CLINICAL MICROBIOLOGY REVIEWS, Oct. 1998, p.589–603 0893-8512/98/$04.0010 Copyright © 1998, American Society for Microbiology. All Rights Reserved. Vol. 11, No. 4 Klebsiella spp. as Nosocomial Pathogens: Epidemiology, Taxonomy, Typing Methods, and Pathogenicity Factors R. PODSCHUN* AND U. ULLMANN Department of Medical Microbiology and Virology, University of Kiel, Kiel, Germany INTRODUCTION .......................................................................................................................................................589 EPIDEMIOLOGY .......................................................................................................................................................589 TAXONOMY OF THE GENUS KLEBSIELLA ......................................................................................................591 DIFFERENTIATION OF KLEBSIELLA SPECIES. ..............................................................................................591 TYPING OF KLEBSIELLA ISOLATES...................................................................................................................592 Biotyping ..................................................................................................................................................................592 Serotyping ................................................................................................................................................................592 Phage Typing ...........................................................................................................................................................592 Bacteriocin Typing ..................................................................................................................................................592 Molecular Typing Methods ...................................................................................................................................592 PATHOGENICITY FACTORS OF KLEBSIELLA .................................................................................................592 Capsular Antigens ..................................................................................................................................................593 Pili (Fimbriae).........................................................................................................................................................594 Type 1 (common) pili .........................................................................................................................................594 Type 3 pili ............................................................................................................................................................595 Serum Resistance and Lipopolysaccharide .........................................................................................................595 Siderophores ............................................................................................................................................................596 VACCINATION EFFORTS .......................................................................................................................................597 Lipopolysaccharides................................................................................................................................................597 Capsular Polysaccharides ......................................................................................................................................597 CONCLUDING REMARKS ......................................................................................................................................597 REFERENCES ............................................................................................................................................................598 by Klebsiella. The urinary tract is the most common site of infection. Klebsiella accounts for 6 to 17% of all nosocomial urinary tract infections (UTI) and shows an even higher incidence in specific groups of patients at risk, e.g., patients with neuropathic bladders or with diabetes mellitus (25, 133). As a cause of nosocomial gram-negative bacteremia, Klebsiella is second only to Escherichia coli (35, 70, 181, 258). In pediatric wards, nosocomial Klebsiella infections are especially troublesome—particularly in premature infants and intensive care units. Klebsiella species are often the pathogens involved in neonatal sepsis (Table 1), in both early-manifestation and late-manifestation infections (90). Due to the extensive spread of antibiotic-resistant strains, especially of extended-spectrum b-lactamase (ESBL)-producing strains, there has been renewed interest in Klebsiella infections. INTRODUCTION Klebsiella is well known to most clinicians as a cause of community-acquired bacterial pneumonia, occurring particularly in chronic alcoholics (40) and showing characteristic radiographic abnormalities (81) due to a severe pyogenic infection which has a high fatality rate if untreated. The vast majority of Klebsiella infections, however, are associated with hospitalization. As opportunistic pathogens, Klebsiella spp. primarily attack immunocompromised individuals who are hospitalized and suffer from severe underlying diseases such as diabetes mellitus or chronic pulmonary obstruction. Nosocomial Klebsiella infections are caused mainly by Klebsiella pneumoniae, the medically most important species of the genus. To a much lesser degree, K. oxytoca has been isolated from human clinical specimens. It is estimated that Klebsiella spp. cause 8% of all nosocomial bacterial infections in the United States and in Europe. No great geographical variations in frequency have been noted. In the United States, Klebsiella accounts for 3 to 7% of all nosocomial bacterial infections, placing them among the eight most important infectious pathogens in hospitals (104, 211), and data collected from the United Kingdom (26) and from Germany (242) are remarkably similar to those reported by the Centers for Disease Control and Prevention. Table 1 lists the most frequent nosocomial infections caused EPIDEMIOLOGY Klebsiella spp. are ubiquitous in nature. Klebsiellae probably have two common habitats, one being the environment, where they are found in surface water, sewage, and soil and on plants (15, 33, 71, 140, 214), and the other being the mucosal surfaces of mammals such as humans, horses, or swine, which they colonize. In this respect, the genus Klebsiella is like Enterobacter and Citrobacter but unlike Shigella spp. or E. coli, which are common in humans but not in the environment. In humans, K. pneumoniae is present as a saprophyte in the nasopharynx and in the intestinal tract. Carrier rates differ considerably from study to study. The detection rate in stool samples ranges from 5 to 38%, while rates in the nasopharynx * Corresponding author. Mailing address: Department of Medical Microbiology, Christian-Albrechts-Universita¨t, Brunswiker Str. 4, 24105 Kiel, Germany. Phone: 431 5973305. Fax: 431 5973296. E-mail:
