Facklamia Species as an Underrecognized Pathogen.

Facklamia species are a rarely reported etiology of clinical infection with few cases described in literature. However, the prevalence of infection may be underestimated due to challenges in species identification. We describe 3 cases of Facklamia species bacteremia and the unique microbiologic aspects inherent to this genus that make it particularly challenging to identify. In addition, given the unique susceptibility profile of Facklamia species, we discuss the importance of fully identifying this organism when it is a suspected as a pathogen, to optimize therapy based on its distinct antibiotic resistance profile.

Facklamia species are Gram-positive, α-hemolytic, catalase-negative, facultative anaerobic cocci that remain challenging to accurately identify with current microbiologic identification systems. We describe 3 cases of Facklamia spp bacteremia to illustrate the pitfalls in laboratory identification of this genus.

CASE ONE

A 64-year-old homeless male with history of active intravenous drug use was found unresponsive in a nearby street surrounded by needles. On admission, he was hypothermic with leukocytosis of 21 K/µL. Two of 2 blood culture sets isolated Gram-positive cocci in chains after 72 hours. Colonies were pinpoint, sticky, pyrrolidonyl arylamidase (PYR)-negative, and α-hemolytic with no zone around A- or P-disks and with better growth in ambient air than 5% CO2. The organism was initially reported as viridans group Streptococcus (VGS). Susceptibility by E-test per manufacturer’s recommendations for VGS (AB Biodisk, Solna, Sweden) was read at 48 hours due to poor growth. The pattern was unusual with elevated minimal inhibitory concentrations (MICs) to cefotaxime (32 μg/mL) and penicillin (4 μg/mL), later confirmed by broth microdilution method at a reference laboratory (Table 1). Matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry (Vitek MS; bioMerieux, Durham, NC) yielded no identification. Transthoracic echocardiogram and subsequent cardiac magnetic resonance imaging demonstrated an extensive 5.3 × 3.8 × 2.2-cm left atrial mass involving the anterior mitral valve leaflet. He was a high-risk surgical candidate and managed medically. With limited microbiologic data, the patient was treated with 6-weeks of vancomycin and gentamicin similar to treatment for penicillin-resistant enterococci. Sequencing of the first 500 base pairs of the 16S recombinant ribonucleic acid (rRNA) gene was performed, which yielded an identification of Facklamia ignava (99.2% identity to American Type Culture Collection [ATCC] 700631 with 4 ambiguous base pairs) [1]. The patient remained clinically stable after 6 months but refused further cardiac imaging as recommended.

Table 1.

MIC (μg/mL) of the Three Facklamia spp Cases Based on Broth Microdilution Methoda

Antibiotics	Case 1Facklamia ignava	Case 2Facklamia languida	Case 3F languida
Penicillin	1 (I)	0.06 (S)	0.06 (S)
Ceftriaxone	>2 (R)	>2 (R)	>2 (R)
Cefepime	2 (I)	4 (R)	2 (I)
Vancomycin	≤0.5 (S)	≤0.5 (S)	≤0.5 (S)
Ertapenem	≤0.5 (S)	4 (NS)	4 (NS)
Levofloxacin	>4 (R)	≤0.5 (S)	4 (I)
Erythromycin	≤0.25 (S)	0.5 (I)	>2 (R)
Daptomycin	0.12 (S)	0.25 (S)	0.12 (S)

Abbreviations: I, intermediate; MIC, minimal inhibitory concentrations; NS, nonsusceptible; R, resistant; S, susceptible.

aInterpretations given in parentheses are based on standard guidelines for viridans group streptococci [14].

CASE TWO

A 36-year-old male was admitted for suicide attempt with overdose on antidepressants. He developed acute respiratory distress syndrome from aspiration pneumonia after an observed seizure requiring intubation. Blood cultures were drawn 2 weeks after admission for fever and leukocytosis. One of 2 sets became positive after 3 days for Gram-positive cocci in chains for which he was treated with vancomycin. Colonies were pinpoint after 24 hours, non-hemolytic, and PYR-negative. The MALDI-TOF mass spectrometry identified the isolate as Abiotrophia defectiva (95% confidence). However, the organism displayed better growth on sheep blood than chocolate agar, a finding atypical for Abiotrophia species. 16S rRNA gene sequencing performed at a reference laboratory revealed the true organism identity as Facklamia languida. Broth microdilution susceptibility testing showed elevated MICs to cefepime, ceftriaxone, and ertapenem (Table 1). Transthoracic echocardiogram revealed no evidence of valvular vegetation. Two subsequent blood cultures were negative. The patient expired from respiratory failure 4 weeks after admission.

CASE THREE

A 59-year-old female with diabetes, chronic kidney disease requiring hemodialysis, and nonalcoholic cirrhosis with refractory ascites was admitted with abdominal pain. She denied fevers or chills. Blood cultures at the time of admission were positive after 2 days, isolating Staphylococcus aureus, Peptostreptococcus anaerobius, and a Gram-positive coccus in chains. The latter grew in 1 aerobic bottle of 3 sets and was PYR-positive, pinpoint, and non-hemolytic on sheep blood agar. It could not be identified biochemically (RapID Strep; Remel, Lexington, KY) and was referred for 16S rRNA gene sequencing and broth microdilution susceptibility testing. It was identified as F languida remarkable for an elevated MIC to ceftriaxone (Table 1). Abdominal fluid cultures also grew S aureus. The patient was initially treated with vancomycin, cefepime, and metronidazole. Her antibiotic regimen was further narrowed to oxacillin targeting only S aureus. Subsequent blood cultures obtained 2 days and 3 weeks later were negative. However, due to continued clinical deterioration and a repeat abdominal fluid culture again growing S aureus, she was empirically treated with linezolid and ceftriaxone. The patient had a prolonged hospital course, was deemed ineligible for liver transplantation, and eventually expired from cardiorespiratory failure.

