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MICROBIOLOGY

The genus Klebsiella consists of non-motile, aerobic and facultatively anaerobic, Gram negative rods. At the time of writing, the genus Klebsiella comprises K. pneumoniae subsp. pneumoniae, K. pneumoniae subsp.ozaenae, K. pneumoniae subsp. rhinoscleromatisK. oxytoca, K. ornithinolytica, K. planticola, and K. terrigena (1). However, comparison of the sequences of each species shows that the genus is heterogeneous, and may be more reasonably arranged in three clusters (76). Cluster 1 contains the three subspecies of K. pneumoniae, cluster 3 contains K. oxytoca and cluster 2 contains the other species (which are notable for growth at 10° C and utilization of L-sorbose as a carbon source). It has been proposed that the genus Klebsiella be divided into two genera and one genogroup, with the name Raoultella being the genus name for those organisms in cluster 2 (76).

For the purpose of conforming to current clinical usage, the clinically important species and subspecies will be referred to as K. pneumoniae, K. ozaenae, K. rhinoscleromatis and K. oxytoca in this chapter.

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EPIDEMIOLOGY

Klebsiella spp. are amongst the most common causes of a variety of community-acquired and hospital-acquired infections. K. pneumoniae is an important emerging pathogen in community-acquired liver abscess worldwide, especially in Taiwan, Asia and the USA (36,55,66,150,190). The prevalence rate of K. pneumoniae in pyogenic liver abscess is as high as 78% in Taiwan and 41% in the USA (55, 218,267). They rank fourth as causes of intensive care unit (ICU) acquired pneumonia, fifth as causes of ICU acquired bacteremia and sixth as causes of ICU acquired urinary tract infection (225). K. pneumoniae is the leading cause of disease followed by K. oxytoca. K. ozaenae and K. rhinoscleromatis are rarely isolated, but can cause defined clinical syndromes (ozena and rhinoscleroma, respectively). K. ornithinolytica and K. planticola are rare causes of disease (178). K. terrigena (like K. pneumoniae on occasion) can be grown from soil and water; it can also be grown from human feces and from clinical specimens (1). It possesses a number of the virulence characteristics of K. pneumoniae (211) so is likely to be an occasional cause of disease.

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CLINICAL MANIFESTATIONS

Hospital-acquired Klebsiella infections are not easily distinguished clinically from other bacterial causes of infection. However, community-acquired Klebsiella infections do have some characteristic features. Traditionally,Klebsiella has been regarded as an important cause of community-acquired pneumonia. The classic clinical presentation is dramatic: toxic presentation with sudden onset of high fever and hemoptysis (currant jelly sputum). Chest radiographic abnormalities such as bulging interlobar fissure and cavitary abscesses are prominent (118, 146). Recent work suggests that community-acquired Klebsiella pneumonia is now exceedingly rare in North America, Western Europe and Australia (accounting for less than 1% of cases of pneumonia requiring hospitalization) (143). However the classic syndrome of bacteremic Klebsiella pneumonia remains common in Asia and Africa. In these regions there is an association of the syndrome with alcoholism, although previously healthy people have been affected (143).

An unusual invasive presentation of Klebsiella infection has also been described, occurring particularly in Asia (especially Taiwan). The predominant manifestation is liver abscess occurring in the absence of underlying hepatobiliary disease (36,55,59,143, 288). Seventy percent of such patients have diabetes mellitus. In some patients, other septic metastatic lesions are observed including endophthalmitis, pyogenic meningitis, brain abscess, septic pulmonary emboli, prostatic abscess, osteomyelitis, septic arthritis or psoas abscess.

K. oxytoca can produce community-acquired infections similar to those produced by K. pneumoniae but is substantially less common. K. rhinoscleromatis produces rhinoscleroma, a rare granulomatous infiltration of the mucosa of the nose and upper respiratory system (7). Cases have been reported in patients with human immunodeficiency virus (HIV) infection and in immigrants from parts of the world where the disease is endemic (202, 264). K. ozaenae may be responsible for a form of chronic atrophic rhinitis called ozena. K. ozaenae is also considered to be an opportunistic pathogen in immunocompromised hosts (65,145, 257).

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LABORATORY DIAGNOSIS

The members of the genus Klebsiella are Gram negative, nonmotile, facultative anaerobic rods ranging from 0.3 to 1.0 μm in width to 0.6-6.0 μm in length (1). Most strains grown readily on standard media, although occasionally cysteine requiring urinary isolates of K. pneumoniae are encountered. These strains will appear as pinpoint colonies on routine media, and require supplementation of media with cysteine for more adequate growth (1). The vast majority of Klebsiella spp. are encapsulated - contrary to popular belief it is probably not capsule which primarily contributes to the mucoid appearance that some Klebsiella strains exhibit.  The Klebsiella which has been linked to the invasive syndrome presenting as liver abscess have a mucoid appearance.