[email protected]. 589 62. a disc of clavulanic acid and a disc of an extended-spectrum cephalosporin such as ceftazidime are placed close together on an agar surface inoculated with the test organism (111). Klebsiella spp. 104 34. 116. strains that produce ESBLs. account for 8% of endemic hospital infections and 3% of epidemic outbreaks (227). 64. 206. Of the 145 epidemic nosocomial infections reported in the literature published in English between 1983 and 1991. but it should definitely be positive if a high percentage of ceftazidime-resistant strains is to be expected. 181. In Europe. 108. Even years after discontinuation of ceftazidime and other extended-spectrum cephalosporins. pneumoniae strains which showed an additional resistance to imipenem have been isolated (30). These strains possessed a transmissible plasmid-mediated AmpC-type b-lactamase. Because gram-negative bacteria do not find good growth conditions on the human skin (207). 46. 35. 44. continued colonization of patients by ESBLproducing Klebsiella strains has been observed (101). In one study. 85. 226. Both antibiotics are the drugs of choice in the treatment of infections due to ESBL-producing organisms. Previous antibiotic therapy is significantly associated with acquisition of Klebsiella by the patient. 142. pneumoniae strains tested in the National Nosocomial Infection Study system (108). 60. 104. the emergence of these multiply resistant Klebsiella strains is unfortunately accompanied by a relatively high stability of the plasmids encoding ESBLs. So far. Since ESBL production frequently is accompanied by multiresistance to antibiotics. pneumoniae and K. two diagnostic tests have been most commonly used for the detection of such isolates. ESBLproducing isolates are resistant to a variety of classes of antibiotics. REV. Enhancement of the zone of inhibition around the cephalosporin disc towards the clavulanate-containing disc indicates the presence of an ESBL-producing strain. This method is based on the evaluation of the difference between the antimicrobial activity of ceftazidime alone compared to that of ceftazidime plus clavulanic acid (119). 242. this increase occurred primarily in patients receiving antibiotics. widespread use of antimicrobial therapy has often been held responsible for the occurrence of multiply resistant Klebsiella strains in hospitals (215. Since 1982. 242 26. 245). 43. the incidence can reach 25 to 40% (38). 208.590 PODSCHUN AND ULLMAN CLIN. the question has arisen whether it is necessary to determine if each isolated Klebsiella strain is an ESBL producer. 240. Sweden). 200). These carrier rates change drastically in the hospital environment. 144. 235. the percentage of ceftazidime-resistant strains may be much higher. 52). 53. However. however. 247 Infection a Ranking of Klebsiella compared to all other bacterial pathogens. 19% in the pharynx. A commercially available product is the ESBL screening E test strip (AB Biodisk. demands for strategies to avoid the overuse of antibiotics in prophylaxis and empirical therapy are increasingly being expressed. the b-lactamases of ceftazidime-resistant Klebsiella strains are commonly of the SHV-5 type. 104. Moreover. % of infections caused by Klebsiella Ranka References UTI Pneumonia Septicemia 6–17 7–14 4–15 5–7 2–4 3–8 Wound infections Nosocomial infections in intensive care unit patients Neonatal septicemia 2–4 4–17 6–11 4–9 26. a recent observation is very disturbing. In the hospital setting. The answer depends on the epidemiologic situation of a country or a hospital. 179. In the last several years. 198). accumulation of resistance genes results in strains that contain multiresistant plasmids. 112. 45–47. 242 26. ESBLproducing K. The significance of increased colonization was illustrated by the observation that the attack rate of Klebsiella nosocomial infection in patients carrying hospital-acquired intestinal Klebsiella was four times as high as for noncarriers (215). range from 1 to 6% (62. 225). In particular regions or hospitals. are rarely found there and are regarded simply as transient members of the flora (126). For this reason. have evolved (22. especially in neonatal units (98). a two. therapeutic options become limited. 2 weeks after admission to the hospital. MICROBIOL. 85. To date. where colonization rates increase in direct proportion to the length of stay. the local antibiotic policy is a major determinant of the colonization pattern. Solna. ESBLs are usually plasmid mediated. A percentage of 14 to 16% ESBL producers among clinical Klebsiella isolates has been reported for France and England (221). 144. 96. Klebsiella spp. resistance to ceftazidime. According to the statistics of the Centers for Disease Control and Prevention. 243. Hospital-acquired bacterial infections caused by Klebsiella spp. 13 were caused by Klebsiella (68). 236). the frequency of such strains seems to be even higher. Even hospital personnel have elevated rates of Klebsiella carriage (42. whereas TEM-10 and TEM-12 are more prevalent in the United States (22. Furthermore. Since these plasmids are easily transmitted among different members of the Enterobacteriaceae. TABLE 1. In Europe. 193. is observed in both K. 130. In the double-disc synergy test. and 42% on the hands of patients (52. because the conventional disc diffusion criteria used in the routine laboratory underestimate the incidence of these isolates (109). 135. 160). In the 1970s. The hallmark of these strains. 84. Apart from medical equipment (contaminated due to faulty hygienic procedures) and blood products (89. 258 104. 215. In this respect. oxytoca isolates (224). 113. these strains were chiefly aminoglycoside-resistant Klebsiella strains (48. Risk factors for acquisition of these strains seem to be the length of stay in hospital and the performance of invasive procedures (132). This development should be monitored closely. The high rate of nosocomial Klebsiella colonization appears to be associated with the use of antibiotics rather than with factors connected with delivery of care in the hospital (193. Reported carrier rates in hospitalized patients are 77% in the stool. ESBL-producing Klebsiella strains have been susceptible to carbapenems such as imipenem or meropenem. since the emergence of imipenem-resistant ESBL-producing Klebsiella strains will have a serious impact on remaining therapeutic options. 206). For the first time. 70. 63.to fourfold increase in the colonization rates with Klebsiella was observed (193). 146. 213. the principal reservoirs for transmission of Klebsiella in the hospital setting are the gastrointestinal tract of patients and the hands of hospital personnel (156). especially in persons receiving broad-spectrum or multiple antibiotics. Strict adherence to basic epidemiological standards for . 206. 138. 168. which render them resistant to extended-spectrum cephalosporins. The ability of this organism to spread rapidly (129) often leads to nosocomial outbreaks. 239). Because these undesired effects may be reversed by strict control of antibiotic use. It should be kept in mind that a number of measures have been recommended to prevent the nosocomial spread of Klebsiella. The incidence of ESBL-producing Klebsiella isolates in the United States has been reported to be 5% of the K. Especially feared are epidemic hospital infections caused by multiresistant strains. 242 3–20 2–8 24. rhinoscleromatis K. 210. wound and urine isolates were the next most common (189). oxytoca K. Species classification of the genus Klebsiella by different taxonomic systemsa Classification by: Cowan Bascomb Ørskov K. those of Cowan. 174. K. ornithinolytica (210). 1 1 1 . As the taxonomy became increasingly refined due to the development of new methods such as numerical taxonomy. L. terrigena and K. and K. Biochemical reactions of Klebsiella speciesa Characteristic Indole Ornithine decarboxylase Lysine decarboxylase Pectate degradation Gas from lactose at 44. and Ørskov (Table 2). 189. 190). terrigena and TABLE 3. aerogenes in another. and M). at present it seems possible that in addition to K. Detailed information on this subject is given in an excellent review by Montgomerie (156). atlantae K. ornithinolytica 2 2 2 2 2 2 1 2 1 1 2 1 2 2 1 2 2 1 vb 2 1 2 2 1 1 1 1 2 2 1 2 2 v 1 1 1 2 1 2 2 2 1 1 2 1 v 1 1 1 2 1 1 v 1 2 2 1 2 1 v 1 2 1 subsp. K. rhinoscleromatis 2 2 1 2 1 2 2 2 v 2 2 2 2 v 2 v 1 2 1 Data summarized from references 14. 