, Amsterdam, The Netherlands.
From the cohort, we selected patients with C fetus meningitis. Additional information on risk factors was retrospectively collected from the discharge letters. Patients were considered immunocompromised if they had cancer, diabetes mellitus, alcoholism, asplenia, HIV-infection, or use of immunosuppressive medication. 1 Individual predictive factors in the cerebrospinal fluid were defined as follows: a glucose level of <34 mg/dL (1.9 mmol/L), a ratio of CSF glucose to blood glucose of <0.23, a protein level of >220 mg/dL, or a leukocyte count of >2000/mL (Spanos criteria). 3

Review of the Literature
We performed a literature search using the search terms ''Campylobacter fetus AND meningitis,'' ''Vibrio fetus AND meningitis,'' and ''Spirillum serpens AND meningitis.'' Studies written in English, German, French, Dutch, Spanish, Italian, and Portuguese were included. Articles describing animals and articles describing children were excluded. We also excluded articles in which no subanalysis for C fetus meningitis cases was performed, or when no clinical characteristics were described. Additional studies were identified by cross-checking references.
In a meta-analysis of clinical data we systematically scored clinical presentation, predisposing factors, ancillary investigations, and outcome. Differences between groups were calculated by means of Fisher's Exact Test.

Case Reports in Prospective Nationwide Cohort Study
Two patients with C fetus meningitis were identified in our nationwide cohort consisting of 1732 patients (0.1%). The calculated annual incidence of C fetus meningitis in the Netherlands was 0.02 per 1,000,000 adults.

CASE 1
A 23-year-old woman presented at the emergency department with fever, headache, and earache since 4 weeks and severe neck pain since 3 days. She was previously healthy and had been in regular contact with horses, dogs, rabbits, and guinea pigs. Physical examination showed fever and neck stiffness but no other abnormalities. Blood laboratory examination was normal. CSF examination was consistent with meningitis (Table 1) and the patient was treated with amoxicillin, ceftriaxone, and acyclovir. Cultures became positive for C fetus subspecies fetus after 9 days. Amoxicillin and acyclovir were discontinued and ceftriaxone was continued for 2 weeks. The patient was discharged, but mild vertigo and a decreased sense of smell remained. One week after discharge, the patient presented with a subfebrile temperature (38-38.58C) and headache. Repeated CSF examination was consistent with meningitis (Table 1). Despite prolonged treatment with meropenem, the patient's complaints lasted for a total of 4 weeks. Extensive ancillary investigations did not reveal any underlying illness. The patient was not able to resume her studies due to persisting fatigue and cognitive defects.

CASE 2
A 52-year-old previously healthy farmer presented at the emergency department with headache and fever since 10 days and a stiff neck since 2 days. Physical examination showed fever and neck stiffness. Blood laboratory examination showed 11.9 Â 10 9 leukocytes/L and a C-reactive protein of 206 mg/L. CSF examination was consistent with meningitis ( Table 1). The patient was treated with ceftriaxone and amoxicillin for 2 weeks and received adjunctive dexamethasone 10 mg 4 times a day for 4 days. CSF and blood cultures were positive for C fetus subspecies fetus. The patient was discharged in good clinical condition, but after a week, he came back to the hospital because of recurrent headache and fever. Physical examination showed fever but no other abnormalities. Blood laboratory examination showed 10.8 Â 10 9 leukocytes/L, and CSF examination was consistent with bacterial meningitis (Table 1). CSF cultures were not repeated. The patient was treated with meropenem for 3 weeks and fully recovered.

Review of the Literature
We identified a total of 18 relevant articles published between 1960 and 2013 ( Figure 1)  mellitus in 6, use of immunosuppressive medication in 2, and leukemia and asplenia in 1 patient each. The source of infection was identified in 13 out of 19 patients (68%, 95% CI 47-89%) and consisted of frequent contact with domestic animals in 5 patients (38%, 95% CI 12-64%), working on a farm in 4 (31%, 95% CI 10-52%), frequent contact with rats in 3, consuming raw meat in 2, and working in an abattoir and chewing khat in an animal sanctuary in 1 patient each (Table 1). One patient cared for sick animals before developing meningitis. 20 Both an immunocompromised state and an identified source of infection were present in 7 out of 19 patients (37%, 95% CI 15-59%).
Antibiotic treatment was highly diverse and the primary antibiotic treatment mainly consisted of beta-lactam antibiotics, such as penicillin (between 1960 and 1970), amoxicillin, ampicillin, and ceftriaxone (from 1985 onwards). In 11 patients (50%, 95% CI 29-71%), the antibiotic treatment was altered after the cultures became positive for C fetus. The duration of antibiotic treatment was reported in 9 patients: 7 patients were treated for 4 weeks, 1 patient for 5 weeks (case 2), and 1 patient for 6 weeks (case 1).
Including our 2 patients, 4 out of 22 patients (18%, 95% CI 2-34%) had persisting or recurrent fever and headache, for which they were readmitted to the hospital for antibiotic treatment. 8,18 In 1 patient, the isolated C fetus strain was resistant to the prior administered antibiotics (penicillin), and repeated blood and CSF cultures remained positive until another  antibiotic agent (tetracycline) was administered. 18 However, in the other 3 patients, the C fetus isolate was susceptible to the antibiotics administered during the first admission (ceftriaxone and amoxicillin in 2 and cefotaxime and vancomycin in 1). After a 3-week treatment with meropenem (2 cases) and ofloxacin and gentamicin (1 case), fever and headache disappeared. In 2 of these 3 patients (case 1 and case 2), no new cultures were performed before this treatment, and in the other patient, new CSF and blood cultures remained negative. 8

