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30 years of study of Kingella kingae: post tenebras, lux

CERONI, Dimitri, et al.

Abstract

Kingella kingae is a Gram-negative bacterium that is today recognized as the major cause of joint and bone infections in young children. This microorganism is a member of the normal flora of the oropharynx, and the carriage rate among children under 4 years of age is approximately 10%. K. kingae is transmitted from child to child through close personal contact. Key virulence factors of K. kingae include expression of type IV pili, Knh-mediated adhesive activity and production of a potent RTX toxin. The clinical presentation of K. kingae invasive infection is often subtle and may be associated to mild-to-moderate biologic inflammatory responses, highlighting the importance a high index of suspicion. Molecular diagnosis of K. kingae infections by nucleic acid amplification techniques enables identification of this fastidious microorganism. Invasive infections typically respond favorably to medical treatment, with the exception of cases of endocarditis, which may require urgent valve replacement.

Reference

CERONI, Dimitri, et al. 30 years of study of Kingella kingae: post tenebras, lux. Future Microbiology, 2013, vol. 8, no. 2, p. 233-45

DOI : 10.2217/fmb.12.144 PMID : 23374128

Available at: http://archive-ouverte.unige.ch/unige:33314

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1 / 1 For reprint orders, please contact: [email protected] Review 30 years of study of Kingella Future Microbiology kingae: post tenebras, lux

Dimitri Ceroni*1, Victor Dubois-Ferrière1, Abdessalam Cherkaoui2, Léopold Lamah1, Gesuele Renzi2, Pierre Lascombes1, Belaieff Wilson1 & Jacques Schrenzel2,3 1Paediatric Orthopaedic Service, University of Geneva Hospitals, 6 Rue Willy-Donzé, 1211 Geneva 14, Switzerland 2Clinical Microbiology Laboratory, Service of Infectious Diseases, University of Geneva Hospitals, 4 Rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland 3Genomic Research Laboratory, Service of Infectious Diseases, University of Geneva Hospitals, 4 Rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland *Author for correspondence: [email protected]

Historical review the family Neisseriaceae; it has since been known Kingella kingae is a species of gram-negative as K. kingae [7,8]. In the same year, two additional aerobic coccobacilli, which belongs to the family species, Kingella oralis and Kingella denitrificans, Neisseriaceae. This organism was initially referred were added to the Kingella genus [9]. Finally, in to as Moraxella new species 1 [1,2] or group M 2005, Lawson et al. reported the isolation and organisms [1,3]. The first description of the characterization of a hitherto-unknown Gram- bacterium, later to become known as K. kingae, negative, rod-shaped Neisseria-like organism was made in the 1960s by Elizabeth King, an from an infected wound resulting from a bite American bacteriologist of the US CDC. In from a kinkajou [10]. Based on both phenotypic 1968, Henriksen and Bovre formally described and phylogenetic evidence, it was proposed the new Moraxella species, analyzing nine strains that the unknown organism be classified as (including two obtained from Elisabeth King) a new species, Kingella potus. Currently, the that had been isolated from blood, joint fluid, Kingella genus therefore consists of four species: bone, nose and throat [4]. All isolates were K. kingae, K. denitrificans, K. potus and K. oralis. characterized by b-hemolysis, acid production from glucose and maltose and a lack of catalase Microbiologic features activity [4]. The authors distinguished this new Bacterial characteristics microorganism from all other known Moraxella K. kingae is a coccoid, medium-sized rectilinear species, and named it Moraxella kingii in honor rod, appearing as pairs or short chains of short of Elisabeth King [4]. A further taxonomic bacilli with tapered ends [4,11]. K. kingae is an b modification was made in 1974, when the isolate aerobic and facultative, anaerobic -hemolytic Keywords was renamed Moraxella kingae [5]. This change bacterium that is Gram negative, with some to the feminine gender reflected the naming of tendency to resist decolorization [6]. The isolate n bacteremia n colonization the organism after the female scientist. Although is nonmobile and has no endospores; contrary n endocarditis n invasive infections n Kingella kingae Kingella organisms shared several characteristics to the initial assumption, a recent paper suggests n oropharyngeal carriage with Moraxella species, DNA homology studies that K. kingae elaborates a surface-associated n osteoarticular infection n PCR assays n RTX toxin revealed sufficient differences to suggest the polysaccharide capsule [12]. On the basis of studies need for a separate genus [6]. The final change in by Henriksen and Bovre [13], many characteristics nomenclature was thus made in 1976, when the of K. kingae have been recognized; for example, organism was assigned to the genus Kingella in K. kingae is oxidase positive and exhibits negative part of