174. Most European countries follow the American example and recognize the worldwide predominant classification of Ørskov. ozaenae subsp. rhinoscleromatis K. three main classifications emerged. nonmotile. terrigena K. Furthermore. planticola. the species classification in this genus was continually revised. and 228. rhinoscleromatis. the medical importance of the genus Klebsiella (family Enterobacteriaceae) led to its being subdivided into three species corresponding to the diseases they caused: K. “unnamed group” Enterobacter aerogenes K. intravenous tracheostomies. K. ornithinolytica a Data from references 18. and 228. nosocomial infection surveillance is necessary to collect data that are used in the prevention and control of nosocomial Klebsiella infection rates. variable reaction. In time. Thus. usually encapsulated rod-shaped bacteria of the family Enterobacteriaceae. planticola K. pneumoniae K.5°C Growth at 10°C Acid from: D-Melezitose L-Sorbose Utilization of: m-Hydroxybenzoate Hydroxy-L-proline Malonate Methyl red test Voges-Proskauer reaction a b Klebsiella pneumoniae K. terrigena K. which produce lysine decarboxylase but not ornithine decarboxylase and are generally positive in the Voges-Proskauer test (75). and soil environments. ozaenae K. However. 31. pneumoniae in one country and K.5 to 18. pneumoniae. According to these findings. The genus is defined as containing gram-negative. pneumoniae and K. Bascomb. edwardsii subsp.5% among clinical isolates of Klebsiella species.KLEBSIELLA SPECIES AS NOSOCOMIAL PATHOGENS VOL. trevisanii (82). Consequently. maintenance and care of equipment. pneumoniae subsp. planticola (14). Whereas most Klebsiella species can be identified by standard microbiological laboratory tests. the management of urinary catheters. particularly K. While originally considered to be without clinical significance and restricted to aquatic. edwardsii subsp. aerogenes K. Nevertheless. terrigena (107). were increasingly being classi- 591 fied into provisional taxa (87). K. oxytoca K. which had previously been classified as “Klebsiella-like organisms” (groups J. aerogenes/oxytoca/ edwardsii K. Klebsiella isolates from the environment. Originally. Within the genus Klebsiella. and good hand-washing practices all help to prevent the spread of nosocomial Klebsiella infections. 154. DIFFERENTIATION OF KLEBSIELLA SPECIES Klebsiella species are usually identified and differentiated according to their biochemical reactions. the individual species can be differentiated on the basis of the features listed in Table 3. since most of the isolates were obtained from polymicrobial specimens. K. ozaenae. TAXONOMY OF THE GENUS KLEBSIELLA The taxonomy of Klebsiella is characterized by a nomenclature reflecting its colorful taxonomic history. pneumoniae sensu stricto sensu lato K. because of their extensive DNA sequence homology (86). More than half of these isolates were recovered from respiratory tract secretions. 153. K. a third Klebsiella species exists that is able to cause human infections. ozaenae subsp. pneumoniae subsp. and wounds. the last two species were combined into one species. 11. planticola (syn. the same bacterium may be called K. the species K. 79. it is difficult to estimate the significance of these strains as causative agents of disease. In 1986. planticola has been isolated from human infections with a surprisingly high frequency of 3. trevisanii) K. 6 of the 94 isolates were recovered from monomicrobial specimens and could be assigned to corresponding infections. In the early 1980s. Another measure to control Klebsiella infections is the regulation of antibiotic use in the hospital to prevent misuse and overuse of antibiotics. The adoption of a consistent nomenclature has been further complicated by the fact that Great Britain and the former Commonwealth countries adhere to the classification of Cowan while the USA prefers Ørskov’s classification. and K. These groups gave rise to four new species: K. rhinoscleromatis K. K. pneumoniae subsp. 107. v. ozaenae K. 54. oxytoca. planticola have recently been reported as occurring in human clinical specimens (158. botanical. 110. 1998 TABLE 2. Moreover. 97). Although the phage reaction is easily read and the reproducibility of the method is acceptable. 27. Instead. Biotyping Biotyping based on an extended panel of biochemical and culture tests is certainly the most practicable method of typing for smaller laboratories that are epidemiologically not optimally equipped. A variety of methods have been used with various degrees of success in Klebsiella typing and are discussed below. 99. Bacteriocins are bactericidal substances. This is particularly important in endemic and epidemic nosocomial outbreaks of Klebsiella infections to improve the management of such outbreaks. 161). this technique shows a relatively poor typing rate of 19 to 67% (209. An isolate can be characterized either by its ability to inhibit specific indicator strains or by its sensitivity to bacteriocins synthesized by a set of producer strains. multilocus enzyme analyses (51. 192).and O-antigen-specific phage typing if appro- Although capsule typing is the preferred method for Klebsiella. It is based mainly on a division according to the capsule antigens (177). 217). because of the large number of reactions to be tested and the often long cultivation times—up to 90 days for demonstration of gelatinase (228)—biotyping of Klebsiella spp. 222). ribotypes (8. the latter technique has become the method of choice for bacteriocin typing of organisms belonging to this genus. the conventional cross-streak method results in low typability of strains (36. Of 82 capsule antigens described. 180. 223). or growth at 10°C). produced by bacteria to inhibit the growth of other bacteria. However. is not very suitable as an epidemiological tool. in contrast to capsule typing. Phage Typing Phage typing of Klebsiella was first developed in the 1960s (196. Thus. 97. individual sera have to be absorbed with the cross-reacting K-antigens. the term “pathogenicity” defines the ability of a bacterium to cause disease while “virulence” is the measurement or degree of pathogenicity of any bacterial species. 157. 53. as a number of reports have demonstrated (143. planticola require special. 188) as well as of nosocomial outbreaks of Klebsiella (22). However. nor phage typing alone is sufficiently discriminative and reproducible for epidemiological purposes except under certain conditions (177). Since it is not an alternative to capsule typing. Since anti-capsule antisera are not commercially available. The procedures vary from laboratory to laboratory and lack standardization. that it is possible to develop capsule. 237). 73. Since the synthesis of bacteriocins is not frequent enough in Klebsiella. by contrast. The limitations of both of these methods have been surmounted by a modification of the “scrape-and-point” procedure (20). usually members of the same species. CLIN. while others lay emphasis on a clear-cut distinction between them. animal models have been . This method has proven superior for bacteriocin typing of clinical and environmental Klebsiella strains (21. The use of animal models has been a critical element in the study of Klebsiella pathogenicity by providing vital information that cannot be obtained from in vitro studies. 185. In particular. 28. REV. 250). which give their colonies their characteristic mucoid appearance. 