Central nervous system infections due to Abiotrophia and Granulicatella species: an emerging challenge?

Diagnostic Microbiology and Infectious Disease 48 (2004) 161–165

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Bacteriology

Central nervous system infections due to Abiotrophia and Granulicatella species: an emerging challenge? Elizabeth Cerceoa, Jason D. Christieb,c,d, Irving Nachamkine, Ebbing Lautenbachc,d,f,* b

a University of Medicine and Dentistry of New Jersey, Newark, NJ 07107-3000, USA Department of Medicine, Division of Pulmonary and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA c Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA d Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA e Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA f Department of Medicine, Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA

Received 12 August 2003; accepted 6 October 2003

Abstract Although Abiotrophia and Granulicatella species, previously referred to as nutritionally variant streptococci, were initially identified over 40 years ago, isolation of these pathogens from the central nervous system (CNS) was first noted only recently. Recognition of CNS involvement with these organisms is of great concern given the association of Abiotrophia/Granulicatella infections with increased morbidity and mortality as well as greater bacteriologic failure and relapse rates. We describe A. defectiva and G. adiacens CNS infections in two patients and review the existing literature of CNS involvement with these bacteria. The clinical presentation and initial cerebrospinal fluid analysis has varied substantially across reported patients. While most infections have been characterized primarily by a localized infection (e.g., abscess), evidence of meningitis has usually also been present. Furthermore, nearly all cases have followed neurosurgical procedures suggesting possible introduction of the organism into the CNS at the time of surgery. Given the significant negative clinical impact of Abiotrophia/Granulicatella infections, elucidation of the emerging epidemiology of CNS infections with these bacteria is warranted. © 2004 Elsevier Inc. All rights reserved. Keywords: Abiotrophia; Granulicatella; Central nervous system; Infection; Focal infection

1. Introduction Abiotrophia and Granulicatella species, first described as nutritionally variant (deficient) streptococci in 1961 (Frenkel and Hirsch, 1961), were originally discovered as small satellite colonies around coagulase-negative bacteria or with supplementation of complex media with cysteine or pyridoxal (Carey et al., 1975). Taxonomic studies of the Abiotrophia spp. concluded that this group of organisms should be reclassified separately into Abiotrophia defectiva and Granulicatella adiacens, G. balaenopterae, and G. elegans (Collins and Lawson, 2000). Although Abiotrophia/ Granulicatella are part of the normal flora of the oral cavity, the genitourinary tract, and the intestinal tract, the pathogenic potential of these organisms has been well established. They have been estimated to cause approximately * Corresponding author. Tel.: ⫹1-215-898-6977; fax: ⫹1-215-573-5315. E-mail address: [email protected] (E. Lautenbach). 0732-8893/04/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2003.10.009

5-6% of microbiologically proven cases of endocarditis (Roberts et al., 1979), and have likewise been implicated in the pathogenesis of culture-negative endocarditis (Roggenkamp et al., 1998). In addition, Abiotrophia/Granulicatella have been reported as etiologic agents of postpartum or postabortal sepsis, pancreatic abscess, wound infection, vertebral osteomyelitis or discitis, conjunctivitis, cirrhosis, endophthalmitis, infectious crystalline keratopathy, and otitis media (Namdari et al., 1999; Ormerod et al., 1991; Gephart and Washington, 1982; Ruoff, 1991). While Abiotrophia/Granulicatella were initially identified over four decades ago, isolation of these pathogens from the central nervous system (CNS) was first noted only in 1999 (Biermann et al., 1999). Since that time, two additional cases of CNS infection have been reported (Michelow et al., 2000; Schlegel et al., 1999). We now describe the isolation of A. defectiva and G. adiacens from the CNS in two patients with recent neurosurgical interventions. We also review the existing literature of CNS involvement with

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Table 1 Summary of reported cases of neurological infections with Abiotrophia/Granulicatella species Author (year)

Cerceo (2003)

Cerceo (2003)

Schlegel (1999)

Michelow (2000)

Biermann (1999)

Age Underlying Conditions

32 Ethmoid sinus carcinoma Craniotomy with resection of ethmoid sinus carcinoma

53 SAH secondary to MCA aneurysm Clipping of middle cerebral artery aneurysm and VP shunt placement 11 days 100.5°F Disorientation

