CASE REPORT Kluyvera cryocrescens Finger Infection: Case Report and Review of Eighteen Kluyvera Infections in Human Beings Burton C. West, Hemalatha Vijayan, and Raja Shekar We report a case of soft tissue infection with Kluyvera cryocrescens and a critical review of Kluyvera infections. A 31year-old diabetic man used a new chemical for stripping the floor with his bare hands. Two days later he developed a blister on a finger which progressed to tenosynovitis in spite of intravenous nafcillin therapy. After 11 days culture and sensitivity results dictated treatment with intravenous ticarcillin/clavulanic acid. The wound was debrided twice, and later a skin flap was done. Wound cultures became sterile after 7 days of treatment with ticarcillin/clavulanic acid, and he recovered. This case represents the fourth clinical infection with K. cryocrescens and the eighteenth of Kluyvera to be reported. Four others were K. ascorbata, and the remaining ten Kluyvera infections in humans were not identified beyond genus. Our case and review of the 17 previous cases emphasize that while Kluyvera rarely cause disease, these opportunistic Gramnegative bacilli may be virulent in a variety of sites under as yet poorly defined host conditions. Sites of infection varied, but the brain and meninges were not among them. Two patients had diabetes mellitus, none had AIDS, and four died. Once shown clinically to be the cause of an infection, Kluyvera deserve aggressive treatment which acknowledges their ampicillin resistance. © 1998 Elsevier Science Inc. INTRODUCTION CASE REPORT The genus Kluyvera has been isolated from a variety of human clinical specimens, but it is rarely implicated as the significant pathogen. Only 17 cases of Kluyvera infection have been documented in the literature (Table 1). We report a patient with a softtissue finger infection caused by Kluyvera cryocrescens, the fourth K. cryocrescens human infection to be reported. A 31-year-old black man, who had insulindependent diabetes mellitus for 6 years, used a new chemical for stripping the floor with his bare hands. Two days later he developed a painful blister on the right middle finger. He was treated with dicloxacillin. Three days later, because the finger was swollen and its range of motion decreased, the patient was admitted to Meridia Huron Hospital. His temperature was 37.2°C, pulse 76 beats/min, respiratory rate 20/min and blood pressure 130/80 mm Hg. The finger was erythematous, tender, and swollen from the proximal interphalangeal joint to its tip. There was no sensory loss, lymphangitis, or lymphadenopathy. The rest of the physical examination was normal. The white count was 5,240/mL, erythrocyte sedimentation rate 7 mm/h and blood glucose 367 mg/dL. An X-ray showed soft-tissue From the Department of Medicine, Meridia Huron Hospital, Cleveland, Ohio, USA. Address reprint requests to Dr. Burton C. West, Meridia Huron Hospital Department of Medicine, 13951 Terrace Road, Cleveland OH 44112. Received 27 February 1998; accepted 10 July 1998. DIAGN MICROBIOL INFECT DIS 1998;32:237–241 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010 0732-8893/98/$19.00 PII S0732-8893(98)00087-X Author and Reference Braunstein et al. (1980) Fainstein et al. (1982) Aevaliotis et al. (1985) Wong (1987) Thaller et al. (1988) Year Location Age/Sex 79 San Bernardino, 63/F California, USA 81 Houston, Texas, 71/M USA 52/M 75/M 72/M 67/M 85 Brussels, 3 wks/F Belgium 17 months/M 87 Los Angeles, California, USA 88 Rome, Italy 76/F Tristram and Forbes (1988) 88 Syracuse, New York, USA 11 months/F Luttrell et al. (1988) 37/F 88 Johnson City, Tennessee, USA 90 Jerusalem, Israel 5/F Underlying Disease Clinical Presentation 238 TABLE 1 Clinically Significant Cases of Kluyvera Infection in Humans Source of the Organism Kluyvera Species Treatment Outcome None Acute pancreatitis Gallbladder fluid ND Not stated Not stated None Diarrhea (severe) Stool ND Symptomatic Cured AML Bladder carcinoma Bladder carcinoma CML None Diarrhea (severe) Diarrhea (severe) Diarrhea (mild) Diarrhea (mild) Diarrhea Stool Stool Stool Stool Stool ND ND ND ND ascorbata TMP/SMZ Symptomatic Symptomatic TMP/SMZ Symptomatic Cured Cured Cured Cured Cured Congenital heart disease Blood Sepsis/Broviac catheter infection Gallbladder pus Acute emphysematous