73. The combined use of biotyping and capsule typing enables the differentiation of a large number of bioserotypes (202). it has been advised to include an additional feature independent of the capsule type to enable more precise epidemiological analysis. usually proteins. Although 12 different O-antigen types of Klebsiella have also been described. pectate degradation. Nosocomial Klebsiella infections most commonly involve the urinary and respiratory tracts. The drawback of this method is the large number of serological cross-reactions that occur among the 77 capsule types. Biotyping can be carried out by using macrotube tests alone (100. However. The search for the pathogenic mechanisms of Klebsiella infections has identified a number of bacterial factors that contribute to the pathogenesis of these bacteria. this procedure has never become widespread and is useful mainly as a secondary method in combination with serologic testing (48. It should be stressed. which avoids the use of potentially unstable preproduced and stored bacteriocins. this technique is practiced mostly in specialized laboratories. they are difficult to classify because their determination is hampered by the heat-stable capsules (175. Because of the instability of bacteriocin preparations. Klebsiellae usually have welldeveloped polysaccharide capsules. In this review. and applications of pulsed-field gel electrophoresis (8. 36. neither biochemical typing. it should be expected that the pattern of virulence factors found in UTI-causing strains of Klebsiella will differ from that observed in strains isolated from pulmonary sources of patients with pneumonia. acid from melezitose. Since these two body sites differ considerably with respect to the host defense mechanisms. Many authors recommend typing Klebsiella via bacteriocins (20. making it difficult to compare them. MICROBIOL. 202) or by combining a commercially available miniaturized system such as the API 20E system with additional macrotube tests (185. the bacteriocins are synthesized on an agar medium immediately before the strains to be typed are inoculated by a multipoint inoculator. 223). 28). shows good reproducibility and is capable of differentiating most clinical isolates (12). priate efforts are made. Serotyping Serotyping is currently the most widely used technique for typing Klebsiella spp. 187. Molecular Typing Methods Molecular typing methods. 53. bacteriocin typing. 91. the typing procedure is cumbersome because of the time needed to perform the test and is susceptible to subjective interpretations because of weak reactions that are not always easy to interpret. Preliminary descriptions have been presented on plasmid profiles (22. Both in vitro and in vivo models have been established to investigate the interaction of bacterial cells and the host. Capsule typing.592 PODSCHUN AND ULLMAN K. 77 types form the basis for an internationally recognized capsule antigen scheme (176). however. 177). the reproducibility of the growth-in-broth method is low. nonconventional reactions (such as utilization of m-hydroxybenzoate or hydroxy-L-proline. 113). are still in their infancy. the two principal early methods—the growth-in-broth method and the cross-streak method—both show considerable disadvantages. it is often necessary to determine the clonality of the strains. In addition. as applied to the genus Klebsiella. Bacteriocin Typing TYPING OF KLEBSIELLA ISOLATES From an epidemiological point of view. PATHOGENICITY FACTORS OF KLEBSIELLA The terms “pathogenicity factor” and “virulence factor” are used synonymously by some authors (212). In experi- mentally induced skin lesions in mice. this consideration has recently been abandoned because of the great differences in virulence observed among different capsular types: strains expressing the capsule antigens K1 and K2 were found to be especially virulent in a mouse peritonitis model. complement. especially C3b (254). and subsequently kill Klebsiella serotypes containing the CPS repeating sequences Mana2/3Man or L-Rhaa2/3L-Rha. 69. 1. Apart from their antiphagocytic function. The molecular mechanism presumably consists of inhibiting the activation or uptake of complement components. strains expressing capsule types K1 and K2 are considered especially likely to be virulent. Capsular types with low virulence. 151). 185. on the other (252). 202. strains that lack these repeating sequences are not recognized by macrophages and hence phagocytosis does not take place. such as the K7 or K21a antigen (166. that K2 is the predominant serotype of human clinical isolates worldwide whereas K2 strains are very rarely encountered in the environ- . Capsules are essential to the virulence of Klebsiella (56. These sequences are recognized by a surface lectin of macrophages. Geographical differences in serotypes may have contributed to this confusion. 218. that the K2 serotype is among the most common capsule types isolated from patients with UTI. 191). or bacteremia. consisting of four to six sugars and. Moreover. established to study Klebsiella virulence factors in UTIs. 166). K2. 203. 191. 1998 593 FIG. The capsular material forms thick bundles of fibrillous structures covering the bacterial surface in massive layers (Fig. It can be assumed. The capsular repeating subunits. which mediates opsonin-independent (i. The current research into the pathogenicity of Klebsiella focuses on the group of five factors shown in Fig. 76. While Klebsiella CPS were generally considered to mediate virulence properties. 261). both models include scanning electron microscopy of the surface of the bladder or renal pelvis. Klebsiella strains of serotypes K1. Lectinophagocytosis has been defined as nonopsonic phagocytosis that is based on recognition between surface lectins on one cell and surface carbohydrates on the opposing cell (164). Macrophages with the mannose-a-2/3-mannose-specific lectin or mannose receptor recognize. however. 2) (7). 241). Schematic representation of Klebsiella pathogenicity factors. very often. known as lectinophagocytosis (9). Thus. Frequently. although only a few of the 77 different K antigens have been systematically studied in this regard.e. mice and rats seem to be appropriate animal types. whereas isolates of other serotypes showed little or no virulence (120. 219). Capsular Antigens As mentioned above. 11. on the one hand (186. Each study reports different capsular types as predominant (41. uronic acids (as negatively charged components). At present. The degree of virulence conferred by a particular K antigen might be connected to the mannose content of the CPS.KLEBSIELLA SPECIES AS NOSOCOMIAL PATHOGENS VOL. Previous attempts to establish a correlation between individual Klebsiella serotypes and the site of infection or clinical symptoms have produced a profusion of contradictory results. K4. and K5 were more virulent than were those expressing other capsule types (220). 1. Lower UTIs have been investigated in the diuresis mouse or rat model of cystitis by intravesicular injection of organisms (77. pneumonia. Most reports do agree. therefore. 134). 59. can be classified into 77 serological types (177). 