catalase, urease and indole reaction. It produces strains circulate within the pediatric population, acid from glucose and maltose, but not from a small subset is responsible for most clinical other sugars, hydrolyzes indoxyl phosphate and infections, and only a few exhibit significant l-propyl-b-naphthylamide and, finally, shows associations with particular clinical diseases positive alkaline and acid phosphatase reactions [20]. A recent study demonstrated that only five [4,11,13,14]. K. kingae grows on trypticase soy strains (B, H, K, N and P) caused 72.9% of all agar with added hemoglobin (blood agar) and invasive infections [19,20]. Clone K exhibits an chocolate agar, but fails to grow on MacConkey optimal balance between transmissibility and or Krigler media [15]. A selective medium invasiveness, and it is significantly associated consisting of blood agar with 2 µg/ml of added with bacteremia. Clone N shows remarkable tis- vancomycin has been developed to inhibit the sue invasiveness and it is responsible for arthri- growth of competing Gram-positive flora and tis and osteomyelitis. The genome from septic facilitate recognition of K. kingae in respiratory arthritis strains has been recently sequenced;

specimens [16]. A CO2-enriched atmosphere K. kingae strain PYKK081 is recognized to enhances growth [11], but only a small proportion cause infections of the skeletal system in young

of strains is truly capnophilic (requires CO2 for children [25], but may also be responsible for its growth) [17]. K. kingae is relatively fastidious infective endocarditis in children and adults. in its growth requirements. It is an aerobe that K. kingae strain 11220434 is another strain that grows optimally at 33–37°C. Growth at room is responsible for acute arthritis [26]. Finally, temperature (20°C) is slight. Growth is adequate clone P organisms are strongly associated with on both nutrient and blood agar, and this bacterial endocarditis [20]. organism has no requirement for X (hemin) and V (nicotinamide adenine dinucleotide) factors. Oropharyngeal carriage of K. kingae Normal oropharyngeal flora Member of the HACEK group The normal flora of the oropharynx contains a K. kingae is the fifth member of the HACEK large number of regular bacterial inhabitants. group. The acronym HACEK refers to a The most important group of microorganisms grouping of Gram-negative bacilli that forms a native to this body niche are the a-hemolytic normal part of the human flora: Haemophilus streptococci. This group includes Streptococcus species, Aggregatibacter actinomycetemcomitans, mitis, Streptococcus mutans, Streptococcus milleri Cardiobacterium hominis, Eikenella corrodens and Streptococcus salivarius. It is believed that and Kingella species. All of these Gram-negative these bacteria act as antagonists against invasion bacteria are part of the normal oropharyngeal by pathogenic streptococci. Additionally, cultures flora, which grow slowly, prefer a carbon dioxide- from this region usually show large numbers of enriched atmosphere and share an enhanced diphtheroids, Moraxella (formerly Branhamella) capacity to produce endocarditis, especially catarrhalis, Neisseria species and HACEK in children and young adults. Based on large organisms, such as Kingella. Invasive infections reviews, HACEK organisms are responsible for in young children are frequently caused by approximately 3–10% of cases of native valve- organisms carried asymptomatically in the infective endocarditis [18]. Because of their respiratory tract [27,28]. Similar to Streptococcus fastidious and slow growth, they are often a pneumoniae, Haemophilus influenzae type b or cause of culture-negative endocarditis, although Neisseria meningitidis, K. kingae resides in the modern culture and genetic identification mucosal surface and is able to penetrate the techniques are challenging this paradigm. bloodstream, disseminate and invade distant organs [28–30]. Colonization of the respiratory tract Different strains of K. kingae by these organisms is, therefore, a prerequisite More than 450 strains of K. kingae have been for later invasion; human populations with high isolated from healthy carriers; these differents rates of carriage of these pathogens are also at strains were gathered in different studies on the increased risk of acquiring disease [28–31]. carriage of K. kingae conducted among children living in southern and central Israel during the Oropharyngeal carriage of K. kingae last 25 years [19–24]. Among them, 181 invasive K. kingae is a member of the normal commensal K. kingae strains have been isolated between flora of the oropharynx; it may be present on 1992 and 2012 from Israeli patients with bacte- tonsilar cultures, but it has never been isolated remia, skeletal system infections and endocar- from nasopharyngeal cultures, implying a ditis [20]. Although a great variety of K. kingae restricted anatomical niche [22]. Children usually

