Kingella species
Authors: Pablo Yagupsky
Author, First/Second Editions: Michael L. Towns, M.D.
Members of the genus Kingella of the Neisseriaceae family are small gram-negative capnophilic and facultatively anaerobic coccobacilli that inhabit the buccal cavity and upper respiratory tract (64). The genus currentlycomprises four species: Kingella denitrificans, which is a rare and opportunistic etiology of bacteremia, endocarditis, pediatric vaginitis, peritonitis in peritoneal dialysis patients, chorioamnionitis, and septicemic granulamatosis in AIDS patients (64); Kingella oralis which is associated with periodontitis; Kingella potus which has been isolated from a wound caused by the bite of an exotic animal (41);Kingella kingae, which is an emerging pathogen of young children and the prime cause of skeletal system infections below the age of 4 years (21, 46), and will be discussed in depth in this chapter.
Microbiology
Kingella kingae is a ß-hemolytic bacterium that appears as short chains of plump bacilli with tapered ends (Figure 1). Kingella kingae grows on blood- and chocolate-agar plates producing marked impressions on the medium’s surface and fails to grow on enteric media such as MacConkey or Krigler agar (64). The organism is non-motile, exhibits positive oxidase activity, negative catalase reaction, produces acid from glucose and maltose but not from other sugars, and can be readily identified by commercial systems such as API NH and VITEK 2 (bioMérieux, Marcy-l’Etoile, France), matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) technology, and 16S rDNA gene sequencing (22, 64).
Epidemiology
Kingella kingae colonizes the human tonsills and is rarely isolated from the nasopharynx (3, 56, 59). Colonization does not usually start before the age of 6 months. The carriage rate gradually increases thereafter, reaching a prevalence rate of 9-12% in the second year of life, declines in older children, and is close to nil in adults, paralleling the age-related epidemic curve of invasive infections (2, 3, 16, 24, 59, 64). The colonized pharyngeal surfaces are the source of infectious fomites that disseminate the organism between young family members and playmates (34, 51, 59). Carriage and transmission are enhanced in daycare center attendees among whom clusters of invasive K. kingae disease have been reported, especially in the context of a concomitant upper respiratory viral infection or stomatitis (11, 40, 56, 63). It is plaussible that increased drooling induced by bucal ulcers facilitates the dissemination of the bacterium among young children with poor hygienic habits (25).
Invasive K. kingae diseases are almost limited to young children. Over 95% of cases occur below the age of 5 years (Figure 2), and an annual incidence rate of 9.4/100,000 infections has been reported in this population group, although because of the suboptimal culture detection of the organism, this figure can be only considered a minimal estimate (24).Kingella kingae infections are exceptional in the first 6 months of age suggesting that maternal antibodies confer protection against both colonization and disease in early infancy (52). Most affected young patients are otherwise healthy, whereas older children and adults often have immunosuppressing conditions, malignancy, or antecedent cardiac valve pathology (23, 24). Although the carriage rate remains remarkably constant along the year, invasive K. kingae infections are most common during late fall and early winter, coinciding with the seasonal increase of viral upper respiratory infections (24, 64).
Clinical Manifestations
With the exceptions of cases of endocarditis, pediatric patients with invasive K. kingae infections usually present in good general condition, are frequently afebrile or have moderate fever and no leukocytosis, and acute phase reactants are normal or only slightly elevated, requiring a high index of clinical acumen (4, 5, 14, 15, 24). Blood cultures in children with skeletal system infections are usually negative, suggesting that the antecedent K. kingae bacteremia is transient and has short duration (64). The frequency distribution of the different clinical syndromes caused by the organism is shown in Figure 3.
Skeletal System Infections
Septic arthritis
Arthritis is the single most common clnical presentation of K. kingae disease. The disease usually involves the large joints of the lower extremities and, less frequently, the wrist, shoulder, or elbow (24, 64). The small metacarpo-phalangeal, sternoclavicular, and tarsal joints, which are rarely infected by other organisms, are over-represented in K. kingae arthritis (43, 64).