103). This model is consistent with the marked virulence of K2. Klebsiella strains bearing capsule types devoid of these mannose or rhamnose sequences should be more closely associated with infectious diseases. Klebsiella capsule polysaccharides have been reported to inhibit the differentiation and functional capacity of macrophages in vitro (260.. Lectinophagocytosis may be mediated either by bacterial surface lectins such as fimbriae or by phagocyte lectins that act as receptors. In contrast. a rat model of experimental retrograde pyelitis has been established (78). ingest. as has been demonstrated in mice that showed a dose-dependent decrease in the production of antibodies to the specific capsular antigen (19). To study Klebsiella-mediated upper UTI. 217. klebsiellae usually develop prominent capsules composed of complex acidic polysaccharides. which completely lacks mannose-a-2/3-mannose structures (117. This protects the bacterium from phagocytosis by polymorphonuclear granulocytes.and antibody-independent) phagocytosis. and prevents killing of the bacteria by bactericidal serum factors. contain repetitive sequences of mannose-a-2/3-mannose or L-rhamnose-a-2/3-L-rhamnose. injection of large doses of Klebsiella capsular polysaccharide (CPS) may even produce immunological paralysis. respectively (178). or in saliva (13). the authors suggested that bacterial binding is mediated by the macrophage mannose receptor. the observed predominance of the K2 serotype in Klebsiella infections is quite consistent with the concept of lectinophagocytosis. Type 1 fimbriae are also capable of binding to soluble. Of the different types of pili described in enterobacteria. 184. Type 1 (common) pili. The relevance of these pili to bacterial virulence is thought to arise mainly from binding of the bacteria to mucus or to epithelial cells of the urogenital. Pili are demonstrated mainly on the basis of their ability to agglutinate erythrocytes of different animal species. These findings provide an explanation for the fact that type 1 pili mediate bacterial colonization of the urinogenital and respiratory tracts (50). Israel.594 PODSCHUN AND ULLMAN CLIN. Type 1 pili are the best investigated of the bacterial adhesins. Since the reaction was inhibited by mannan. The sugar structures presumably consist of short oligomannose chains bound via N-glycosidic linkages to the glycoproteins (216). Transmission electron micrograph of K. which do not bear such structures. these adhesins are designated as mannose-sensitive or mannose-re- sistant hemagglutinins (MSHA and MRHA). Although associated primarily with the pathogenesis of lower UTI (106). Ofek. The significance of capsular mannose-a-2/3-mannose sequences to the clearance of Klebsiella in the host is further illustrated by recent findings of Ofek’s group (118). Depending on whether the reaction is inhibited by D-mannose. these structures have been shown to bind effectively to proximal tubulus cells (248). they consist of polymeric globular protein subunits (pilin) with a molecular mass of 15 to 26 kDa (115). Pili (Fimbriae) As a critical first step in the infectious process. The adhesion protein in this pilus type is located on the fimbrial shaft and is capable of binding to mannose-containing trisaccharides of the host glycoproteins (13. 83). In this setting. 244). Thus. Pili (otherwise known as fimbriae) are nonflagellar. 78. Since the host innate immune mechanisms interact with structures commonly found on microorganisms. enhances the phagocytosis by alveolar macrophages of Klebsiella K21a strains (which bear a mannose-a-2/3-mannose containing capsule) but not of K2 isolates. 162. (171. These structures are up to 10 mm long and have a diameter of 1 to 11 nm (163). 195). 74. 182). with a subsequent proliferation of facultative pathogenic bacteria. type 1 pili may also be involved in the pathogenesis of pyelonephritis (78. and intestinal tracts (16. REV. such as the TammHorsfall protein (199). microorganisms must come as close as possible to host mucosal surfaces and maintain this proximity by attaching to the host cell (adherence). the main protein component of lung surfactant. particular Klebsiella serotypes. FIG. Their role in the pathogenesis of UTI was clarified mostly in studies on E. Adherence of bacteria to cells of the respiratory tract (11) leads to impairment of colonization resistance in the upper airways. They are MSHA which agglutinate guinea pig erythrocytes. respiratory. become selected. 140. . there are two predominant types in Klebsiella spp. Tel Aviv University. pneumoniae in animal models (77. 134). This impairment may result in the development of pneumonia. such as the K2 type. especially in patients undergoing long-term mechanical ventilation (254). Reprinted from reference 163 with permission of the publisher. coli but has also been described for K. 141). They observed that surfactant protein A (SP-A). 2. MICROBIOL. pneumoniae cells surrounded by thick layers of fibrillous capsular material. Courtesy of I. filamentous projections on the bacterial surface. mannosyl-containing glycoproteins in urine. The adhesive properties in the Enterobacteriaceae are generally mediated by different types of pili. ment (33. The serum bactericidal activity is mediated primarily by complement proteins. however. whereas pathogenic strains often exhibit serum resistance properties (172). While the two adhesins mentioned above are nonfimbrial. In response to this host defense. type 3 pili apparently are not identical in all genera of enterobacteria. the exact mechanism underlying bacterial serum resistance is unknown. and the feature “serum resistance” has been correlated with the onset of infection (172. pneumoniae expressing type 3 pili adhere to endothelial cells. two hypotheses have been propounded (145).VOL. For Klebsiella. this type of adhesin mediates bacterial colonization of the host mucosal surfaces via a rather nonspecific binding. since serological studies showed considerable antigenic diversity (170). which ultimately leads to phagocytosis and intracellular killing of the bacterium (131). Strains of K. capsule polysaccharides may cover and mask the underlying LPS and exhibit a surface structure that does not activate complement. the type 1 pili are no longer of use to the bacteria. 237. pneumoniae has been demonstrated to mediate adherence to the human intestinal cell lines Intestine-407 and CaCo-2 (61). no experimental animal model has been established investigate the role of these pili in infection. thus enabling the adhesins to bind to specific mannose-containing receptors on the leukocyte surface (205). pathogenic microorganisms have developed strategies to counter the serum bactericidal effect. Unlike other fimbriae. the phenomenon of “phase variation” has to be taken into account. Both complement pathways lead. 1998 In the appraisal of the pathogenic role of type 1 pili. In pathogenic microorganisms. with all of the subsequent events of infectious pathogenesis. To date. 92). Once in the host tissue. later studies demonstrated that type 3 pili occur in many enteric genera (50). 252). pneumoniae strains in the human intestine. via the activation of C3. primarily CPS and O antigens (lipopolysaccharides [LPS]) have been implicated (49. Serum Resistance and Lipopolysaccharide The first line of defense by the host against invading microorganisms includes. their site of isolation from the host. A particular adherence pattern characterized by aggregative adhesion to intestinal cell lines is mediated by another new Klebsiella adhesin that seems to be composed of capsule-like extracellular material (80). Three new types of Klebsiella adhesins have been recently reported. these pili were later found to be capable of binding to various human cells. which enables the host to react to invading microorganisms even before specific antibodies are formed (114). The repulsion forces separating bacterium and leukocyte are weakened by the hydrophilic character of these pili (169). their expression by different species of Klebsiella. This species is not a common cause of UTI in short-term-catheterized or noncatheterized persons but has a much higher prevalence in the urine of patients with long-term indwelling catheters. these pili mediate bacterial adhesion to tubular basement membranes. Unfortunately. The role of this fimbrial type in the pathogenetic process is largely unknown. the bactericidal effect of serum. 