234 Future Microbiol. (2013) 8(2) future science group 30 years of study of Kingella kingae: post tenebras, lux Review first acquireK. kingae after the age of 6 months; Box 1. Asymptomatic oropharyngeal carriage of Kingella kingae. the colonization rate then increases among infants aged between 12 and 24 months, and Kingella kingae is a member of the normal commensal flora of the oropharynx finally declines among older children and adults Its anatomical niche is the tonsillar bed [22,27]. The fact that the colonization rate declines Children usually first acquire K. kingae after the age of 6 months in older children and adults probably suggests (maternal‑derived immunity) an age-related immune response that eradicates The colonization rate increases among infants aged between 12 and 24 months the organism from the pharynx in older people (9–12%) The colonization rate declines among older children and adults (age-related [22,27]. The carriage rate among children less than 4 years of age and older children is immune response that eradicates the organism from the pharynx in older people) approximately 10 and 6%, respectively. The Oropharyngeal carriage is a prerequisite for later invasive K. kingae infections colonization rate is probably largest between the ages of 12–24 months, reaching 9–12% Mechanisms of invasive infections [27,32–34]. There are no sex differences in the rate Concomitant viral infections of carriage of K. kingae (Box 1) [27]. Although the current knowledge of the pathogenesis of K. kingae remains incomplete, Transmission in the community available evidence suggests that interactions The results of many studies strongly support occur with viral infection. Concomitant upper child-to-child transmission of K. kingae respiratory tract infection and stomatitis, among young children [21,24,35], and that 50% including varicella-induced oral ulcers, are of children carry this microrganism for long frequently present in affected patients [38–43]. It periods (at least twice during a 12-month seems that K. kingae organisms colonizing the follow-up period) [36]. Because, on average, oropharynx penetrate a mucosal layer previously young children put their hands or objects in damaged by a viral disease [18]. The bacterium their mouth once every 3 min, commensal might then progess throughout the airways, respiratory organisms such as K. kingae that causing lower respiratory tract infection and/or are disseminated by large droplets are likely invade the bloodstream [18]. Transient benign to spread to young children who share toys bacteremia may follow and the bacterium coated with saliva [23,37]. In addition, many viral might be seeded in the endocardium, joint infections that occur in daycare centers (DCCs) space, bone or intervertebral discs, resulting in can increase child-to-child transmission of a focal suppurative infection [18]. The reasons for K. kingae through contaminated respiratory the striking predilection of K. kingae for these secretions [23]. DCC attendees frequently exhibit localizations remain unknown [18]. the same strain continuously or intermittently for weeks or even months, which is then replaced Type IV pili expression by a new strain, suggesting that this carriage An essential step in both colonization of the is a dynamic process with a frequent turnover respiratory tract and seeding of distal sites is of strains [21]. It is important to highlight adherence to tissues, including the respiratory that a few strains recovered at the level of the epithelium and the synovium [44,45]. K. kingae oropharynx of DCC attendees are genotypically expresses type IV pili that are essential for medi- indistinguishable from organisms from patients ating adherence to respiratory epithelial and with invasive infections, thus suggesting that synovial cells, presumably facilitating the colo- some children may be asymptomatic carriers of nization of the respiratory tract and the seeding potentially virulent K. kingae strains [21]. The of joints [44]. Previous work described the pres- correlation between asymptomatic carriage and ence of two K. kingae colony types called spread- the subsequent incidence of invasive infections, ing/corroding and nonspreading/noncorroding, such as osteoarticular infections (OAIs), which correlate with high- and low-density pili- remains unclear. A recent study demonstrated ation, respectively. Kehl-Fie et al. observed an that the probability for asymptomatic children additional spontaneously occurring colony type carrying K. kingae in the oropharynx to develop that correlated with the absence of pili and a an OAI due to this pathogen is lower that 1%. lack of bacterial adherence [46]. This nonpiliated Oropharyngeal carriage of K. kingae does not colony type is similar in size to the nonspread- imply the subsequent development of invasive ing/noncorroding colony type, but is slightly infection, but suggests that other cofactors more domed and lacks any fringe, and is virtu- may play a role in the pathogenesis of invasive ally identical to the colonies produced by pilA1 K. kingae infections [32]. mutants [46]. In the same study, Kehl-Fie et al.

future science group www.futuremedicine.com 235 Review Ceroni, Dubois-Ferrière, Cherkaoui et al.