49 Lower back pain

2.5 Downs syndrome

46 Recurrent astrocytoma

CT-guided myelography with injection of contrast medium 4 days 99.5°F “Severe signs of meningitis”

None

Excision of recurrent astrocytoma

Meningitis/Brain abscess WBC ⫽ 630/mm3 (78% PMNs) Glucose ⫽ 53 mg/dL Protein ⫽ 190 mg/dL

Meningitis

Not applicable 104.0°F Lethargy Nausea/vomiting Diarrhea Brain abscess

60 days Afebrile Headache Nausea/ Vomiting Stiff neck Brain abscess

WBC 6940/mm3 (81% PMNs; 15% bands) Glucose ⬍20 mg/dL Protein ⫽ 505 mg/dL RBC ⫽ 250/mm3 CSF GS: gram-positive cocci in pairs and chains CX: G. adjacens

Not reported

Prior Neuro-surgical Procedures

Incubation* Temperature Signs/Symptoms

Primary Infection CSF Profile (on day of first positive culture)

Culture results

6 days 101.3°F Frontal headache Chronic nasal obstruction Meningitis/Epidural abscess WBC ⫽ 250/ mm3 (93% PMNs) RBC-7050/␮L Glucose ⫽ 89 mg/dL Protein ⫽ 67 mg/dL

WBC ⫽ 320/ mm3 (90% PMNs) Glucose ⫽ 3 mM Protein ⫽ 55mg/dL

CSF GS: rare WBCs, no bacteria

CSF GS: few gram positive cocci

CSF GS: no bacteria

CSF: no growth

Culture: few A. defectiva Wound CX: few A. defectiva

CX: A. defectiva

Epidural collection GS: rare WBCs, no bacteria CX: moderate G. adjacens Antibiotic susceptibility

Penicillin (MIC 12.00ug/mL) Vancomycin (MIC 2.00 ug/mL)

Penicillin (MIC 0.047ug/mL) Vancomycin (MIC 3.00ug/mL)

Penicillin (MIC 0.032ug/mL) Cefotaxime (MIC 0.75ug/mL) Vancomycin (MIC 2.00ug/mL)

Treatment (based on final susceptibility data)

Penicillin (28 d) Gentamicin (14 d)

IV Penicillin (28 d) Gentamicin (28 d)

Outcome

Stable 17 months after discharge

Stable 8 weeks after discontinuation of antibiotics

Vancomycin (10 d) Fosfomycin (10 d), then Cefixine (10 d) Rifampin (10 d) Stable 2 weeks after discontinuation of antibiotics

Penicillin (MIC 0.06ug/mL) Cefotaxime (MIC 0.125ug/mL) Clindamycin (MIC 0.064ug/mL) Vancomycin (MIC 2.00ug/mL) Ampicillin (32 d) Rifampin (32 d) Gentamicin (7d) Recurrent seizures; Persistent sequelae (i.e., left hemiplegia, hypo-tonia) 8 weeks after diagnosis

Abscess GS: ⫹ PMNs; no bacteria CX: no growth CSF GS: gram variable cocco-bacilli CX: no growth; G. adjacens identified by PCR Not available

Ceftriaxone (10 d) Gentamicin (10 d)

Discharged from hospital in stable condition after 15 days

* Time from procedure to infection. Note: All subjects were female. Co-infecting organisms were not present in any case. GS: Gram’s Stain; CX: culture.

Abiotrophia/Granulicatella to help characterize the emerging epidemiology of these infections. 2. Case #1 A 32-year-old female in the second trimester of pregnancy presented to her physician with nasal obstruction of approxi-

mately three months duration. She described a persistent frontal headache but no subjective fever. Physical examination was notable only for a palpable mass in the medial canthal region. A subsequent magnetic resonance imaging (MRI) scan revealed a mass involving the right anterior ethmoid with extension into the anterior orbit and cribiform plate. Endoscopic biopsy revealed a papillary squamous carcinoma.