DISCUSSION
Meningitis caused by C fetus is a rare disease, which is associated with an immunocompromised state. Nine patients diagnosed with C fetus meningitis had a previous history of alcoholism, and 5 patients had diabetes mellitus. Alcoholism and diabetes mellitus are both risk factors for bacterial meningitis 22 and have been associated with a high rate of unfavorable outcome. 23,24 Cancer has been reported to be a risk factor for C fetus bacteremia, 25 but was only present in 1 patient with C fetus meningitis.
Although C fetus is a zoonotic pathogen, contact with animals or animal products could only be identified in 68% of patients with C fetus meningitis. In most patients in whom a source of infection was identified, frequent contact with domestic animals was reported to be the source of infection (38%). However, $164 million American households have domestic animals, 26 implying that the risk at developing C fetus meningitis after frequent domestic animal contact is very low.
CSF abnormalities were present in all patients with C fetus meningitis. However, only 53% of the cases had at least 1 individual CSF predictor for bacterial meningitis, 3 as compared to 88% of the patients with community-acquired bacterial meningitis in a large prospective cohort study. 27 Furthermore, CSF cultures were negative in 23% of the C fetus meningitis cases, whereas blood cultures were positive. As blood cultures were positive in 86% of all cases, they can therefore be useful to confirm the diagnosis of C fetus meningitis in the case of CSF abnormalities and a negative CSF culture. When C fetus meningitis is suspected but cultures remain negative, PCR targeting 16S rRNA encoding gene sequencing followed by sequencing of the PCR product may provide the diagnosis. 28 C fetus has been described to be resistant to several antimicrobial agents. In a multicenter study of 25 isolates of C fetus ssp. fetus recovered from blood and synovial fluid samples, a significant proportion of isolates was interpreted as intermediate or resistant to ampicillin (12%), cefotaxime (80%), and erythromycin (100%). 29 Several case reports describe human C fetus isolates resistant to ceftriaxone, 30 cefotaxime, 4,7,8 and penicillin. 8,12 In C fetus, the genes tet(44) and ant(6)-lb have been associated with resistance to tetracycline, minocycline, and streptomycin. 31 Other genes may play a role in reduced susceptibility of C fetus for antimicrobial agents which are commonly used for the treatment of bacterial meningitis, such as ceftriaxone. 32 In our study, 4 patients were known to be readmitted to the hospital because of persisting fever and CSF abnormalities, and received prolonged treatment with antibiotics, although the C fetus isolate was sensitive to the primarily received antibiotics in 3 of these cases. There might even be some cases where the patients might have persisting or recurrent fever but not readmitted to the hospital for treatment. Relapsing and persisting infection have also been reported in other manifestations of C fetus. 33 This is interesting and suggests inconsistency between the in vivo and in vitro susceptibility of C fetus. However, as repeated cultures remained negative in most cases, it is also possible that the recurrent clinical parameters are a postinfectious syndrome or inflammatory response. Nevertheless, cases appeared to do best with carbapenem therapy. Based on the apparent slow clinical response seen in this limited number of cases, the authors of this study recommend a prolonged course of antimicrobial therapy when C fetus is identified as a causative agent of bacterial meningitis. 28 Our study had several limitations. First, only patients with a positive CSF culture were included. In our literature review, 23% of the patients had a negative CSF culture, which means we could have missed cases of C fetus meningitis. Second, patients may not have undergone a lumbar puncture due to spaceoccupying lesions on cranial CT or coagulation problems. Furthermore, we did not include neonates with C fetus meningitis, as predisposing factors, etiology, and clinical characteristics in neonates are not comparable to those in adults. Also, specific characteristics of interest were not always available in the retrieved case-reports included in our meta-analysis. Therefore, we reported the number of patients in who the specific characteristic was known.
Finally, the recommendations that can be made are limited by small numbers of affected patients.
In conclusion, C fetus is a rare cause of bacterial meningitis and is associated with an immunocompromised state. Based on the apparent slow clinical response seen in this limited number of cases, the authors of this study recommend a prolonged course of antimicrobial therapy when C fetus is identified as the causative agent of bacterial meningitis. Cases appeared to do best with carbapenem therapy.