Lack of leukocytosis has been recorded in one-half of children with K. kingae arthritis, one-quarter had <50,000 WBC/mm3 in synovial fluid, and the Gram-stain examination usually is negative due to the low bacterial concentration in the exudate (4, 5, 23, 24). Because of the mild symptomatology and benign laboratory findings, the established Kocher’s predictive score based on the height of the body temperature, refusal to bear weight, blood leukocyte count, and erythrocyte sedimentation rate, does not reliably distinguish between K. kingae arthtritis of the hip and transient synovitis (62). Children younger than 3 years presenting with an “irritable hip” should undergo blood cultures drawing and tap of the affected joint, and the aspirated synovial fluid should be inoculated into blood culture vials and submitted for nucleic acid amplification testing (62).
Osteomyelitis
K. kingae osteomyelitis generally affects the tubular bones, although involvement of the calcaneus, talus, sternum, or clavicle is not unusual (24, 43, 64). Primary invasion of the epiphysis or apophysis of the long bones, which is exceptionally observed in osteomyelitis caused by traditional pathogens, is frequently documented in K. kingae infections (19). When studied by MRI imaging, patients with K. kingae osteomyelitis exhibit lesser degrees of bone and soft tissue reaction than children with infections caused by other bacterial pathogens, whereas epiphyseal or apophyseal involvement and cartilage abscesses formation are almost exclusively observed in K. kingae disease (35). Onset of K. kingae osteomyelitis is generally more insidious than that observed in septic arthritis, and most children are diagnosed after more than one week of evolution (64). Despite the diagnostic delay of K. kingae osteomyelitis, evolution towards chronicity and orthopedic sequelae are exceptional (64).
Spondylodiscitis
With the decrease in the incidence of tuberculosis, K. kingae is currently the most common etiology of spondylodiscitis in children younger than 4 years in the Developed World (28, 64). Circulating organisms appear to reach the intervertebral dics through a blood vessels network that enters the annulus from the cartilaginous vertebral endplates and obliterates in older children (28). The disease generally involves a single intervertebral space, usually the lumbar discs, followed in decreasing frequency by the thoracolumbar, lumbosacral and cervical ones. Patients present with limping, refusal to sit or walk, lumbar pain, back stiffness and/or neurologic symptoms (64). Plain radiograph or MRI demonstrate narrowing of the intervertebral space and, less frequently, epidural abscess formation (44, 64). Because blood cultures are negative in the majority of patients and obtaining a tissue specimen for culture is difficult, nucleic-acid amplification techniques play an important role in establishing the etiology (13, 17). Children with K. kingae spondylodiskitis respond well to antibiotic therapy and recover without functional sequelae (28).
Abortive skeletal system infections
Transient limping during a bacteremic K. kingae episode, has been reported in young children, many of whom improve without antibiotics. As a matter of caution, however, adequate antimicrobial therapy should be administered to all patients from whom K. kingae is isolated from a normally sterile site (64).
Bacteremia
Bacteremia without a focal infection (also known as “occult bacteremia”) is the second most frequent presentation of K. kingae infections in young children (24, 55). The clinical presentation is frequently mild: only one half of patients have a body temperature ≥ 39 ºC, and one-third had a leucocyte count <15,000 WBC/mL; therefore the current guidelines for obtaining blood cultures in young febrile children, which rely on the height of fever and the WBC count, are not sensitive enough to detect K. kingae bacteremia (64). A maculopapular rash, resembling disseminated neisserial infection, has been described in a few bacteremic pediatric and adult patients (64).