cholecystitis Sepsis & UTI Blood and urine Chronic cholecystitis Bilateral vesicoureteral reflux None cryocrescens Ampicillin and gentamicin Died cryocrescens Gentamicin Cured ND Tobramycin and cefoxitin Cured Soft tissue infection Wound culture ND Cefaperazone, TMP/SMZ, Cured ticarcillin/clavulanic acid None Pyelonephritis Urine ND Cefazolin 90 Chicago, Illinois, 13/M USA Friedreich’s ataxia Peritonitis and urinary tract infection Sierra-Madero et al. (1990) 90 Cleveland, Ohio, 74/M USA Diabetes mellitus, CABG, and CRF Mediastinitis Sanchis Bayarri et al. (1992) 92 Valencia, Spain 18/M Prolapsed colostomy, Gross purulent discharge urethral-rectal fistula (posttraumatic) None stated Acute pyelonephritis Chronic renal failure, Peritonitis CAPD Endotracheal tube ascorbata aspirate, peritoneal fluid, urine and lung tissue Blood, mediastinal ND wound, and sputum Purulent exudate ascorbata Dollberg et al. (1990) Yogev and Kozlowski (1990) 36/M 96 Antalya, Turkey 57/F Present report 96 Cleveland, Ohio, 31/M USA Moxalactam and gentamicin Died Ceftizoxime and gentamicin Died Not stated Not stated Not stated Not stated Urine ascorbata CAPD fluid cryocrescens Vancomycin and amikacin, Died with multiple then ciprofloxacin, then organ imipenem and amikacin failure cryocrescens Dicloxacillin, then nafcillin, Cured then ticarcillin/clavulanic acid Wound culture Soft tissue and Diabetes mellitus (insulin dependent), flexor tendon sheaths (finger) local chemical and physical trauma AML, Acute myelogenous leukemia; CABG, coronary artery bypass graft; CAPD, chronic ambulatory peritoneal dialysis; CML, chronic myelogenous leukemia; CRF, chronic renal failure; ND, not done; TMP/SMZ, trimethoprim/sulfamethoxazole. B.C. West et al. Sezer et al. (1996) Cured Kluyvera Finger Infection and Review swelling of the right middle finger without evidence for osteomyelitis. Cellulitis was diagnosed, but a Gram stain and culture of an aspirate of the finger were negative. On admission, nafcillin, 1 g, q.4.h., was administered intravenously. Because the infection had spread to the flexor tendon sheaths, on hospital day 6 the finger was debrided and the drainage from the wound was aerobically and anaerobically cultured. The Gram stain showed moderate Gram-positive cocci in pairs, chains and clusters, a few Grampositive rods, and many neutrophils. The culture revealed moderate growth of Kluyvera and diphtheroids after 5 days (hospital day 11). On the same day the patient underwent the second debridement because he had not improved. Gram stain of pus obtained from the surgical debridement showed many Gram-negative bacilli, few Gram-positive cocci in pairs, and moderate neutrophils. On the same day (hospital day 11) intravenously administered ticarcillin/clavulanic acid 3.1 g, q.6.h. and vancomycin, 1 g, q.12h., were substituted for nafcillin. Aerobic and anaerobic cultures once again grew Kluyvera now accompanied by Bacteroides spp. After 7 days of treatment with ticarcillin/clavulanic acid, a wound culture showed no growth. Skin grafting with a groin flap was done. The patient remained afebrile throughout the hospital course and was discharged on ciprofloxacin after 21 days. A month later the groin flap was detached, and the donor site was closed. Kluyvera was identified to genus using the API 20 E system (Analytab, Inc., Plainview, NY, USA) and Vitek AMS (Vitek Systems, Hazelwood, MO, USA) at the hospital and to species at the Cleveland Biological Institute; K. cryocrescens was confirmed by the Ohio Department of Health. It demonstrated intermediate susceptibility to ampicillin and cefazolin. It was sensitive to cefotaxime, cefoxitin, ciprofloxacin, gentamicin, piperacillin, trimethoprim/sulfamethoxazole, and ticarcillin. RESULTS, DISCUSSION, AND REVIEW In 1956, Asai and coworkers identified a group of flagellated Gram-negative bacilli that produced large amounts of alpha-ketoglutaric acid during glucose fermentation, excluding them from classification as Pseudomonas. Asai named these organisms Kluyvera because of the similarity to an organism predicted by Kluyver and van Niel in 1936, but later proposed Kluyvera be transferred to the genus Escherichia, since they have peritrichous flagella. The genus Kluyvera was abolished and did not appear on the “Approved Lists of Bacterial Names” published in 1976 (Farmer et al. 1981). 