11. so far. This complex consists of the terminal complement proteins C5b–C9. 256). So far. which produce a transmembranous pore in the outer membrane of gram-negative bacteria (197). To date. it has been suggested that MR/K hemagglutination is mediated by spermidine (88). which can be activated even in the absence of antibodies. the only evidence of a correlation between the type 3 MrkD hemagglutinin and disease has been the observation of expression of type 3 pili in Providencia stuartii in catheter-associated bacteriuria (152). Thus. their geographical variations. 246.or heat-treated erythrocytes but not to untreated erythrocytes. Aside from various proteins of the outer membrane. such as the TraT lipoprotein or porins (3. it was demonstrated that the higher prevalence of P. while type 1 pili are important for host colonization. and uroepithelial cells (105. This might explain why type 3 pili bind to tannic acid. stuartii in catheter-associated bacteriuria was due to its ability to adhere and persist to the catheter in the catheterized urinary tract by expression of the MR/K hemagglutinin. 194. however. Klebsiella-like hemagglutination (MR/K-HA). After their cascade-like activation. This adhesin type seems to be identical to the CS31-A adhesive protein of human diarrheal E. in addition to phagocytosis by polymorphonuclear granulocytes. The available data suggest that CF29K KLEBSIELLA SPECIES AS NOSOCOMIAL PATHOGENS 595 probably is a product of the transfer of CS31A genetic determinants from E. leading to an influx of Na1 and subsequent osmotic lysis of the bacteria (234). On the other hand. Type 3 pili. mannose-resistant. Although its name. epithelia of the respiratory tract. Adhesin-binding triggers stimulation of the leukocyte (137). Most commensal gram-negative bacteria are sensitive to the bactericidal effect of human serum. type 3 pili agglutinate only erythrocytes that have been treated with tannin. In the above-mentioned study. 230. Interestingly. to the formation of the opsonin C3b. Moreover. Since the main role of the serum bactericidal system is thought to prevent microorganisms from invading and persisting in the blood. these proteins accumulate as membrane attack complex on the surface of the microorganism (233). 232. 173. Binding to tannic acid-treated erythrocytes is inhibited by spermidine. little is known about the frequency and distribution of these newly described adhesins. The complement cascade can be activated by two different mechanisms: the classic complement pathway. coli to K. The structure of the corresponding host receptors is unknown. colonization of the mucous membrane is followed by invasion of the underlying tissue. 155). and the alternative complement pathway. implies that this fimbrial type is synthesized only by Klebsiella. which ultimately results in formation of the terminal C5b–C9 complex and thus plays a key role in this defense system. The R-plasmid-encoded CF29K adhesin of K. Thus. since they trigger an opsonin-independent leukocyte activity known as lectinophagocytosis (167). even differences in the degree of bacterial serum susceptibility may determine whether a strain is able to infect as well as the length of time it takes the organisms to establish the infection. clinical isolates of enterobacteria often show resistance to serum (249). As mentioned above. First. coli strains (66) and belongs to the K88 adhesin family. however. In the kidneys. Since spermidine is exposed on the cell surface of damaged erythrocytes. The bacterium counters this form of host defense by switching off the expression of type 1 pili in tissue (134). Originally described as the adhesion organelles of Klebsiella inhabiting plant roots (128). and renal vessels (231). which typically requires specific antibodies to be activated. this fimbrial type has been found in the majority of K. pneumoniae strains producing CAZ-5/SHV4 type ESBL. their contribution to subsequent steps of pathogenesis is less clear. or their significance in pathogenicity. a polyamine that is also secreted in urine (88). Bowman’s capsules. The alternative pathway is also regarded as an early defense system of innate immunity. 204) and severity of symptoms (29. the O side chains of the LPS may reach through the capsule layer and be exposed to the . a third putative colonization factor of the human gut is a new fimbria that has been termed KPF-28 (67). Nevertheless. ferritin. Their best-known representative. the same bacterial strain may be serum resistant at host body sites with a high-osmolarity milieu. while enterobactin becomes hydrolyzed by an esterase after delivery of iron. even within a given O serotype.. since it is fixed preferentially to the longest O-polysaccharide side chains. Correspondingly. are known. cells cultivated at high osmolarity were resistant to normal human serum while bacteria grown at low osmolarity proved to be serum sensitive. the ferrichromes (which are synthesized only by fungi). that all previous studies in this field were done with strains expressing the O1 serotype. the aerobactin gene was cloned from the plasmids of some K. pneumoniae strains of serotypes K1 and K2 and transferred to a nonvirulent (siderophore-negative) strain. but the results of structural investigations later reduced the number of Klebsiella O antigens to 8 (151). Indeed. shows a high incidence of aerobactin synthesis (. However. the production of both enterobactin and aerobactin has been demonstrated. In contrast to enterobactin. the susceptibility to K. 251). It should be borne in mind. environmental factors affect the composition and effect of LPS. have been observed rarely (139. and Salmonella. such as the urinary tract. Even though O1 is the most common O antigen found among clinical Klebsiella isolates. The level of free. C3b is far away from the bacterial cell membrane. Among the hydroxamate-type siderophores. the smooth LPS of serum-resistant strains activates only the alternative pathway. is a cyclic trimer of 2. while the iron source of aerobactin is host cells (32). phores and one consisting of the hydroxamate-type siderophores.20%) comprises genera such as Serratia. Enterobactin-positive Klebsiella isolates in animal models were no more virulent than enterobactin-negative strains (147). functioning mainly as a redox catalyst in proteins participating in oxygen and electron transport processes (93). irrespective of the species or source of isolation. In addition to this steric hindrance of the lytic complement action by LPS. it is unclear whether serum resistance is mediated solely by the O1 antigen or whether this feature is generally conferred by Klebsiella LPS. in the host milieu. Since LPS is generally able to activate complement. one consisting of the phenolate-type sidero- CLIN.40%). the contribution of aerobactin to bacterial virulence has been clearly demonstrated (65). (23) found no association between virulence and the ability to synthesize enterobactin. Recently. (257) reported that Salmonella typhimurium mutants unable to produce this siderophore were less virulent in mice. pneumoniae infections increased dramatically (121). This siderophore appears to comprise the main iron uptake system of enterobacteria and is synthesized by almost all clinical isolates of E. low-molecular-weight iron chelators. while enterobactin is synthesized by almost all strains (183. which includes the genus Escherichia. an association between aerobactin synthesis and the virulence of Klebsiella strains was unequivocally demonstrated by Nassif and Sansonetti (159). the influence