Endocarditis
Kingella kingae is included in the HACEK group of fastidious upper respiratory or buccal commensal organisms that is collectively responsible for up to 5% of cases of bacterial endocarditis. In contrast to other K. kingae infections, endocarditis has been diagnosed also in older children and adults (64). Typically the left side of the heart is involved, usually the mitral valve (27). Congenital cardiac malformations or rheumatic disease are common predisposing factors, but many pediatric patients have previously normal valves (27, 64). In approximately one-half of patients the infection affects a native valve. In contrast to other manifestations of K. kingae disease, patients with endocarditis generally present with high fever, look sick, and the blood leuocyte count and acute-phase reactants are markedly elevated (24). Despite the remarkable susceptibility of the bacteriumto antibiotics and the relatively benign clinical picture observed in other invasive K. kingae infections, the course of endocarditis is unusual in that serious and life-threatening complications such as cardiac failure, valvular incompetence or rupture, septic shock, mycotic aneurisms, pulmonary infarctions, embolic occlusion of peripheral arteries, meningitis, and cerebrovascular accidents frequently occur, and the case-fatality rate exceeds 10% (27, 29, 31, 64). Because of the serious implications of endocardial invasion by K. kingae, routine echocardiographic evaluation of all individuals from whom the organism is isolated from a normally sterile site is recommended (64).
Meningitis
Kingella kingae meningitis has been described as a primary infection, or secondary to a rupture of a mycotic aneurism or embolic phenomena in patients with endocarditis. The age distribution of patients with K. kingae meningitis is noticeable in that half of the cases have occurred in adolescents and young adults (12, 64). The disease follows a severe clinical course, and surviving patients are frequently left with significant neurological sequelae such as hemiplegia, aphasia, or ophtalmoplegia (64).
Other infections
Kingella kingae has been isolated from the blood or respiratory secretions of previously healthy and immunocompromized adult and pediatric patients with lower respiratory tract disease. In addition, the organism has been uncommonly isolated from patients with with a variety of ocular infections, soft tissue infections, peritonitis and pericarditis (64).
Laboratory Diagnosis
Culture detection
Isolation of K. kingae on routine solid media is frequently unsuccessful, and recovery of the organism can be substantially improved by inoculating synovial fluid aspirates and bone exudates into blood culture vials of a variety of commercial blood culture systems. It appears that purulent exudates inhibit growth of K. kingae (30, 54), and dilution of clinical specimens in a large nutrient broth volume decreases the concentration of harmful factors, facilitating recovery of the organism.
Detection by nucleic acid amplification
In recent years, nucleic acid amplification assays have been developed for the rapid microbiologic diagnosis of skeletal system infections. This approach has the capability of completing detection and identification of the causative organism within a few hours, and is effective also in cases of partially treated disease (26). The method consists of DNA extraction from synovial fluid and bone exudates, followed by a PCR procedure employing universal primer that anneal to conserved portions of the 16S rRNA gene, resulting in the amplification of the intervening species-specific sequence. The amplification products are then sequenced and the results matched with data deposited in genomic databases, or the products are hybridized with organism-specific probes. The method has the obvious advantage of not requiring a prioriknowledge of the causative pathogen. Alternatively, a real-timePCR assay may be performed employing primers that selectively target the most probable etiologic agents, based on clinical and epidemiological considerations (i.e. Kingella kingae in children younger than 4 years or Staphylococcus aureus in older patients) (20, 32, 42, 45, 50, 53). This organism-specific approach has a one-order of magnitude higher sensitivity than the broad-range primers method, and home made real-time assays that amplify K. kingae’s RTX toxin orcpn60 encoding genes show a detection threshold of 30 colony-forming units of the organism (64). Recent experience demonstrated that the use of K. kingae-specific PCR assays increases the diagnostic yield by four-fold compared with routine and blood culture vial cultures, and demonstrated that the organism is responsible for a large fraction of culture-negative cases of septic arthritis and osteomyelitis, and is the most common cause of bone and joint infections in young children (64).