found that a high percentage of respiratory and gene, which encodes the RTX toxin [48], and nonendocarditis blood isolates and a low per- a few studies have demonstrated that the most centage of joint fluid, bone and endocarditis virulent strains of the species harbored a 33‑bp blood isolates expressed pili [46]. Additionally, duplication or triplication in their rtxA sequence, they observed that only piliated isolates were suggesting that this genetic trait could represent capable of adherence to respiratory epithelial a genetic determinant of virulence [48,49]. Finally, and synovial cells. They also discovered that Bendaoud et al. reported that K. kingae forms the major pilus subunit PilA1 displays a rela- biofilms in a microtiter plate assay [50]. Biofilm tively high degree of strain-to-strain variabil- formation is likely to play an important role in ity in sequence [46]. Recent work demonstrated the ability of K. kingae to colonize the pharynx that K. kingae type IV pili are regulated by a and the oral cavity and therefore might be transcription factor called s-54 and by a two- crucial in the pathogenesis of septic arthritis, component sensor/regulator system referred to osteomyelitis, endocarditis and other localized as PilS/PilR [45]. A recent study described a novel infections caused by K. kingae [50]. adherence mechanism that allows K. kingae to adhere efficiently to human epithelial cells while Epidemiology remaining encapsulated and thus more resis- Prevalence of invasive infections due to tant to immune clearance [12]. These authors K. kingae discovered a novel surface protein called Knh Invasive K. kingae infections particularly affect that mediates K. kingae adherence of organisms children between 6 and 48 months of age, and lacking pili; thus, pilus retraction is necessary over 60% of episodes occur below the age of for maximal Knh-mediated adherence in the 2 years [16,51–55]. The annual incidence of invasive presence of the capsule [12]. infections due to K. kingae ranged from 9.4 to 27.4 per 100,000 children aged under 4 years RTX toxin production [36,56], and peaked in the 6–11‑month-old group The pathogenesis of K. kingae, including (40.3 cases/100,000) [57]. An interesting study invasion of the bloodstream and osteoarticular has demonstrated that antibody concentrations damage, has been related to the production of to K. kingae outer membrane proteins were a potent cytotoxin, RTX. This toxin has been high at 2 months of age, reached nadir values shown to be responsible for in vitro cytoxicity on at 6–7 months of age, remained low until the respiratory epithelial, synovial and macrophage- age of 18 months and gradually increased in like cells, with sensitivity levels up to fourfold older children [57,58]. This pattern represents higher for synovial and macrophage-like cells a mirror image of the age-related incidence of than for respiratory cells [47]. The RTX locus invasive K. kingae infections. The low attack from K. kingae strains is comprised of the rate in the first 6 months of life is suggestive tolC, rtxA, rtxC, rtxD and rtxB genes, which of maternally derived immunity [57,58]. The are necessary for the production and secretion increased incidence of invasive infections in of an active RTX toxin [47]. Disruption of 6–24-month-old children coincides with the the K. kingae RTX locus results in a loss of age at which antibody values are lowest. Finally, cytotoxicity for respiratory epithelial, synovial increasing antibody levels among older children and macrophage cell lines [47]. The K. kingae probably represents cumulative exposure to rtxA, rtxC and rtxB genes encode proteins that K. kingae antigens, resulting in the decline of have more the 70% identity with their Moraxella clinical infections [57,58]. Therefore, occurrence bovis homologs. The two remaining genes in of invasive infections beyond the fourth year of the locus – tolC and rtxD – encode proteins age occurs predominantly among children with with substantial homology to their M. bovis chronic health conditions, such as underlying homologs, but even greater homology to their immunodeficiency or chronic inflammatory N. meningitidis counterparts [47]. The results diseases (e.g., amyloidosis or systemic lupus of the homology analysis therefore suggest erythematous) [59]. that the K. kingae RTX locus was acquired via horizontal gene transfer from common donor Rate of invasive infections due to organisms, such as M. bovis or N. meningitidis K. kingae considering respiratory [47]. All K. kingae clinical strains possess the carriage rtxA toxin gene, making this gene a relevant In an epidemiological study conducted between target to diagnose K. kingae infection by PCR. 1998 and 2002, the prevalence of respiratory However, there is a polymorphism of the rtxA carriage of K. kingae (detected on throat swabs

236 Future Microbiol. (2013) 8(2) future science group 30 years of study of Kingella kingae: post tenebras, lux Review sent for isolation of Streptococcus pyogenes) did not seem to be unable to survive in the bloodstream differ between the February–May (4.3%) and for long, focal bacteremia due to this strain is October–December (2.0%) periods in young therefore unusual. children, even if a difference (not statistically K. kingae nonfocal bacteremia without evi- significant) in carriage rate was noted [27]. dence of invasive infection has been observed Another study showed that monthly respiratory most frequently in children [18,56,58,60], and carriage demonstrated peaks in December and clone K organisms are probably the more fre- April [22]. Nevertheless, it is important to note quent etiologic agents of these bacteremias [20]. that the period of the year when the prevalence A maculopapular rash resembling disseminated of the organism in the respiratory tract seems meningococcal or gonococcal infection may be maximal does not coincide with that of invasive present [61], the mean maximal fever is 39°C and infection [27]. Whereas almost three-quarters the mean erythrocyte sedimentation rate reaches of patients with invasive K. kingae disease 50 mm/h [58]. Patients with K. kingae nonfocal are diagnosed between July and December, bacteremia should be studied in order to exclude the oropharyngeal carriage usually shows an invasive infection. Because of the risk for endo- an opposite, albeit not significant, trend [27]. carditis, for example, evaluation of all patients The same authors postulated that exposure with K. kingae bacteremia in order to exclude of children to antibiotics (for streptococcal endocardial invasion has been strongly advocated pharyngitis or respiratory infections) probably [59]. Patients with K. kingae nonfocal bacteremia accounts for the unexpected low carriage rate without endocarditis respond favorably to a short found in the October–December period [27]. It course of antibiotics [18,60]. appears then that the striking epidemiological features of invasive K. kingae infections cannot Bacterial endocarditis be explained on the basis of the characteristics K. kingae is included in the HACEK group of of the respiratory carriage of the organism, and organisms that are collectively responsible for up therefore, additional factors should be present. to 5% of cases of bacterial endocarditis [28]. Since Most of the time, signs of upper respiratory the first description ofK. kingae endocarditis by tract infection, stomatitis or diarrhea are Christensen and Emmanouilides in 1967 [62], found on admission in many children who close to 50 cases have been reported involving later demonstrate invasive K. kingae infection. native as well as prosthetic valves [63]. In contrast This suggests that the peculiar epidemiological to other K. kingae infections, endocarditis features of invasive K. kingae infections result is diagnosed primarily in older children, from the interplay of the respiratory carriage of teenagers and adults [18,64]. In approximately the organism with viral infections and probably 50% of patients, there is a predisposing cardiac other still-unidentified factors [27]. malformation or rheumatic heart disease, and typically the left side of the heart in involved, Clinical presentation of K. kingae usually the mitral valve [28]. Fever and acute- infections phase reactants seem to be more elevated in Transient nonfocal bacteremia patients with endocarditis compared with those As mentioned previously, K. kingae is able to with uncomplicated bacteremia, even if there is penetrate a mucosal layer previously damaged currently no cutoff value that can distinguish by a viral disease and to invade the bloodstream. accurately between the two conditions [28,56]. In Transient bacteremia is thus a prerequisite for many patients with endocarditis due to K. kingae, an invasive infection, as it enables the bacte- valve replacement is not always necessary, since rium to be seeded in distant organs. Therefore, the response to antimicrobial therapy is good if concomitant infections of the skeletal, respira- administered quickly [63]. However, serious life- tory, vascular or central nervous systems may threatening complications may happen, such as be present in most of these patients, even if a destruction of heart valves, cardiac failure, septic single focus is the rule in invasive K. kingae shock, mycotic aneurisms and cerebrovascular infections. Strains that show remarkable inva- accidents, and the overall mortality rate remains siveness for bone or joint tissues are usually high, at approximately 15% [18,28,56,58,63,65–69]. rapidly cleared from the respiratory tract and For these reasons, echocardiographic evaluation the bloodstream, implying that persistence in of patients from whom the organism is isolated blood may require a different biological spe- from a normally sterile site, especially blood, cialization [20]. As clone N organisms (which has been recommended by a few authors [70]. are responsible for arthritis and osteomyelitis) Bacterial endocarditis is strongly associated with