239 In 1979 Braunstein et al. (1980) isolated the same type of organism from the sputum of a 6-year-old boy with pulmonary tuberculosis. It was considered a contaminant. They also isolated it from the gallbladder drainage of a 63-year-old woman with acute pancreatitis. The Center for Disease Control (Atlanta, GA, USA) identified them as “Enteric Group 8” or “CDC Group 8” or “Citrobacter-Enterobacter intermediate” (Braunstein et al. 1980). Based on extensive investigations, in 1981 Farmer et al. placed these microorganisms formerly known as CDC Group 8 in a separate genus Kluyvera in the family Enterobacteriaceae. They can be identified by biochemical criteria, including positive reactions for catalase, ornithine decarboxylase, indole, citrate, malonate, and esculin. They ferment arabinose, mannitol, maltose, melibiose, raffinose, rhamnose, glucose, and sucrose. They have negative reactions for inositol, adonitol, urea, H2S, arginine, Voges-Proskauer, and tryptophan deaminase (Farmer et al. 1981, 1985). At present the genus Kluyvera is composed of two species: K. ascorbata and K. cryocrescens and some strains designated Kluyvera species 3. In contrast to the observation that K. ascorbata was more frequently isolated from clinical specimens while K. cryocrescens was isolated primarily from the environment and rarely from clinical specimens (Farmer et al. 1985), we tabulated four well-documented cases of K. ascorbata and four of K. cryocrescens (including our case) as causes of human disease (Table 1). The number of isolates of each species remains small, making generalization risky. The species are differentiated by the ability of K. ascorbata to utilize ascorbate and K. cryocrescens to grow and ferment d-glucose at 5°C. Our isolate grew luxuriantly at 5°C, which was the key to consideration of this species. They are also differentiated by differences in the zone of inhibition around disks of carbenicillin (100-mg disk) and cephalothin (30-mg disk). The carbenicillin disk usually produces a zone of inhibition .17 mm with K. cryocrescens, but carbenicillin produces a much smaller zone of inhibition with K. ascorbata (Farmer et al. 1985). In our case, carbenicillin produced a zone of inhibition of 26 mm. In addition, a positive reaction for lysine decarboxylase is observed in 97% of isolates of K. ascorbata, while only 23% of K. cryocrescens have a positive reaction (Farmer et al. 1995, Sanchis Bayarri et al. 1992). Dulcitol fermentation occurs with 25% of K. ascorbata, while zero isolates of K. cryocrescens demonstrate this fermentation (Farmer et al. 1995). The strains can be differentiated by their response to irgasan (Altwegg et al. 1986). Kluyvera ascorbata shows no zone of inhibition while K. cryocrescens shows a zone of .15 mm around a disk containing 5 mg of irgasan. In our case the organism was identified at both reference laboratories as K. cryocrescens 240 by utilizing all biochemical tests except irgasan disk testing. In our patient, the chemical and physical injury to his hand contributed to his local susceptibility and implies an environmental source. The cellulitis at first was treated with dicloxacillin that might have controlled streptococci or staphylococci in a mixed infection including K. cryocrescens or a primary infection that later became infected with K. cryocrescens. The various Gram-positive cocci on the smear from hospital day 6 suggest that despite dicloxacillin and nafcillin treatment, both streptococci and staphylococci had been present. At the same time, Grampositive rods on the Gram stain suggest that the diphtheroids isolated in mixed culture with K. cryocrescens were also part of a mixed infection. Later as the infection spread into the tendon sheath and after five more days of nafcillin therapy, K. cryocrescens emerged as the dominant pathogen by Gram stain and by culture, although Bacteroides spp. accompanied its growth. No diphtheroids grew again and never did streptococci or staphylococci grow. One might designate this an opportunistic infection emerging from a mixed infection. We were impressed by the severity of the cellulitis and tenosynovitis that progressed during treatment with semisynthetic penicillins. We did not think this was a trivial secondary infection because at presentation