Because of the exquisite sensitivity of the K. kingae-specific nucleic acid amplification assays and the suboptimal recovery of the organism in cultures, it has been proposed to apply the molecular test to oropharyngeal specimens to establish the bacteriologica diagnosis of pediatric joint and bone infections (18). Because invasive K. kingae disease results from the bloodstream invasion by organisms residing in the upper respiratory tract, a negative pharyngeal PCR assay practically excludes K. kingae as the etiology of septic arthritis or osteomyelitis. However, because of the substantial carriage rate of the organism in the relevant age group (approximately 10% below the age of 4 years and much higher in children attending out-of-home care (2, 3), the positive predictive value of the test is more limited (64).
Pathogenesis
The pathogenesis of invasive K. kingae disease begins with adherence of the bacterium to the oropharyngeal epithelium that is mediated by type IV pili (37, 38, 39, 49, 58). AllKingella kingae strains produce a potent RTX toxin that is harmful to leukocytes, epithelial, synovial, and macrophage cells, which probably breaches the respiratory epithelium and damages joint and bone tissues (36, 42). The organism also elaborates a polysaccharide capsule that enables survival in the bloodstream, explaining the tendency of the organism to infect young children who have not yet develop a mature T-lymphocyte independent immune response (49). Children with K. kingae disease frequently exhibit symptoms consistent with a non-specific viral respiratory infection, herpetic gingivostomatitis, hand-foot-and mouth disease, or herpangina, and organisms isolated from the blood and skeletal system are genotypically identical to those carried in the pharynx, indicating that a disrupted mucosal lining is the portal of entry of the bacterium to the bloodstream (7, 9,58, 64). Kingella kingae strains show wide differences in virulence. Some strains are frequently carried by asymptomatic carriers but are rarely isolated from patients with invasive disease (59), while others are significantly associated with bloodborne infections and show tropism towards skeletal or endocardial tissues (1, 6). A few clones cause a large fraction of invasive infections worldwide, indicating enhanced transmissibility and virulence, while others have a more restricted or country-specific geographic distribution (6).
SUSCEPTIBILITY IN VITRO AND IN VIVO
According to the Clinical and Laboratory Standards Institute (CLSI) guidelines, antibiotic susceptibility of HACEK organisms should be determined by the microdilution method on cation-adjusted Mueller-Hinton broth containing 5% (vol/vol) lysed horse blood. However, a large fraction of HACEK isolates, as well as approximately 7% of K. kingae strains show poor growth on this medium, precluding reliable interpretation of susceptibility results. As a practical alternative, these organisms can be studied employing the epsilon (E-test) on trypticase soy agar plates with added hemoglobin (routine blood-agar medium) instead (60).
Kingella kingae is usually susceptible to penicillins and cephalosporin drugs that are empirically administered to children with suspected invasive and skeletal system infections, pending culture results (33, 57, 60, 61). b-lactamase production is limited to a few distinct clones and its prevalence shows wide geographic variation, being rare among invasive isolates from continental Europe and Israel but common in Minnessota and Iceland (8). The enzyme, which belongs to the TEM-1 class, is encoded in the chromosome and/or in a plasmid (10) and confers low-level resistance to penicillin and ampicillin with MIC values between 0.25 and 8 mg/ml and a MIC90 of 4 mg/ml, but the organism remains susceptible to cephalosporins. Clavulanate fully restores the antibacterial activity of ampicillin, and the MICs of the amoxicillin-clavulanate combination are ≤0.25 mg/ml (8). As a measure of caution, all K. kingaeisolates from normally sterile body sites should be routinely tested for b-lactamase production by the cephinase disk method (64).
With rare exceptions, K. kingae is susceptible to aminoglycosides, macrolides, trimethoprim-sulfamethoxazole, fluoroquinolones, tetracycline, and chloramphenicol (64). Kingella kingae exhibits relatively high oxacillin MICs (MIC50: 3 mg/ml; MIC90: 6 mg/ml), 40% of invasive isolates are clindamycin nonsusceptible, and all strains are highly resistant toglycopeptide antibiotics, a serious concern in regions where joint and bone infections caused by community-associated methicillin-resistant Staphylococcus aureus are prevalent, and clindamycin or vancomycin are initially prescribed to children with skeletal system infections (60).
