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Case twenty seven: turning the tables on the rollover-accident bug.

Case Follow up

The Biomeriux MALDI-TOF MS plus (Research Use Only database) (bioMeriux, Laurent, Kansas) was used to establish a preliminary identification of the isolate from the bone sample. The top 4 spectra showed a likely match for the identification of Enterobacter cancerogenes.

Identification using the Vitek 2 system confirmed the presumptive identification from the MALDI system. The bacterial isolate obtained from the swab of the wound site showed an identical identification. The susceptibility profile generated using Vitek 2 is shown in Table 1.

Introduction

According to the Consumer Product Safety Commission, there have been more than 11,000 ATV-related deaths from 1982 to 2010. One-quarter of the fatalities were under the age of 16. (1) Of those deaths, 43% were under the age of 12. (1), 2 Additionally, emergency departments have received more than 28,000 visits due to ATV-related injuries in children. (1,2) A study by Rebeccah L Brown, M.D., associate director of Trauma Services at Cincinnati Children's Hospital Medical Center, showed that almost half of all ATV injuries at the Trauma Center required surgical intervention, and 23% required care in the intensive care unit. (2)

Osteomyelitis is usually suspected in a chronic wound that does not heal with standard treatments. (3) Staphylococcus aureus is the principle pathogen in most osteomyelitis cases all age groups. (4) Enterobacter species have a smaller role in most osteomyelitis cases, but it is not as age-dependent as other organisms (such as streptococci). (4) Commonality of organisms indicated in osteomyelitis cases by age is shown in Table 2. In the age group ranging from 4 to 18 years-old, 80% of the osteomyelitis cases have been attributed to Staphylococcus aureus. (5) Of the Enterobacter species, the most common implicated in human infection are E. aerogenes and E. cloacae. (4)

Enterobacter cancerogenus is a rare opportunistic infection. However, this organism may be underreported as there are limitations of some identification schemes and not all Enterobacter spp. are fully speciated. There is an estimated 17 cases of E. cancerogenus infection reported. (6) They generally involve a crush injury or laceration followed by environmental contamination of the wounds. Five of those cases have been isolated in the patient's blood cultures. (6)

The crush injuries often seen in ATV accidents can lead to opportunistic infection of the wound sites. Additionally, these opportunistic infections tend to be more complex in children due to an incomplete development of the immune system. Both human and animal studies show that traumatic injury is correlated with a decrease in immune functions that are dependent on T-cell response. (7) For example, there is evidence that there is a significant decrease in T-1 helper function and cytokine production following traumatic injury. (7) Injury leads to changes that influence how innate and adaptive immune systems interact, which is one of a multitude of factors that raise the risk of opportunistic infections.

Taxonomy

In 1966, an organism was isolated and presumptively indicated in a canker disease in poplar trees in Czechoslovakia. (8) It was first described by Urosevi? and designated as Erwinia cancerogena referring to the "cancer inducing" effect on the poplars. (8) Positive reactions for arginine and ornithine decarboxylase suggested that Erwinia cancerogena may have been a species of Enterobacter. Robert S. Dickey and Cathy H. Zumoff analyzed additional phenotypic characteristics in a study from 1988. (8) The isolates showed phenotypic characteristics that supported the suggestion that the organism belonged in the family Enterobacteriaceae. (8) The genera Citrobacter, Hafnia, Serratia, and Klebsiella were ruled out due to several characteristics of the organism, including motility, lack of capsulation, gelatin hydrolysis, and production of lipase, urease, and deoxyribonuclease. (8) Based on three strains, the closest relationship for genus assignment was Enterobacter. Enterobacter cancerogenus was proposed by Dickey and Zumoff, with the description of Gram-negative, straight bacilli that are a facultative anaerobe and are motile with peritrichous flagella. (8)

At around the same time, a new opportunistic human pathogen was described from blood in five cases of septicemia and one bacterial meningitis case. (9) A summary of the proposed Enterobacter taylorae was made from the previously described CDC Enteric Group 19. (9) From there the case history of Enterobacter taylorae became more involved, including four cases of severe nosocomial infections acquired within 6 months. (10) In 1994, E. taylorae was found biochemically identical to E. cancerogenus. (11) Thus, the taxonomic shift was made to use only the name E. cancerogenus when referring to the species. (11) There is further speculation that E. cancerogenus strain MSA2 is a plant growth promoting bacterium that may not fit into what is now defined as E. cancerogenus. (12) Enterobacter cancerogenus is a member of the class of proteobacteria called Gammaproteobacteria, order Enterobacteriales, Family Enterobacteriaceae, Genus Enterobacter. (13)