In practice, K. pneumoniae and K. oxytoca are distinguished by indole production by K. oxytoca but not K. pneumoniae. It should be noted however that K. ornitholytica is also an indole producer. The five clinically important species can be distinguished by tests for indole production, ornithine decarboxylase production, he Voges-Proskauer reaction, malonate utilization and o-nitrophenyl-β-D-galactopyranoside (ONPG) production (1).

Production of plasmid-mediated extended-spectrum beta-lactamases (ESBLs) by Klebsiella spp. has become a major problem (197). The nature and characteristics of ESBLs are described in greater detail below. Detection of ESBLs in clinical isolates of Klebsiella spp. is problematic since a significant proportion of ESBL producing isolates appear susceptible to third generation cephalosporins or aztreonam. Yet, poor clinical outcomes have been observed when these same antibiotics have been used to treat serious infections due to apparently susceptible ESBL producers (198). A single surrogate marker for ESBL production, such as ceftazidime resistance, is insufficient for the detection of ESBLs. Virtually all reliable laboratory tests used for detection of ESBLs rely on the change in in vitro activity of oxyimino containing beta-lactams in the presence of a beta-lactamase inhibitor such as clavulanic acid. Examples of ESBL detection methods include the double disk diffusion test, Etest strips containing ceftazidime or cefotaxime with and without clavulanic acid, the Vitek ESBL detection card and the Microscan ESBL plus detection system (34). Clinical and Laboratory Standards Institute (CLSI) has also developed screening and confirmatory tests for detection of ESBLs (67). It should be noted that these are standardized for K. pneumoniae and K. oxytoca only.

In some circumstances there is a need to detect ESBL producing Klebsiella spp. from stool or rectal swabs. Examples of such media include Drigalski agar supplemented with cefotaxime 0.5 mg/L (246), MacConkey agar supplemented with ceftazimide 4 mg/L (205) and nutrient agar supplemented with ceftazimide 2 mg/L, vancomycin 5 mg/L and amphotericin B 1667 mg/L (106).

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PATHOGENESIS

Members of the genus Klebsiella usually have prominent capsules composed of complex acidic polysaccharides. Capsules appear essential to the virulence of Klebsiella, protecting the bacterium from phagocytosis by neutrophils and preventing killing of the bacteria by bactericidal serum factors (212). Strains expressing capsular types K1 or K2 may be particularly virulent. We have demonstrated the high prevalence (63.4%) of serotype K1 in K. pneumoniae liver abscess and 85.7% in complicated endophthalmitis in which those K1 isolates are highly resistant to neutrophil phagocytosis (94, 158). Although Fang et al have identified a virulence gene magA that caused K. pneumoniae liver abscess and septic metastatic complications (84), they have not correlated the virulence between the gene and serotype specificity. Struve et al have further investigated the above correlation (251) and found that 495Klebsiella isolates from a worldwide collection isolated from unknown different sites, all 39 magA-positive isolates were of the serotype K1 and none of the 456 non-K1 serotypes contained magA. They concluded that magA is only restricted to the capsular gene cluster of serotype K1. We have sequenced the whole K1 capsular gene clusters and we have investigated on the prevalence of magA among serotypes K1, K2 and other serotypes from liver abscess patients. Our results with the results from Struve et al show that magA is only present in serotype K1 in liver and non-liver abscess isolates (285). In conclusion, the magA is a component of K1 capsule formation but is not an independent virulence gene in K. pneumoniae liver abscess. In contrast, K1 capsule is an important virulence factor for K. pneumoniae liver abscess. However some strains belonging to the K2 capsular serotype, for example, may be less virulent than others. This suggests that other pathogenicity factors may be present; possibilities include pili (fimbriae), siderophores and extracapsular polysaccharides.

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SUSCEPTIBILITY IN VITRO AND IN VIVO

Klebsiella pneumoniae

Single Drug In Vitro Studies

An overview of the susceptibility of K. pneumoniae to antimicrobial agents is given in Table 1. K. pneumoniaeis intrinsically resistant to penicillin, ampicillin, amoxicillin, oxacillin, carbenicillinand ticarcillin, with mean minimum inhibitory levels ranging from 200 to > 1000 mg/L (51). The vast majority of K. pneumoniae strains produce a chromosomally encoded SHV-1 beta-lactamase, which accounts for this resistance (14, 56). Some strains possess plasmid-mediated SHV-1, TEM-1 or TEM-2 beta-lactamases as well (14, 56). Strains that hyperexpress these beta-lactamases or produce both SHV-1 and TEM-1 may be resistant to piperacillin or first generation cephalosporins. Beta-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam are active against the SHV-1 and TEM-1 beta-lactamases of K. pneumoniae. However, clinical isolates have been described that are resistant to beta-lactam/beta-lactamase inhibitor combinations (27, 52, 100,152,186). One potential mechanism is production of inhibitor-resistant TEM (IRT) beta-lactamases (52). The IRT beta-lactamases differ from their parental TEM-1 or TEM-2 beta-lactamases by one, two or three amino acid substitutions at different locations. These substitutions are listed in detail at http://www.lahey.org/studies/temtable.htm.  Studies of IRT beta-lactamases produced by E. coli have shown that IRT-producers have high-level resistance to amoxicillin and ticarcillin (MIC90 > 4096 mg/L); addition of clavulanic acid reduces the MIC by only two dilutions. A lower degree of resistance was observed to piperacillin, and tazobactam substantially reduced the piperacillin MIC (52). An inhibitor-resistant beta-lactamase derived from a parent SHV enzyme has also been described (214). Of note is that IRT producers are usually susceptible to the third generation cephalosporins.