ANTIMICROBIAL THERAPY
Because no specific guidelines for the treatment of K. kingae infections have been developed yet, patients have been administered different antibiotics, dosages, and drug combinations for variable periods of time, and/or treated according to protocols recommended for infections caused by traditional pyogenic bacteria (64). Table 1 summarizes the current antibiotic drugs recommended for the treatment of invasiveK. kingae infections in children aged 6 months to 4 years.
Skeletal System Infections
The empiric drug therapy for skeletal infections in children usually consists of intravenous administration of a second- or third-generation cephalosporin, pending culture results. Because vancomycin and clindamycin are not adequate for K. kingae, in areas where community-associated methicillin-resistant Staphylococcus aureus is prevalent, a b-lactamase-stable b-lactam drug should be added in children younger than 4 years. When K. kingae is isolated, the initial regimen frequently is changed to parenteral ampicillin (once b-lactamase production is ruled-out). Additional therapeutic options are cefuroxime, or ceftriaxone.
Septic Arthritis
Traditionally, patients with K. kingae arthritis have been administered a total of 2 to 3 weeks of antibiotics (64). Recent studies suggest that a total 10-day course of sequential and high doses of parenteral and oral antibiotic drugs may be sufficient for uncomplicated bacterial arthritis, but the experience with this novel approach in the treatment of K. kingaeinfections is still limited (47).
Osteomyelitis
Treatment for this condition has varied from 3 weeks to 6 months. Nowadays, shorter duration of antibiotic therapy, early switch to oral antibiotics guided by sequential determination of CRP levels and without need to measure serum bactericidal levels, and limiting surgery to a minimum, have replaced the traditional modalities for managing pediatric bone infections caused by highly virulent bacteria such as S. aureus. Because of the benign course of K. kingae osteomyelitis, the novel approach is, probably, also adequate for osteomyelitis caused by this low-grade pathogen (48, 64).
Spondylodisckitis
Children with intervertebral disk infections have been treated with antibiotics for 3 to 12 weeks (64).
Bacteremia
Children with K. kingae bacteremia and no focal infection generally are administered an intravenous cephalosporin, such as crfuroxime or ceftriaxone, and treatment is subsequently switched to oral b-lactam antibiotics. Patients respond favorably to a 1-2-week antibiotic course (64).
Endocarditis
Patients with K. kingae endocarditis are usually treated with an intravenous b-lactam drug alone or in combination with an aminoglycoside for 4 to 7 weeks (64).
ADJUNCTIVE THERAPY
Septic arthritis
Although some children with K. kingae septic arthritis have been managed with repeat joint aspirations and lavage, most patients do not require invasive surgical procedures (64).
Osteomyelitis
Surgical interventions have been recommended when bacteremia persists after 48 hours of antibiotic therapy, or abscess, fistula, or sequestrum formation. These untowards event, however, rarely occur in K. kingae infections and, therefore, patients usually improve with medical treatment only (64).
Spondylodiscitis
Although supplemental treatment with a body brace has been advocated to stabilize the spine and enable early mobilization (44), most children has been managed with antibiotics and non-steroidal anti-inflammatory drugs only (64).
Endocarditis
Early surgical intervention including abscess drainage, valvular repair or replacement, vegetation excision, may be necessary for life-threatening complications unresponsive to conservative medical therapy (27,29, 31).
ENDPOINTS FOR MONITORING THERAPY
Clinical response including normalization of body temperature, improvement of local signs in joint and bone infections, and decreasing levels of acute-phase reactants, and especially serum CRP levels falling below 20 mg/L, are used to guide switching to oral antibiotics (amoxicillin or cefuroxime) and determine duration of therapy (47, 48).