future science group www.futuremedicine.com 237 Review Ceroni, Dubois-Ferrière, Cherkaoui et al.

clone P organisms, which are seldom carried also interesting to highlight that the epiphysis asymptomatically and are rare in other infected or apophysis, which are almost never invaded sites [20,24]. by other organisms, may be commonly involved in K. kingae osteomyelitis [51,77,85,88,89]. Today, Osteoarticular infections K. kingae is probably responsible for many cases Since the 1980s, the reported number of cases of of hematogenous spondylodiscitis in children K. kingae OAIs has markedly increased, mainly younger than 4 years of age [90–93]. Patients owing to improvements in culture techniques usually present with limping, back pain, refusal [16,71–76] and to the utilization of molecular to sit or walk, abdominal pain or, in rare methods [32,51–55,77–81]. Many studies have thus instances, neurologic symptoms. Most of the demonstrated that K. kingae has become the time, infection involves the lumbar discs, and major bacterial cause of OAIs in children aged radiograph or MRI studies reveal narrowing of between 6 and 48 months; this microorganism the intervertebral space. is currently recognized to account for 30–93.8% Onset of K. kingae OAIs may be insidious, of all culture-positive OAIs [18,32,51–54,77]. and the disease is frequently diagnosed with However, the presentation of K. kingae OAIs considerable delay (after more than 1 week in is often characterized by a mild-to-moderate 70% of patients) [51,55,64,75]. As described pre- clinical and biologic inflammatory responses viously, the clinical course is usually better for to infection, with the consequence that these children with OAIs due to K. kingae than with children present few, if any, criteria evocative other classical pathogens, as evidenced by shorter of OAIs. In fact, only 10–33% of children hospitalization and fewer adverse events. Some with OAIs caused by K. kingae have a body reports even suggest that transient involvement temperature ≥38°C at admission [51–53,55,77], of the skeletal system during an episode of and most patients have normal or near normal K. kingae bacteremia may occur, and that fever white blood cell counts and C-reactive protein and skeletal complaints may resolve without levels [51,52,58,77]. Erythrocyte sedimentation rate antimicrobial therapy, thus supporting an abor- and platelet counts seem to be the most sensitive tive clinical course [15,82,94]. Evolution towards markers of inflammation when a K. kingae chronic osteomyelitis and orthopedic sequelae OAI is present [51,77]. A model to allow the seems to be uncommon [18,75,95], but not impos- differentiation of K. kingae OAIs from those due sible, as any case may develop serious epiphyseal to typical pathogens, in children aged less than lesions [Ilharreborde B, Unpublished data]. Caution 4 years of age, has been described and consists is therefore recommended, and adequate anti of the following four parameters: temperature at biotics should be administered to all patients for admission <38°C; C-reactive protein <55 mg/l; whom the organism is recovered from a normally 3 white blood cell count <14,000 leukocytes/mm ; sterile body fluid (Box 2) [28]. 3 and band shift <150 forms/mm [77]. This model is a subject of controversy, but it highlights the Culture detection of K. kingae need for prospective studies to better define the The primary isolation of K. kingae from joint, clinical presentation according to the children’s bone or blood samples appears to be strongly age and the causative organisms. dependent on the methodology used [87]. In fact, K. kingae septic arthritis generally involves the recovery of K. kingae from purulent specimens the large weight-bearing joints such as the hip, seeded onto solid culture media is suboptimal knee, ankle, shoulder or elbow [18,51–53,58,77]. and most of the time results in a frustrating In addition, atypical joints such as small proportion of negative cultures [18,32,51,77,87]. metacarpophalangeal/metatarsophalangeal, The yield of cultures has been significantly sternoclavicular, acromioclavicular or tarsal improved by inoculating clinical specimens into joints are overrepresented in K. kingae arthritis aerobic blood culture vials [73,76] from a variety of compared with septic arthritis due to other automated or manual blood culture systems such pathogens [18,51–53,58,77,82]. The anatomical as BACTEC™ (Becton Dickinson, MD, USA) ® sites involved in patients with K. kingae [18,87], BacT/Alert (Organon Teknika Corp., osteomyelitis include long bones, such as NC, USA) [72–75], Isolator™ 1.5 Microbial the femur, tibia, humerus, radius and ulna Tube (Wampole Laboratories, NJ, USA) [16] [51–53,77,83–87]. Nevertheless, any bone rarely or Hemoline™ DUO (bioMérieux, France) infected by other pathogens, such as the [71,96]. However, no controlled study has been calcaneum, talus, sternum or clavicle, may also performed to identify the best blood culture be affected by K. kingae osteomyelitis [18]. It is system for this purpose [18]. When positive