Although almost all isolates of K. pneumoniae were initially considered to be susceptible to cephalosporins, studies over the last two decades have shown variable susceptibility to this antibiotic class. This reduced susceptibility has been predominantly mediated by plasmid-mediated extended-spectrum beta-lactamases (ESBLs) and to a lesser extent, plasmid-mediated AmpC type beta-lactamases.

Extended spectrum beta-lactamases (ESBLs) were first described in Germany in 1983 (142). They were subsequently described in France (41, 243) and by the late 1980s numerous outbreaks had occurred in the United States (174,185,216), Australia (79,181) and many other parts of the world (69,123,208,230). These enzymes are now found in every inhabited continent. The ESBLs can confer resistance to third generation cephalosporins such ascefotaxime, ceftriaxone and ceftazidime, as well as the monobactam, aztreonam (208). The cephamycins (cefoxitin, cefotetan and cefmetazole) and the carbapenems (imipenem and meropenem) are not hydrolyzed by the ESBLs (208). It should be pointed out that the MICs for third generation cephalosporins or aztreonam may not reach widely used breakpoints for resistance with some ESBL producing isolates. The clinical significance of this is discussed below.

The molecular basis of extended spectrum beta-lactamases is most often mutation in the genes encoding the common plasmid-mediated SHV-1, TEM-1 and TEM-2 beta-lactamases (124). The resulting amino acid changes lead to alteration in the active site of these enzymes, thus expanding their spectrum of activity (204,245). A change in only one amino acid in the structure of a TEM beta-lactamase may dramatically alter the susceptibility to cephalosporins. At least one hundred such modifications of the TEM and SHV beta-lactamases have been described. An up to date listing of TEM and SHV beta-lactamases is maintained on the Internet by George Jacoby and Karen Bush at www.lahey.org/studies/webt.htm. 

A number of other ESBL types have been detected in K. pneumoniae which are not related to parent TEM or SHV beta-lactamases. The most prevalent of these is the CTX-M-type ESBLs. The name "CTX" is an abbreviation for cefotaximase. This reflects the potent hydrolytic activity of these beta-lactamases against cefotaxime. Organisms producing CTX-M type beta-lactamases typically have cefotaxime MICs in the resistant range (>64 μg/mL), whilst ceftazidime MICs are usually in the apparently susceptible range (2-8 μg/mL). Aztreonam MICs are variable. CTX-M-type beta-lactamases hydrolyze cefepime with high efficiency (269). Cephamycins and carbapenems are not appreciably affected. Tazobactam exhibits an almost 10-fold greater inhibitory activity than clavulanic acid against CTX-M-type beta-lactamases (42). It should be noted that the same organism may harbor both CTX-M-type and SHV-type ESBLs or CTX-M-type ESBLs and AmpC type beta-lactamases, which may alter the antibiotic resistance phenotype (282,283). Other non-TEM, non-SHV type ESBLs which have been described in K. pneumoniae include PER-2 (23) and GES-1 (213).

AmpC type beta-lactamases (also termed group 1 or class C beta-lactamases) are chromosomally encoded in organisms such as Enterobacter cloacae, Citrobacter freundii, Serratia marcescens and Pseudomonas aeruginosa. However in 1989, Bauernfeind et al described a K. pneumoniae isolate possessing a plasmid-mediated beta-lactamase, termed CMY-1, which had many characteristics of a class C beta-lactamase (24). In 1990, Papanicolaou et al described a novel plasmid-mediated beta-lactamase, termed MIR-1, produced by K. pneumoniae (193). The gene encoding MIR-1 was 90% identical to the ampC gene of E. cloacae. Subsequently numerous plasmid-encoded ampC beta-lactamases have been discovered in K. pneumoniae (207). These include FOX-1, 2 and 3, CMY-2, 4 and 8, MOX-1 and 2, DHA-1 and 2, LAT-1 and 2 and ACC-1 (207).

Strains with plasmid-mediated AmpC beta-lactamases are consistently resistant to aminopenicillins (ampicillin or amoxicillin), carboxypenicillins (carbeni


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