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At the time of admission, a right medial maxillectomy was performed via an anterior craniofacial approach. Preoperative antibiotic prophylaxis consisted of cefazolin and metronidazaole, which were continued for two days postoperatively. On the fifth post-operative day, the patient developed a fever to 101.3°F. A computed tomography (CT) scan revealed an epidural fluid collection exerting a significant mass effect on the frontal lobe. On surgical exploration, a small segment of the pericranial flap was swollen and discolored and therefore removed. Drainage of the epidural fluid collection was then performed. The cerebrospinal fluid (CSF) profile revealed glucose of 89 mg/dL, protein of 67 mg/dL, WBC of 250/␮L (polymorphonuclear leukocytes (PMN)s 93%), and red blood cell (RBC) count of 7050/␮L. The Gram stain of the CSF revealed rare PMNs but no bacteria, and the culture demonstrated no growth. The Gram stain of the epidural collection revealed no bacteria and rare white blood cells. The epidural collection culture grew moderate G. adiacens, resistant to penicillin (MIC 12.00ug/mL) but susceptible to vancomycin (MIC 2.00 ug/mL). Of note, bacteria were identified by conventional phenotypic methods based on catalase, PYR reaction, ONPG, and acid production from trehalose, lactose and raffinose (using cysteine supplemented purple broth base) (Koneman et al., 1997). In vitro susceptibilities were determined by E-test using chocolate agar medium. Given the patient’s excellent clinical response to surgical drainage and parenteral penicillin prior to availability of susceptibility data, the patient was continued on penicillin, with gentamicin added for synergy. Following discharge, the patient completed a 4-week course of penicillin and a 2-week course of gentamicin. She was in stable condition with no recurrent infection at the most recent follow-up approximately 1.5 years later.

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mg/dL, RBC count of 15/␮L, and a WBC count of 630/␮L (78% PMNs). A Gram stain of the CSF revealed no bacteria and rare PMNs with the culture subsequently growing A. defectiva. The patient was treated with intrathecal gentamicin and vancomycin, as well as iv vancomycin. The next day, the patient remained febrile (101.3°F), and a repeat CSF Gram’s stain and culture revealed few Grampositive cocci, many polymorphonuclear leukocytes, and few A. defectiva. CSF WBC count was 2950/␮L (88% PMNs). The following day she remained febrile (101.5°F) and the VP shunt was removed. At the time of VP shunt removal, a small amount of purulent material was identified in the anterior pole of the wound. Culture of this purulent material revealed moderate growth of A. defectiva. A CT scan demonstrated a ring-like lesion in the left frontal region in the previous track of the VP shunt catheter. Repeat CSF profile two days following VP shunt removal revealed a glucose of 62 mg/dL, protein of 87 mg/dL, and WBC of 60/␮L. Susceptibility testing for the organism revealed a vancomycin MIC of 3.0 ug/mL and a penicillin MIC of 0.047 ug/mL. Her antibiotic regimen was thus changed to i.v. penicillin and gentamicin. As the patient’s condition improved, a new VP shunt was placed 13 days after admission. She was discharged seven days after this procedure in stable condition, to continue a 4-week course of penicillin and gentamicin. The patient was readmitted five days later with new onset confusion and CT scan identified two ring-enhancing lesions within the left frontal region with surrounding mass effect. Drainage of these intracerebral abscesses was undertaken two days later. A culture of the intracerebral abscess yielded no bacteria, few PMNs, and no growth. The patient was discharged in stable condition, and instructed to continue her course of antibiotic therapy with penicillin and gentamicin. She was in stable condition with no relapse of infection eight weeks after discontinuation of antibiotic therapy.

3. Case #2 4. Discussion A 53-year-old female was admitted to the hospital due to subarachnoid hemorrhage following rupture of a middle cerebral artery (MCA) bifurcation aneurysm. She underwent clipping of the MCA aneurysm and placement of a ventriculopleural (VP) shunt. Preoperative antibiotic prophylaxis consisted of cefazolin, which was continued for two days post-operatively. She was discharged in stable condition 22 days later. Eleven days later, she again presented to the hospital with acute onset of disorientation. On admission, her examination was remarkable for a temperature of 100.5°F and erythema localized to the VP shunt site of the anterior chest wall. MRI of the head revealed extensive edema in the left frontal lobe surrounding the path of the VP shunt. The VP shunt was tapped using sterile technique. The CSF profile revealed a glucose of 53 mg/dL, protein of 190