there was neither a break in the skin nor purulent drainage from the cellulitis. Inoculation of K. cryocrescens must have occurred primarily, i.e., at the time of injury. Moreover, the emergence of K. cryocrescens as the dominant pathogen was a response to antimicrobial pressure in killing other pathogens or potential pathogens in the infectious inoculum, leaving K. cryocrescens less opposed by microbial competition. Seventeen clinical cases of significant Kluyvera infection reported in the literature and the present case are summarized in Table 1. The sex ratio is 11:7 (M:F). The age ranges from 3 weeks to 74 years. There is no specific site of infection favored by this genus of bacteria and no favored body fluid or tissue infected by these organisms. However, no brain or meningeal infections are reported. Deaths occurred in 4 of the 15 patients for whom we know an outcome. Of the four deaths, three had blood cultures; in two, the blood cultures were positive. In one death associated with peritonitis, multiorgan failure was observed, but this patient did not have blood cultures reported (Sezer et al. 1996). Other blood isolates are known, but clinical details are lacking (Brenner 1984). Treatment with ampicillin to which Kluyvera is usually resistant may have contributed to the death B.C. West et al. of one case (Table 1). Our isolate was typical in lacking susceptibility to ampicillin. Host factors and a poor underlying condition might be more important in determining susceptibility or a fatal outcome than the infecting organism, but no host defect has been defined. No acquired immunodeficiency syndrome associated cases have been reported to our knowledge. Our nonfatal case and a fatal case (Sierra-Madero et al. 1990) had diabetes mellitus, a common predisposition to serious infections, but two cases hardly define a predisposition to Kluyvera. Kluyvera was isolated from stools of 12 persons, of whom five were asymptomatic cancer patients (Aevaliotis et al. 1985; Fainstein et al. 1982). Seven patients had diarrhea, six of whom are listed in Table 1. One was omitted because of the concurrent isolation of Salmonella enteritidis, the probable cause of diarrhea. Because of those reports, it appeared that Kluyvera might become an important separate cause of bacterial diarrhea, but no cases have been reported since 1985. An association with a diseased biliary tract was made in two other cases, but stool was not cultured (Braunstein et al. 1980; Thaller et al. 1988). Neither was stool cultured in cases of urethral-rectal fistula or pyelonephritis where there might have been an intestinal source (Sanchis Bayarri et al. 1992). Although more than one organism was isolated from the tenosynovitis in our case, K. cryocrescens was isolated consistently and became dominant by Gram stain and culture over time. We think it was the significant pathogen because the patient did not improve until he received ticarcillin/clavulanic acid to which the K. cryocrescens was susceptible. Our case and review emphasize that Kluyvera may cause serious human infections. Whether Kluyvera are “simple” opportunistic invaders or are simply rare but virulent remains unresolved. Microbiologists should be aware of the significance of Kluyvera and identify them fully when they are suspected. Physicians should be aware of the potential virulence of Kluyvera species and treat them, aware of their resistance to ampicillin. They must not be dismissed as saprophytes, whenever found in a clinically significant infection. We thank Linda Church, M.S., of Meridia Huron Hospital and Mario Markowic, M.S., of Cleveland Biological Institute, Cleveland, Ohio, for isolating and identifying the organism. We thank Billy Brown, M.D., Damian Laber, M.D., Ann Tekancic, and Cindy Storm for assistance. Financial support is from The Meridia Huron Hospital Department of Medicine. Kluyvera Finger Infection and Review 241 REFERENCES Aevaliotis A, Belle AM, Chanione JP, Serruys E (1985) Kluyvera ascorbata isolated from a baby with diarrhea. Clin Microbiol Newsl 7:51. Altwegg M, Zollenger-Iten J, von Graevenitz A (1986) Differentiation of Kluyvera cryocrescens from Kluyvera ascorbata by irgasan susceptibility testing. Ann Inst Pasteur Microbiol (Paris) 137A:159–168. 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