of different osmolarity conditions on LPS was demonstrated in Aeromonas hydrophila serotype O:34 (1). e. serum resistance does not seem to be a stable characteristic. the formation constant for ferric enterobactin is 1052. Data on the incidence of aerobactin-producing Klebsiella . might derive from aerobactin. aerobactin-positive Klebsiella isolates. Originally there were 12 chemically different O types. and myoglobin and extracellularly to high-affinity iron-binding proteins such as lactoferrin and transferrin. (93). Many bacteria attempt to secure their supply of iron in the host by secreting high-affinity. which is magnitudes higher than that of transferrin (93). The great advantage of enterobactin over aerobactin is its high iron affinity. and subsequent membrane damage and cell death do not take place. the highest ever recorded for a ferric iron chelator. While the thermodynamic stability constant of ferric enterobactin indicates a much higher affinity for Fe(III) than that of ferric aerobactin (Ks 1052 and 1023. Moreover. and serum sensitive at low-osmolarity body locations like the respiratory tract. The transformant then exhibited markedly enhanced virulence in a mouse peritonitis model.596 PODSCHUN AND ULLMAN exterior milieu in certain Klebsiella capsule types (238). To date. Thus. which belong to two different chemical groups. enterobactin (also known as enterochelin). The second group. Iron is an essential factor in bacterial growth. The activation of both complement pathways by serum-sensitive strains leads to higher levels of deposited C3b. For example. The more common group consists of the phenolate-type siderophores. coli and Salmonella spp. bioavailable iron (10218 M) is several thousandfold too low for normal bacterial growth (37). The supply of free iron available to bacteria in the host milieu is extremely low. cells grown at high osmolarity showed smooth LPS. While serum-sensitive strains activate both the classical and the alternative complement pathways. whereas growth at low osmolarity resulted in rough LPS. The marked effect of the iron supply in the host body on the pathogenesis of infections has been demonstrated for Klebsiella. many of them neutral polysaccharides. the role of enterobactin in virulence remains uncertain. aerobactin is not an effective competitor for transferrin-bound iron because of its much lower affinity for ferric iron. aerobactin still seems to be far more effective than enterobactin because of a number of physical advantages such as greater stability and better solubility (255).3-dihydroxy-benzoyl-serine.4. To date. aerobactin can be recycled after each turn of iron transport. investigations have demonstrated that enterobactin sequesters iron predominantly from transferrin. while Benjamin et al. MICROBIOL. The group with a low rate of aerobactin-producing strains (. In contrast to enterobactin. the formation of the lytic membrane attack complex (C5b–C9) is prevented. the ferrioxamines.g. Studies on the contribution of enterobactin to virulence have produced conflicting results. hemosiderin. C3b is subsequently deposited onto the LPS molecules. 253). the quantity of deposited C3b also determines the degree of serum resistance (2). REV. Under iron-deficient conditions. (139) indicate that enterobacterial genera can be divided into two groups according to their incidence of aerobactin synthesis. At pH 7. however. respectively). since this element is bound intracellularly to proteins such as hemoglobin. called siderophores. which already synthesizes enterobactin. After parenteral administration of iron in a guinea pig model. Thus. it has been speculated for a long time what additional advantage a bacterium. resulting in greater damage and bacterial killing. Yancey et al. Thus. production of these two siderophores may give access to both sources of iron. a number of different O serotypes. 183. However. In the genus Klebsiella. In this study. Siderophores The growth of bacteria in host tissue is limited not only by the host defense mechanisms but also by its supply of available iron. In contrast. and aerobactin are the most important. Proteus. enterobacteria synthesize a variety of siderophores. 201. The observations of Martinez et al. that are capable of competitively taking up iron bound to host proteins (94). Because of the common ability of strains to produce enterobactin. resulting in enhanced growth in the host. demonstrated surface exposure of Oantigens in strains expressing particular capsular serotypes (238). only eight O types are known. this vaccine seems to be the most promising approach for preventing sepsis caused by Klebsiella and has already passed phase I human trials (72). planticola. are often caused by a new type of strain. The aerobactin-mediated iron uptake system would thus be an indirect contributor to the pathogenicity of the genus Klebsiella. formerly regarded as “environmental” Klebsiella species. Although the production of cytotoxins (102. 127. other factors have also been demonstrated in Klebsiella spp. remain high despite the use of appropriate antibiotic therapy. two surface components are mainly being discussed as candidates for an antiKlebsiella vaccine: LPS and CPS. these features probably play a rather minor role in Klebsiella. pneumonia. Klebsiella neonatal infections are becoming a major concern of the pediatrician. VACCINATION EFFORTS As stated above. Lipopolysaccharides Due to their endotoxic properties. which do not synthesize aerobactin themselves. most Klebsiella infections are acquired during hospital stays and account for 5 to 7. and as has been especially well studied in E. Moreover. that clinical K. the ESBL producers. observed that only 25 serotypes made up 70% of all bacteremic strains (59). the administration of monoclonal antibodies to the Klebsiella O1 antigen has been reported to be protective in a mouse model of lethal endotoxemia (136). These findings. By synthesizing only the intrinsically expressed aerobactin receptor. immunocompromised patient with underlying diseases is the main target of these bacteria. Thus. taken together with the emergence of ESBL-producing multiresistant strains. 148) and hemolysin (4–6. Fatality rates of 20 to 50% in Klebsiella bacteremia and of more than 50% in Klebsiella pneumonia have been reported (35. such as bacteremia and pneumonia. Since more and more of these outbreaks have been caused by multidrug-resistant strains. Frequencies of up to 40% have been reported in certain regions. they formulated a 24-valent Klebsiella CPS vaccine that subsequently was proven to be safe and immunogenic (58). 17) has been sporadically described. Cryz et al. and soft tissue infection. enterotoxins (95. In contrast to the K antigens. In neonatal intensive care units. have been dem- . O1 being the most commonly found O type in clinical isolates. (i) An increasing number of endemic and epidemic outbreaks in pediatric wards has been reported. LPS are considered important in the pathology of septicemia. Klebsiella is one of the three or four most common pathogens (98). are entirely capable of using exogenously introduced aerobactin as their sole source of iron (253). 229). Among the different cell constituents. especially those in neonatal intensive care units are more likely than other neonates to develop an intestinal flora in which Klebsiella spp. Klebsiella LPS O antigens were generally considered to be masked by the capsule polysaccharides and thus not to be exposed on surface. It should be pointed out. are highly prevalent. Klebsiella infections may serve as a paradigm of hospital-acquired infections. 