VACCINES
There are no vaccines in use or in development against Kingella spp.
PREVENTION OR INFECTION CONTROL MEASURES
Because K. kingae is normally carried as part of the upper-respiratory and oral microbiome without symptoms of disease, there is no indication to eradicate the organism from the colonized mucosal surfaces. However, the risk of acquisition of K. kingae organisms with progression to a severe and even life-threatening infection is significantly increased among youngsters attending daycare centers where clusters of disease occur. The attack rate in affected daycare facilities may reach 24%, and up to 88% of attendees may be colonized by the highly virulent outbreak strain (25, 40, 63, 64). Under these circumstances, administration of prophylactic antimicrobial drugs aimed to eradicate colonization in contacts and prevent further cases of disease has been attempted (25, 40, 63, 64).
Antibacterial Agent Prophylaxis
Antibiotic regimens have consisted of rifampin 20 mg/kg/day twice daily for 2 days, alone or in combination with amoxicillin (80 mg/kg/per day) in two divided doses for 2 days or 4 days were prescribed (63, 64). Although only partial eradication of the causative strain was usually achieved, no further cases of disease were detected in the affected facilities (63, 64). It is possible that reducing the bacterial density in the pharynx of colonized children was enough to prevent bloodstream invasion and also limited ongoing child-to-child transmission. Alternatively, prolonged mucosal carriage could have induced an effective immune response, decreasing the infection risk (64).
Infection Control
Infection control measures, including exclusion of children with symptoms of respiratory tract infection and encouraging hand washing should be reinforced in affected day-care facilities until termination of the outbreak (64).
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Tables
Table 1. Recommended antibiotic therapy for invasive K. kingae infections in children aged 6 months to 4 years.
Syndrome
|
Drug(s) of choice |
Alternative therapy |
||||
|---|---|---|---|---|---|---|
antibiotic |
mg/kg/day |
doses/day |
antibiotic |
mg/kg/day |
doses/day |
|
Skeletal-initial regimen (pending culture/PCR results) |
BLRBLa plus cefuroxime or ceftriaxone |
150
150
100 |
4
3
1 |
vancomycinb or clindamycinc or co-trimoxazole plus cefuroxime or ceftriaxone |
40-60
30-40
50-60
150
100 |
2 or 3
3 or 4
2
3
1 |
Skeletal-K. kingaeconfirmed or K. kingae bacteremia with no focus |
ampicillind or cefuroximee or ceftriaxonee |
100-200
150
100 |
4
3
1 |
co-trimoxazole or ciprofloxacin (?) |
50-60
30 |
2
2 or 3 |
Endocarditis-initial regimen (pending culture/PCR results) |
BLRBLa plus gentamicin |
200
7.5 |
4 or 6
3 |
vancomycin plus gentamicin |
40-60
7.5 |
2 or 3
3 |
Endocarditis-K. kingaeconfirmed
|
ampicillind plus gentamicin |
300
7.5 |
4 or 6
3 |
ceftriaxonee plus gentamicin |
100
7.5 |
1
3 |
Meningitis-initial regimen (pending culture/PCR results) |
ceftriaxone |
100 |
1 |
|
|
|
Meningitis-K. kingaeconfirmed |
ampicillind or ceftriaxonee |
200
100 |
4 or 6
1 |
meropenem or ciprofloxacin |
120
80 |
3
2 or 3 |
a: b-lactamase-resistant b-lactam (nafcillin, cloxacillin, flucloxacillin, or dicloxicillin)
b: in regions where community-associated MRSA is prevalent (>10% of S. aureus isolates)
c: in regions where community-associated MRSA is prevalent (>10% of S. aureus isolates) and clindamycin resistance is <10%
d: for b-lactamase negative isolatese: for b-lactamase-producing isolates or if b-lactamase-production has not been ruled-out (PCR-positive/culture-negative cases)