DISCUSSION

The genus Facklamia was first described in 1997 using 16S rRNA sequencing and has since been identified from both a wide range of animal sources and infrequently as a human pathogen [2-4]. Bacteremia has been associated with endocarditis, necrotizing gangrene, chorioamnionitis, and central nervous system disease [5-9]. Only 2 cases of possible F ignava infection have been reported [10], and we add a case in which it was a likely contributor to a case of endocarditis.

Although Facklamia spp have been implicated in invasive infections, the virulence of this organism has not been fully determined. The true extent of morbidity and mortality is further convoluted not only by the relative scarcity of reported cases, but also by the co-occurrence of Facklamia with other bacteria and often in patients with significant comorbidities. In addition to blood cultures, Facklamia has been isolated from vaginal specimens, urine, cerebrospinal fluid, bone, skin, and gall bladder [11, 12]. Because the majority of collected specimens have been from women, it has been speculated that this organism may be normal flora in the female genital tract [11, 12]. However, based on our case series, we are unable to exclude the possibility that Facklamia may have originated from other sources such as the gastrointestinal tract or skin.

Similar to other uncommon Streptococcus-like organisms that may be isolated from clinical specimens, such as Dolosigranulum, Inavigranum, or Vagococcus spp, the clinical significance of Facklamia spp is not well understood. Although it is conceivable that all 3 of our cases of Facklamia isolated from blood were true pathogens, we cannot establish with absolute certainty that this organism significantly contributed to the clinical outcome of our patients. This is particularly challenging in cases 2 and 3 because Facklamia was only isolated from 1 set of blood cultures, which could be interpreted as contamination. On the other hand, our first case demonstrated multiple positive blood culture sets for Facklamia in the setting of endocarditis, which compels us to believe that Facklamia does have pathogenic potential.

Facklamia species are easily misidentified by traditional laboratory methods [13]. In contrast, organisms have been erroneously identified as Facklamia only to be later identified as Enterococcus faecalis, Cardiobacterium valvarum, or Streptococcus mutans by 16S rRNA gene sequencing [1]. Facklamia spp are similar to VGS in Gram stain, colony morphology, and catalase reaction. However, Facklamia spp are usually PYR-positive [10, 13], although in 2 of our cases this was not true. In each case, Facklamia spp grew fastidiously, requiring at least 2–3 days for blood culture bottles to flag positive. With the v2.0 Knowledge Base, the Vitek MS was unable to provide identification for F ignava and misidentified F languida as A defectiva. Facklamia spp are also not currently claimed in the Bruker Biotyper MALDI-TOF system. This underscores the continuing need for bench microbiologist expertise in spite of advances in technology. With limited experience in Facklamia identification for most laboratories, it appears at the current time that definitive identification is best made by deoxyribonucleic acid sequence analysis.

It is important to distinguish Facklamia spp from VGS and Streptococcus-like organisms because of its unusual susceptibility profile. Limited antimicrobial susceptibility studies have shown F ignava and F languida isolates to possess elevated MICs to cefotaxime, erythromycin, clindamycin, and trimethoprim-sulfamethoxazole and low MICs to levofloxacin and vancomycin. Facklamia ignava, but not F languida, may have elevated penicillin MICs. For F languida, elevated carbapenem MICs have also been observed [12]. Recognition of the susceptibility profiles for Facklamia spp could help in raising suspicion if the organisms were misidentified, eg, as VGS or Abiotrophia spp cases of Facklamia spp bacteremia with associated necrotizing gangrene, chorioamnionitis, and central nervous system disease were previously treated effectively with vancomycin, amoxicillin/clavulanic acid, and ceftriaxone plus vancomycin, respectively [5, 7, 9]. Endocarditis due to Facklamia spp has only been described in 2 cases of Facklamia hominis where 1 case was treated successfully with ceftriaxone and gentamicin [6] and 1 case resulted in fatal myocardial infarction despite 2 days of vancomycin and gentamicin [8]. Because there are no guidelines for treatment of Facklamia spp bacteremia, clinical decisions must be made based on data from nonstandardized susceptibility testing; empiric treatment with vancomycin would be appropriate given the variable susceptibility profiles of Facklamia to β-lactam drugs. Based on limited published clinical experience and our own case, for Facklamia endocarditis, treatment with 6 weeks of β-lactam antibiotic or vancomycin with 2 weeks of gentamicin may be a reasonable choice.

CONCLUSIONS

Facklamia spp are organisms whose true virulence and pathogenesis are poorly understood. They may cause infection in a susceptible host, but clarifying the risk factors has proven to be difficult based on the scarcity of literature. Due to challenges in its identification, the true burden of disease may be underrecognized. However, the importance of appropriate identification should not be discounted because susceptibilities for Facklamia may differ significantly from the VGS for which it may be misidentified. This potential resistance to β-lactams may have significant clinical treatment implications.