1998 ~ndicates that this siderophore does not play a central role in the pathogenicity of the genus Klebsiella. However. Until recently. Especially peculiar has been the repeated frequent isolation of multidrug-resistant Klebsiella isolates expressing serotype K55. each Klebsiella vaccine composed of O antigens has to be rendered safe by sufficient detoxification of the LPS. Thus. A serious disadvantage of a Klebsiella CPS vaccine is the great number of K antigens (77 different antigens). This is apparently related to the observation that premature neonates. the available data suggest a further increase in the incidence of ESBL-producing isolates. however. 149. Typically. however. Their incidence of 5 to 7% of all hospital-acquired infections ranks them among the most important nosocomial pathogens. 150. as has been demonstrated for the Klebsiella O3 lipopolysaccharide (259). Currently. Moreover. 55. A multivalent LPS vaccine composed of these eight O antigens or at least the inclusion of the common O1 antigen in a broad spectrum capsular polysaccharide vaccine might be a promising approach. pneumoniae and K.KLEBSIELLA SPECIES AS NOSOCOMIAL PATHOGENS VOL. As a result. in a study of the incidence of the capsule types among bacteremic Klebsiella isolates. K. Recently. 122–125. 64). Klebsiella infections in pediatric wards have become a major concern. To date. In this context. A great drawback of active 597 immunization with LPS-containing vaccines. so that in the near future there will be an urgent need for hospital infection control measures that counter the spread of ESBL-producing bacteria. 11. coli. which must be expected because of the endotoxin content. The most recent study of the 24valent Klebsiella CPS vaccine demonstrated an excellent antibody response after active immunization in patients with acute blunt or penetrating trauma (39). (iii) Until recently. Capsules are produced by almost all Klebsiella strains. some new trends have been observed in the past several years. the newer species K. The hospitalized. The incidence of ESBL-producing strains among clinical Klebsiella isolates has been steadily increasing over the past several years. The morbidity and mortality of severe systemic infections. Klebsiella infections are nosocomial. Such measures may include immunoprophylaxis (active vaccination of patients who are at risk) as well as immunotherapy (passive immunization by hyperimmune sera). However. The small number of different Klebsiella O-types is a great advantage with respect to their applicability as vaccines. pneumoniae isolates. oxytoca have been considered to be the only pathogenic Klebsiella species. and they have been proven to be highly immunogenic and nontoxic (57). Recent studies. is adverse toxic reactions. UTI. It remains to be seen whether this observation reflects the spread of a particular “neonatal” Klebsiella clone. Based on their seroepidemiological findings. terrigena and K. they represent the outermost layer of surface structures in contact with the host milieu. the therapeutic options are becoming limited. the inclusion of O antigens in a multivalent Klebsiella vaccine formulation might be of additional benefit due to strong adjuvant action. leaving them inappropriate as vaccine candidates. (ii) Hospital outbreaks of multidrug-resistant Klebsiella spp. Especially common are Klebsiella infections causing septicemia and meningitis in newborns in neonatal intensive care units. As in many enterobacteria. indicate the need for a means of immunological control of Klebsiella infections. such strains could derive an advantage over other aerobactin-synthesizing bacteria in mixed infections. CONCLUDING REMARKS Klebsiellae are opportunistic pathogens and can give rise to severe diseases such as septicemia.5% of all nosocomial infections. however. Capsular Polysaccharides CPS have been the obvious vaccine candidates for several reasons. Choodnovskiy. 36:178–185. The ability of Salmonella typhimurium to produce the siderophore enterobactin is not a virulence factor in mouse typhoid. Bacteriocins as tools in analysis of nosocomial Klebsiella pneumoniae infections. there is a general agreement that further progress in prevention of hospital-acquired infections will require new approaches to infection control. 7. S. R. So far. Zetterstro¨m. Most cases of bacterial pyelonephritis are not caused by Klebsiella but by E. Takade. K. 59:1673–1682. C. M.. Bennet. Can. Nosocomial Klebsiella infections continue to be a heavy burden on the economy and on the life expectancy of patients in developed countries. Presse Med. 17. and J. 1995. Hospital infection prevention and control programs led in the past to considerable improvements in the management and control of these infections. Immun. Latinoam. Use of ribotyping in epidemiological surveillance of nosocomial outbreaks. 1981.. 21. J. and R. S. Microbiol. Bingen. REV.. E. Microbiol. and L. Molecular epidemiology of Klebsiella pneumoniae strains that produce SHV-4 b-lactamase and which were isolated in 14 french hospitals. A good example in this respect is Klebsiella UTI in elderly individuals. Baer. Altman. 3. 32:884–888. 7: 311–327. A. 13. J. Merino. Albesa. 1985. Pa ´jaro.. I. Rosenthal. As mentioned above. Albesa. 24. A.. A.. 1994. Beachey. pneumoniae. Infect. 5. N. the question has to be raised about whom to vaccinate. MICROBIOL. infections with these uropathogens are more likely to lead to death than are infections with most E.. I. W. and N. While little controversy is to be expected for vaccinating immunocompromised hospitalized patients to prevent fatal Klebsiella pneumonia and septicemia. 16:213–224. E. Benedı´.. Immun. Marque´s. 67:263–266. Gen. 27.. One possible measure is the vaccination of persons at risk. Immun. J. Ayars. E. Rubires. Ofek. B. and M. Benedı´. the justification of immunological measures in other patient groups is being debated. C. Elion. L. Posey. Infect. Albesa. The use of cranberry juice cocktail in the hospital setting might be a paradigm for cheap and simple preventive intervention without the use of antibiotics or vaccines. and V. Immun. Merino. T. and E. As a future challenge for the advancement of preventive measures against nosocomial Klebsiella infections. Barberis. 31:297–300. incidence. 1995. Briles. S. C. Eraso. Molecular weight determination and partial characterization of Klebsiella pneumoniae hemolysins. Microbiol. 1985. J. M. 1994. it is unclear what kind of pathogenicity factors K. Tomas. Differences in urinary tract infection in male and female spinal cord injury patients on intermittent catheterization. and M. 27:83–87. J. 1997. Investigations in the near future will show whether surfactant proteins may be useful in new therapeutic approaches and CLIN. and I. Immunologic paralysis produced in mice by Klebsiella pneumoniae type 2 polysaccharide. 1985. Sharon. J. T. 1986. and the question remains whether the identification of this species by standard laboratory procedures should be recommended. M. L. J. J. 1982. L. 4. Eriksson. H. Denamur. 6. Dabbous. J. D. J. G. 1984. S. Seidler. A. and H. However. J. Albertı´. Microbiol. Microbiol. The question whether a Klebsiella vaccine should be recommended for persons older than 60 years has to be clarified by cost-benefit analyses. G. 8. C. I. in particular. Infect. 11. E. Numerical classification of the tribe Klebsiellae. Turnbough. Immunol. Microbiol. Avorn. 9. Microbiol. K. P. Merino. Meno. L. P. Environ.. A. planticola can. Petermu ¨ller. M. Bauernfeind. lung SP-A increases phagocytosis of Klebsiella by acting as an opsonin and by activating alveolar macrophages. 1993. 22. 1993. Y. Immun. Monane. S. M. J.. and A. Willcox. Bacteriol. and A. 1988. 10. Bauernfeind. Uehling. However. Immun. 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