238 Future Microbiol. (2013) 8(2) future science group 30 years of study of Kingella kingae: post tenebras, lux Review blood culture bottles are subcultured onto blood Box 2. When to suspect a Kingella kingae invasive osteoarticular agar or chocolate agar plates, K. kingae usually infection. grows without any difficulty, demonstrating that routine solid media are able to support Children aged between 6 and 48 months its nutritional requirements. The hypothesis Presence of concomitant viral infections (upper respiratory tract infection, for explaining this contradictory phenomenon stomatitis or diarrhea) suggests that exudates exert an inhibitory effect Oropharyngeal carriage of Kingella kingae on the bacterium and that dilution of purulent Osteoarticular infection with mild clinical presentation samples in a large volume of broth may decrease Osteoarticular infection with subnormal acute-phase reactants (only erythrocyte the concentration of such inhibitory factors, sedimentation rate and platelet counts may be affected) thus improving the recovery of this fastidious Involvement of atypical joints (e.g., sternoclavicular, acromioclavicular joints or spondylodiscitis) organism [87]. Nevertheless, even when blood culture vials are used for culturing synovial fluid Involvement of epiphysis or apophysis aspirates, K. kingae is isolated in only 37.5–67% of children with proven arthritis [52,54,55,83], cross-reactivity with several related species and which indicates that PCR detection of this common osteoarticular pathogens [80]. organism should be routinely used to improve Ideally, three bacteriological investigations the bacteriological diagnosis. should be performed when a K. kingae invasive infection is suspected. First, the presence of Detection of K. kingae by PCR assay K. kingae should be proven by a real-time PCR In recent years, molecular diagnosis of K. kingae assay. Second, one should keep materials and infections by novel nucleic acid amplification perform a broad-range 16S rRNA gene PCR techniques has enabled the identification of assay when the precedent test is negative in order K. kingae in invasive infections within 24 h to exclude infections caused by other fastidious [32,51,53,77,82,97]. There are currently two differ- microorganisms. Third, clinical specimens ent nucleic acid amplification approaches. The should be inoculated into aerobic blood culture broad-range 16S rRNA gene assay involves vials for studying the organism’s antibiotic extracting DNA from clinical samples, incu- susceptibility profile (Box 3). bating the DNA with broad-range oligonucleo tide primers that anneal to constant regions of Antibiotic susceptibility of K. kingae the 16S rRNA gene and amplification of the The susceptibility of K. kingae to antimicro- intervening sequence, which varies accord- bial drugs that are commonly administered to ing to the bacterial species [97]. The resulting children with confirmed or suspected invasive amplification products are either sequenced infection has been better recognized over recent and compared with sequences in the GenBank years. K. kingae is considered highly susceptible database or hybridized with organism-specific to penicillin, ampicillin, second- and third- probes [28]. Some authors have reported detec- generation cephalosporins, macrolides, cotri- tion of K. kingae from culture-negative speci- moxazole, ciprofloxacin, tetracyclineand chlor- mens by using broad-range PCR amplifica- amphenicol [18,28]. Occasional in vitro resistance tion [54,55,83,98]. The use of the broad-range to erythromycin, cotrimoxazole and ciprofloxa- 16S rRNA gene assay offers the tremendous cin has been reported [17,64,99–101]. The organ- advantage of not requiring any a priori knowl- ism exhibits decreased susceptibility to oxacil- edge of the causative bacteria. However, this lin and clindamycin [17,61], and is fully resistant method is hampered by an insufficient sensi- to trimetoprim and vancomycin [17,64,99–102]. tivity to detect all agents directly from clinical samples, as the analytical sensitivity of Box 3. Bacteriological investigations of suspected Kingella kingae the broad-range 16S rRNA gene PCR is only invasive infections. 300 CFU [80]. Currently, real-time PCR assays Take samples of normally sterile body fluid (joint fluid, bone aspirate or blood that amplify K. kingae-specific targets such as samples) cpn60 or RTX toxin genes have been devel- Perform usual cultures in order to exclude classical pathogens oped and are associated with high reliability Perform a specific PCR assay to confirm or infirm the presence of Kingella kingae [32,51–53,77,80]. Real-time PCR assays that are Keep residual material to perform a broad-range 16S rRNA gene PCR when the specific to K. kingae targets, such as the RTX precedent test is negative in order to exclude infections due to other fastidious toxin, are tenfold more sensitive than the broad- microorganisms range 16S rRNA gene PCR (30 vs 300 CFU) Inoculate a part of the sample into aerobic blood culture vials for studying the organism’s antibiotic susceptibility profile [80]. In addition, this assay does not show any

