Please read the article and answers these questions

2) Briefly explain what is meant by "community onset" as used in the paper (based on context, not necessarily a definition you can look up). (1 point) 3) What factors probably led to the patient contracting the Clostridium difficile infection (CDI)? Be specific. (4 points) 4) Name and briefly describe the specific disease caused by Clostridium difficile in this patient (may need to consult textbook or other reputable source). (3 points) 5) What is a carbapenemase? What category of antibiotics does it function against? Where did the carbapenemase come from in the patient? Explain cross-resistance and its relevance here. (4 points)6) What specific treatment(s) did healthcare providers administer for the CDI? Include doses in your answer. What do you notice about the antibiotics used to treat the patient and the MICs for the KPC- Kp (remember what you wrote in #4 and think about the infection the patient got after the CDI)? Why are these values important? (4 points) 7) What do the authors of the paper think may have led to the KPC-Kp infection and resulting BSI? What do you think ultimately caused the patient's death? (Hint: read discussion and be specific) (4 points)CASE REPORT Open Access Severe community onset healthcare-associated Clostridium difficile infection complicated by carbapenemase producing Klebsiella pneumoniae bloodstream infection Simone Giuliano , Maurizio Guastalegnamelt, Miryam Jenco?, Andrea Morelli , Marco Falcone and Mario Venditti Abstract Background: Clostridium difficile infection (CDI) and Klebsiella pneumoniae carbapenemase producing-Klebsiella pneumoniae (KPC-Kp) bloodstream infection (BSI) are emerging health-care associated (HCA) diseases of public health concern, in terms of morbidity, mortality, and insufficient response to antibiotic therapy. Both agents can be acquired in the hospital but clinical disease can develop in a community setting, after discharge. We report here a putative link between the above-mentioned healthcare associated infections that appeared as a dramatic community onset disease with a fulminant fatal outcome. Case presentation: We describe the case of a 63 year old man affected by severe CDI. Even though the patient underwent 72 hours of standard CDI antibiotic treatment, the clinical course was complicated by toxic megacolon and KPC-Kp BSI. The patient died 24 hours after total colectomy. Conclusion: The impact of HCA-BSIs in complicating CDI is still unknown. Intestinal inflammatory injury and disruption of intestinal flora by standard antibiotic treatment could be responsible for promoting difficult-to-treat infections in CDI. By preserving intestinal flora, Fidaxomicin could have a crucial role in preventing BSIs complicating severe CDI. Keywords: Clostridium difficile, Klebsiella pneumoniae, KPC, Bloodstream infections, Intestinal flora, Fidaxomicin Background Case presentation The impact of health-care associated (HCA) bloodstream We report the case of a 63 year old man, who was ad- infection (BSI) in complicating Clostridium difficile infect mitted on the 6th of February 2014 to the Intensive Care tion (CDI) is still unknown. We describe for the first time Unit (ICU) of a 1300-bed teaching Institution in Rome a case of community onset healthcare-associated severe because of septic shock syndrome. His past medical his- CDI complicated by Klebsiella pneumoniae Carbapene tory was remarkable for high blood pressure, multi-infarct mase producing Klebsiella pneumoniae (KPC-Kp) BSI. dementia, Parkinson's disease and depressive disorder. CDI and KPC-Kp BSI are recently emerging as two of the The patient had been hospitalized on the 15th of January more concerning HCA diseases in terms of morbidity, 2014 in a peripheral center for a febrile syndrome due to a mortality, and inefficient response to antibiotic therapy. A urinary tract infection caused by Escherichia coli. During relation between the above-mentioned infections have his hospital stay, he underwent a ten-day course of anti- never been reported until now. microbial therapy with intravenous ciprofloxacin and was discharged on the 28th of January on treatment with oral Cefditoren pivoxil. On the 3rd of February, the patient * Correspondence: mario.venditti@uniromalit Equal contributors was readmitted to the same hospital because of confusion, Department of Public Health and Infectious Diseases Policlinico Umberto I, fever and diarrhea. Clostridium difficile infection (CDI) "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy test was performed (Alere" C. DIFF QUICK CHECK Full list of author information is available at the end of the article BioMed Central 0 2014 Giuliano et al; licensee BioMed Central Lid. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http:/creativecommonsorg/licenses/by/40), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http//creativecommonsorg/publicdomain/zero/1.WV) applies to the data made available in this article, unless otherwise stated.COMPLETE for simultaneous detection of both glutamate mortality rates [5,6], that are probably due to the spread of dehydrogenase antigen and toxin A and B). Oral vanco- the epidemic strain ribotype 027 CD [6-8]. In the present mycin 500 mg qoh, intravenous metronidazole 500 mg case, because the initial diagnosis was made in a peripheral 46h and intravenous Piperacillin/tazobactam 4.5 g q8h center, ribotyping test was not performed. We describe, for were immediately started. After 72 hours of persistent de- the first time, a fatal case of severe CDI complicated by terioration despite standard antibiotic therapy administra- KPC-Kp BSI. This led us to question about the role of se- tion, the patient was transferred to the ICU of our vere CDI on predisposing to HCA-BSIs, and vice-versa, on hospital. At the admission the patient was unconscious the role of HCA-BSIs in determining the prognosis of se- (Glasgow Coma Scale of 3), presenting with ileus and sep- vere CD colitis. To our knowledge this issue has never been tic shock syndrome. Oro-tracheal intubation and fluid re- thoroughly evaluated in the literature until now. suscitation were performed followed by intravenous We already disserted on the putative correlation be- norepinephrine. Tigecycline was empirically added to the tween CDI and Candida spp. BSI [9]. Analogous mecha- combination antimicrobial therapy. Three blood cultures nisms could be advocated to explain the link between CDI were drawn and blood test showed 24000 white blood and KPC-Kp BSI. Recently, Perez et al. demonstrated in a cells/jil, creatinine 3.6 mg/dl, albumin 2.2 g/dl, lactate mouse model the impact of the administration of antibi- 4 mmol/1. Computed tomography scans demonstrated otics effective against intestinal flora on promoting the findings compatible with toxic megacolon. A total colec- persistence of KPC-Kp colonization of the gastrointestinal tomy was performed but the patient died 24 h after the tract [10]. Edlund et al., evaluating the ecological distur- surgical intervention. All blood cultures drawn at the time bances of oral vancomycin following cephalosporin of admission to the ICU were positive for a carbapenem- administration in 20 healthy volunteers, showed intes- resistant strain of Klebsiella pneumoniae (Vitek 2 system, tinal Klebsiella spp. overgrowth within 3 days of vanco- AST-N089 card bioMerieux, Marcy l'Etoile, France, MICs: mycin treatment (11]. In the present case, KPC-Kp Amikacin 2 64 mg/1, Amoxicillin/Clavulanic acid 2 32 mg/1, colonization was acquired in a non-ICU setting, an Cefepime 2 64 mg/l, Cefotaxime 2 64 mg/l, Ceftazidime 2 emerging phenomenon already described in our country 64 mg/l, Ciprofloxacin 2 4 mg/1, Colistin 2 16 mg/1, Ertape- [12]. Oral vancomycin administration, highly active nem 2 8 mg/l, Fosfomycin 2 256 mg/1, Gentamicin 4 mg/l, against the intestinal flora [13], could have been respons Imipenem 2 16 mg/1, Meropenem 2 16 mg/l, Piperacillin/ sible for persistence and overgrowth of KPC-Kp in the Tazobactam 2 128 mg/l, Tigecycline 4 mg/1, Trimethoprim/ gastrointestinal tract. Gut inflammatory injury caused Sulfamethoxazole 2 320 mg/1). Production of KPC enzyme by severe CDI could be considered the "second hit" was documented by using a phenotypic test based on the allowing bacterial translocation and BSI. The role of se- inhibitory activity of boronic acid compounds as reported vere intestinal inflammation predisposing to bacterial by Pournaras et al. [1], and carbapenemase producing- mucosal penetration and blood invasion has been Klebsiella pneumoniae (KPC-Kp) was identified. In already showed in murine and human models [14,15]. addition, one blood culture was positive for vancomycin- Moreover, K. pneumoniae has been demonstrated to be susceptible Enterococcus faecium. Histologic examination one of the most efficient microorganisms in translocat- of the colon confirmed diagnosis of pseudomembraneous ing to extraintestinal sites, presenting a very low colitis. bacteremia clearance in the liver and spleen [16]. Colonic inflammation induced by severe CDI and stand- Discussion and conclusion ard CD antibiotic treatment could promote difficult-to- We believe that this case report is of great interest because treat infections/colonizations (ie. KPC-Kp BSI, Candida our patient contemporarily developed two community- spp. BSI [6], or vancomycin resistant-enterococci intestinal onset healthcare associated infections with a rapidly fatal colonization [17]. Fidaxomicin, a newly licensed macro- outcome. Carbapenem-resistant Enterobacteriaceae (CRE) cyclic antibiotic recently approved to treat CDI, is charac- are an emerging issue of great public health concern. In terized by a narrow spectrum of activity almost limited to our country, the problem is almost completely represented CD and consequent preservation of intestinal flora com- by carbapenem-resistant K. pneumoniae. Even though data pared to vancomycin [13]. Preservation of intestinal flora related to incidence are missing, percentage of invasive K. could represent a useful therapeutic option not only in re- prieumonine isolates with resistance to carbapenems report- ducing CDI recurrence rate [9], but also in preventing edly ranges between 25% and 50% in Italy [2]. Recently, BSIs secondary to severe CDI. cases of healthcare-associated carbapenem resistant K. In conclusion, clinical impact of BSIs on complicating pneumoniae BSIs have been reported in Northern Italy [3]. CDI has not been systematically evaluated until now. The phenomenon is also well known in Rome [4] and par- Fidaxomicin could represent a useful therapeutic option allels to an epidemiological shift of CDI occurring in our re- in preventing difficult-to-treat BSIs secondary to severe gion and consisting of increased disease incidence and CDI. Studies are necessary to validate this hypothesis.Consent 11. Edlund C. Barkholt L. Olsson-Lijequist B. Nord CE: Effect of vancomycin on Written informed consent was obtained from the next intestinal flora of patients who previously received antimicrobial therapy. of a kin of the patient for publication of this Case report. Oin Infect Dis 1997, 25(3):729-732. 12. Richter SN, Frasson I, Franchin E, Bergo C, Lavezzo E, Cavallaro A, Pali G: A copy of the written consent is available for review by KPC-mediated resistance in Klebsella pneumonice in two hospitals in the Editor of this journal. Padua, Italy, June 2009-December 201 1: massive spreading of a KPC-3-encoding plasmid and involvement of non-intensive care units. Gut Pathog 2012, 4(1):7. Competing interests 13. Louie TJ, Cannon K, Byme B, Emery J. Ward L, Eyben M, Krulicki W. The authors declare that they have no competing interests. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin Authors' contribution reexpression and recurrence of CDI. All authors read and approved the final manuscript. SG and MG have made Cin Infect Dis 2012, 55(Supply)5132-5142. substantial contribution to concept and design of the manuscript MJ has 14. Johansson ME, Gustafsson JK, Holmen-Larsson J, Jabbar KS, Xia L, Xu H, made contribution to acquisition of data. AM, MF and MV revised the Ghishan FK, Carvalho FA, Gewirtz AT, Sjovall H, Hansson GC: Bacteria manuscript for important intellectual content and final approval. penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 2014, 63 (2):281-291. Ackowledgements 15. Mainous MR, Tso P, Berg RD, Deitch EA: Studies of the route, magnitude, The authors are grateful to Dr M.A. Arc for his contribution in revising the and time course of bacterial translocation in a model of systemic article critically for important intellectual content. inflammation. Arch Surg 1991, 126(1):33-37. 16. Eaves-Pyles T, Alexander JW: Comparison of translocation of different Author details types of microorganisms from the intestinal tract of burned mice. Department of Public Health and Infectious Diseases Policlinico Umberto I, Shock 2001, 16(2):148-152. "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. 17. Nerandzic MM, Mullane K. Miller MA, Babakhani F. Donskey Cit Reduced "Department of Anesthesiology and Intensive Care, "Villa San acquisition and overgrowth of vancomycin-resistant enterococci and Pietro-Fatebenefratelli" Hospital, Rome, Italy. 'Department of Anesthesiology Candida species in patients treated with fidaxomicin versus vancomycin and Intensive Care, "Sapienza" University of Rome, Rome, Italy. for Clostridium difficile infection. Chin Infect Dis 2012, 55(52):5121-5126. Received: 14 April 2014 Accepted: 18 August 2014 doi: 10.1186/1471-2334-14-475 Published: 1 September 2014 Cite this article as: Giuliano et al: Severe community onset healthcare-associated Clostridium difficile infection complicated by carbapenemase producing Klebsella pneumoniae bloodstream infection. References BMC Infectious Diseases 2014 14:475. 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Submit your manuscript at www.biomedcentral.com/submit (BioMed CentralHW 3: Carbapenem Resistant Enterobacteriaceae: A Case Report See schedule for due date (25 points) Carefully read the following article and answer the questions in your own words below: Giuliano et al. Severe community onset healthcare-associated Clostridium difficile infection complicated by carbapenemase producing Klebsiella pneumoniae bloodstream infection. BMC Infectious diseases. 2014: 14(475). To receive full credit, answers should be typed or neatly handwritten. Do not use quotes or copy and paste from the article or any other websites/sources. Summarize your answers in your own words. Some outside research will be necessary beyond the article. 1) Complete the following: a. Write out the following acronyms (most of these are defined in the paper): (3 points) i. HCA ii. BSI iii. CDI iv. KPC-Kp V. MIC vi. CRE b. Define the following: (2 points) i. Morbidity rate (epidemiology) ii. Mortality rate (epidemiology) iii. Minimal Inhibitory Concentration