Clinical Presentation

In a study by the National Healthcare Safety Network at the Centers for Disease Control and Prevention, it was found that Enterobacter were the fourth most common cause of Gram-stained negative bacteria in hospital acquired infections in the United States. (14) This accounted for 5% of all hospital acquired infections. (14) In pediatric hospitals, Enterobacter species accounts for 9.8% of pneumonia, 9.5% of urinary tract infections, and 6.8% of bloodstream infections in data collected in between 1992 and 2004. (15) The species E. cloacae and E. aerogenes are the principal human pathogens in this genus. Most of the other species in the genus are mainly isolated from environmental sources and are generally phytopathogenic. (16) The other Enterobacter species have routinely been implicated as opportunistic pathogens.

[FIGURE 2 OMITTED]

There are case reports that notate E. cancerogenus as the primary pathogen implicated in an infection, both nosocomial and from environmental sources. Garazzino et al reported on one environmental source in a case of osteomyelitis caused by E. cancerogenus. (16) An otherwise healthy 56 year-old male was involved in a severe motorcycle crash, resulting in an open fracture to his right leg. While being treated with amoxicillin-clavulanic acid and metronidazole, the patient showed signs of infection four weeks after the injury. (16) A culture of the purulent wound showed E. cancerogenus with a resistance to aminopenicillins and cefazolin. (16) Due to the susceptibility report, the patient's antimicrobial therapy was switched to include both levofloxacin and ceftriaxone. (16)

Injuries that result in environmental contamination of the wound site account for the majority of the cases reported, but there are cases that describe opportunistic infections of normal microbiota. An example is a case of Enterobacter cancerogenus bacteremia that was documented in a 56-year-old with sclerosing cholangitis. (6) While awaiting liver transplantation, he was admitted to the hospital with nausea and hematemesis. (6) Blood cultures were collected on the patient. (6) After a 16 hour incubation they grew Enterobacter cancerogenus and viridans group Streptococcus. (6) The patient was initially treated with piperacillin-tazobactam, but was switched to ceftriaxone after the organism tested resistant to first-generation cephalosporins, amoxicillin-clavulanic acid, and ampicillin. (6) The patient was observed to have many dental carries and overall poor dentition. (6) Since oral flora had been isolated on three previous occasions within two months, the source of the infection was thought to be oral. (6) Previous studies demonstrate that E. cancerogenus is found in dental roots, but this was the first case documented where endogenous mouth flora was implicated in the cause of infection. (17)

Laboratory identification

Enterobacteriaceae grow well on routine agar, including typticase soy agar with 5% sheep blood, chocolate agar, and MacConkey agar. (13) Most genera in the Enterobacteriaceae family demonstrate similar growth. Colonies will appear large and grey, usually within 24 hours. (13) Enterobacter species will be slightly mucoid due to a polysaccharide capsule and will be pink on MacConkey agar (MAC), yellow on Hektoen enteric agar (HE), and yellow on Xyloselysine-deoxycholate agar (XLD). (13) The biochemical profile listed on the bioMeriux API 20E is 3305113 (shown in Figure 2). A search for the biochemical profile resulted in a 99.9% confidence in an identification of Enterobacter cancerogenus.

Antimicrobial Agents and Therapy

Initial antibiotic therapy for most enteric Gram negative bacilli would often include either a fluoroquinolone or a third-generation cephalosporin. (19) Administration of treatment for osteomyelitis is often difficult to ascertain. The observed improvement in a patients condition could be due to the process of debridement, not from the antimicrobials themselves. (20) Sustained remission must also be demonstrated. (20) The factors surrounding the cases also tend to be variable and complex, especially in pediatric institutions. While debridement is one of the main avenues of treatment, antibiotics serve as a necessary compliment. Quick identification and susceptibility profiles play an important role in the outcome of the patient, since start time to appropriate antibiotics is imperative. (21) It has been recommended that treatment should be administered for at least four weeks, and ideally closer to six weeks. (20) In a recent review, Travakoli recommends that surgery is necessary in children with osteomyelitis who show no improvement within two days of beginning treatment, or when there is pus when bone aspiration takes place. (22)