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Yagupsky et al. demonstrated that 38.5% of levels of acute-phase reactants, and therefore, isolates from respiratory carriers and patients these parameters can often not be used to guide with invasive infection contained K. kingae switching to oral antibiotics and defining the strains that were resistant to clindamycin [17]. duration of treatment. Third, some reports More worrying is the discovery of the produc- even suggest that invasive K. kingae infections tion of b-lactamase found in an isolate recovered may resolve without treatment, and question from an HIV-positive patient in the USA [103] the necessity of antimicrobial therapy [15,82,94]. and in three isolates from children in Iceland However, this statement has to be considered [104]. The culture detection of K. kingae, even to be controversial, since K. kingae organisms when inoculating the samples from infected may be seeded elsewhere more easily, causing joint or bone directly into blood culture vials, more precarious complications. Thus, patients remains suboptimal. In addition, as a result of from whom the organism is recovered from a the widespread use of nucleic acid amplification normally sterile body site should be treated. assays, the susceptibility of the organism to anti Many patients with skeletal system involvement microbial drugs that are administred to children respond promptly to conservative treatment with invasive infection due to K. kingae is being with appropriate antibiotics, but we currently less frequently investigated. Therefore, in many continue to perform surgical procedures clinical situations, clinicians do not have any (especially taking samples for bacteriology) information about the antibiotic susceptibility in these cases only to confirm that there is no profile of the organism, with the potential risk pyogenic infection. of an antimicrobial-resistant organism infection being treated ineffectually. On this subject, a Recommended antibiotic regimes recent study demonstrated that the throat- Drug therapy for OAIs usually consists of intra- isolated strain was responsible for arthritis, venous administration of nafcillin or a second- or and thus highlighted the possibility of isolat- third-generation cephalosporin while pending ing the K. kingae strain responsible for arthritis culture results [51,53,60], whereas some authors using throat swabs with significant effectiveness still recommend oxacillin despite K. kingae [105]. Thus, there is a real interest performing demonstrating decreased susceptibility to this throat swabs to isolate the bacteria and study its antibiotic [53]. In areas in which community- antimicrobial sensitivity. associated methicillin-resistant Staphylococcus aureus is prevalent and when the clinical pre- Treatment sentation of OAIs is acute, a combination of a General considerations about antibiotic b-lactam antibiotic and vancomycin may be sug- treatment gested [106]. Clinical response and acute-phase Today, there are still too few controlled studies reactants (when abnormal) are then used to guide that permit the formulation of evidence-based switching to oral antibiotics (usually after 3 days) recommendations on the preferable antibiotic, and defining the duration of therapy. Antiobiotic on the necessity or not to research the bacterium’s treatment generally varies from 2 to 3 weeks for production of b-lactamase and on the optimal K. kingae arthritis, from 3 to 6 weeks for osteomy- length of therapy for K. kingae disease [28]. elitis and from 3 to 12 weeks for spondylodiscitis However, the antimicrobial drug resistance [18]. However, in the future, we can expect that profile of the organism is quite consistent and OAIs due to K. kingea, characterized by subacute predictable [17,64,99–102] and, with the exception course and low bacterial concentrations, could be of cases of endocarditis, infections promptly treated by shorter oral antibiotherapy. Patients respond to antibiotics that are empirically with K. kingae bacteremia are treated with an administered to young febrile children or those intravenous b-lactam antibiotic, which is subse- with presumptive skeletal system infections. quently switched for an oral b-lactam once the Nevertheless, the treatment of invasive K. kingae clinical situation has improved. Usually, the total infections faces three unexpected problems. duration of treatment ranges from 1 to 2 weeks First, most of the infections due to K. kingae [18,60]. Patients with K. kingae endocarditis must are currently detected by novel nucleic acid be treated longer with an intravenous b-lactam amplification techniques, and clinicians often alone or in combination with an aminoglycoside do not have any information about the antibiotic for 6–7 weeks. In rare cases, early surgical pro- susceptibility profile of the organism. Second, cedures may be mandatory for life-threatening the clinical presentation of K. kingae disease complications that are unresponsive to medical is subtle and may be associated with normal therapy [18,28,56,58,63,65–69].