CNS involvement with A. defectiva and G. adiacens has only recently been recognized. Including the two cases presented here, there have been five reports of CNS Abiotrophia/Granulicatella reported (Biermann et al., 1999; Michelow et al., 2000; Schlegel et al., 1999). It is unclear why cases of CNS infection due to Abiotrophia/Granulicatella have only recently been reported. A possible explanation lies in the traditional difficulty in identifying these organisms because of their requirement for pyridoxal (Ruoff, 1999). Abiotrophia/Granulicatella spp., when present in blood cultures or other normally sterile sites, should be suspected when direct gram-stain of the blood culture bottle or other clinical specimen reveals streptococcal-like morphotypes that fail to grow on routine sub-culture. The recent recognition of CNS Abiotrophia/Granulica-

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tella spp. infections is concerning for several reasons. First, these infections (specifically endocarditis) have been associated with greater morbidity and mortality when compared to infections caused by other streptococci (Roberts et al., 1979; Stein and Nelson, 1987). Second, Abiotrophia/ Granulicatella infections respond poorly to antibiotics, with greater bacteriologic failure and relapse rates than other streptococci (Stein and Nelson, 1987). Given these findings, it is imperative that clinicians recognize the possible role of Abiotrophia/Granulicatella spp. in CNS infections. Our review of the literature suggests several common features of CNS Abiotrophia/Granulicatella spp. infections. Perhaps most importantly, four of the five cases reviewed had undergone a recent neurosurgical procedure (range 4 to 60 days before identification of Abiotrophia/Granulicatella spp. infection). This suggests possible introduction of the organism into the CNS (perhaps from the oral mucosa of the patient) at the time of surgery. The only case without antecedent neurosurgery was a 30month old female with Down’s syndrome who sustained a severe tongue laceration two weeks before admission (Michelow et al., 2000). In this case, it was felt that oral mucosal ulceration with concomitant dental caries likely allowed invasion of commensal Abiotrophia/Granulicatella spp. In the cases reported in the literature to date, there has been marked variation in the clinical presentation and CSF profile. Furthermore, while most infections were characterized primarily by a localized infection (e.g., abscess), evidence of meningitis (e.g., headache, stiff neck, CSF leukocytosis) was also often present. The fact that all cases of Abiotrophia/Granulicatella spp CNS infections reported to date occurred in female patients is an interesting observation without clear explanation. Based on in vitro data, therapeutic options for CNS Abiotrophia/Granulicatella spp. infections may be limited; a recent evaluation of clinical Abiotrophia/Granulicatella isolates noted intermediate or high-level resistance to penicillin and ceftriaxone in 85% and 36% of isolates, respectively (Tuohy et al., 2000). However, in vitro susceptibility does not correlate well with clinical response in these organisms (Johnson and Tunkel, 1995). Among the isolates reviewed in this report for which susceptibility data were available, 3 of 4 were susceptible to penicillin while all were susceptible to vancomycin (although one isolate demonstrated intermediate susceptibility to this agent). Considering these data, it is advisable that if Abiotrophia/Granulicatella spp. CNS infection is suspected, combination therapy with vancomycin and an aminoglycoside (and perhaps rifampin) should be initiated empirically, particularly since synergy between penicillin or vancomycin and the aminoglycosides has been demonstrated both in vitro and in animal models (Henry et al., 1986; Bouvet, 1995). Of note, it has been recommended that combination therapy be used for Abiotrophia/Granulicatella spp. endocarditis with penicillin for at least 4 weeks and aminoglycosides for 2 weeks

(Bisno et al., 1989). Once susceptibility data are available, consideration should be given to tailoring therapy accordingly, particularly in the setting of poor clinical response to empiric therapy. However, as demonstrated in several reviewed cases, if in vitro testing suggests the organism is resistant to an agent to which the patient has responded to clinically, continuation of the agent with careful monitoring may be reasonable. Although this case series is limited by the lack of a control group, our observations should serve to generate hypotheses that can be formally tested in future controlled studies. This report and literature review is a first step in elucidating the epidemiology of CNS infections due to these important pathogens. In particular, further research designed at exploring reasons for the apparent connection between Abiotrophia/Granulicatella spp. infections with recent surgery and female gender, and the optimal treatment of such infections is most warranted.

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