E. cancerogenus has a natural resistance to amoxicillin, amoxicillin/clavulanic acid, cefazolin, cefaclor, cefazoline, loracarbef, and cefloxitin. (23) It should be noted that in agar diffusion MIC antibiotic studies on five Enterobacter species, (E. cancerogenus, E. amnigenus, E. gergoviae, and E. sakazakii), was the only one that demonstrated this resistance pattern. (23) This pattern of resistance indicates the presence of chromosomal AmpC [beta]-lactamases. (23) This resistance is present in the Enterobacter genus, and includes E. cloacae and E. aerogenes. (23)

The drugs of choice for Enterobacteriaceae have long been carbapenems, but increasing infections from Extended-Spectrum Beta-lactamase producing organisms have suggested the use of [beta]-lactam/[beta]-lactam inhibitor combinations. (24) However, in a review by Vardakas et al. these [beta]-lactam/[beta]-lactam inhibitor combinations have resulted in a higher mortality than carbapenems. (24) The current recommendations by the American Academy of Pediatrics for a gram-negative aerobic organism with chromosomally mediated ampC beta-lactamase suggest the use of meropenem in most infections. (21) Meropenem is not suggested for carbapenemase-producing strains. (21)

Environmental Reservoir

Enterobacter species are present in environmental samples from all types of ecosystems.

Enterobacter cancerogenus has been indicated as a cause of disease in plants other than in poplar trees, including mulberry wilt disease in China. (25,26) Isolates of Enterobacter species have been reported in environmental samples from studies all over the globe. Given this, the organism's presence in environmentally contaminated wound sites can be expected. Enterobacter cancerogenus is not solely a cause of disease in plants. As previously mentioned, the E. cancerogenus strain MSA2 has been shown to be a plant growth promoting bacterium. (12) It is not yet been determined if this bacterium will remain being defined as Enterobacter cancerogenus.

Conclusion

In the case of the 16-year-old male in the ATV-rollover accident, Enterobacter cancerogenus was likely obtained from the environment. Although rare, the presence and role of Enterobacter cancerogenus in opportunistic infections should be considered when an Enterobacter species is isolated. This is especially true with the potential of resistance to aminopenicillins and cephalosporins.

There is evidence of an increasing number of opportunistic infections involving Enterobacter species, including a novel Enterobacter of clinical relevance described by Harald Hoffmann, et al. (27) Enterobacter ludwigii has been the subject of at least five case reports since 2005. (27) Further analysis of the E. cloacae complex could reveal more taxonomically, phenotypically, and genetically distinct species within the genus Enterobacter. (27) The E. cancerogenus strain MSA2 described in this article is an example how this species could still soon be split into two, or possibly more, species. (12) The evolving resistance to antibiotics in the family has also been of concern, especially in the case of Carbapenem-Resistant Enterobacteriaceae (CRE). (28) There has been a dramatic increase in CRE in the United States, and it correlates with an overall trend toward pan-resistant organisms with genetic components which may be highly mobile between microbial species. (28)

The 16 year-old patient discussed in this study showed no more signs of infection following the course of treatment. Extensive nerve damage remains, presumably unrelated to the acquired infection. No further infections of the wound site have occurred in the six months following the positive cultures.

References

(1.) Brown RL, Koepplinger ME, Mehlman CT, Gittelman M, Garcia VF. 2002. All-terrain vehicle and bicycle crashes in children: epidemiology and comparison of injury severity. Journal of pediatric surgery 37:375-380.

(2.) Cook RS. 2012. 2012 AAP National Conference and Exhibition.

(3.) Mathur P. 2008. Infections in traumatised patients: A growing medico-surgical concern. Indian Journal of Medical Microbiology 26:212.

(4.) Dirschl DR, Almekinders LC. 1993. Osteomyelitis. Drugs 45:29-43.

(5.) Burnett MW, Bass JW, Cook BA. 1998. Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 101:296-297.

(6.) Bowles DW, Truesdale AE, Levi M, Trotter JF. 2006. Enterobacter cancerogenus bacteremia in a patient with poor dentition, cirrhosis, and a variceal bleed. Journal of clinical gastro enterology 40:456-457.

(7.) Lederer JA, Rodrick ML, Mannick JA. 1999. The effects of injury on the adaptive immune response. Shock 11:153-159.

(8.) Dickey RS, Zumoff CH. 1988. Emended description of Enterobacter cancerogenus comb. nov.(formerly Erwinia cancerogena). International journal of systematic bacteriology 38:371-374.

(9.) Farmer J, Fanning G, Davis B, O'hara C, Riddle C, Hickman-Brenner F, Asbury M, Lowery V, Brenner D. 1985. Escherichia fergusonii and Enterobacter taylorae, two new species of Enterobacteriaceae isolated from clinical specimens. Journal of clinical microbiology 21:77-81.