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Prophylactic treatment in cases of normal acute-phase reactants. There is thus outbreaks of invasive infections among a need for new diagnostic tests in order to child DCC attendees improve the diagnosis of these infections. The Young children in DCCs have an excess of next years will probably see the emergence of infectious morbidity, especially of that caused noninvasive methods for diagnosing invasive by respiratory organisms [23]. Enhanced trans- K. kingae infections. As mentioned previously, mission of bacterial pathogens in this setting a recent study demonstrated that the throat- is related to a complex inter-relation between isolated strain was responsible for arthritis and increased exposure to these microorganisms thus highlighted the possibility of isolating and the immunologic status of this particu- the K. kingae strain responsible for the lar population [23]. Thus, dissemination of arthritis using throat swabs with significant K. kingae in a young susceptible population effectiveness [105]. In another forthcoming may result in ‘veritable’ outbreaks of invasive study, the authors demonstrate that a simple disease [23,68,107]. Although no treatment is cur- technique of detecting K. kingae DNA in the rently recommended to eliminate the carriage oropharynx can provide strong evidence that state, clusters of K. kingae invasive infections this microorganism is responsible for the OAIs, in children attending DCC facilities raise ques- or even stronger evidence that it is not [108]. tions about the management of contacts in Although these results need to be validated by this setting, and thus represent a public health other prospective studies, one can legitimately consideration. Even if solid data are still lack- expect that the use of novel microbiologic ing, many authors consider it more prudent to methods will improve the indirect identification offer empiric antimicrobial therapy to close of K. kingae. This is particularly useful because contacts of infected children in case of out- most children with K. kingae OAIs respond breaks of invasive infections due to K. kingae promptly to conservative treatment with in DCCs [23,68,107]. Similar to N. meningitidis, appropriate antibiotics and do not require prompt administration of antibiotic prophy- invasive surgical procedures. Therefore, we laxis is therefore advised when a case of inva- believe that the results of the oropharyngeal sive disease is detected in the daycare setting swab PCR might become an early decision- [23,68,107]. Most of the time, contacts of infected making tool for treating K. kingae OAIs in children receive prophylaxis with rifampicin young children in a near future. By using a (10 mg/kg) orally twice daily for 2 days [68,107], combination of oropharyngeal swab PCR tests, but one must keep in mind that prophylactic the predictive score for K. kingae and radiologic rifampicin is only moderately successful (67%) investigations [89], when appropriate, it should in eliminating K. kingae colonization [107]. become possible to achieve a higher accuracy of invasive infection diagnosis at lower cost, in Future perspective less time and with less danger and distress for The use of specific PCR assays has completely the patient [108]. revolutionized the diagnosis of K. kingae and Last but not least, one field of investigation changed the microbiological ecology for OAIs has recently focused on the differences of in young children. Since the early 1990s, there pathogenicity of K. kingae strains. In fact, it is has been an explosion of reports of K. kingea currently thought that not all K. kingae strains disease, deriving mostly from European and have the same capacity to cause human disease, Israeli sources, whereas limited reports have and questions are being asked as to whether been described in the USA. This discrepancy certain clones are associated with particular is probably attributable to the fact that specific clinical syndromes. On this subject, a recent PCR assays are not in broad use in US hospitals. study demonstrated that five clones ofK. kingae However, we can expect that future studies (B, H, K, N and P) were responsible for the focusing on children aged between 6 and majority of the invasive infections, exhibiting 48 months and performing specific PCR assays genetic stability, long-term persistence and will demonstrate that OAIs due to K. kingae wide geographic dispersal [20]. Recently, an are a worldwide phenomenon among young animal model has been developed and may children. contribute to the discrimination between high- Improving recognition of infections due to and low-virulence clones in the future, and K. kingae is the next problem to resolve, since would point to clones to be further investigated the clinical presentation of K. kingae disease in order to identify genetic determinants of is often subtle and may be associated with virulence [49].

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Executive summary Bacterial characteristics of Kingella kingae Kingella kingae is a Gram-negative bacterium and a member of the normal flora of the oropharynx. More than 450 strains of K. kingae have been isolated. Five of these strains (B, H, K, N and P) are responsible for most invasive infections. Mechanisms of infection Type IV pili expression is essential for mediating adherence to respiratory epithelial and synovial cells. Pathogenesis is related to the production of a potent cytotoxin, RTX. Interactions occur with viral infections. Invasive infections due to K. kingae K. kingae is the major bacterial cause of osteoarticular infections in children less than 4 years of age. All patients with bacteremia have to be evaluated in order to exclude endocardial invasion. Endocarditis due to K. kingae may develop into serious life-threatening complications. Detection of K. kingae Improvement of the yield of cultures can be obtained by inoculating clinical specimens into aerobic blood culture vials. PCR assays specific to K. kingae targets are tenfold more sensitive than broad-range 16S rRNA gene PCR. Detecting K. kingae DNA in the oropharynx can provide strong evidence that this microorganism is responsible for invasive infection. Treatment Drug therapy consists of the administration of b-lactam or a second- or third-generation cephalosporin. Antibiotic treatment duration varies from 2 to 4 weeks for osteoarticular infections, 1 to 2 weeks for nonfocal bacteremia and 6 to 8 weeks for endocarditis. No treatment is currently recommended to eliminate the carriage state.

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