(10.) Rubinstien E, Klevjer-Anderson P, Smith C, Drouin M, Patterson J. 1993. Enterobacter taylorae, a new opportunistic pathogen: report of four cases. Journal of clinical microbiology 31:249-254.

(11.) Krag ML, Schonheyder HC. 1997. Enterobacter cancerogenus (syn. Enterobacter taylorae) from a case of traumatic tibial osteomyelitis. Clinical Microbiology Newsletter 19:31-32.

(12.) Jha CK, Patel B, Saraf M. 2012. Stimulation of the growth of Jatropha curcas by the plant growth promoting bacterium Enterobacter cancerogenus MSA2. World Journal of Microbiology and Biotechnology 28:891-899.

(13.) Forbes S, Sahm D. 2007. Weissfeld. Bailey & Scott's diagnostic microbiology, Mosby. Inc., St. Louis, Mo.

(14.) Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK. 2008. Antimicrobial?resistant pathogens associated with healthcare?associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. infection control and hospital epidemiology 29:996-1011.

(15.) Cardo D, Horan T, Andrus M, Dembinski M, Edwards J, Peavy G, Tolson J, Wagner D. 2004. National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992 through June 2004, issued October 2004. American journal of infection control 32:470-485.

(16.) Garazzino S, Aprato A, Maiello A, Masse A, Biasibetti A, De Rosa F, Di Perri G. 2005. Osteomyelitis caused by Enterobacter cancerogenus infection following a traumatic injury: case report and review of the literature. Journal of clinical microbiology 43:1459-1461.

(17.) Nakajo K, Nakazawa F, Iwaku M, Hoshino E. 2004. Alkali?resistant bacteria in root canal systems. Oral microbiology and immunology 19:390-394.

(18.) Grimont F, Grimont PA. 2006. The genus Enterobacter, p. 197-214, The prokaryotes. Springer.

(19.) Lew DP, Waldvogel FA. 2004. Osteomyelitis. The Lancet 364:369-379.

(20.) Carek PJ, Dickerson LM, Sack JL. 2001. Diagnosis and management of osteomyelitis. American family physician 63:2413.

(21.) Pickering LK. 2003. Red book[R]: 2003 report of the committee on infectious diseases. American Academy of Pediatrics.

(22.) Tavakoli M, Davey P, Clift BA, Davies HT. 1999. Diagnosis and Management of Osteomyelitis. Pharmacoeconomics 16:627-647.

(23.) Stock I, Wiedemann B. 2002. Natural antibiotic susceptibility of Enterobacter amnigenus, Enterobacter cancerogenus, Enterobacter gergoviae and Enterobacter sakazakii strains. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 8:564-578.

(24.) Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. 2012. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum [beta]-lactamases: a systematic review and meta-analysis. Journal of antimicrobial chemotherapy 67:2793-2803.

(25.) Wang G, Praphat K, Xie G, Zhu B, Li B, Liu B, Zhou Q. 2008. Bacterial wilt of mulberry (Morus alba) caused by Enterobacter cloacae in China. Plant Disease 92:483-483.

(26.) Urosevic B. 1966. Poplar canker caused by the bacterium Erwinia cancerogena sp. nov. Lesnicky Casopis 12:493-505.

(27.) Hoffmann H, Stindl S, Stumpf A, Mehlen A, Monget D, Heesemann J, Schleifer KH, Roggenkamp A. 2005. Description of Enterobacter ludwigii sp. nov., a novel Enterobacter species of clinical relevance. Systematic and applied microbiology 28:206-212.

(28.) Gupta N, Limbago BM, Patel JB, Kallen AJ. 2011. Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. Clinical infectious diseases 53:60-67.

Scott Bielewicz is a Medical Lab Scientist at Cincinnati Children's Hospital Medical Center in the Diagnostic Infectious Disease Testing Laboratory.

Joel Mortensen Ph.D., is the Director of the Diagnostic Infectious Diseases Testing Laboratory.
Table 1. Sensitivities on patient isolate obtained
by Vitek 2.

        Antimicrobial            MIC     Interpretation

Ampicillin                      >=32           R
Ampicillin/Sulbactam            >=32           R
Cefazolin                       >=64           R
Ceftriaxone                     <=1            S
Ceftazidime                     <=1            S
Cefoxitin                       >=64           R
Cefepime                        <=1            S
Gentamycin                      <=1            S
Tobramycin                      <=1            S
Amikacin                        <=2            S
Trimethoprim/sulfamethoxazole   <=1            S
Ciprofloxacin                   <=0.25         S
Levofloxacin                    <=0.12         S
Imipenem                        <=1            S
Ertapenem                       <=0.5          S
Meropenem                       <=0.25         S
Nitrofurantoin                  <=16           S

Table 2. Commonality of organisms indicated in
osteomyelitis cases by age. Adapted from
Burnett5.

                      Most Common Bacteria
Age of Patient        Responsible for Osteomyelitis

<4 Months             Staphylococcus aureus,
                      Enterobacter spp, Streptococcus
                      agalactiae, Streptococcus
                      pyogenes

4 Months to 4 Years   Staphylococcus aureus,
                      Streptococcus pyogenes,
                      Haemophilus influenzae and
                      Enterobacter species

4 to 18 Years         Staphylococcus aureus, less
                      commonly Streptococcus
                      pyogenes, Haemophilus
                      influenzae, and Enterobacter spp.

18 Years +            Staphylococcus aureus,
                      sometimes Enterobacter spp.,
                      Streptococcus spp.

Table 3. Differentiating
biochemical properties
for Enterobacter
species.

                  Urease   Voges-Proskauer   Methyl-Red   Citrate

E. aerogenes        +             -              +           +
E. asburiae         +             V              +           V
E. cancerogenus     +             -              -           -
E. cloacae          +             V              +           +
E. cowanii          +                            +           +
E. gergoviae        +             +              +           +
E. hormaechei       +             V              +           -
E. kobei            +             -              V           +

                  Acid from lactose   Acid from adonitol

E. aerogenes              +                   -
E. asburiae               +                   V
E. cancerogenus           -                   +
E. cloacae                +                   +
E. cowanii                +                   +
E. gergoviae              -                   +
E. hormaechei             -                   V
E. kobei                  +                   +

                  Acid from melibiose   Arginine dihydrolase

E. aerogenes               +                     +
E. asburiae                -                     -
E. cancerogenus            -                     -
E. cloacae                 +                     V
E. cowanii                 +                     -
E. gergoviae               +                     -
E. hormaechei              -                     -
E. kobei                   +                     -

                  Acid from sorbitol   Acid from raffinose

E. aerogenes              +                     +
E. asburiae               V                     +
E. cancerogenus           -                     +
E. cloacae                +                     +
E. cowanii                +                     +
E. gergoviae              V                     +
E. hormaechei             -                     +
E. kobei                  +                     +

                  Acid from sucrose

E. aerogenes              -
E. asburiae               +
E. cancerogenus           -
E. cloacae                -
E. cowanii                -
E. gergoviae              -
E. hormaechei             V
E. kobei                  -

* Information adapted from Grimont (18)

Table 4. Reported antimicrobial sensitivities of E. cancerogenus
compared with patient isolate information obtained with the Vitek
2 system.

          Antibiotics                            Sensitivities

 Class                    Drug       Literature        Patient Isolate

                                                  MIC    Interpretation

Aminoglycoside        Amikacin           S       <=2           S
                      Gentamicin         S       <=1           S
                      Tobramycin         S       <=1           S

Antifolate            Sulfonamide        S
                      Trimethoprim       S
                      Trimethoprim/      S       <=1           S
                      Sulfonamide

Penicilins            Ampicillin/       S,I      >=32          R
                      Sulbactam
                      Amoxicillin        R
                      Penacillin         R

Cephalosporins
          1st         Cefazolin          R       >=64          R
          Generation  Cephalothin        R
          2nd         Cefoxitin          R       >=64          R
          Generation
          3rd         Ceftazidime        S       <=1           S
          Generation  Ceftriaxone        S       <=1           S
          4th         Cefepime           S       <=1           S
          Generation

Carbapenems           Imipenum           S       <=1           S
                      Meropenem          S       <=0.25        S
                      Ertapenem                  <=0.25        S

Monobactams           Aztreonam          S

Fluroquinolones/      Ciprofloxacin      S       <=0.25        S
Quinolones            Nalidixic          S
                      Acid

Data adapted from Stock, I. et al. (2002), Grimont et al. (2006)
(18, 23)
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Title Annotation:CASES IN CLINICAL MICROBIOLOGY; osteomyelitis
Author:Bielewicz, Scott J.; Mortensen, Joel
Publication:Journal of Continuing Education Topics & Issues
Article Type:Clinical report
Date:Jan 1, 2014
Words:3186
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